imagine (Institute of molecular genetics and genetic engineering)
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Trendovi u molekularnoj biologiji/Trends in Molecular Biology
No full textRazvoj je imperativ za opstanak. Tako Zbornik “Trendovi u molekularnoj biologiju 4” ove godine donosi novine u svoj sadržaj. Pored radova internacionalno priznatih stručnjaka iz pojedinih oblasti, tu su i prvi radovi mladih istraživača, Z-molekularaca. Mladi naučnici su prikazali teme svojih istraživanja koja su otpočeli kao studenti master studija.Tako ovaj Zbornik postaje bogatiji sa tendencijom da ima što aktuelnije i zanimljivije teme. Ove godine je vodeći rad posvećen vakcinama baziranim na RNK, otkriću koje je nagrađeno Nobelovom nagradom prošle godine. Rad su napisali naši naučnici koji takođe razvijaju ovaj tip vakcine. Vakcine su dale neverovatno veliki doprinos zdravlju na svetskom nivou. Razvijaju se već 228 godina, i od tada su spasile milione života. Poslednji uspešni iskorak vakcina je napravljen razvojem „vakcina“ protiv kancera. Uzimajući u obzir da jedan od pet ljudi oboli od kancera u toku svog života, ovaj inovativni terapijski pristup će doneti revolucionarni napredak medicini 21. veka. Na kraju, jedna moderna basna o razgovoru dva virusa. Prvi: „Ma kako je moguće da smo još živi kad ljudi imaju vakcine da nas unište?“ Drugi: „Ćuti, dobro je! Imamo sreću da živimo u civilizaciji u kojoj je naučna istina stvar ličnog mišljenja.“ TMB4 stoji kao čvrsta odbrana naučne istine zasnovane na naučnim dokazima
Transcriptome profile of phenylalanine treated NT2-derived neurons – a step towards novel PKU model system PO-576
No full textBackground: Phenylketonuria (PKU) is the most common inherited disorder of amino acid metabolism, characterized by high levels of phenylalanine (Phe) in the blood and brain, causing cognitive impairment if not treated. Despite PKU being well-researched, the Phe-mediated brain dysfunction isn’t fully understood. Existing models such as Pahenu mice and cerebral organoids are costly and time-consuming. Hence, for the first time we studied NT2-derived neurons (NT2-N), a known and suitable model of human neurons, as a novel PKU model. We investigated the transcriptome of NT2-N treated with 5 concentrations of Phe, simulating varying PKU severity. Case Study/Methods: NT2/D1 cells were differentiated in culture using retinoic acid for 4 weeks. A neuron-enriched population was isolated and treated with different concentrations of Phe (1.25, 2.5, 5, 10 and 30 mM) for 7 days, following whole iRNA short read sequencing, using nontreated NT2-N as control. Differentially expressed genes (DEG) were analyzed by gene set enrichment analysis using Gene Ontology database. Results: We detected 1554 DEGs in total. While treatment with 1.25 mM Phe didn’t show any DEGs, similar trends were notable for 2.5, 5 and 10 mM Phe, and DEGs noted at 30 mM Phe didn’t correspond to the ones described at lower concentrations. For the middle 3 Phe treatments, axonogenesis, axon guidance and regulation of neuron projection development were among the most enriched pathways, with up-regulated genes including PREX1, PCSK9, LRP4 and downregulated such as PRMT8 within individual DEGs. Discussion/Conclusion: Difference in DEGs between 30 mM Phe and other treatments, suggested different mechanisms of Phe-mediated effect on NT2-N. With enriched pathways for middle 3 treatments, we outlined the effect of PREX1 and LRP4 overexpression in neurite differentiation and dendrite terminals mobility, and role of PRMT8 in neuronal excitability, synaptic formation and axon guidance. We introduced a new PKU model and identified potential contributors to Phe-induced brain dysfunction.SSIEM Annual Symposium 2024, 3–6 September 202
Worm Profiler: Surveillance and population genetics of Echinococcus in Serbia (WORM_PROFILER)
Get PDFEchinococcus, tapeworms of the Taeniidae family, can infect humans and animals and cause
serious, even lethal disease. Global population genetics data suggests that disease presentation,
severity, immune response, as well as relative host susceptibility and resistance to infection
depend on the species, genotype and haplotype. The species of significant clinical relevance in
Europe are E. granulosus, the causative agent of cystic echinococcosis (CE) and E. multilocularis,
which causes the most severe disease, alveolar echinococcosis (AE). Analysis of the population
genetics of Echinococcus is an ongoing effort in some parts of Europe, while the Balkans
represent a significant knowledge gap. This project aims to comprehensively survey the entire
transmission cycle consisting of intermediate and definitive animal hosts and the environment
using sample processing and analytical methods which have been standardized, validated and
harmonized at the EU level to obtain high quality population genetics data via mitochondrial gene
(cox1 and nad1) sequencing and characterization of the EmsB microsatellite from single eggs,
worms and protoscolices. As a main novelty, comprehensive Echinococcus population genetics
data, through a survey of underexplored reservoirs with a high transmission capacity to humans,
will be systematized and graphically displayed through an interactive bioinformatics database,
WormProfiler, with a user interface tailored to physicians and veterinarians. The impact of the
