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One of the directions for improving the training of future specialists in higher education institutions is the formation of professionally relevant personality characteristics. Emotional stability is one of these characteristics. Physical education and sport are one of the few spheres of life of modern students in which this issue can be effectively resolved. The authors provide data on the positive impact of specially organized physical education classes on the formation of such emotional stability in students.

There is a number of directions regarding the use of physical education for training for a professional work. One of the authors of the article proposed a direction called psycho-physical training. The research aims to determine the fundamentals of psycho-physical training of students in physical education. It is suggested that the development of the foundations of psycho-physical training of students should be based on the factors determined from the analysis of professiograms and qualification characteristics of a specific profession. In the article, such issues are revealed: directions of psycho-physical training in the process of physical education, its means, organization, control.

Updated immunization strategies are needed to address multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Here we report interim results from an ongoing, open-label phase 2/3 trial evaluating the safety and immunogenicity of the bivalent Coronavirus Disease 2019 (COVID-19) vaccine candidate mRNA-1273.211, which contains equal mRNA amounts encoding the ancestral SARS-CoV-2 and Beta variant spike proteins, as 50-µg (n = 300) and 100-µg (n = 595) first booster doses administered approximately 8.7–9.7 months after the mRNA-1273 primary vaccine series (NCT04927065). The primary objectives were to evaluate the safety and reactogenicity of mRNA-1273.211 and to demonstrate non-inferior antibody responses compared to the mRNA-1273 100-µg primary series. Additionally, a pre-specified immunogenicity objective was to demonstrate superior antibody responses compared to the previously authorized mRNA-1273 50-µg booster. The mRNA-1273.211 booster doses (50-µg or 100-µg) 28 days after immunization elicited higher neutralizing antibody responses against the ancestral SARS-CoV-2 and Beta variant than those elicited 28 days after the second mRNA‑1273 dose of the primary series (NCT04470427). Antibody responses 28 days and 180 days after the 50-µg mRNA-1273.211 booster dose were also higher than those after a 50-µg mRNA-1273 booster dose (NCT04405076) against the ancestral SARS-CoV-2 and Beta, Omicron BA.1 and Delta variants, and all pre-specified immunogenicity objectives were met. The safety and reactogenicity profile of the bivalent mRNA-1273.211 booster (50-µg) was similar to the booster dose of mRNA-1273 (50-µg). Immunization with the primary series does not set a ceiling to the neutralizing antibody response, and a booster dose of the bivalent vaccine elicits a robust response with titers that are likely to be protective against COVID-19. These results indicate that bivalent booster vaccines can induce potent, durable and broad antibody responses against multiple variants, providing a new tool in response to emerging variants.

The article emphasizes that at today's stage of development of Ukrainian society, the problem of legal regulation of relations in the field of health care is extremely relevant. The patient is the main participant in medical legal relations, therefore, important attention should be devoted to the study of his personal non-property rights and their protection. The authors highlight the features and main features of the patient, his personal non-property rights and obligations, methods and forms of protection of the patient's personal non-property rights. It is concluded that a patient is a natural person who receives medical care for any disease, pathological condition or other health and vital activity disorder, and also uses medical services regardless of the presence of a disease. The legal structure of the mechanism for protecting the patient's rights is given, which includes the object, subjects, forms and guarantees of protection. The article emphasizes that the institution of protection of personal non-property rights of the patient is insufficiently regulated in the legislation. Special attention is paid to the patient's right to seek protection from the European Court of Human Rights. The authors point out that there is still a need to improve relevant current regulations in order to ensure conditions for health protection of citizens and the realization of the right to health care. It is concluded that there is a need to adopt a separate regulatory act - the Law of Ukraine "On the Protection of Patients' Rights", which would correspond to modern realities and reflect the basic principles of the protection of patient rights, which would include the main issues of legal regulation of relations between medical institutions, doctors and patients regarding provision of medical care, mechanism of legal protection for both patients and doctors.

Mathematical competence plays an essential role among subject-specific competences of primary school teachers. One should be able to think mathematically, understand mathematical proofs, communicate in “the language of mathematics” and use appropriate codification resources, which makes the concept of mathematical competence rather vital. The concept of primary school teachers’ mathematical competence can be specified through its structure. In this regard, this article analyzes scientific approaches to determining the components of this phenomenon. The structure of future primary school teachers’ mathematical competence is viewed as a system of the following components: motivational-axiological, cognitive, activity-related, communicative, reflexive-creative. It must be noted that the process of developing the structure of this competence and its components, especially content- and activity-related ones, required the authors of the article to analyze regulatory documents and syllabi of the mathematics course of six higher education institutions (HEIs) in Ukraine. All the analyzed syllabi indicate which knowledge, skills and abilities future graduates should possess. The chosen HEIs distribute academic workload differently; at the same time, the content of educational material to be studied is almost identical. The elements of future primary school teachers’ mathematical competence are as follows: arithmetic, algebraic, geometric, that of identical transformations of mathematical expressions, logical

BackgroundOmicron-containing bivalent boosters are available worldwide. Results of a large, randomized, active-controlled study are presented.MethodsThis phase 3, randomized, observer-blind, active-controlled trial in the United Kingdom evaluated the immunogenicity and safety of 50-µg doses of omicron-BA.1-monovalent mRNA-1273.529 and bivalent mRNA-1273.214 booster vaccines compared with 50-µg mRNA-1273 administered as boosters in individuals ≥16 years. Participants had previously received 2 doses of any authorized/approved Covid-19 vaccine with or without an mRNA vaccine booster. Safety and immunogenicity were primary objectives; immunogenicity was assessed in all participants, with analysis conducted based on prior infection status. Incidence of Covid-19 post-boost was a secondary (mRNA-1273.214) or exploratory (mRNA-1273.529) objective.ResultsIn part 1 of the study, 719 participants received mRNA-1273.529 (n=362) or mRNA-1273 (n=357); in part 2, 2813 received mRNA-1273.214 (n=1418) or mRNA-1273 (n=1395). Median durations (months [interquartile range]) between the most recent Covid-19 vaccine and study boosters were similar in the mRNA-1273.529 (4.0 [3.6-4.7]) and mRNA-1273 (4.1 [3.5-4.7]) (part 1), and mRNA-1273.214 (5.5 [4.8-6.2] and mRNA-1273 (5.4 [4.8-6.2]) groups (part 2).Both mRNA-1273.529 and mRNA-1273.214 elicited superior neutralizing antibody responses against omicron BA.1 with geometric mean ratios (99% CIs) of 1.68 (1.45-1.95) and 1.53 (1.41-1.67) compared to mRNA-1273 at day 29 post-boost. Although the study was not powered to assess relative vaccine efficacy, the incidence rates/1000 person years (95% CI) of Covid-19 trended lower with mRNA-1273.529 (670.5 [528.3-839.3]) than mRNA-1273 (769.3 [615.4-950.1]) and mRNA-1273.214 (633.0 [538.1-739.7]) than mRNA-1273 (711.6 [607.5-828.5]).Sequence analysis in part 2 showed that this was driven by lower incidence of Covid-19 in the mRNA-1273.214 cohort with BA.2 and BA.4 sublineages but not BA.5 sublineages. All study boosters were well-tolerated.ConclusionThe bivalent omicron BA.1-containing booster elicited superior neutralizing antibody responses against omicron BA.1 with acceptable safety results consistent with the BA.1 monovalent vaccine. Incidence rates for Covid-19 were numerically lower in participants who received mRNA-1273.214 compared to the original booster vaccine mRNA-1273, driven by the BA.2 and BA.4 sublineages.

