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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new coronavirus responsible for the current pandemic of coronavirus disease 2019 (COVID-19). This virus attacks cells of the airway epithelium by binding transmembrane angiotensin-converting enzyme 2 (ACE2). Hydroxytyrosol has anti-viral properties. Alpha-cyclodextrin can deplete sphingolipids and phospholipids from cell membranes. The aim of the present experimental study was to evaluate the efficacy of α-cyclodextrin and hydroxytyrosol in improving defenses against SARS-CoV-2 infection in in vitro cell models and humans.For in vitro experiments on Vero E6 cells, RNA for RT-qPCR analysis was extracted from Caco2 and human fibroblast cell lines. For study in humans, the treatment group consisted of 149 healthy volunteers in Northern Cyprus, considered at higher risk of SARS-CoV-2 infection than the general population. The volunteers used nasal spray containing α-cyclodextrin and hydroxytyrosol for 4 weeks. The control group consisted of 76 healthy volunteers who did not use the spray.RT-qPCR experiments on targeted genes involved in endocytosis showed a reduction in gene expression, whereas cytotoxicity and cytoprotective tests showed that the compounds exerted a protective effect against SARS-CoV-2 infection at non-cytotoxic concentrations. None of the volunteers became positive to SARS-CoV-2 RT-qPCR assay during the 30 days of treatment.Treatment with α-cyclodextrin and hydroxytyrosol nasal spray improved defenses against SARS-CoV-2 infection and reduced synthesis of viral particles.

The article describes various models of training mediators for the education system in the Russian Federation and the Republic of Kazakhstan. A comparative analysis of the mediation services development in Siberia and Kazakhstan for the possibilities and prospects of cooperation and interaction is carried out. The article presents specific features of the model for training intercultural mediators for resolving interethnic conflicts in the Krasnoyarsk Krai. This model meets the needs of multinational Siberian society and is aimed at solving regional problems in the education system. A peculiar characteristic of the model for the Krasnoyarsk Krai is its multi-level nature, openness and continuity of preparation, with the inclusion of formal and non-formal education elements. Interdisciplinary nature of interaction of the network partners involved in the training and retraining of mediators for the education system gives an opportunity to use the potential and resources of professional mediators and trainers of Siberia (Kemerovo, Irkutsk), Federal Institute of Mediation, Moscow, and National Academy of Education named after Y. Altynsarin (Kazakhstan). The model for the intercultural mediators training developed at the School of Education, Psychology and Sociology has been tested for two years as a part of its implementation in the Master programme of the School of Education, Psychology and Sociology within the frames of the educational programme “Mediation in Education”, advanced training courses, three International Youth Summer Schools “Multicultural Mediation in Education”, expert seminars, intensive schools “Mediation is the Profession of the 21st Century”, and a competition for high school students of the Krasnoyarsk Krai “Mediation Is The Profession Of The Future”

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new coronavirus responsible for the current pandemic of coronavirus disease 2019 (COVID-19). This virus attacks cells of the airway epithelium by binding transmembrane angiotensin-converting enzyme 2 (ACE2). Hydroxytyrosol has anti-viral properties. Alpha-cyclodextrin can deplete sphingolipids and phospholipids from cell membranes. The aim of the present experimental study was to evaluate the efficacy of alpha-cyclodextrin and hydroxytyrosol in improving defenses against SARS-CoV-2 infection in in vitro cell models and humans.

The food choices are due to a mixture of sensory signals including gustatory, olfactory, and texture sensations. The aim of this quality review was to update data about studies concerning genetics of taste, olfactory and texture receptors and their influence on the health status in humans.An electronic search was conducted in MEDLINE, Pubmed database and Scopus, for articles published in English until December 2018. Two independent researches selected the studies and extracted the data.The review confirms the importance of inter-individual variations in taste, olfactory and texture related genes on food choices and their implications in the susceptibility to nutrition-related conditions such as obesity, dental caries, diabetes, cardiovascular disease, hypertension, hyperlipidemia and cancer.The knowledge of variants in taste, olfactory and texture related genes can contribute to the prevention of diseases related to unhealthy nutrition. Further studies would be useful to identify other variants in the genes involved in these systems.

