Severe Congenital Disease Research Articles

Effects of growth hormone-replacement therapy in patients with Prader-Willi syndrome - review of recent clinical trials

Introduction and objective: Prader-Willi syndrome (PWS) is a severe genetic disorder being manifested by several symptoms such as infantile hypotonia and poor thriving outcomes, low height, hyperphagia, endocrine, reproductive and internal malfunctions and malformations. In the disease treatment, growth hormone (GH)-replacement therapy is commonly carried on. In this article, we sum up the latest clinical trials’ results concerning the effectiveness and safety of GH-replacement therapy.Abbreviated description of the state of knowledge: Taking into consideration six clinical trials performed in the years 2019-2020, most of them showed positive results of GH-replacement therapy in PWS patients, not only in case of better motor skills or body composition, but also concerning their social and adaptive functioning. Moreover, as for the cessation of GH treatment, some authors seem to highlight no deterioration in cognitive functioning in patients who attained adult height after GH-treatment.Summary: GH-replacement therapy seems to be a good therapeutic option for PWS-affected individuals. Nonetheless, in our research we did not come across on any clinical trials with more than one-year-long observations. Thus, on the long term, these results can not exclude a gradual deterioration of cognitive functioning.

Effect of temperature maintenance by forced-air warming blankets of different temperatures on changes in inflammatory factors in children undergoing congenital hip dislocation surgery.

BackgroundHypothermia is associated with many adverse clinical outcomes in pediatric patients, and thus, it is important to find an effective and safe method for preventing peri-operative hypothermia and its associated adverse outcomes in pediatric patients. This study aimed to investigate the effect of forced-air warming blankets with different temperatures on changes in the transforming growth factor-β (TGF-β), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-10 levels in children undergoing surgical treatment for developmental displacement of the hip (DDH).MethodsThe study included 123 children undergoing surgery for DDH under general anesthesia. The patients were randomly assigned to three groups, using a random number table: the 32, 38, and 43°C groups according to the temperature setting of the forced-air warming blankets. For each patient, body temperature was recorded immediately after anesthesia induction and intubation (T0), at initial incision (T1), at 1 h after incision (T2), at 2 h after incision (T3), at the end of surgery (T4), immediately upon return to the ward after surgery (T5), and then at 12 h (T6), 24 h (T7), 36 h (T8), and 48 h (T9) after the surgery. The serum levels of TGF-β, TNF-α, IL-1β, and IL-10 were measured at T0 and T4 for all groups.ResultsThe number of patients with fever in the 38°C group was significantly less than those in the 32 and 43°C groups (χ2 = 6.630, P = 0.036). At T0, the body temperatures in the 38 and 43°C groups were significantly higher than that in the 32°C group (F = 17.992, P < 0.001). At T2, the body temperature was significantly higher in the 43°C group than those in the 32 and 38°C groups (F = 12.776, P < 0.001). Moreover, at T4, the serum levels of TGF-β (F = 3286.548, P < 0.001) and IL-10 (F = 4628.983, P < 0.001) were significantly increased in the 38°C group, and the serum levels of TNF-α (F = 911.415, P < 0.001) and IL-1β (F = 322.191, P < 0.001) were significantly decreased in the 38°C group, compared with the levels in the 32 and 43°C groups.ConclusionForce-air warming blankets set at 38°C maintained stable body temperature with less adverse outcome and effectively inhibited the inflammatory response in pediatric patients undergoing surgery for DDH.Clinical trial registrationChiCTR1800014820; http://www.chictr.org.cn/showproj.aspx?proj=25240.

Cardiolipin-deficient cells have decreased levels of the iron–sulfur biogenesis protein frataxin