Relevance of the problem under research is due to the fragmentary character of the regulatory framework for concluding a surrogacy agreement both in Ukraine and foreign countries, which does not solve the full range of problems that arise in law enforcement practice. Moreover, the issue of notarization of the surrogacy agreement is not clearly regulated. The study aims to analyze the existing legal regulation of theoretical and practical aspects of the conclusion of a surrogacy agreement and draw certain conclusions and scientific provisions on the notarization of the surrogacy agreement. The leading research methods used for a comprehensive examination of surrogacy and surrogacy agreement, in particular, were the following: normative semantic method, general logical methods of cognition, comparative and formal legal methods, generalization, historical method, and systemic and structural-functional method. The results of the research proved the need for the legislative regulation of surrogacy. The implementation of a notarial form of the surrogacy agreement will significantly reduce the risk of adverse consequences for the parties and the criminal component in this segment of this service. A separate law on the regulation of surrogacy should be adopted in Ukraine, which also concerns all other types of assisted reproductive technologies.

Along with horizontal drilling techniques, multi-stage hydraulic fracturing has improved shale gas production significantly in past decades. In order to understand the mechanism of hydraulic fracturing and improve treatment designs, it is critical to conduct modelling to predict stimulated fractures. In this paper, related physical processes in hydraulic fracturing are firstly discussed and their effects on hydraulic fracturing processes are analysed. Then historical and state of the art numerical models for hydraulic fracturing are reviewed, to highlight the pros and cons of different numerical methods. Next, commercially available software for hydraulic fracturing design are discussed and key features are summarised. Finally, we draw conclusions from the previous discussions in relation to physics, method and applications and provide recommendations for further research.

The aim of the article is to solve the scientific problem of outlining the issue of protection of patent law objects created using artificial intelligence technologies, and to establish whether it is possible to recognize artificial intelligence technologies as inventor at the present stage of development of legal systems. Philosophical, comparative-legal and system-structural methods were used in the research process. Based on the analysis of the European Patent Convention, the main generally accepted conditions of patentability of the invention are determined: novelty, inventive step, industrial applicability. It has been established that inventions created by artificial intelligence technologies will meet such criteria provided that certain requirements are met. In the context of the study, the case of the invention of artificial intelligence «DABUS» is analyzed and the results of its consideration in the European Patent Organization, the United Kingdom and the United States are summarized. In particular, it has been established that artificial intelligence technologies are currently not considered as inventors in either the Romano-Germanic or Anglo-Saxon legal systems.

Nowadays dental caries and periodontal diseases are among the most pressing problems in Paediatric Dentistry. Young patients with psychoneurological disorders are a special category among children with somatic pathology. At the same time, the issue of providing dental care to such children is underrepresented. Today, traditional schemes used for the prevention and treatment of caries and periodontal disease in children with mental retardation requires further improvement taking into account the clinical status of children with particular forms of mental retardation, including oligophrenia. Thus, the aim of our study was to develop and evaluate the effectiveness of a complex of measures to prevent dental caries in children with oligophrenia. To assess the effectiveness of the elaborated preventive complex, 56 children aged 12 years with the diagnosis of oligophrenia of I degree of severity (mild mental backwardness) were under observation during 2 years; 27 children received the complex we developed. The group of comparison included 29 children; caries prevention measures for these children were based on regional protocols (hygienic education, keeping oral hygiene, use of fluoride toothpastes). The effectiveness of the developed preventive complex was evaluated 6, 12 and 24 months after the beginning of its implementation according to the following criteria: the growth of dental caries intensity; reduction in the growth of dental caries intensity; level of oral hygiene (OHI-S index); changes in the biocenosis of the oral cavity (in 1 and 6 months of the observation). The results of the examination after the 6 month observation period have shown the dental caries intensity in children of the main group is 6.65 ± 0.45 teeth that is 1.02 times lower than in the children of the comparison group (6.79 ± 0.26 teeth, p ˃0.05). Thus, the growth of dental caries intensity in the children of the main group is, on average, 0.41 ± 0.05 tooth, which is significantly lower than in children of the comparison group (0.58 ± 0.06 tooth, p

Summary. The aim of the study. To improve the results of patients with tumors and non-neoplastic diseases of the colon treatment, to introduce into clinical practice the original surgical technique and methods of creating of colon anastomoses, which were tested in experiment. Materials and methods. Original methods of invaginational ileo-transverse and colon anastomoses creating were developed in the experiment on rabbits. Taking into account the obtained positive results, the methods of anastomoses formation were transferred to the surgical clinic and patents of Ukraine were obtained. In 2020, ileo-transverse and colonic anastomoses were formed in 134 patients on the basis of Transcarpathian Antitumor Center: one-row invaginational anastomosis according to the developed method in 22 patients (16.4 %), two-row manual — in 58 (43.3 %), circular stapler — in 36 (26.9 %), linear stapler anastomosis — in 4 (3 %), laparoscopic (linear stapler) — in 14 (10.4 %). Results and discussion. The most of complications occurred in the group with manual two-row anastomosis (16), in two cases the anastomotic leakage was recorded. When using a circular stapler suture, anastomotic leakage was observed in 1 patient, and anastomositis — in 4. When using linear stapler anastomoses, postoperative wound suppuration was observed in 1 patient. Conclusions. The most of early postoperative complications was observed after using a two-row manual colonic anastomosis (27.5 %). When using a circular stapler suture, the number of early postoperative complications was less than with a two-row manual anastomosis (22.2 % vs. 27.5 %, respectively). The least number of complications was recorded after the creation of a one-row invaginational anastomosis in the proposed original technique.

ABSTRACT: In this paper we describe various approaches used to capture heterogeneity within the reservoir undergoing hydraulic fracturing treatment and their implication on modelling of fracture propagation. In highly laminated reservoirs with soft and/or weak layers, capturing heterogeneity at an appropriate resolution is the key for successful prediction fracture growth and other crucial treatment parameters. Our focus is on studying several strategies to average fracture toughness and assess their suitability for use in advanced computational methods such as FE/BEM. In practice the well log and petrophysical data deduced from various measurements and observations are upscaled and/or homogenized to the spatial approximation size. The fracture toughness is one of the most delicate physical parameters and application of the homogenization techniques are rather uncertain, hence any proposed averaging will depend on process conditions and the toughness distribution. We propose and analyse a notion of an average toughness and show that it is a process dependent variable and provide some recommendations how to implement the defined measure into the numerical modelling. As an example, we use periodic distributions and consider model without leak off that allows us straightforward handling different regimes (toughness/viscosity). 1. INTRODUCTION Typically, when using computational methods such as Finite Element Method, the well log and petrophysical data obtained from various measurements and observations are upscaled and/or "homogenized" to the element size. From all in-situ parameters, toughness is one of the most delicate physical parameters to handle, as application of the homogenization techniques are rather questionable here as commented on by Caiulo and Kachanov (2010) and Kachanos (1994). Compared to other types of fracture evolution, hydraulic fracturing is probably the most stable crack propagation process and thus, fortunately, some estimates can be provided here. We estimate errors introduced by various strategies to incorporate heterogeneous fracture toughness into numerical modelling (Dontsov and Suarez-Rivera (2021), Da Fies et al. (2021)). We use periodic distributions and consider model without leak off that allows us straightforward handling different regimes (toughness/viscosity). For the simulations, we use an extremely effective in house-built time – space adaptive solver utilizing main ideas from those reported by Wrobel and Mishuris (2015). The solver is capable to compute rather arbitrary distribution of the toughness.

Dutko A. Protection of Family Rights of a Person by a Court / Alyona Dutko // Societas et iurisprudentia. - 2020. - Vol. 8. - No. 4. - Pp. 36-50.