Recurrent molecular markers have been routinely used in acute myeloid leukemia (AML) for risk assessment at diagnosis, whereas their post-induction monitoring still represents a debated issue. We evaluated the prognostic value and biological impact of minimal residual disease (MRD) and of the allelic ratio (AR) of FLT3-internal-tandem duplication (ITD) in childhood AML. We retrospectively screened 494 children with de novo AML for FLT3-ITD mutation, identifying 54 harboring the mutation; 51% of them presented high ITD-AR at diagnosis and had worse event-free survival (EFS, 19.2 versus 63.5% for low ITD-AR

Cooks syndrome (CS) is an ultrarare limb malformation due to in tandem microduplications involving KCNJ2 and extending to the 5' regulatory element of SOX9. To date, six CS families were resolved at the molecular level. Subsequent studies explored the evolutionary and pathological complexities of the SOX9-KCNJ2/Sox9-Kcnj2 locus, and suggested a key role for the formation of novel topologically associating domain (TAD) by inter-TAD duplications in causing CS. Here, we report a unique case of CS associated with a de novo 1;17 translocation affecting the KCNJ2 locus. On chromosome 17, the breakpoint mapped between KCNJ16 and KCNJ2, and combined with a ~ 5 kb deletion in the 5' of KCNJ2. Based on available capture Hi-C data, the breakpoint on chromosome 17 separated KCNJ2 from a putative enhancer. Gene expression analysis demonstrated downregulation of KCNJ2 in both patient's blood cells and cultured skin fibroblasts. Our findings suggest that a complex rearrangement falling in the 5' of KCNJ2 may mimic the developmental consequences of in tandem duplications affecting the SOX9-KCNJ2/Sox9-Kcnj2 locus. This finding adds weight to the notion of an intricate role of gene regulatory regions and, presumably, the related three-dimensional chromatin structure in normal and abnormal human morphology.

Background Milroy‐like disease is the diagnostic definition used for patients with phenotypes that resemble classic Milroy disease (MD) but are negative to genetic testing for FLT4. In this study, we aimed at performing a genetic characterization and biochemical analysis of VEGF‐C variations found in a female proband born with congenital edema consistent with Milroy‐like disease. Methods The proband underwent next‐generation sequencing‐based genetic testing for a panel of genes associated with known forms of hereditary lymphedema. Segregation analysis was performed on family members by direct sequencing. In vitro studies were performed to evaluate the role of a novel identified variant. Results Two VEGF‐C variations were found in the proband, a novel p.(Ser65Arg) and a pathogenic c.148‐3_148‐2delCA, of paternal and maternal origin, respectively. Functional characterization of the p.(Ser65Arg) variation in vitro showed alterations in VEGF‐C processing. Conclusions Our findings reveal an interesting case in which biallelic variants in VEGF‐C are found in a patient with Milroy‐like lymphedema. These data expand our understanding of the etiology of congenital Milroy‐like lymphedema., A genetic and biochemical analysis of VEGF‐C variations were performed on a female proband affected by primary lymphedema of the right lower limb and on her entire family. Biallelic variants of VEGF‐C variations were found in the proband: a novel p.(Ser65Arg) and a pathogenic c.148‐3_148‐2del, of paternal and maternal origin, respectively. Clinical examination of the family by lymphoscintigraphy as well as biochemical analysis show that both variants are required to the development of the proband Milroy‐like lymphedema.

Lipedema is an often underdiagnosed chronic disorder that affects subcutaneous adipose tissue almost exclusively in women, which leads to disproportionate fat accumulation in the lower and upper body extremities. Common comorbidities include anxiety, depression, and pain. The correlation between mood disorder and subcutaneous fat deposition suggests the involvement of steroids metabolism and neurohormones signaling, however no clear association has been established so far. In this study, we report on a family with three patients affected by sex-limited autosomal dominant nonsyndromic lipedema. They had been screened by whole exome sequencing (WES) which led to the discovery of a missense variant p.(Leu213Gln) in AKR1C1, the gene encoding for an aldo-keto reductase catalyzing the reduction of progesterone to its inactive form, 20-&alpha, hydroxyprogesterone. Comparative molecular dynamics simulations of the wild-type vs. variant enzyme, corroborated by a thorough structural and functional bioinformatic analysis, suggest a partial loss-of-function of the variant. This would result in a slower and less efficient reduction of progesterone to hydroxyprogesterone and an increased subcutaneous fat deposition in variant carriers. Overall, our results suggest that AKR1C1 is the first candidate gene associated with nonsyndromic lipedema.