Cardiolipin (CL) is the signature phospholipid of mitochondrial membranes, where it is synthesized locally and plays an important role in mitochondrial bioenergetics. Previous studies in the yeast model have indicated that CL is required for optimal iron homeostasis, which is disrupted by a mechanism not yet determined in the yeast CL mutant, crd1Δ. This finding has implications for the severe genetic disorder, Barth syndrome (BTHS), in which CL metabolism is perturbed because of mutations in the CL-remodeling enzyme, tafazzin. Here, we investigate the effects of tafazzin deficiency on iron homeostasis in the mouse myoblast model of BTHS tafazzin knockout (TAZ-KO) cells. Similarly to CL-deficient yeast cells, TAZ-KO cells exhibited elevated sensitivity to iron, as well as to H2O2, which was alleviated by the iron chelator deferoxamine. TAZ-KO cells exhibited increased expression of the iron exporter ferroportin and decreased expression of the iron importer transferrin receptor, likely reflecting a regulatory response to elevated mitochondrial iron. Reduced activities of mitochondrial iron-sulfur cluster enzymes suggested that the mechanism underlying perturbation of iron homeostasis was defective iron-sulfur biogenesis. We observed decreased levels of Yfh1/frataxin, an essential component of the iron-sulfur biogenesis machinery, in mitochondria from TAZ-KO mouse cells and in CL-deleted yeast crd1Δ cells, indicating that the role of CL in iron-sulfur biogenesis is highly conserved. Yeast crd1Δ cells exhibited decreased processing of the Yfh1 precursor upon import, which likely contributes to the iron homeostasis defects. Implications for understanding the pathogenesis of BTHS are discussed.

Unified inference of missense variant effects and gene constraints in the human genome.

A challenge in medical genomics is to identify variants and genes associated with severe genetic disorders. Based on the premise that severe, early-onset disorders often result in a reduction of evolutionary fitness, several statistical methods have been developed to predict pathogenic variants or constrained genes based on the signatures of negative selection in human populations. However, we currently lack a statistical framework to jointly predict deleterious variants and constrained genes from both variant-level features and gene-level selective constraints. Here we present such a unified approach, UNEECON, based on deep learning and population genetics. UNEECON treats the contributions of variant-level features and gene-level constraints as a variant-level fixed effect and a gene-level random effect, respectively. The sum of the fixed and random effects is then combined with an evolutionary model to infer the strength of negative selection at both variant and gene levels. Compared with previously published methods, UNEECON shows improved performance in predicting missense variants and protein-coding genes associated with autosomal dominant disorders, and feature importance analysis suggests that both gene-level selective constraints and variant-level predictors are important for accurate variant prioritization. Furthermore, based on UNEECON, we observe a low correlation between gene-level intolerance to missense mutations and that to loss-of-function mutations, which can be partially explained by the prevalence of disordered protein regions that are highly tolerant to missense mutations. Finally, we show that genes intolerant to both missense and loss-of-function mutations play key roles in the central nervous system and the autism spectrum disorders. Overall, UNEECON is a promising framework for both variant and gene prioritization.

A fully-automated method discovers loss of mouse-lethal and human-monogenic disease genes in 58 mammals.

Gene losses provide an insightful route for studying the morphological and physiological adaptations of species, but their discovery is challenging. Existing genome annotation tools focus on annotating intact genes and do not attempt to distinguish nonfunctional genes from genes missing annotation due to sequencing and assembly artifacts. Previous attempts to annotate gene losses have required significant manual curation, which hampers their scalability for the ever-increasing deluge of newly sequenced genomes. Using extreme sequence erosion (amino acid deletions and substitutions) and sister species support as an unambiguous signature of loss, we developed an automated approach for detecting high-confidence gene loss events across a species tree. Our approach relies solely on gene annotation in a single reference genome, raw assemblies for the remaining species to analyze, and the associated phylogenetic tree for all organisms involved. Using human as reference, we discovered over 400 unique human ortholog erosion events across 58 mammals. This includes dozens of clade-specific losses of genes that result in early mouse lethality or are associated with severe human congenital diseases. Our discoveries yield intriguing potential for translational medical genetics and evolutionary biology, and our approach is readily applicable to large-scale genome sequencing efforts across the tree of life.