SUMMARY We present unambiguous evidence that the Mahogany salt body, located in the Northern part of the Gulf of Mexico, is seismically anisotropic. Evidence of anisotropy comes from shear wave splitting data obtained from a vertical seismic profile VSP. The data set consists of 48 vertically aligned receivers in a borehole drilled through the salt body. Splitting analysis is performed on shear wave phases that are converted from compressional waves at the top and bottom of the salt body. The phase converted at the top of the salt layer shows a clear signature of seismic anisotropy, while the phase at the base of the salt layer shows negligible splitting. We investigate the possibility of rock salt halite LPO as a cause of the observed anisotropy. A finite element geomechanical salt deformation model of the Mahogany salt body is developed, where deformation history is used as an input to the texture plasticity simulation program VPSC. Assuming a halite salt body, a full elasticity model is then calculated and used to create a synthetic VSP splitting data set. The comparison between the synthetic and real VSP data set shows that LPO of rock salt can explain the observed anisotropy remarkably well. This is the strongest evidence to date of seismic anisotropy in a deforming salt structure. Furthermore, for the first time, we are able to demonstrate clear evidence that deforming halite is the most likely cause of this anisotropy, combining data set analysis and synthetic full wave form modelling based on calculated rock salt elasticities. Neglecting anisotropy in seismic processing in salt settings could lead to potential imaging errors, for example the deformation models show an averaged delta parameter of δ = –0.06, which would lead in a zero offset reflection setting to a depth mismatch of 6.2 per cent. Our work also show how observations of salt anisotropy can be used to probe characteristics of salt deformation.

Objective. To establish the impact of intraintestinal pressure on the intestinal anastomosis integrity and to propose a prophylactic measures of its insufficiency in surgical treatment of the colon diseases. Materials and methods. Intraintestinal pressure was measured in 30 patients, using Waldman method during 72 h postoperatively - before and after the transanal lavage (every 4 h). Primary operation - resection of sigmoid colon with formation of a one-barrel colostomy. The restoration intervention was performed in 3 mo with formation of a large-bowel anastomosis in accordance to the method elaborated (n=17), hand-made two-layered large-bowel anastomosis (n=3), and the apparatus large-bowel anastomosis (n=10). Results. There was noted the intraintestinal pressure raising during first 24 - 36 h up to (5.3 ± 0.1) mm Hg with its further lowering during 12 - 20 h down to (2.1 ± 0.3) mm Hg. In 20 min after the transanal drain lavage the intraintestinal pressure have lowered by (3.0 ± 1.3) mm Hg, and in 3 - 5 h - gradually raised. While application of a hand-made two-layered large-bowel anastomosis its insufficiency was observed (n=1) and anastomositis (n=1); and in the apparatus large-bowel anastomosis formation - anastomositis (n=1). While disorder of the intestinal suture healing the intraintestinal pressure have raised in 16 - 60 h up to (11.4 ± 0.2) mm Hg with peak at (16.3 - 17.1) mm Hg, which persisted 12 -18 h. Prophylactic measures were directed towards lowering of intraintestinal pressure and elimination of unfavorable local and general factors. Conclusion. While persisting noncorrected, the intraintestinal pressure in the 16.3 - 17.1 mm Hg borders during 12 - 18 h leads to complicated course of postoperative period. Direct and nondirect methods of decompression of the interintestinal anastomoses constitutes a basic prophylactic principle for it.

The aim of the article is to describe the principles of cloud technology and the scope of its use at a lesson of the Russian language in a polylingual class. Following the analysis of scientific and methodological literature on digital education, new technologies are suggested which have been introduced in a new type of handbook – a course navigator. The authors present a model to construct a course «Theatrical readings» for primary and secondary schoolchildren. The methodical constructor is oriented not only on reading as a kind of speech activity but also on material visualization and audio perception. The system of tasks reflects the specific nature of teaching Russian by means of fiction texts, teaching reading strategies and fiction understanding with the application of differential, problem search methods of teaching. When constructing the educational navigator the resources of the Google Network were used, which is a useful instrument for a teacher of Russian. This service allows for a favorable combination of various forms of tasks which form a motivation for cognitive activity. The article concludes that cloud technology as an element of digital learning in the modern educational process should emerge as a set of teaching tools to create methodical products contributing to the effective study of Russian linguistic culture.

The contribution describes the peculiarities of the protection of the right to property in the case law of the European Court of Human Rights. It has been found that, given the peculiarities of the legal nature of the right to property, it requires state regulation and may be subject to restriction and interference. Attention is drawn to the predication of any potential interference with the right to property on a general principle, according to which everyone has the right to peacefully enjoy their property. The article further clarifies the forms of interference with the ownership of individuals and legal entities by the state, such as expropriation of property and control over use of property. The triple normative regulation of property relations is investigated, and the elements of the relevant structure were covered in detail. The contents of the three-component test, in particular, its elements, such as the legality of interference with the right to property, the legitimacy of the purpose of such interference, and a fair balance between the interests of protection of the right to property and public interests, are expounded with reference to the awards of the European Court of Human Rights. Particular attention was paid to legality provisions. The contribution further dwells on the conceptual and categorical framework of the terms “general interest” and “public interest.” The authors complete their scientific inquiry with appropriate generalisations and a summary.

Summary. Aim of the study. Development and implementation of colon anastomoses formation method to improve their mechanical strength and biological hermeticity. Materials of the study. A comparative morphological study of the original and traditional two-row colonic anastomoses was performed in the experiment on 18 rabbits, and an assessment of their mechanical strength and biological hermeticity. The assessment of mechanical strength was defined by using a pneumopression technique. The assessment of biological hermeticity was defined by the method of culturing flushing water from the area of the anastomosis to the growth medium, species identification of isolated microorganisms using test systems and calculating the number of colony-forming units by quantitative method. Results of the research. The mechanical strength of one-row manual intra-nodular colonic anastomosis is higher by 66.3–85.4 %, respectively, of the first and seventh day of observations compared with the two-row manual anastomosis. During biological hermeticity assessment in the experimental group, in which colonic anastomosis was performed in the original method, the cultures were sterile at all stages of the sampling, whereas in the control group, where the traditional two-row manual anastomosis was formed, only from the seventh day all the cultures were sterile. Conslusions. The mechanical strength of one-row manual intra-nodular colonic anastomosis using atraumatic suture 4/0 without suturing the mucosa is higher by 66.3-85.4 %, respectively, of the first and seventh day of observations compared with the two-row manual anastomosis. Biological hermeticity of one-row manual intra-nodular colonic anastomosis is 100 % compared with the two-row manual anastomosis (28,5 %).

The legal regime of separation is a complex institute in which establishment entails several legal consequences for both the spouses and other members of the family and concerns both the property and personal non-property rights of the parties. It is characterized by the features common to a particular model of legal regulation of this institute. The purpose of the study is to analyze the characteristics of legal regulation of family relations, which arise out of the establishment, operation, and suspension of spousal separate residence regime in the countries of the European Union and Ukraine and their representation from the perspective of correlation of institutes of separation and divorce. During the study of models of legal regulation of the institute of spousal separate residence, general and special methods of legal phenomena identification were used. In particular, the dialectical method was used to determine the place of the institute of separation in the system of law and its relation with the institute of divorce. The social purpose of this institute was also established. The hermeneutical method helped to interpret the main features inherent in each of the models of legal regulation of separation. Logical-legal and systematic methods were used for the formulation of logically relevant conclusions, and consistent presentation of study materials. The legal comparative method is aimed at comparing the models of legal regulation of the institute of spousal separate residence in the current family law of Ukraine and the legislation of the countries of the European Union. On grounds of a comprehensive analysis of the legislation and practice of its application regarding the legal regime of spousal separate residence in the countries of the European Union and Ukraine, the features of each of the four models for legal regulation are distinguished. Keywords: Divorce, the European Union, separation, spousal separate residence regime, Ukraine.