project is the translation of population genetics data to physicians and veterinarians, key
stakeholders for transmission prevention to facilitate education of the public and raise awareness
of echinococcosis. The project should provide the insight into the genetic diversity of
Echinococcus and identification of transmission foci, as well as a software supported framework
for systematic surveillance and future development of targeted transmission control actions to
reduce echinococcosis case burden.Principal Investigator: Dr. Aleksandra Uzelac, Institute for Medical Research, University of
BelgradeCoordinator for IMGGE: Dr. Jelena KaranovićDuration period: 2024-202
Expression Pattern and Prognostic Significance of the Long Non-Coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 in Chronic Lymphocytic Leukemia
Get PDFDysregulated expression of the long non-coding RNA MALAT1 has been implicated in the pathogenesis and progression of a variety of cancers, including hematological malignancies, but it has been poorly investigated in chronic lymphocytic leukemia (CLL). In this study, the expression of MALAT1 was measured using a quantitative reverse-transcriptase polymerase chain reaction in the peripheral blood mononuclear cells of 114 unselected, newly diagnosed CLL patients in order to analyze its association with clinical, laboratory, and molecular patients’ characteristics at diagnosis, as well as its prognostic relevance. MALAT1 was found to be upregulated in CLL patients in comparison to healthy controls, and expression levels were not related to age, leukocyte, lymphocyte and platelet count, serum β2-microglobulin, and IGHV somatic hypermutational status. On the other hand, high MALAT1 expression was associated with several favorable prognostic markers (high hemoglobin, low serum lactate dehydrogenase, earlier clinical stages, CD38-negative status), but also with unfavorable cytogenetics. Furthermore, an association between high MALAT1 levels and longer time to first treatment and overall survival in IGHV-unmutated CLL subtype was observed. In summary, our results imply that high MALAT1 expression at diagnosis may be a predictor of better prognosis and point to MALAT1 expression profiling as a candidate biomarker potentially useful in clinical practice
Assessment of Factor VIII Activity and D-Dimer Levels in the Post-COVID Period
No full textChanges in the hemostatic system during COVID infection lead to hypercoagulability. Numerous studies have evaluated hemostatic abnormalities in COVID patients during acute infection, in the period of hospitalization. However, the hemostatic status following hospital discharge has not been sufficiently assessed. Considering the importance of FVIII and D-dimer levels as markers for the assessment of thrombosis, our study aimed to evaluate changes in these markers, as well as the influence of patient's age and clinical presentation of COVID infection on those hemostatic markers in the post-COVID phase. This prospective study (July 2020 to December 2022) included 115 COVID patients, 68 (59%) with asymptomatic/mild and 47 (41%) with moderate/severe clinical presentation. Patient follow-up included laboratory evaluation of FVIII and D-dimer levels at 1, 3, and 6 months following the COVID infection. Three months after the COVID infection, elevated FVIII was recorded in 44% of younger versus 65% of older individuals, p = 0.05, respectively, and 30 versus 57% (p = 0.008) 6 months post–COVID infection. With a focus on clinical presentation, a higher number of patients with moderate/severe COVID had elevated FVIII activity, but a statistically significant difference was observed only for the 6 months (32% mild vs. 53% moderate/severe, p = 0.041) post-infection time point. Following a COVID infection, an increase in FVIII activity suggests a continued hypercoagulable state in the post-COVID period and correlates with elevated D-dimer levels. This increase in FVIII is more pronounced in patients with moderate/severe clinical picture and those patients older than 50 years
Computational Modeling and Characterization of Peptides Derived from Nanobody Complementary-Determining Region 2 (CDR2) Targeting Active-State Conformation of the β2-Adrenergic Receptor (β2AR)
Get PDFThis study assessed the suitability of the complementarity-determining region 2 (CDR2) of the nanobody (Nb) as a template for the derivation of nanobody-derived peptides (NDPs) targeting active-state β2-adrenergic receptor (β2AR) conformation. Sequences of conformationally selective Nbs favoring the agonist-occupied β2AR were initially analyzed by the informational spectrum method (ISM). The derived NDPs in complex with β2AR were subjected to protein–peptide docking, molecular dynamics (MD) simulations, and metadynamics-based free-energy binding calculations. Computational analyses identified a 25-amino-acid-long CDR2-NDP of Nb71, designated P4, which exhibited the following binding free-energy for the formation of the β2AR:P4 complex (ΔG = −6.8 ± 0.8 kcal/mol or a Ki = 16.5 μM at 310 K) and mapped the β2AR:P4 amino acid interaction network. In vitro characterization showed that P4 (i) can cross the plasma membrane, (ii) reduces the maximum isoproterenol-induced cAMP level by approximately 40% and the isoproterenol potency by up to 20-fold at micromolar concentration, (iii) has a very low affinity to interact with unstimulated β2AR in the cAMP assay, and (iv) cannot reduce the efficacy and potency of the isoproterenol-mediated β2AR/β-arrestin-2 interaction in the BRET2-based recruitment assay. In summary, the CDR2-NDP, P4, binds preferentially to agonist-activated β2AR and disrupts Gαs-mediated signaling