RULES OF INTERNATIONAL LAW REGARDING APPLICATION OF THE RESULTS OF SCIENTIFIC RESEARCHES IN THE FIELD OF BIOTECHNOLOGY (ON THE EXAMPLE OF THERAPEUTIC AND REPRODUCTIVE CLONING AND HUMAN GENE EDITING) AND THEIR PATENT PROTECTION

The article is aimed at highlighting a number of issues in the field of legal regulation of innovative medical technologies based on interference in the human genome and cloning (therapeutic and reproductive) in the context of international law (conventions, declarations, bilateral agreements). In this format, the author examined some international acts that created the legal paradigm for regulating scientific research in the field of study, determining the limits of the admissibility of the implementation of the indicated achievements of modern science in clinical medicine, which are designed to be an effective tool in the fight against severe hereditary diseases, etc., which potentially predetermines their demand. The focus of the author’s attention is on the patentability of these biotechnologies. The relevance of such a study is due to the range of issues addressed, since in the absence of proper regulatory regulation of the studied sphere of public relations, domestic high-tech medicine will be forced to engage in “catch-up” development. In the study, such methods of scientific knowledge were used as general scientific dialectics, formal logic and comparative legal methods. At the same time, the author proceeds from both subjective and objective presetting of processes and phenomena, and their interconnection. The novelty of the study is determined by its purpose, subject and range of sources considered. Thus, the author explores the provisions of both normative acts and documents (acts of so-called “soft law”), emphasizing the peculiarities of their legal nature. In this format, the author comes the conclusion that the system of international principles and standards, formed by the considered acts and documents, does not contain explicit permission to carry out scientific research in the biotechnology field with the subsequent commercialization of its results, which can be patented as inventions, that leads to the need to create national legal frameworks by modern states wishing to advance in this field that will result in a mosaic legal map of the world. Where innovative biotechnologies will be spread in the countries -“scientific offshores” providing loyal to these kinds of scientific researches legislation. The theoretical and practical significance of the results is determined by the fact that Russian readers will be provided with up-to-date scientific information on the state of international law in the field under study, which in practical terms will contribute to the awareness of the sufficiency (or insufficiency) of the developed international legal mechanism for regulating the sphere of biotechnology, including positions of patent and legal protection of a number of“breakthrough” biotechnologies of applied nature, and will also help to establish the unification level of domestic legislation with the approaches laid down in the studied international acts and documents.

Prenatal alcohol exposure induced congenital heart diseases: From bench to bedside.

Alcohol consumption is increasing worldwide. Many child-bearing-aged women consume alcohol during pregnancy, intentionally or unintentionally, thereby increasing the potential risk for severe congenital diseases. Congenital heart disease (CHD) is the most common birth defect worldwide and can result from both hereditary and acquired factors. Prenatal alcohol exposure (PAE) is considered a key factor that leads to teratogenesis in CHD and its specific phenotypes, especially defects of the cardiac septa, cardiac valves, cardiac canals, and great arteries, adjacent to the chambers, both in animal experiments and clinical retrospective studies. The mechanisms underlying CHD and its phenotypes caused by PAE are associated with changes in retinoic acid biosynthesis and its signaling pathway, apoptosis and defective function of cardiac neural crest cells, disturbance of the Wntβ-catenin signaling pathway, suppression of bone morphogenetic protein (BMP) signaling, and other epigenetic mechanisms. Drug supplements and early diagnosis can help prevent PAE from inducing CHDs.

DMD Pluripotent Stem Cell Derived Cardiac Cells Recapitulate in vitro Human Cardiac Pathophysiology.

Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by the lack of functional dystrophin. DMD is associated with progressive dilated cardiomyopathy, eventually leading to heart failure as the main cause of death in DMD patients. Although several molecular mechanisms leading to the DMD cardiomyocyte (DMD-CM) death were described, mostly in mouse model, no suitable human CM model was until recently available together with proper clarification of the DMD-CM phenotype and delay in cardiac symptoms manifestation. We obtained several independent dystrophin-deficient human pluripotent stem cell (hPSC) lines from DMD patients and CRISPR/Cas9-generated DMD gene mutation. We differentiated DMD-hPSC into cardiac cells (CC) creating a human DMD-CC disease model. We observed that mutation-carrying cells were less prone to differentiate into CCs. DMD-CCs demonstrated an enhanced cell death rate in time. Furthermore, ion channel expression was altered in terms of potassium (Kir2.1 overexpression) and calcium handling (dihydropyridine receptor overexpression). DMD-CCs exhibited increased time of calcium transient rising compared to aged-matched control, suggesting mishandling of calcium release. We observed mechanical impairment (hypocontractility), bradycardia, increased heart rate variability, and blunted β-adrenergic response connected with remodeling of β-adrenergic receptors expression in DMD-CCs. Overall, these results indicated that our DMD-CC models are functionally affected by dystrophin-deficiency associated and recapitulate functional defects and cardiac wasting observed in the disease. It offers an accurate tool to study human cardiomyopathy progression and test therapies in vitro.