ImportanceDue to the emergence of highly transmissible SARS-CoV-2 variants, evaluation of boosters is needed.ObjectivesEvaluate safety and immunogenicity of 100-µg of mRNA-1273 booster dose in adults.DesignOpen-label, Phase 2/3 study.SettingMulticenter study at 8 sites in the U.S.ParticipantsThe mRNA-1273 100-µg booster was administered to adults who previously received a two dose primary series of 100-µg mRNA-1273 in the phase 3 Coronavirus Efficacy (COVE) trial, at least 6 months earlier.InterventionLipid nanoparticle containing 100-µg of mRNA encoding the spike glycoprotein of SARS-CoV-2 (Wuhan-HU-1).Main Outcomes and MeasuresSolicited local and systemic adverse reactions, and unsolicited adverse events were collected after vaccination. Primary immunogenicity objectives were to demonstrate non-inferiority of the neutralizing antibody (nAb) response against SARS-CoV-2 based on the geometric mean titer (GMTs) and the seroresponse rates (SRRs) (booster dose vs. primary series in a historical control group). nAbs against SARS-CoV-2 variants were also evaluated.ResultsThe 100-µg booster dose had a greater incidence of local and systemic adverse reactions compared to the second dose of mRNA-1273 as well as the 50-µg mRNA-1273 booster in separate studies. The geometric mean titers (GMTs; 95% CI) of SARS-CoV-2 nAbs against the ancestral SARS-CoV-2 at 28 days after the 100-µg booster dose were 4039.5 (3592.7,4541.8) and 1132.0 (1046.7,1224.2) at 28 days after the second dose in the historical control group [GMT ratio=3.6 (3.1,4.2)]. SRRs (95% CI) were 100% (98.6,100) at 28 days after the booster and 98.1% (96.7,99.1) 28 days after the second dose in the historical control group [percentage difference=1.9% (0.4,3.3)]. The GMT ratio (GMR) and SRR difference for the booster as compared to the primary series met the pre-specified non-inferiority criteria. Delta-specific nAbs also increased (GMT fold-rise=233.3) after the 100-µg booster of mRNA-1273.Conclusions and RelevanceThe 100-µg mRNA-1273 booster induced a robust neutralizing antibody response against SARS-CoV-2, and reactogenicity was higher with the 100-µg booster dose compared to the authorized booster dose level in adults (50-µg). mRNA-1273 100-µg booster dose can be considered when eliciting an antibody response might be challenging such as in moderately or severely immunocompromised hosts.Trial Registration: NCT04927065Key PointsQuestion: What is the safety and immunogenicity of a booster dose of 100 µg of mRNA-1273 in adults who previously received the primary series of mRNA-1273?Findings: In this open-label, Phase 2/3 study, the 100 µg booster dose of mRNA-1273 had a greater incidence of local and systemic adverse reactions compared to a 50 µg booster dose of mRNA- 1273 or after the second dose of mRNA-1273 during the primary series. The 100 µg booster dose of mRNA-1273 induced a robust antibody response against the ancestral SARS-CoV-2 and variants.Meaning: mRNA-1273 100 µg booster dose might be considered when eliciting an antibody response might be challenging, such as in moderately or severely immunocompromised hosts.

Background: Breast cancer is the second most common cancer in women. In 2022, it accounted for 15% of total new cancer cases and is the number four cause of death among all cancer types. To benefit from precision medicine, distinguishing molecular subtypes for prognosis and treatment in a clinical setting is essential. While intrinsic subtype classification from NGS results of patients is well established, the approach has not been comprehensively described for patient-derived xenograft (PDX) models, which have been shown to be powerful in translational research. The National Cancer Institute's Patient-Derived Models Repository (NCI PDMR; https://pdmr.cancer.gov) provides rich information in developing the method. Materials and Methods: Normalized gene expression data of breast cancer PDX and patient specimens (originators) were extracted using tximport and DESeq2 based on RNA-seq analysis. The immunohistochemistry (IHC) was used to determine the status of ER, PR and HER2 receptor expression in these tumor specimens. The PAM50 classification was performed by the R package Genefu. For further analysis, the PAM50 centroids for all 5 subtypes were also obtained from Genefu. Results: Using the RNA-seq data from 43 PDX models (180 PDX samples, 4~6 samples/model), we were able to predict subtypes at the model level based on the PAM50 method: There are 1 Luminal A subtypes, 5 Luminal B; 6 Her2; 30 Basal and 1 Normal, which encompasses the whole spectrum of PAM50. Thirty originators were also included and there are 8 Luminal A, 9 Luminal B, 2 Her2 and 11 Basal. With the matched 11 originators and the PDX models, 91% of their predicted subtypes are identical; 0.80 Cohen’s kappa was obtained, indicating high inter-rater agreement. We also described subsequent analysis with IHC data-based subtypes. For the 10 originators having IHC-based subtypes, 90% agreement was observed; for 24 PDX models with IHC data, 88% was observed. Of all the 180 PDX samples, 33 of the 43 PDX models (77%) have consistent predicted PAM50 molecular subtypes across different passages and lineages. Within the discordant samples, we observed cases such as a mixture of luminal B and Basal, which can be reasonably interpreted by AR positive signal from IHC. The discrepancy encourages further PDX subclassification from the Basal subtype. Conclusions: Using our high-throughput gene expression profiles from many patients and samples from patient derived models, we have demonstrated the feasibility of applying classic PAM50 classification algorithm, which was originally developed with microarray data, to be able to recognize the expression signals from our RNA-seq data. Overall, this study should set a primer for the identification of PDX-based subtypes, starting from breast cancer. Citation Format: Peter I. Wu, Lindsay Dutko, Shahanawaz Jiwani, Li Chen, Biswajit Das, Ting-Chia Chang, Yvonne A. Evrard, Chris A. Karlovich, Alyssa Chapman, Brandie Fullmer, Ashley Hayes, Ruth Thornton, Nikitha Nair, Kelly Benauer, Gloryvee Rivera, Thomas Forbes, John Carter, Suzanne Borgel, Tiffanie Miner, Chelsea McGlynn, Justine Mills, Shannon Uzelac, Tia Shearer, Lauren Hicks, Michelle Norris, Carley Border, Sergio Alcoser, Thomas Walsh, Michael Mullendore, Michelle Eugeni, Dianne Newton, Melinda G. Hollingshead, P. M. Williams, James H. Doroshow. Molecular subclassification of NCI PDMR breast cancer models using PAM50 gene expression signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2050.

Introduction: Structural variants (SVs) are a unique class of mutations which have certain therapeutic implications for the tumor. Certain SVs, such as chromosomal aneuploidy, whole-genome doubling (WGD), have specific therapeutic implications. The underlying cellular processes present in the tumor are reflected in mutational signatures. Here, we describe the landscape of chromosomal aneuploidy, WGD and mutational signatures in the National Cancer Institute’s Patient-Derived Models Repository (NCI PDMR) to facilitate the investigation of their roles in therapeutic responses of the preclinical models. Method: Chromosome arm-level aneuploidy was called by scoring at the individual arm level if >90% of the arm copy number (CN) was gained/lost based on whole-exome sequencing (WES) data. Aneuploidy score was defined as number of arms with aneuploidy. WGD was determined by derived allelic specific CN, purity and ploidy from tumor/normal matched samples and permutation test. Mutational signatures (COSMIC v3) including single base substitutions (SBS), doublet base substitutions (DBS), small insertions and deletions (ID) and CN signatures were derived using SigProfiler for specimens with somatic mutations and CNs. Results: A large fraction (85%) of patient-derived xenograft (PDX) models (N=755) have at least one arm -level aneuploidy. Certain chromosomes and arms (7, 8, 17p and 18) are more frequently aneuploid, which might be biased due to the overrepresentation of gastrointestinal cancer in the cohort. Histology specific differences were observed in the frequency of arm level aneuploidies. For example, synovial sarcoma (SYNS) and endometrioid carcinoma (UEC) have much lower level of aneuploidy than non-small cell lung cancer (NSCLC) or clear cell renal carcinoma (ccRCC) models. 61% of PDX models (N=277) have WGD, in which certain histologies have more WGD [NSCLC: 81%, head and neck squamous cell carcinomas (HNSCC): 71%] than others. Samples having WGD have a higher degree of aneuploidy and chromosomal instability. WGD and aneuploidy remain stable along the passages in 78% PDX models. Intra-model heterogeneity of WGD was observed due to lineage difference. Mutational signatures (SBS6,15,20) indicating concurrent DNA polymerase epsilon (POLE) mutation and defective DNA mismatch repair were highly enriched in microsatellite instability-high models (p Conclusion: We have characterized chromosomal aneuploidy, WGD and mutational signatures in NCI PDMR models. The models with SVs can be utilized in preclinical drug studies to understand their role in therapeutic response in patients. Citation Format: Li Chen, Biswajit Das, Ting-Chia Chang, Yvonne A. Evrard, Chris A. Karlovich, Alyssa Chapman, Brandie Fullmer, Ashley Hayes, Ruth Thornton, Nikitha Nair, Shahanawaz Jiwani, Lindsay Dutko, Kelly Benauer, Gloryvee Rivera, Corinne Camalier, John Carter, Suzanne Borgel, Tiffanie Miner, Chelsea McGlynn, Justine Mills, Shannon Uzelac, Tia Shearer, Lauren Hicks, Michelle Norris, Carley Border, Sergio Alcoser, Thomas Walsh, Michael Mullendore, Michelle Eugeni, Dianne Newton, Melinda G. Hollingshead, P. Mickey Williams, James H. Doroshow. Chromosomal aneuploidy, whole-genome doubling and mutational signatures in NCI PDMR models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6072.

