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The fine structure of huge thermomagnetic flux jumps in V3Si single crystal was analyzed in detail. Structure of avalanches consists of several hundreds of microavalanches. The magnitude of the flux of the microavalanches and their duration were determined. The histograms of the distribution of microflux jumps magnitudes are plotted (the number of microavalanches as a function of the outgoing flux size) for different temperatures. The role of microstructure pinning centers was discussed on the assumption that microavalanches are jumps of flux bundles. In such case, fine structure of the avalanche can characterize the parameters of the pinning centers (size, number of pinned vortices, etc.). [ABSTRACT FROM AUTHOR]

Enzymatic site-specific bioconjugation techniques, in particular sortase-mediated ligation, are increasingly used to generate conjugated proteins for a wide array of applications. Extension of the utility and practicality of sortagging for diverse purposes is critically dependent on further improvement of the efficiency of sortagging reactions with a wider structural variety of substrates. We present a comprehensive comparative mass spectrometry screening study of synthetic nonpeptidic incoming amine nucleophile substrates of Staphylococcus aureus Sortase A enzyme. We have identified the optimal structural motifs among the chemically diverse set of 452 model primary and secondary amine-containing sortagging substrates, and we demonstrate the utility of representative amine linkers for efficient C-terminal biotinylation of nanobodies.

Background & Aims: Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Herein, we aimed to uncover the mechanisms of HB pathobiology and to identify new biomarkers and therapeutic targets in a move towards precision medicine for patients with advanced HB., Methods: We performed a comprehensive genomic, transcriptomic and epigenomic characterization of 159 clinically annotated samples from 113 patients with HB, using high-throughput technologies., Results: We discovered a widespread epigenetic footprint of HB that includes hyperediting of the tumor suppressor BLCAP concomitant with a genome-wide dysregulation of RNA editing and the overexpression of mainly non-coding genes of the oncogenic 14q32 DLK1-DIO3 locus. By unsupervised analysis, we identified 2 epigenomic clusters (Epi-CA, Epi-CB) with distinct degrees of DNA hypomethylation and CpG island hypermethylation that are associated with the C1/C2/C2B transcriptomic subtypes. Based on these findings, we defined the first molecular risk stratification of HB (MRS-HB), which encompasses 3 main prognostic categories and improves the current clinical risk stratification approach. The MRS-3 category (28%), defined by strong 14q32 locus expression and Epi-CB methylation features, was characterized by CTNNB1 and NFE2L2 mutations, a progenitor-like phenotype and clinical aggressiveness. Finally, we identified choline kinase alpha as a promising therapeutic target for intermediate and high-risk HBs, as its inhibition in HB cell lines and patient-derived xenografts strongly abrogated tumor growth., Conclusions: These findings provide a detailed insight into the molecular features of HB and could be used to improve current clinical stratification approaches and to develop treatments for patients with HB., Lay Summary: Hepatoblastoma is a rare childhood liver cancer that has been understudied. We have used cutting-edge technologies to expand our molecular knowledge of this cancer. Our biological findings can be used to improve clinical management and pave the way for the development of novel therapies for this cancer., Competing Interests: Conflict of interest Prof. Josep M. Llovet is receiving research support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb and Ipsen, and consulting fees from Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai Inc, Celsion Corporation, Eli Lilly, Exelixis, Merck, Ipsen, Glycotest, Navigant, Leerink Swann LLC, Midatech Ltd, Fortress Biotech, Sprink Pharmaceuticals and Nucleix and CANFITE. CA has a research contract with CHIOME Biosciences Inc. The other authors report no conflicts of interest in this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Experimental evidence of tremendous magnetic moment dynamical inversion, from metastable trapping state to the state with essentially the same moment oriented in the opposite direction, appearing during giant flux jump connected to thermomagnetic avalanche process in superconducting YBa 2 Cu 3 O 7-δ single crystal, is presented. Magnetization inversion takes place in the system, without thermal contact between sample and sample holder, with a tremendous stored energy once the avalanche process is completed in quasi-adiabatic conditions. A model of magnetic moment inversion, caused by the jump between two metastable states of superconductor with the same energy storage, is presented and discussed in terms of the critical state with peculiar evolution of the critical-current spatial distribution. Importantly, knowledge of conditions of the appearance of such a phenomenon is crucial for applications of bulk superconductors as "permanent" magnets, for example, in superconducting levitation devices, etc.