INTRODUCTION Vascular anomalies encompass an extremely heterogeneous group of congenital abnormalities of the vascular system. They include vascular tumors and malformations and have a prevalence of 4.5%. Vascular anomalies are frequently sporadic and associated with somatic mutations and/or a double-hit mechanism and are characterized by considerable phenotypic and genetic heterogeneity. The aim of this review was to provide a genetic description of vascular anomalies, the sequencing technologies used for their diagnosis and the drugs that may potentially be used for their treatment. EVIDENCE ACQUISITION PubMed, OMIM, Orphanet, Genetic Testing Registry and ClinicalTrials.gov were searched for monogenic vascular anomalies in order to evaluate the genetic tests (based on sequencing) currently used for their diagnosis, and for any drugs that could be useful to treat them. EVIDENCE SYNTHESIS From the search of the clinical synopsis section of OMIM and PubMed for vascular anomalies we selected 19 disorders with a known molecular etiology. From the search for pharmacological trials and therapies in the ClinicalTrials.gov and PubMed databases we selected 87 drugs. CONCLUSIONS Most genetic tests with validated clinical utility are based on a next generation sequencing (NGS) approach. Targeted NGS is indeed the best approach for the analysis of disorders with complex phenotypes and genetics and involvement of somatic mutations. Genetic diagnosis provides data for determine genotype-phenotype correlations, segregation and recurrence risk in families, and new targets for gene- or mutation-specific pharmacological therapies. Improvement of diagnostic techniques is needed to offer patients appropriate care, more focused follow-up, and hopefully drugs to treat their disorders.

Neuropilins are transmembrane coreceptors expressed by endothelial cells and neurons. NRP1 and NRP2 bind a variety of ligands, by which they trigger cell signaling, and are important in the development of lymphatic valves and lymphatic capillaries, respectively. This study focuses on identifying rare variants in the NRP1 and NRP2 genes that could be linked to the development of lymphatic malformations in patients diagnosed with lymphedema. Two hundred and thirty-five Italian lymphedema patients, who tested negative for variants in known lymphedema genes, were screened for variants in NRP1 and NRP2. Two probands carried variants in NRP1 and four in NRP2. The variants of both genes segregated with lymphedema in familial cases. Although further functional and biochemical studies are needed to clarify their involvement with lymphedema and to associate NRP1 and NRP2 with lymphedema, we suggest that it is worthwhile also screening lymphedema patients for these two new candidate genes.