The National Cancer Institute’s Patient-Derived Models Repository (NCI PDMR; https://pdmr.cancer.gov) has developed a national repository of Patient-Derived Models (PDMs) comprised of patient-derived xenografts (PDXs), in vitro patient-derived tumor cell cultures (PDCs) and cancer associated fibroblasts (CAFs) as well as patient-derived organoids (PDOrg). These PDMs are clinically annotated with molecular information available in an easily accessible database for the extramural community. A key effort in developing these models is to develop matched models sets allowing for larger scale screening efforts using 2D or 3D models to prioritize selection of PDX models for preclinical translational research. To date, over 220 model sets with a PDX, PDOrg, and PDC from a single patient have been developed; 40 of these have matched CAF models allowing for exploration of research questions focused on tumor microenvironment. The largest model sets are in colorectal cancer (COADREAD, n=76), gynecologic cancers (n=33), pancreatic adenocarcinoma (PAAD, n=29), melanoma (MEL, n=19), and head and neck squamous cell carcinomas (HNSCC, n=17). Every model undergoes several quality control assessments that serve as go/no-go criteria including pathology assessment, STR validation, NGS concordance assessment and for PDXs, human:mouse DNA content assessment. It should be noted that not every model is successful in the development or QC phase so additional model sets with only one or two of the model types are also available for researcher requests, for example there are over 125 PDX/PDOrg matched model sets. The NCI is currently performing parallel preclinical screening of PDXs and PDCs or PDOrgs to determine the ability of the in vitro lines to predict in vivo activity. Genetic and histopathologic assessment of these matched model sets have demonstrated a high degree of stability by somatic mutation, copy number alteration (CNA) and gene expression data. Gene expression correlation analysis shows that mean of Spearman r between PDXs 0.89, between matched PDC/PDXs 0.79, and between matched PDOrg/PDXs 0.82. As expected, some variation at the gene expression level when comparing PDX to in vitro cultures by t-SNE can be observed, likely due to the differences in culture conditions. Funded by NCI Contract No. HHSN261200800001E Citation Format: Yvonne A. Evrard, Li Chen, Sergio Alcoser, Gareth Bliss, Carrie Bonomi, Suzanne Borgel, John Carter, Ting-Chia Chang, Alice Chen, Kevin Cooper, Biswajit Das, Kelly Dougherty, Lindsay Dutko, Marion Gibson, Michelle M. Ahalt-Gottholm, Tara Grinnage-Pulley, Keegan Kalmbach, Chris Karlovich, Kimberly Klarmann, Shahanawaz Jiwani, Tiffanie Miner, Michael Mullendore, Matthew Murphy, Kevin Plater, Gloryvee Rivera, Jessica Steed, Luke Stockwin, Cindy R. Timme, Dianne L. Newton, Paul Mickey Williams, Melinda G. Hollingshead, James H. Doroshow. NCI patient derived models repository: PDX, organoid and cell lines from the same patient - bridging the translational pipeline [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 40.

A new approach to defining the effective fracture toughness for heterogeneous materials is proposed. This temporal averaging approach is process-dependent, incorporating the crack velocity and material toughness. The effectiveness of the new technique is investigated in the context of hydraulic fracture through heterogeneous rock with a periodic material toughness. The plane strain model is considered without fluid leak-off, to more easily investigate different regimes (toughness/viscosity). Numerical simulations are used to examine the effectiveness of the new homogenisation strategy, with comparison against the recently-proposed maximum toughness strategy. Simulations are conducted using an extremely effective (in house-built) time-space adaptive solver. The regimes in which each strategy is effective are determined., Comment: 43 pages, 22 figures

With the increasing demand for CO 2 storage in the subsurface, it is important to recognize that candidate formations may present complex stress conditions and material characteristics. Consequently, modelling of CO 2 injection requires the selection of the most appropriate constitutive material model for the best possible representation of the material response. The authors focus on modelling the geomechanical behaviour of the reservoir material, coupled with a multiphase flow solution of CO 2 injection into a saline-saturated medium. It is proposed that the SR3 critical-state material model is used, which considers a direct link between strength–volume–permeability that evolves during the simulation; furthermore, the material is considered to yield prior to reaching a peak strength in agreement with experimental observations. Verification of the material model against established laboratory tests is conducted, including multiphase flow accounting for relative permeabilities and fluid densities. Multiphase flow coupled to advanced geomechanics provides a holistic approach to modelling CO 2 injection into sandstone reservoirs. The resulting injection pressures, CO 2 migration extent and patterns, formation dilation, and strength reduction are compared for a range of in situ porosities and incremental material enhancements. This work aims to demonstrate a numerical modelling framework to aid in the understanding of geomechanical responses to CO 2 injection for safe and efficient deployment, and is particularly applicable to CO 2 sequestration in less favourable aquifers with a relatively low permeability, receiving CO 2 from a limited number of injection wells at high flow rates. The proposed framework can also enable additional features to be incorporated into the model such as faults and detailed overburden representation. Thematic collection: This article is part of the Geoscience for CO 2 storage collection available at: https://www.lyellcollection.org/cc/geoscience-for-co2-storage

Rising breakthrough infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in previously immunized individuals have raised concerns for the need for a booster vaccine dose to combat waning antibody levels and new variants. Here we report the results of the open-label, non-randomized part B of a phase 2 trial in which we evaluated the safety and immunogenicity of a booster injection of 50 µg of the coronavirus disease 2019 (COVID-19) vaccine mRNA-1273 in 344 adult participants immunized 6–8 months earlier with a primary series of two doses of 50 µg or 100 µg of mRNA-1273 (NCT04405076). Neutralizing antibody (nAb) titers against wild-type SARS-CoV-2 at 1 month after the booster were 1.7-fold (95% confidence interval (CI): 1.5, 1.9) higher than those at 28 days after the second injection of the primary series, which met the pre-specified non-inferiority criterion (primary immunogenicity objective) and might indicate a memory B cell response. The nAb titers against the Delta variant (B.1.617.2) (exploratory objective) at 1 month after the booster were 2.1-fold (95% CI: 1.8, 2.4) higher than those at 28 days after the second injection of the primary series. The seroresponse rate (95% CI (four-fold rise from baseline)) was 100% (98.7, 100.0) at 28 days after the booster compared to 98.3% (96.0, 99.4) after the primary series. The higher antibody titers at 28 days after the booster dose compared to 28 days after the second dose in the phase 3 COVE study were also observed in two assays for anti-spike IgG antibody measured by ELISA and by Meso Scale Discovery (MSD) Multiplex. The frequency of solicited local and systemic adverse reactions after the booster dose was similar to that after the second dose in the primary two-dose series of mRNA-1273 (50 µg or 100 µg); no new signals were observed in the unsolicited adverse events; and no serious adverse events were reported in the 1-month follow-up period. These results show that a booster injection of mRNA-1273 more than 6 months after completing the primary two-dose series is safe and elicited nAb titers that were statistically significantly higher than the peak titers detected after the primary vaccination series, suggesting that a booster dose of mRNA-1273 might result in increased vaccine effectiveness against infection and disease caused by SARS-CoV-2.