The rate and spectrum of mosaic mutations during embryogenesis revealed by RNA sequencing of 49 tissues

BackgroundMosaic mutations acquired during early embryogenesis can lead to severe early-onset genetic disorders and cancer predisposition, but are often undetectable in blood samples. The rate and mutational spectrum of embryonic mosaic mutations (EMMs) have only been studied in few tissues, and their contribution to genetic disorders is unknown. Therefore, we investigated how frequent mosaic mutations occur during embryogenesis across all germ layers and tissues.MethodsMosaic mutation detection in 49 normal tissues from 570 individuals (Genotype-Tissue Expression (GTEx) cohort) was performed using a newly developed multi-tissue, multi-individual variant calling approach for RNA-seq data. Our method allows for reliable identification of EMMs and the developmental stage during which they appeared.ResultsThe analysis of EMMs in 570 individuals revealed that newborns on average harbor 0.5–1 EMMs in the exome affecting multiple organs (1.3230 × 10−8 per nucleotide per individual), a similar frequency as reported for germline de novo mutations. Our multi-tissue, multi-individual study design allowed us to distinguish mosaic mutations acquired during different stages of embryogenesis and adult life, as well as to provide insights into the rate and spectrum of mosaic mutations. We observed that EMMs are dominated by a mutational signature associated with spontaneous deamination of methylated cytosines and the number of cell divisions. After birth, cells continue to accumulate somatic mutations, which can lead to the development of cancer. Investigation of the mutational spectrum of the gastrointestinal tract revealed a mutational pattern associated with the food-borne carcinogen aflatoxin, a signature that has so far only been reported in liver cancer.ConclusionsIn summary, our multi-tissue, multi-individual study reveals a surprisingly high number of embryonic mosaic mutations in coding regions, implying novel hypotheses and diagnostic procedures for investigating genetic causes of disease and cancer predisposition.

Modern neurogenetic representations of MELAS syndrome. Clinical cases (the lecture)

This lecture with a description of clinical cases presents information on such a mitochondrial disease from the group of hereditary metabolic diseases, like MELAS syndrome (OMIM: 540000). The main manifestations of this progressive disease are stroke-like episodes and a specific form of encephalopathy, including epileptic seizures with the presence of a phenomenon of "ragged red fibers" and early dementia. Clinical cases, given in this lecture, supplement the piggy bank of genetically verified mitochondrial diseases leading to the development of polymorphic neurological disorders and characteristic neuroimaging picture, namely the appearance of polymorphic ischemic changes in the temporal, parietal or occipital regions of the brain, that do not correspond to the zones of the main vascular blood supply, as the basis for the formation of such focus is the phenomenon of mitochondrial angiopathy, and not thrombosis. The description of clinical cases reflects our own observations and the main steps in the diagnosis of this severe hereditary disease, taking into account of the latest neurogenetic representations. In addition to the data given in the clinical course of the disease, the results of the genetic interpretation of the MELAS syndrome are given; modern methods of diagnosis and therapy are considered.

Structural Basis of Activin Receptor-Like Kinase 2 (R206H) Inhibition by Bis-heteroaryl Pyrazole-Based Inhibitors for the Treatment of Fibrodysplasia Ossificans Progressiva Identified by the Integration of Ligand-Based and Structure-Based Drug Design Approaches