Interfering with tumor metabolism is an emerging strategy for treating cancers that are resistant to standard therapies. Featuring a rapid proliferation rate and exacerbated glycolysis, hepatocellular carcinoma (HCC) creates a highly hypoxic microenvironment with excessive production of lactic and carbonic acids. These metabolic conditions promote disease aggressiveness and cancer-related immunosuppression. The pH regulatory molecules work as a bridge between tumor cells and their surrounding milieu. Herein, we show that the pH regulatory molecules CAIX, CAXII and V-ATPase are overexpressed in the HCC microenvironment and that interfering with their pathways exerts antitumor activity. Importantly, the V-ATPase complex was expressed by M2-like tumor-associated macrophages. Blocking ex vivo V-ATPase activity established a less immune-suppressive tumor microenvironment and reversed the mesenchymal features of HCC. Thus, targeting the unique cross-talk between tumor cells and the tumor microenvironment played by pH regulatory molecules holds promise as a strategy to control HCC progression and to reduce the immunosuppressive pressure mediated by the hypoxic/acidic metabolism, particularly considering the potential combination of this strategy with emerging immune checkpoint-based immunotherapies.

Background & Aims: Agents that induce an immune response against tumors by altering T-cell regulation have increased survival times of patients with advanced-stage tumors, such as melanoma or lung cancer. We aimed to characterize molecular features of immune cells that infiltrate hepatocellular carcinomas (HCCs) to determine whether these types of agents might be effective against liver tumors., Methods: We analyzed HCC samples from 956 patients. We separated gene expression profiles from tumor, stromal, and immune cells using a non-negative matrix factorization algorithm. We then analyzed the gene expression pattern of inflammatory cells in HCC tumor samples. We correlated expression patterns with the presence of immune cell infiltrates and immune regulatory molecules, determined by pathology and immunohistochemical analyses, in a training set of 228 HCC samples. We validated the correlation in a validation set of 728 tumor samples. Using data from 190 tumors in the Cancer Genome Atlas, we correlated immune cell gene expression profiles with numbers of chromosomal aberrations (based on single-nucleotide polymorphism array) and mutations (exome sequence data)., Results: We found approximately 25% of HCCs to have markers of an inflammatory response, with high expression levels of the CD274 molecule (programmed death-ligand 1) and programmed cell death 1, markers of cytolytic activity, and fewer chromosomal aberrations. We called this group of tumors the Immune class. It contained 2 subtypes, characterized by markers of an adaptive T-cell response or exhausted immune response. The exhausted immune response subclass expressed many genes regulated by transforming growth factor beta 1 that mediate immunosuppression. We did not observe any differences in numbers of mutations or expression of tumor antigens between the immune-specific class and other HCCs., Conclusions: In an analysis of HCC samples from 956 patients, we found almost 25% to express markers of an inflammatory response. We identified 2 subclasses, characterized by adaptive or exhausted immune responses. These findings indicate that some HCCs might be susceptible to therapeutic agents designed to block the regulatory pathways in T cells, such as programmed death-ligand 1, programmed cell death 1, or transforming growth factor beta 1 inhibitors., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The onset of cancer is unavoidably accompanied by suppression of antitumor immunity. This occurs through mechanisms ranging from the progressive accumulation of regulatory immune cells associated with chronic immune stimulation and inflammation, to the expression of immunosuppressive molecules. Some of them are being successfully exploited as therapeutic targets, with impressive clinical results achieved in patients, as in the case of immune checkpoint inhibitors. To limit immune attack, tumor cells exploit specific pathways to render the tumor microenvironment hostile for antitumor effector cells. Local acidification might, in fact, anergize activated T cells and facilitate the accumulation of immune suppressive cells. Moreover, the release of extracellular vesicles by tumor cells can condition distant immune sites contributing to the onset of systemic immune suppression. Understanding which mechanisms may be prevalent in specific cancers or disease stages, and identifying possible strategies to counterbalance would majorly contribute to improving clinical efficacy of cancer immunotherapy. Here, we intend to highlight these mechanisms, how they could be targeted and the tools that might be available in the near future to achieve this goal., Competing Interests: The authors declare no conflict of interest.