Мета роботи: покращення результатів лікування хворих із хірургічною патологією ободової кишки шляхом розпрацювання і впровадження патогенетично обґрунтованого алгоритму лікування та техніки створення анастомозу, спрямованого на зниження частоти післяопераційних ускладнень. Матеріали і методи. В групі з 30 пацієнтів вимірювали внутрішньокишковий тиск (ВКТ) у післяопераційному періоді. Під час операції, крім трансанального дренажу, який заводили вище анастомозу на 5–10 см, проводили трубку діаметром 0,5 см, кінець якої встановлювали на рівні товстокишкового анастомозу (ТКА). Вимірювання тиску проводили методом Вальдмана протягом 72 год із моменту операції, кожні 4 години. При цьому виконували 2 вимірювання – до і після промивання трансанального дренажу. При виконанні відновного втручання ТКА за розробленою методикою виконали – 17, ручний дворядний ТКА – 3, апаратний ТКА – 10 хворим. Результати досліджень та їх обговорення. Встановлено, що в післяопераційному періоді в ободовій кишці спостерігається зростання ВКТ (Р) протягом перших 24–36 год (t) в середньому до (5,3 ± 0,1) мм рт. ст., з подальшим зниженням цього рівня протягом наступних 12–20 год до (2,1 ± 0,3) мм рт. ст. Через 20 хв після промивання трансанального дренажу і відходження “промивних вод” рівень ВКТ знижується в середньому на (3,0 ± 1,3) мм рт. ст. Це зниження утримувалося протягом 3–5 год, після чого відбулося поступове зростання рівня ВКТ. При застосуванні традиційного дворядного анастомозу у 2 хворих відмічено в одному спостереженні неспроможність ТКА, у другому – анастомозит. ТКА розробленим способом виконано 17 хворим, апаратний ТКА – 10 хворим, анастомозит розвинувся в одного пацієнта. Ускладнення траплялися переважно при застосуванні ручного традиційного шва (10 %). У всіх хворих з розвиненими порушеннями загоєння анастомозу спостерігається підвищення ВКТ через 16–60 год до (11,4 ± 0,2) мм рт. ст., з піком близько (16,3–17,1) мм рт. ст., що спостерігалось аж до розвитку неспроможності анастомозу, з наступним різким зниженням ВКТ. При анастомозиті подібного зниження ВКТ не було. Мало значення не тільки стійке підвищення ВКТ з критичним рівнем до 16,3–17,1 мм рт. ст., а й тривалість впливу його протягом 12–18 год.

In recent years, digital communications have rapidly entered the lives of modern people. Globalization of digital technologies is solved in Russia at the state level – Federal programs of digitalization are created and implemented. They are aimed at the inclusion a person in the virtual space since the very childhood which undoubtedly affects many aspects of the human life. Thus, children developing in the context of the global spread of digital technologies have been called “generation Z”. Of course, this category of children could not go unnoticed by many domestic and foreign scientists. In this article, the authors provide an overview of studies devoted to the study of the “digital generation”.

The aim of this article is to analyze the capabilities of Google services and their combination with traditional approaches to studying the novel by L.N. Tolstoy’s “War and Peace”. Based on the generalization of the experience of teachers, school practice, the author proposes a model of an educational navigator, which is used in the study of a voluminous epic work – the novel “War and Peace”. Particular attention in the article is paid to ways of introducing students to reading and methods of working with the text of the novel using Google-services. The expediency and efficiency of using this resource for organizing the activities of students in the lesson and in extracurricular activities have been revealed. To build an educational navigator, it is relevant to turn to Google services: electronic encyclopedias, numerous Internet resources, multimedia tools (video encyclopedias, e-books, etc.). Separately, the specifics of the use of Google services in guiding students’ independent work through a specially organized interactive educational and information environment, which saves educational time, ensures long-term memorization of educational material, contributes to the development of the necessary reading skills of students, creates conditions for differentiated learning. The didactic capabilities of Google services are demonstrated using the example of different types of the educational navigator content. The article describes individual navigator modules. Based on the study, it was concluded that the Google services in the modern educational space should become a didactic toolkit for developing methodological recommendations and organizing a system for working with the text of a literary work, aimed at developing the reading activity of schoolchildren, their independence and creativity, and personal growth.

Prevention of hard dental tissue diseases and periodontal diseases in children is one of the urgent issues of pediatric dentistry. This is especially true for the category of children with psychoneurological pathology. Due to the high prevalence of dental diseases, decreased immunity, and sometimes difficult assess to dental care for children with mental retardation, dental disease prevention is the most effective measure to maintain the normal functioning of the dentofacial apparatus. The results obtained by examining the children with oligophrenia allowed us to work up an algorithm for therapeutic and preventive measures aimed at preventing the development of oral tissue diseases in these children. The algorithm included measures for primary and secondary prevention of periodontal diseases. To assess the efficacy of the algorithm, the study involved a group of 55 mentally impaired children. The control group consisted of 50 children with oligophrenia, who were treated by traditional methods. Taking into account the burdened mental status of the children when developing the individual hygiene regimens, a motivational approach was worked out in co-operation with a psychiatrist and a paediatrician. Evaluation of treatment outcomes in the groups was performed in 1 month after the completion of the full course of treatment and prevention and in long-term intervals, in 6 and 12 months. Clinical evaluation of treatment efficacy was performed according to the following criteria: "normalization", "improvement", "progression". In one month following the regimen proposed, the "normalization" of the affected tissues was diagnosed in 40 children of the main group (72,73 ± 6,06%), p

Most of drugs are only slightly soluble in the circulatory system of the human body. This reduces the efficiency of their use and that is why new ways how to increase their solubility are investigated. One way to improve the solubility of the drug is to reduce its particle size. Conventional techniques such as crushing or grinding usually do not guarantee a narrow particle size distribution, which is required for pharmaceuticals. Application of supercritical fluids, especially of supercritical CO₂, seems to be convenient method for the preparation of pharmaceuticals submicron particles or nanoparticles. The method enables the preparation of particles in a narrow size distribution and at the same time it does not leave any unwanted residues of solvents or other chemicals. The aim of this work is the micronization of ibuprofen particles using the supercritical fluid and characterization of formed products. The micronization of the particles was done using commercially available device Spe-ed SFE-4 in rapid expansion of supercritical solution mode. The applied temperatures and pressures were 308.15 K and 313.15 K and 200, 250 and 300 bar. The prepared particles were characterized using methods of X-ray diffraction, infrared spectroscopy, particle size distribution, scanning electron microscopy and tests of dissolution and permeability. Mean particles size was reduced from 180 μm (original ibuprofen) to 2.8-7.3 μm of the processed samples. The dissolution test confirmed better solubility and the permeability of newly formed particles improved.

