imagine (Institute of molecular genetics and genetic engineering)
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Diagnostics of rare diseases new paradigm
Get PDFPo definiciji, retke bolesti obuhvataju oboljenja čija je učestalost manja od 1 u 2000 u Evropi. Do sada je
identifikovano skoro 7000 retkih bolesti uzrokovanih mutacijama u preko 4000 gena, a na svakih 50 osoba
u Evropi jedna ima retku bolest za koju je pokazano ili se smatra da je genetički uzrokovana.
Objavljivanje preliminarne sekvence humanog genoma 2001. godine, kao i automatizacija reakcija PCR-a i
sekvenciranja, omogućilo je otkrivanje velikog broja gena uzročnika retkih bolesti, kao i uspostavljanje i široku
primenu molekularno - genetičke dijagnostike. Na ovaj način je omogućena dijagnostika bolesti koje su se odlikovale
relativno čestim pojavljivanjem, a koje nisu imale posebno izraženu alelsku ili lokusnu heterogenost.
Razvoj metoda masivnog paralelnog sekvenciranja omogućio je širu dijagnostiku poznatih bolesti, ali se
otvorila i mogućnost da se potraži uzrok za svaku retku bolest, međutim, nakon više od 10 godina masovne
primene, preko 70% bolesti verovatno uzrokovanih naslednim faktorima i dalje ima nepoznatu etiologiju.Rare diseases comprise diseases with a frequency less than 1 in 2000 in Europe. So far, almost 7,000 rare diseases
caused by mutations in over 4,000 genes have been identified, and for every 50 people in Europe, one
has a probably genetically caused rare disease.
The draft sequence of the human genome published in year 2001, as well as the automation of PCR and sequencing
techniques enabled the identification of a large number of genes that cause rare diseases, as well
as the establishment and wide application of molecular-genetic diagnostics. Thus, it was possible to establish
the genetic background of relatively frequent and diseases without significant allelic or locus heterogeneity.
The development of massive parallel sequencing methods has enabled a broader diagnosis of known diseases,
but also enabled scientific community to look for the cause of each rare disease. However, after more
than 10 years, over 70% of probably genetically caused diseases still have an unknown etiology
long noncoding rna gaS as a new biomarker in oncology
Get PDFGrowth arrest specific 5 (GAS5) je duga nekodirajuća RNK koja zaustavlja ćelijski ciklus i promoviše apoptozu.
Ponašajući se kao signalni protein, kao mamac za druge molekule ili kao transportni molekul, ova regulatorna
RNK utiče na niz puteva i molekula koji su bitni za rast ćelije i apoptozu, među kojima se ističu p53 mreža,
mTOR signalni put, AKT signalni put, kao i molekuli mikro RNK, PTEN i slični. Brojne studije na različitim tipovima
karcinoma su pokazale da nivo ekspresije GAS5 utiče na razvoj i tok bolesti kod hematoloških maligniteta,
ginekoloških karcinoma, glioma, karcinoma dojke, karcinoma gastrointestinalnog trakta, bubrega,
bešike, prostate i pluća. Shodno tome, GAS5 je novi biomarker u onkologiji, koji ima dijagnostički i prognostički
značaj.Growth arrest specific 5 (GAS5) is a long noncoding RNA which halts the cell cycle and promotes apoptosis.
Acting as a signal protein, as a decoy for other molecules or as a transport molecule, this regulatory RNA influences
a number of pathways and molecules relevant for the growth of the cell and apoptosis, among
them the most important being the p53 network, the mTOR signal pathway, the AKT signal pathway, as well
as molecules of microRNA, PTEN and others.