Fibrodysplasia ossificans progressiva (FOP) is a rare but severe genetic disorder in which acute inflammation elicits progressive heterotopic ossification in the muscles, tendons, and ligaments. Classic FOP is caused by the R206H mutation in ALK2/ACVR1. While several activin receptor-like kinase 2 (ALK2) inhibitors were found to be efficacious in animal models of FOP, most of the ALK2 (R206H) inhibitors lacked sufficient oral bioavailability for efficacy. Previously, the synthesis of a series of novel bis-heteroaryl pyrazole-based ALK2 (R206H) inhibitors that achieved both substantial potency and an improved ADMET profile was reported. In the present study, the detailed procedure of the in silico approach employed to identify the initial bis-heteroaryl pyrazole-based ALK2 (R206H) inhibitor RK-59638 and the analysis of the ALK2 (R206H) RK-59638 complex structure to guide the synthetic optimization of the chemical series, obtaining RK-71807 showing improved potency and metabolic stability, were described. According to the initial in silico screening, the screening efficiencies and chemical diversity of the hit compounds of both ligand-based and structure-based methods were evaluated. Then, X-ray structures of ALK2 (R206H) and the inhibitors were analyzed to assess the structure–activity relationships of the synthesized compounds. The 3D-RISM analysis indicated the existence of the additional hydrogen bond via water molecules restricting the attachment point in the pyrazole scaffold. The quantum mechanics calculation of the newly determined ALK2 (R206H) RK-71807 complex structure using a fragment molecular orbital method and pair interaction energy decomposition analysis was employed to evaluate the interaction energies between the inhibitor and each of the amino acid residues and decompose them to electrostatic, exchange-repulsion, and charge transfer energies. The pattern of decomposed interaction energies was then compared to that formed by RK-59638 and LDN-193189 to investigate the structural basis of ALK2 (R206H) inhibition.

Myostatin: a Circulating Biomarker Correlating with Disease in Myotubular Myopathy Mice and Patients

Myotubular myopathy, also called X-linked centronuclear myopathy (XL-CNM), is a severe congenital disease targeted for therapeutic trials. To date, biomarkers to monitor disease progression and therapy efficacy are lacking. The Mtm1−/y mouse is a faithful model for XL-CNM, due to myotubularin 1 (MTM1) loss-of-function mutations. Using both an unbiased approach (RNA sequencing [RNA-seq]) and a directed approach (qRT-PCR and protein level), we identified decreased Mstn levels in Mtm1−/y muscle, leading to low levels of myostatin in muscle and plasma. Myostatin (Mstn or growth differentiation factor 8 [Gdf8]) is a protein released by myocytes and inhibiting muscle growth and differentiation. Decreasing Dnm2 by genetic cross with Dnm2+/− mice or by antisense oligonucleotides blocked or postponed disease progression and resulted in an increase in circulating myostatin. In addition, plasma myostatin levels inversely correlated with disease severity and with Dnm2 mRNA levels in muscles. Altered Mstn levels were associated with a generalized disruption of the myostatin pathway. Importantly, in two different forms of CNMs we identified reduced circulating myostatin levels in plasma from patients. This provides evidence of a blood-based biomarker that may be used to monitor disease state in XL-CNM mice and patients and supports monitoring circulating myostatin during clinical trials for myotubular myopathy.

Experience with tafamidis in a patient with transthyretin amyloidosis

Transthyretin amyloidosis (ATTR) is a threatening and severe genetic disease characterized by damages to organs and systems caused by a pathological protein transthyretin produced in the liver. Clinical manifestations of this disease vary from injuries of the nervous system to injuries of the cardiovascular system. Prognosis for ATTR-amyloidosis remains unfavorable. The absence of pathognomonic symptoms complicates diagnostics of this disease, which tends to simulate other conditions. At present, medicines exist, which are pathogenetic in the treatment of ATTR-amyloidosis. The article describes a clinical case of ATTR-amyloidosis with primary heart injury complicated with functional class III chronic heart failure during the tafamidis treatment.

Correlations Between Respiratory Manifestations And Nutritional Status In Children With Cystic Fibrosis