Organically modified vermiculites can be used as nanostructured adsorbents of organic compounds from waters or gaseous phases similarly as organically modified smectites or bentonites. There is a large amount of research data focused on adsorption properties of organoclays, however only a little information is about their post-sorption treatment. This work is focused on study of two possible ways of subsequent processing of organovermiculite after its use as sorbent for heavily polluted waste water. At first, the vermiculite modified with hexadecylpyridinium ions was used in batch static sorption against phenol ammonium water from the coke industry to get highly contaminated sorption material, especially containing organic hydrocarbons and their derivatives. The sorbent is known to have excellent sorption properties; however ecotoxicological characteristics of original material showed that sorbent had hazardous properties even before its utilization. For that reason, it was necessary to design a post-sorption treatment. Two possible methods of treatment were investigated, specifically solvent treatment (with dichloromethane) and thermal treatment (thermodesorption) at temperatures of 300 and 1100 °C, respectively. The treated materials were studied using infrared spectroscopy, X-ray diffraction and carbon phase analyses. The solvent treatment confirmed that it is possible to reuse modified vermiculite as adsorbent several times, although adsorption capacity after each extraction decreases. The thermal treatment at 300 °C was not sufficient to remove all organic compounds from the vermiculite structure; however at 1100 °C the only presence of magnesium silicate, magnesium aluminate and ferric oxide confirmed the formation of an inert material convenient for an environmentally harmless disposal of used adsorbent.

A new approach to defining the effective fracture toughness for heterogeneous materials is proposed. This temporal averaging approach is process dependent, incorporating the crack velocity and material toughness. The effectiveness of the new technique is investigated in the context of hydraulic fracture through heterogeneous rock with a periodic material toughness. The plane strain model is considered without fluid leak-off, to more easily investigate different regimes (toughness/viscosity). Numerical simulations are used to examine the effectiveness of the new homogenisation strategy, with comparison against the recently proposed maximum toughness strategy. Simulations are conducted using an extremely effective (in house-built) time–space adaptive solver. The regimes in which each strategy is effective are determined.

We study a nonlinear Schrodinger–Poisson system which reduces to the nonlinear and nonlocal PDE $$\begin{aligned} - \Delta u+ u + \lambda ^2 \left( \frac{1}{\omega |x|^{N-2}}\star \rho u^2\right) \rho (x) u = |u|^{q-1} u \quad x \in {{\mathbb {R}}}^N, \end{aligned}$$ where $$\omega = (N-2)|{\mathbb {S}}^{N-1} |,$$ $$\lambda >0,$$ $$q\in (1,2^{*} -1),$$ $$\rho :{{\mathbb {R}}}^N \rightarrow {{\mathbb {R}}}$$ is nonnegative, locally bounded, and possibly non-radial, $$N=3,4,5$$ and $$2^*=2N/(N-2)$$ is the critical Sobolev exponent. In our setting $$\rho $$ is allowed as particular scenarios, to either (1) vanish on a region and be finite at infinity, or (2) be large at infinity. We find least energy solutions in both cases, studying the vanishing case by means of a priori integral bounds on the Palais–Smale sequences and highlighting the role of certain positive universal constants for these bounds to hold. Within the Ljusternik–Schnirelman theory we show the existence of infinitely many distinct pairs of high energy solutions, having a min–max characterisation given by means of the Krasnoselskii genus. Our results cover a range of cases where major loss of compactness phenomena may occur, due to the possible unboundedness of the Palais–Smale sequences, and to the action of the group of translations.

Significance TGF-β family heterodimeric ligands show increased or exclusive signaling compared to homodimeric ligands in both vertebrate and insect development as well as in therapeutically relevant processes, like osteogenesis. However, the mechanisms that differentiate heterodimer and homodimer signaling remain uncharacterized. We show that BMP antagonists do not account for the exclusive signaling of Bmp2/7 heterodimers in zebrafish development. We found that overexpressed homodimers can signal but surprisingly require two distinct type I receptors, like heterodimers, indicating a required activity of the heteromeric type I receptor complex. We further demonstrate that a canonical type I receptor function has been delegated to only one of these receptors, Acvr1. Our findings should inform both basic and translational research in multiple TGF-β family signaling contexts., Heterodimeric TGF-β ligands outperform homodimers in a variety of developmental, cell culture, and therapeutic contexts; however, the mechanisms underlying this increased potency remain uncharacterized. Here, we use dorsal–ventral axial patterning of the zebrafish embryo to interrogate the BMP2/7 heterodimer signaling mechanism. We demonstrate that differential interactions with BMP antagonists do not account for the reduced signaling ability of homodimers. Instead, we find that while overexpressed BMP2 homodimers can signal, they require two nonredundant type I receptors, one from the Acvr1 subfamily and one from the Bmpr1 subfamily. This implies that all BMP signaling within the zebrafish gastrula, even BMP2 homodimer signaling, requires Acvr1. This is particularly surprising as BMP2 homodimers do not bind Acvr1 in vitro. Furthermore, we find that the roles of the two type I receptors are subfunctionalized within the heterodimer signaling complex, with the kinase activity of Acvr1 being essential, while that of Bmpr1 is not. These results suggest that the potency of the Bmp2/7 heterodimer arises from the ability to recruit both Acvr1 and Bmpr1 into the same signaling complex.

Aim - comparison of biological hermeticity, mechanical strength and differences in morphological characteristics of one-row and two-row colon anastomoses. 20 animals were used in the experiment. Rabbits of both sexes aged from 8 months to 1.5 years and weighing from 1.5 to 2.6 kg were used as experimental animals. The animals were divided into experimental and control groups. In the experimental group we used the developed technique of one-row colon anastomosis (CA) formation, in the control group - the traditional two-row CA. Assessment of mechanical strength was performed by using the original method of pneumopression of colon segment with the anastomosis. The biological hermeticity was assessed by culturing flushing water from the anastomosis line to growth medium. The morphological picture was evaluated by microscopy of histological samples from the anastomosis line. The mechanical strength of the one-row anastomosis, compared with the traditional two-row, was higher at each stage of the study, on the first day by 66.3%, the third - 87.6%, the fifth - 76.1%, the seventh - 85.4%. The formation of a one-row CA allowed to achieve biological hermeticity of the anastomosis area in all periods of the early postoperative period, and when using a double-row suture, the anastomosis area became sterile only from 5 day. Morphologically, the picture was characterized by inflammatory processes in the anastomosis area when using the original technique, which were stopped in 3-5 days, and in the control group they persisted for up to 7 days, accompanied by vascular paresis of the intestinal wall, blood stasis and blood clots, with zones of mucosal necrosis at 3 and 5 day of observation.