Morphological, functional signs of myocardium affection and tolerance to physical loading in animals with isoproterenol-induced affection of myocardium after transplantation of a nuclear-containing cells (NCC) of umbilical blood were analyzed in comparison with a natural course of the model. There was proved, that a transplantation of a NCC promotes acceleration of processes of regeneration and restoration of the damaged myocardium in experimental animals. There were estimated the changes in localization of the transplanted NCC in the zone of damage, and capacity of the peripheral blood NCC, while they were transplanted, using intravenous injection, to migrate into the damage zone. The experimental data obtained need further complex analysis and permit to wait a positive effect while performing clinical investigations in the patients, suffering chronic diseases of the heart.

The detection of possibility differentiation towards adipogenic trend of the cells, which were obtained from adipose tissue, and their impact on the processes of adipose transplant resorption, in condition of its allogenic transplantation, have had constituted the objective of the investigation. Combined transplantation of adipose transplant and multipotent mesenchymal stem cells, obtained from allogenic adipose tissue, causes the destruction-inflammatory processes activation in the adipose transplant, as well as the adipocytes survival worsening in a meanwhile - a significant deficiency in the transplant mass.

There was conducted experimental investigation with objective to study up the influence of transplantation of a native allogenic multipotent mesenchymal stem cells on the processes of implantation and functioning of heterotopically transplanted autologous adipose tissue. In a cellular-tissue graft, in which native allogenic mesenchymal stem cells were applied as a cellular component, there was observed a worsening of the adipocytes survival indices as well as activation of destructive and inflammatory processes.

The migration, integration and differentiation of fetal neural progenitor cells (NPCs) in the ischemic brain have been studied. In our study the ischemic insult in FVB line mice was produced by occlusion of both carotid arteries during 20 min. A day after occlusion NPCs from GFP-transgenic 12.5 dpc embryos were suboccipitally transplanted to the ischemic brain. The migration and differentiation of GFP-positive NPCs in the recipient tissue were observed in different time points after their transplantation by immunohistochemical approaches using confocal scanning microscopy. It has been shown that GFP-positive NPCs survived, migrated and differentiated to the mature neurons and glial cells in CA1 area of hippocampus of ischemic animals.

144 workers of two Ukrainian fodder production plants have been examined. Respiratory troubles such as chest tightness, cough with phlegm, wheezing were revealed not only in the group of workers exposed to high levels of endotoxins but also in the group exposed to low concentrations. The prevalence of ODTS (Organic Dust Toxic Syndrome), mucosal irritation syndrome, bronchial hyperresponsiveness and obstructive changes of lung function were related to levels of endotoxins in the air of work zone. Respiratory challenge test is the principal to reveal the early signs of obstructive changes of lung function. The protective measures for prophylaxy of the development of occupational diseases in workers exposed to organic dust were proposed.

144 workers of two Ukrainian fodder plants have been examined. Respiratory troubles presenting as cough, expectoration, shortness of breath have come to be the case from not only exposure to high concentrations of endotoxins but from low-level exposures as well. The prevalence of the toxic organic dust syndrome, musocal irritation syndrome, bronchial hyper-reactivity and obstructive changes in the ventilation function of the lungs have been found out to be associated with endotoxin levels in the air of the work environment of the production floor-area. Regarded as valid screenring procedures to early identify those persons predisposed to obstructive changes in the function of external respiration are pharmacological loading tests. Sanitary-and-hygienic and treatment-and-prophylactic measures are proposed to prevent development of occupational diseases in workers exposed to organic dust.