Abstract Background: Cystic fibrosis is a multisystemic genetic disease with autosomal recessive transmission, with progressive clinical evolution and potentially fatal, predominantly found in the Caucasian population. It is characterized by chronic lung disease and malabsorption caused by exocrine pancreatic insufficiency. Objective: Screening of patients with persistent respiratory disease and malabsorption syndrome to diagnose cystic fibrosis and monitoring the correlation between respiratory manifestations and nutritional status. Methods: A retrospective study on 8 patients diagnosed with cystic fibrosis, from Department of Pediatrics - Constanta County Emergency Hospital, during the period from 2015 to 2018. Results: 8 patients were diagnosed by genetic test for 34 mutations and polymorphism of CFTR gene; 2 homozygous patients with ∆F508 mutation (second class of mutations) with severe disease, 2 heterozygous patients with ∆F508 mutation del 2,3; 2 heterozygous patients with ∆F508 and R553X mutations, 1 heterozygous patient with N1303K and 394delTT mutations, 1 heterozygous patient with 2183 AA96 and ∆F508 mutation; 7 out of 8 patients were diagnosed in the first year of life by performing the sweat test, with values higher than 120 mmol/L. Clinical manifestations at onset were represented by diarrhea and failure to thrive in 4 cases and in 4 cases respiratory manifestations were associated. More than half of cases had less than 6 months of age at first respiratory exacerbation, which was associated with failure to thrive. Analyzing the correlation between genotype and anthropometric indicators, it was observed that the weight was more affected than the height. The analysis between nutritional status and lung function revealed that obstructive respiratory dysfunction with low FEV1 was correlated with nutritional status. Conclusion: Cystic fibrosis is a severe genetic disease and it is important to diagnose early, because it has been observed that if the diagnosis is established late, the consequences will be severe and lung function will deteriorate earlier.

Tangier disease: update for 2020.

To appraise recent advances in our knowledge of the severe genetic HDL deficiency disorder, Tangier disease. While Tangier disease can cause premature atherosclerotic cardiovascular disease (ASCVD), new evidence suggests that heterozygous ABCA1 variant carriers are also at increased risk. Advances have been made in the study of the neurological abnormalities observed in Tangier disease, both in their assessment and the identification of potential new therapies. Tangier disease is an extremely rare condition and, as such, the published literature around its range of clinical manifestations, including peripheral neuropathy, premature ASCVD and platelet abnormalities is limited. Patient registries may assist in this regard.

Новый вариант р.Cys3024Tyr и частые мутации в гене , выявленные в семьях с аутосомно-рецессивной поликистозной болезнью почек в Российской Федерации

Аутосомно-рецессивная поликистозная болезнь почек (АРПП) - форма поликистозной болезни почек с ранним началом. Она явля- ется важной причиной заболеваемости и смертности детей, связанных с изменениями почек и печени. Ген PKHD1 , мутации в кото- ром приводят к развитию заболевания, локализован на хромосоме 6р21.1-р12. С самого протяженного транскрипта, состоящего из 67 экзонов, синтезируется белок полидуктин. Мутации располагаются во всем гене без признаков кластеризации. Поэтому поиск мутаций является трудоемким, дорогостоящим и требует много времени. В гене PKHD1 идентифицирован новый вариант c.9071G&gt;A (р.Cys3024Tyr) в 14 семьях на 16 хромосомах, что составляет 12,7% найденных мутаций. Данный вариант не встретился на 1008 хро- мосомах контрольной выборки. Частыми мутациями в выборке больных с АРПП являются: c.107C&gt;T (р.Thr36Met), встретившаяся у 53% семей с мутациями на 41% хромосом; мутации c.1486C&gt;T (р.Arg496Ter) и c.9524A&gt;G (р.Asn3175Ser) выявлены в 10% семей каждая. Поиск мутаций в гене PKHD1 важен для подтверждения диагноза молекулярно-генетическими методами, а также для проведения медико-генетического консультирования в семьях с последующей пренатальной диагностикой, особенно в семьях, в которых недо- ступен материал больного ребенка. Autosomal recessive polycystic kidney disease (ARPKD, Polycystic kidney disease 4 with or without hepatic disease, MIM 263200) is a severe genetic disorder with variable clinical spectrum. It is an important cause of renal-related and liver-related morbidity and mortality. ARPKD is caused by mutations in the PKHD1 gene which was mapped to chromosome 6p21-p12. A 67-exon transcript encodes one of the lon- gest continuous open reading frame. Protein polyductin is synthesized from this transcript. Mutations were found to be scattered through- out the gene without evidence of clustering. Searching for mutations is time-consuming and costly. We identified new variant c.9071G&gt;A (р.Cys3024Tyr) in 14 families on 16 chromosomes which makes 12.7% mutations. This variant did not found on 1008 control chromosomes. Mutation c.107C&gt;T (р.Thr36Met) occurs in 53% families with mutation on 41% chromosomes. Mutations c.1486C&gt;T (р.Arg496Ter) and c.9524A&gt;G (р.Asn3175Ser) occur in 10% families each. Mutation analysis in PKHD1 gene is very important for confirming the ARPKD diag- nosis and genetic counseling with following prenatal diagnosis.