Numerous studies on diverse cancer types have confirmed that the expression of GAS5 influences the development
and the course of hematological malignancies, gynecologic carcinoma, gliomas, breast cancer,
gastrointestinal cancer, kidney cancer, bladder cancer, prostate cancer and lung cancer. Therefore, GAS5 is
a promising new diagnostic and prognostic biomarker in oncology
Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL
No full textChronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed "satellites," were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL
The effect of new natural long-chain fatty acid esters from millipede defensive secretion on reactive oxygen species (ROS) production in a cell-free model system
No full textPhenomapping for classification of doxorubicin-induced cardiomyopathy in rats
No full textCardiomyopathy resistant to treatment is the most serious adverse effect of doxorubicin (dox). The mechanisms of dox-induced cardiomyopathy (DCM) have been extensively studied in dilated forms of DCM. However, efficient treatment did not emerge. The aim of the present work was to revisit the experimental model of DCM in rats, to define phenotype/s and associate them to the changes in cardiac transcriptome. Male Wistar rats equipped with radiotelemetry device, were randomized in DOX group (5 mg/0,5 mL/kg, IV dox; n = 18) and CONT group (0,5 mL/kg IV saline; n = 6). Echocardiography, autonomic spectral markers and baroreceptor reflex evaluation was performed prior to, and after treatment. Blood samples were collected at the end of experimentation. Cardiac, renal and hepatic tissues were analysed post-mortem by histology. Changes in expression of key cardiac genes affected by dox were assessed by RT-qPCR. Phenotypes were identified by clustering non-redundant features using four different algorithms averaged by evidence accumulation cluster technique. The results emphasize the existence of two major phenotypes of DCM with comparably high mortality rates: phenotype 1 characterized by, left ventricular (LV) dilatation, thinning of LV posterior wall, reduced LV ejection fraction (LVEF) and fractional shortening (LVFS), decreased HR variability (HRV), decreased baroreceptor effectiveness index (BEI) and increased NT-proBNP; and phenotype 2 with LV hypertrophy - increased LV mass, preserved LVEF, LVFS, no changes in HRV and BEI and moderate NT-proBNP increase. Both phenotypes exhibited a genetic shift to a new-born program
Enterococci from Raw-Milk Cheeses: Current Knowledge on Safety, Technological, and Probiotic Concerns
Get PDFThe present study is focused on the safety, technological characteristics, and probiotic evaluation of Enterococcus species from different artisanal raw milk dairy products, mainly cheeses with ripening. Apart from proteolytic and lipolytic activities, most enterococci show the ability to metabolize citrate and convert it to various aromatic compounds. Long-ripened cheeses therefore have a specific flavor that makes them different from cheeses produced from thermally treated milk with commercial starter cultures. In addition, enterococci are producers of bacteriocins effective against spoilage and pathogenic bacteria, so they can be used as food preservatives. However, the use of enterococci in the dairy industry should be approached with caution. Although originating from food, enterococci strains may carry various virulence factors and antibiotic-resistance genes and can have many adverse effects on human health. Still, despite their controversial status, the use of enterococci in the food industry is not strictly regulated since the existence of these so-called desirable and undesirable traits in enterococci is a strain-dependent characteristic. To be specific, the results of many studies showed that there are some enterococci strains that are safe for use as starter cultures or as probiotics since they do not carry virulence factors and antibiotic-resistance genes. These strains even exhibit strong health-promoting effects such as stimulation of the immune response, anti-inflammatory activity, hypocholesterolemic action, and usefulness in prevention/treatment of some diseases
Untreated PKU patients without intellectual disability: SHANK gene family as a candidate modifier
Get PDFPhenylketonuria (PKU) is an inborn error of metabolism caused by variants in the phenylalanine hydroxylase (PAH) gene and it is characterized by excessively high levels of phenylalanine in body fluids. PKU is a paradigm for a genetic disease that can be treated and majority of developed countries have a population-based newborn screening. Thus, the combination of early diagnosis and immediate initiation of treatment has resulted in normal intelligence for treated PKU patients. Although PKU is a monogenic disease, decades of research and clinical practice have shown that the correlation between the genotype and corresponding phenotype is not simple at all. Attempts have been made to discover modifier genes for PKU cognitive phenotype but without any success so far. We conducted whole genome sequencing of 4 subjects from unrelated non-consanguineous families who presented with pathogenic mutations in the PAH gene, high blood phenylalanine concentrations and near-normal cognitive development despite no treatment. We used cross sample analysis to