Un gruppo di superficie è (isomorfo) al gruppo fondamentale di una superficie orientabile chiusa di genere k (maggiore o uguale a 2). È uno small cancellation group e quindi iperbolico; il suo grafo di Cayley è isomorfo a una tassellatura del piano iperbolico fatta di 2k-goni iperbolici. È possibile definire alcuni sottoinsiemi del grafo di Cayley, detti “coni”, su cui il gruppo agisce con un numero finito di orbite, chiamate “cono tipi”. Una rappresentazione moltiplicativa di un gruppo di superficie è una rappresentazione unitaria definita sullo spazio di Hilbert delle funzioni moltiplicative. Una funzione moltiplicativa su un gruppo di superfici ha valori vettoriali ed è definita mediante la scelta di un insieme di parametri, chiamato “sistema di matrici”. Due funzioni moltiplicative sono equivalenti se differiscono solo su un numero finito di elementi. Si può definire un prodotto interno sulle classi di equivalenza di funzioni moltiplicative. Dimostriamo che almeno per il caso di un gruppo di superficie del genere 2 ed una scelta del sistemi di matrici il prodotto interno non è identicamente nullo; dato che esso non dipende dalla scelta dei rappresentanti per le funzioni moltiplicative, è ben definito. Questa dimostrazione si basa sull'irriducibilità di una certa matrice associata alla geometria del grafo di Cayley; in particolare, un certo autovalore Perron-Frobenius deve essere semplice. Una rappresentazione moltiplicativa agisce semplicemente per traslazione sinistra sul completamento dello spazio di Hilbert dello spazio delle funzioni moltiplicative rispetto al prodotto interno sopra menzionato. La rappresentazione così definita è temperata: mostriamo che i coefficienti di matrice della rappresentazione regolare approssimano quelli della rappresentazione moltiplicativa. Con il termine “rappresentazione sul bordo” intendiamo una rappresentazione di una certa C*-algebra prodotto incrociato, ottenuta dall'azione del gruppo di superficie sulla C*-algebra delle funzioni continue sul bordo - che è omeomorfo ad una circonferenza. Una rappresentazione sul bordo è data da una rappresentazione unitaria del gruppo e una rappresentazione della C*-algebra che soddisfi una condizione di covarianza. Definiamo una famiglia di sottospazi (indicizzata da una quantità reale) di uno spazio di funzioni di quadrato integrabile con valori vettoriali sul gruppo e agiamo su questi sottospazi per traslazione a sinistra con il gruppo e per moltiplicazione con le funzioni continue sulla compattificazione del gruppo di superficie (il gruppo unito al suo bordo). Otteniamo alcune rappresentazioni del gruppo e dell'algebra che soddisfano la covarianza e mostriamo che la famiglia ha una sottosuccessione convergente. Mostriamo quindi che l'azione della C*-algebra coinvolge solo i valori delle funzioni sul bordo: otteniamo quindi una rappresentazione sul bordo. Mostriamo, inoltre, che il limite così ottenuto non dipende dalla sottosuccessione tendente a zero. Abbiamo così una rappresentazione sul bordo ben definita. Mostriamo che la parte unitaria di questa rappresentazione sul bordo è equivalente alla rappresentazione moltiplicativa: infatti, le loro funzioni di tipo positivo coincidono. Infine, mostriamo che la rappresentazione sul bordo è irriducibile. Questo risultato si ottiene sfruttando l'unicità (a meno di prodotto per una costante positiva) dell'autovalore di Perron-Frobenius ottenuto nella dimostrazione della buona positura del prodotto interno: dimostriamo che qualsiasi proiezione che commuta sia con la rappresentazione del gruppo che con la rappresentazione dell’algebra permette di definire un autovettore della stessa matrice corrispondente all'autovalore di Perron-Frobenius. Quindi, dopo alcuni calcoli, otteniamo che la proiezione considerata deve essere banale. Da una versione del Lemma di Schur segue che la rappresentazione del prodotto incrociato è irriducibile. A surface group is (isomorphic to) the fundamental group of a closed orientable surface of genus k greater or equal than 2. It is a small cancellation group (hence hyperbolic); its Cayley graph is isomorphic to a tiling of the hyperbolic plane by 2k-gons. One can define certain subsets of the Cayley graph called cones. The group acts on the set of cones with finitely many orbits, called cone types. A multiplicative representation of a surface group is a unitary representation defined on the Hilbert space of multiplicative functions. A multiplicative function on a surface group is a vector-valued function defined through the choice of a set of parameters, called matrix system. Two multiplicative functions are equivalent if they differ only on finitely many elements. An inner product can be defined for equivalence classes of multiplicative functions. We prove that at least for the case of a surface group of genus 2 and a choice of the matrices as non-negative scalars the inner product is not identically zero; thus, since it does not depend on the representatives for the multiplicative functions, it is well posed. This proof relies on the irreducibility of a certain matrix associated with the geometry of the Cayley graph; in particular, a certain Perron-Frobenius eigenvalue must be simple. A multiplicative representation then simply acts by left translation on the Hilbert space completion of the space of multiplicative functions with respect to the inner product above mentioned. The representation thus defined is tempered: we show that the matrix coefficients of the regular representation approximate those of the multiplicative representation. By the term boundary representation, we mean a representation of a certain crossed product C*-algebra, obtained by the action of the surface group on the C*-algebra of continuous functions on its boundary – which is homeomorphic to the unit circle. Such a boundary representation is given by a unitary representation of the group and a representation of the C*-algebra satisfying a covariance condition. We define a family of subspaces (indexed by a real quantity) of a space of vector-valued square integrable functions on the group and we act on these subspaces by left translation with the group and by multiplication with continuous functions on the compactification of the surface group (the group united with its boundary). Thus, we get some representations of the group and the algebra satisfying covariance and we show that the family has a limit for a subsequence of the indexes tending to zero. We then show that the action of the C*-algebra involves only the values of the functions on the boundary. Hence, we get a boundary representation. We show, moreover, that the limit thus obtained does not depend on the subsequence tending to zero. Hence, we get a well-defined representation of the crossed product C*-algebra. We show that the unitary part of this boundary representation is equivalent to the multiplicative representation: in fact, their functions of positive type coincide. Finally, we show that the boundary representation is irreducible. This result is achieved by exploiting the uniqueness (up to scaling) of the Perron-Frobenius eigenvalue obtained in the proof of the well-posedness of the inner product: in fact, we show that any projection intertwining both the group representation and the algebra representation allows to define an eigenvector of the same matrix corresponding to the Perron-Frobenius eigenvalue. Thus, after some calculations, we get that the projection considered must be trivial. By a version of Schur’s Lemma, this yields the irreducibility of the crossed product representation.