Background: The National Cancer Institute's Patient-Derived Models Repository (NCI PDMR; pdmr.cancer.gov) is developing a variety of patient-derived xenograft (PDX) models for pre-clinical drug studies. All NCI PDMR models undergo quality control (QC) processes. Two unique QC challenges are: a) to assess genomic stability across PDX model passages; and b) to confirm the suitability of PDX-derived cancer associated fibroblasts (CAFs) as germline surrogates when blood is not available. Multiple bioinformatics QC assessments have been developed to measure the genomic fidelity in these PDX models using low-pass whole genome sequencing (LP-WGS) and in CAFs using whole exome sequencing (WES). Methods: LP-WGS was performed on 502 PDX samples from 38 models of rare cancer across passages 2 through 9 and WES was performed on 92 CAFs from 32 different histologies. In the QC workflow for estimating the genomic stability of passages within models, BBSplit was used for the assessment of human/mouse DNA content. CNVkit was utilized for copy number (CN) detection. The fraction of genome changed was calculated by comparing the copy numbers of each passage sample to the original patient sample. To evaluate purity of CAFs, three QC steps were constructed: a) plot of SNP variant allele frequency (ideogram); b) variant annotation using OncoKB (www.oncokb.org); c) percentage of genomic loss of heterozygosity (LOH), based on a set of ~800,000 heterozygous SNPs from a population-level genomic database (gnomAD) based on WES data. Results: PDX models showed genomic stability in CN profile when measured by LP-WGS. Human tumor DNA content remains stable ranging from 75-85% across different tiers of PDX passages from Donor +1 to Donor +6 and more. No models showed statistically significant evolution in CN profile, given the average 5 samples per model in each tier of passages. The QC workflow for CAFs generated five categories based on SNP ideograms, the presence/absence of oncogenic variants and LOH. Following observations were made: a) 72.5% CAFs were confirmed as matched diploid CAFs (category 1); b) 6.6% of CAFs were diploid and had >= 1 germline oncogenic variant - classified as category 2. CAFs in category 1&2 were suitable as germline surrogates; c) 12% of CAFs (category 3) showed putative polyploidy on SNP ideograms with no oncogenic variants and suitable for somatic variant calling; d) 8.8% of CAFs (category 4) had polyploidy and oncogenic variants present; e) LOH high CAF (category 5) - we identified a CAF with 42% LOH, later confirmed to be a tumor cell line by immunohistochemistry (IHC). Other CAFs (n=91) showed little variance, ranging from 0.6%-1.7% LOH. Conclusions: We developed standard QC workflows to evaluate genomic stability of PDX models during passaging and qualify CAFs as germline surrogates for pre-clinical study. Citation Format: Ting-Chia Chang, Li Chen, Biswajit Das, Yvonne A. Evrard, Chris A. Karlovich, Tomas Vilimas, Alyssa Chapman, Nikitha Nair, Luis Romero, Anna J. Lee Fong, Amanda Peach, Brandie Fullmer, Lindsay Dutko, Kelly Benauer, Gloryvee Rivera, Erin Cantu, Shahanawaz Jiwani, Nastaran Neishaboori, Tomas Forbes, Corinne Camalier, Luke Stockwin, Michael Mullendore, Michelle A. Eugeni, Dianne Newton, Melinda G. Hollingshead, Mickey P. Williams, James H. Doroshow. Quality control workflows developed for the NCI Patient-Derived Models Repository using low pass whole genome sequencing and whole exome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1913.

Background: The National Cancer Institute’s Patient-Derived Models Repository (NCI PDMR; https://pdmr.cancer.gov) has developed a large number of patient-derived xenograft (PDX) models from a diverse set of rare cancers. These models have been genomically characterized using whole-exome sequencing (WES) and RNAseq. The resource provides a unique opportunity to explore the genomic features of rare tumor models in NCI PDMR and to understand the oncogenic processes in pre-clinical models to identify biomarkers associated with therapeutic responses. Methods: Genomic characterization was done in 4-6 PDX samples across multiple passages and lineages from each model. As the samples exhibited a high level of genomic stability within each model, consensus mutation and copy number variation (CNV), microsatellite instability (MSI), genomic loss of heterozygosity (LOH), homologous recombination deficiency score (scarHRD), and mutational signature data were generated from WES. Fusions were identified from RNASeq data using Star-Fusion and FusionInspector. Gene set enrichment analysis was conducted from the gene expression data obtained from RNAseq. Results: 1) 233 PDX models have been developed and characterized from more than 45 different rare malignancies. Most frequent cancer types are different sarcomas (n=63), head & neck squamous cell carcinoma (n=61), and malignant fibrous histiocytoma (MFH) (n=11); 2) TP53 was the most frequently altered gene, mutated in 51% of models, followed by NOTCH1 (16%) and PIK3CA (11%). In terms of CNVs, ovarian epithelial cancer (OVT) showed relatively high chromosomal instability, while uterine endometrioid carcinoma (UEC) and synovial sarcoma (SYNS) had low instability; 3) MSI-H was observed in only 7 models. Esophageal adenocarcinoma (ESCA), OVT, and cervical squamous cell carcinoma (CESC) had high scarHRD and genomic LOH scores, while both scores were low in UEC and anal squamous cell carcinoma (ANSC). COSMIC v2 mutational signature 3 is significantly associated with a high scarHRD score (p-value < 0.01, Wilcoxon rank-sum test); 4) Characteristic fusions were observed in certain sarcoma models: SS18-SSX1 and ASPSCR1-TFE3 fusions were observed in SYNS and alveolar soft part sarcoma (ASPS) models respectively. EWSR1-FLI1 fusion was present in 2 out of 3 Ewing sarcoma (ES) models. 5) Gene set enrichment analysis from RNASeq data showed that epithelial-mesenchymal transition score could accurately distinguish carcinoma from sarcoma models, confirming the divergent gene expression programs. Conclusion: Comprehensive genomic characterization of NCI PDMR models generated from rare cancers solves an unmet need in the community. It will serve as a valuable resource for translational researchers interested in pre-clinical drug development and discovery. Citation Format: Li Chen, Rini Pauly, Ting-Chia Chang, Biswajit Das, Yvonne A. Evrard, Chris A. Karlovich, Tomas Vilimas, Alyssa Chapman, Nikitha Nair, Luis Romero, Anna Lee Fong, Amanda Peach, Shahanawaz Jiwani, Nastaran Neishaboori, Lindsay Dutko, Kelly Benauer, Gloryvee Rivera, Erin Cantu, Corinne Camalier, Thomas Forbes, Michelle Gottholm-Ahalt, John Carter, Suzanne Borgel, Chelsea McGlynn, Candace Mallow, Emily Delaney, Tiffanie Miner, Michelle A. Eugeni, Dianne Newton, Melinda G. Hollingshead, P. Mickey Williams, James H. Doroshow. Genomic characterization of PDX models from rare cancer patients in the NCI Patient-Derived Models Repository [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 80.

Neutrophils are recognized to represent significant immune cell mediators for the clearance and elimination of the human-pathogenic fungal pathogen Candida. The sensing of fungi by innate cells is performed, in part, through lectin receptor recognition of cell wall components and downstream cellular activation by signaling components, including spleen tyrosine kinase (Syk). While the essential role of Syk in macrophages and dendritic cells is clear, there remains uncertainty with respect to its contribution in neutrophils. In this study, we demonstrated that Syk is critical for multiple cellular functions in neutrophils responding to major human-pathogenic Candida species. These data not only demonstrate the vital nature of Syk with respect to the control of fungi by neutrophils but also warn of the potential infectious complications arising from the recent clinical development of novel Syk inhibitors for hematologic and autoimmune disorders., Invasive fungal infections constitute a lethal threat, with patient mortality as high as 90%. The incidence of invasive fungal infections is increasing, especially in the setting of patients receiving immunomodulatory agents, chemotherapy, or immunosuppressive medications following solid-organ or bone marrow transplantation. In addition, inhibitors of spleen tyrosine kinase (Syk) have been recently developed for the treatment of patients with refractory autoimmune and hematologic indications. Neutrophils are the initial innate cellular responders to many types of pathogens, including invasive fungi. A central process governing neutrophil recognition of fungi is through lectin binding receptors, many of which rely on Syk for cellular activation. We previously demonstrated that Syk activation is essential for cellular activation, phagosomal maturation, and elimination of phagocytosed fungal pathogens in macrophages. Here, we used combined genetic and chemical inhibitor approaches to evaluate the importance of Syk in the response of neutrophils to Candida species. We took advantage of a Cas9-expressing neutrophil progenitor cell line to generate isogenic wild-type and Syk-deficient neutrophils. Syk-deficient neutrophils are unable to control the human pathogens Candida albicans, Candida glabrata, and Candida auris. Neutrophil responses to Candida species, including the production of reactive oxygen species and of cytokines such as tumor necrosis factor alpha (TNF-α), the formation of neutrophil extracellular traps (NETs), phagocytosis, and neutrophil swarming, appear to be critically dependent on Syk. These results demonstrate an essential role for Syk in neutrophil responses to Candida species and raise concern for increased fungal infections with the development of Syk-modulating therapeutics.