FEATURES OF LEGAL REGULATION OF GENOMIC RESEARCHES: FAILURES, SECURITY CONCERNS AND PROSPECTS

The urgency of the article is determined by the need to ensure biological and ecological safety of Russia. The article gives examples of failures of auxiliary reproductive technologies in the Russian Federation and abroad which at present do not have adequate algorithms of legal resolution and are unsafe for ecology and man. Investigating the existing Russian legislation it has been revealed that passing only of obligatory medico-genetic consultation and incomplete medico-genetic inspection with approximate assessment of the genetic status of the donor does not exclude development of the fetus with severe genetic diseases, which is considered by the consumer of the service as poor quality and unsafe. It is noted that in cases of use of biomaterials from abroad, a comparative study of the genome becomes unlikely due to paragraph 7 of Art. 55 of the Federal Law of 21.11.2011 № 323-FZ "On the fundamentals of public health protection in the Russian Federation" and the order of the Ministry of Health of Russia from 30.08.2012. (ed. 01.02.2018) № 107n "On the order of using assisted reproductive technologies, contraindications and restrictions on their use". The conclusion was drawn on the need to develop and fix organizational and legal mechanisms and develop appropriate procedures.

Mutational Analysis of N-Ethyl-N-Nitrosourea (ENU) in the Fission Yeast Schizosaccharomyces pombe.

Forward genetics in model organisms has boosted our knowledge of the genetic bases of development, aging, and human diseases. In this experimental pipeline, it is crucial to start by inducing a large number of random mutations in the genome of the model organism to search for phenotypes of interest. Many chemical mutagens are used to this end because most of them display particular reactivity properties and act differently over DNA. Here we report the use of N-ethyl-N-nitrosourea (ENU) as a mutagen in the fission yeast Schizosaccharomyces pombe. As opposed to many other alkylating agents, ENU only induces an SN1-type reaction with a low s constant (s = 0.26), attacking preferentially O and O in thymine and O deoxyguanosine, leading to base substitutions rather than indels, which are extremely rare in its resulting mutagenic repertoire. Using ENU, we gathered a collection of 13 temperature-sensitive mutants and 80 auxotrophic mutants including two deleterious alleles of the human ortholog ATIC. Defective alleles of this gene cause AICA-ribosiduria, a severe genetic disease. In this screen, we also identified 13 aminoglycoside-resistance inactivating mutations in APH genes. Mutations reported here may be of interest for metabolism related diseases and antibiotic resistance research fields.

The age-related assessment of pulmonary function in children with cystic fibrosis aged below 6 years

Cystic fibrosis (CF) is a severe hereditary disease associated with progressive impairment of respiratory organs. Pulmonary function test (PFT) in CF patients may be relevant for determination of therapy level and patient management strategy. However, PFT is particularly difficult in children aged below 6 years. Literature data concerning options for pulmonary function analysis in children aged below 6 years with CF for assessment of disease severity, progression and monitoring of treatment efficacy are provided in the article.

Nutritional intervention with cyanidin hinders the progression of muscular dystrophy

Muscular Dystrophies are severe genetic diseases due to mutations in structural genes, characterized by progressive muscle wasting that compromises patients’ mobility and respiratory functions. Literature underlined oxidative stress and inflammation as key drivers of these pathologies. Interestingly among different myofiber classes, type I fibers display a milder dystrophic phenotype showing increased oxidative metabolism. This work shows the benefits of a cyanidin-enriched diet, that promotes muscle fiber-type switch and reduced inflammation in dystrophic alpha-sarcoglyan (Sgca) null mice having, as a net outcome, morphological and functional rescue. Notably, this benefit is achieved also when the diet is administered in dystrophic animals when the signs of the disease are seriously evident. Our work provides compelling evidence that a cyanidin-rich diet strongly delays the progression of muscular dystrophies, paving the way for a combinatorial approach where nutritional-based reduction of muscle inflammation and oxidative stress facilitate the successful perspectives of definitive treatments.