select genes common for more than one patient. Thus, the SHANK gene family emerged as the only relevant gene family with variants detected in 3 of 4 analyzed patients. We detected two novel variants, p.Pro1591Ala in SHANK1 and p.Asp18Asn in SHANK2, as well as SHANK2:p.Gly46Ser, SHANK2:p.Pro1388_Phe1389insLeuPro and SHANK3:p.Pro1716Thr variants that were previously described. Computational analysis indicated that the identified variants do not abolish the function of SHANK proteins. However, changes in posttranslational modifications of SHANK proteins could influence functioning of the glutamatergic synapses, cytoskeleton regulation and contribute to maintaining optimal synaptic density and number of dendritic spines. Our findings are linking SHANK gene family and brain plasticity in PKU for the first time. We hypothesize that variant SHANK proteins maintain optimal synaptic density and number of dendritic spines under high concentrations of phenylalanine and could have protective modifying effect on cognitive development of PKU patients
Upcycling Biodegradable PVA/Starch Film to a Bacterial Biopigment and Biopolymer
Get PDFMeeting the challenge of circularity for plastics requires amenability to repurposing post-use, as equivalent or upcycled products. In a compelling advancement, complete circularity for a biodegradable polyvinyl alcohol/thermoplastic starch (PVA/TPS) food packaging film was demonstrated by bioconversion to high-market-value biopigments and polyhydroxybutyrate (PHB) polyesters. The PVA/TPS film mechanical properties (tensile strength (sigma(u)), 22.2 & PLUSMN; 4.3 MPa; strain at break (epsilon(u)), 325 & PLUSMN; 73%; and Young's modulus (E), 53-250 MPa) compared closely with low-density polyethylene (LDPE) grades used for food packaging. Strong solubility of the PVA/TPS film in water was a pertinent feature, facilitating suitability as a carbon source for bioprocessing and microbial degradation. Biodegradability of the film with greater than 50% weight loss occurred within 30 days of incubation at 37 & DEG;C in a model compost. Up to 22% of the PVA/TPS film substrate conversion to biomass was achieved using three bacterial strains, Ralstonia eutropha H16 (Cupriavidus necator ATCC 17699), Streptomyces sp. JS520, and Bacillus subtilis ATCC6633. For the first time, production of the valuable biopigment (undecylprodigiosin) by Streptomyces sp. JS520 of 5.3 mg/mL and the production of PHB biopolymer at 7.8% of cell dry weight by Ralstonia eutropha H16 from this substrate were reported. This low-energy, low-carbon post-use PVA/TPS film upcycling model approach to plastic circularity demonstrates marked progress in the quest for sustainable and circular plastic solutions
Progressing Plastics Circularity: A Review of Mechano-Biocatalytic Approaches for Waste Plastic (Re)valorization
Get PDFInspirational concepts, and the transfer of analogs from natural biology to science and engineering, has produced many excellent technologies to date, spanning vaccines to modern architectural feats. This review highlights that answers to the pressing global petroleum-based plastic waste challenges, can be found within the mechanics and mechanisms natural ecosystems. Here, a suite of technological and engineering approaches, which can be implemented to operate in tandem with nature's prescription for regenerative material circularity, is presented as a route to plastics sustainability. A number of mechanical/green chemical (pre)treatment methodologies, which simulate natural weathering and arthropodal dismantling activities are reviewed, including: mechanical milling, reactive extrusion, ultrasonic-, UV- and degradation using supercritical CO2. Akin to natural mechanical degradation, the purpose of the pretreatments is to render the plastic materials more amenable to microbial and biocatalytic activities, to yield effective depolymerization and (re)valorization. While biotechnological based degradation and depolymerization of both recalcitrant and bioplastics are at a relatively early stage of development, the potential for acceleration and expedition of valuable output monomers and oligomers yields is considerable. To date a limited number of independent mechano-green chemical approaches and a considerable and growing number of standalone enzymatic and microbial degradation studies have been reported. A convergent strategy, one which forges mechano-green chemical treatments together with the enzymatic and microbial actions, is largely lacking at this time. An overview of the reported microbial and enzymatic degradations of petroleum-based synthetic polymer plastics, specifically: low-density polyethylene (LDPE), high-density polyethylene (HDPE), polystyrene (PS), polyethylene terephthalate (PET), polyurethanes (PU) and polycaprolactone (PCL) and selected prevalent bio-based or bio-polymers [polylactic acid (PLA), polyhydroxyalkanoates (PHAs) and polybutylene succinate (PBS)], is detailed. The harvesting of depolymerization products to produce new materials and higher-value products is also a key endeavor in effectively completing the circle for plastics. Our challenge is now to effectively combine and conjugate the requisite cross disciplinary approaches and progress the essential science and engineering technologies to categorically complete the life-cycle for plastics