Association between Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4) Locus and Early-Onset Anti-acetylcholine Receptor-Positive Myasthenia Gravis in Serbian Patients
No full textGenome-wide association studies (GWAS) have provided strong evidence that early- and late-onset MG have different genetic backgrounds. Recent in silico analysis based on GWAS results revealed rs231735 and rs231770 variants within CTLA-4 locus as possible MG causative genetic factors. We aimed to explore the association of rs231735 and rs231770 with MG in a representative cohort of Serbian patients. We conducted an age-, sex-, and ethnicity-matched case–control study. Using TaqMan allele discrimination assays, the frequency of rs231735 and rs231770 genetic variants was examined in 447 AChR-MG patients and 447 matched controls. There was no significant association of rs231735 and rs231770 with the entire MG cohort (P > 0.05). Nevertheless, when stratifying patients into early-onset (n = 183) and late-onset MG (n = 264), we found early-onset patients had a significantly lower frequency of the rs231735 allele T compared to controls (OR = 0.734, 95% CI = 0.575–0.938, p10e6 permutation < 0.05), and rs231735 genotype TT and rs231770 genotype TT had a protective effect on early-onset MG (OR = 0.548, 95% CI = 0.339–0.888, and OR = 0.563, 95% CI = 0.314–1.011, p10e6 permutation < 0.05). Consequently, we found that individuals with the rs231735-rs231770 haplotype GC had a higher risk for developing early-onset MG (OR = 1.360, P = 0.027, p10e6 permutation < 0.05). Our results suggest that CTLA-4 rs231735 and rs231770 may be risk factors only for patients with early-onset MG in Serbian population
The effect of prothrombin, the precursor of thrombin, on the proliferation and migration of colorectal cancer cells
Get PDFThrombotic disorders are some of the main comorbidities in cancer patients. So far, research has indicated that thrombin, a key regulator of hemostasis, contributes to cancer progression. However, data on its origin in tumor microenvironments remain elusive. Based on previous research, we analyzed the RNA and protein expression of prothrombin, a precursor of thrombin, in selected colorectal cancer (CRC) cell lines. Since the effect of prothrombin in cancer development has not been previously reported, we treated the cells for 24 h and 48 h with different prothrombin concentrations and assessed the effect on cell proliferation and migration. Our results show that the tested CRC cell lines expressed prothrombin and that prothrombin inhibited proliferation and migration. The presented results suggest that prothrombin may contribute to CRC etiopathology and could serve as a potential diagnostic biomarker and therapeutic target. The mechanisms underlying prothrombin expression in cancer cells, potential prothrombin activation, and the underlying processes driving the described effects warrant further investigation
Speech Sounds Production, Narrative Skills, and Verbal Memory of Children with 22q11.2 Microdeletion
Get PDF22q11.2 deletion syndrome (22q11.2DS), the most frequent microdeletion syndrome in humans, is related to a high risk of developing neurodevelopmental disorders. About 95% of patients with 22q11.2DS have speech and language impairments. Global articulation, story generation, and verbal memory tests were applied to compare articulatory characteristics of speech sounds, spontaneous language abilities, and immediate verbal memory between four groups of Serbian-speaking children: patients with 22q11.2DS, children with clinical presentation of 22q11.2DS that do not have the microdeletion, children with non-syndromic congenital heart defects, and their peers with typical speech–sound development. The obtained results showed that children with this microdeletion have impaired articulation skills and expressive language abilities. However, we did not observe weaker receptive language skills and immediate verbal memory compared to healthy controls. Children with 22q11.2DS should be considered a risk category for the development of speech–sound pathology and expressive language abilities. Since speech intelligibility is an instrument of cognition and adequate peer socialization, and language impairment in school-aged children with 22q11DS might be an indicator of increased risk for later psychotic symptoms, patients with 22q11.2 microdeletion should be included in a program of early stimulation of speech–language development immediately after diagnosis is established
NOVEL BACTERIOPHAGE ISOLATION FROM BELGRADE WASTEWATERS
Get PDFAnti-microbial drug resistance (AMR) is one of
the global health threats caused by the misuse
of drugs typically used to treat microbial
infections in humans, animals and plants. AMR
in nosocomial infections not only significantly
hinders treatment and endangers the patients’
lives, but also elevates the costs of healthcare.
Multiple research approaches have been initiated
to combat AMR, and one promising method
is bacteriophage therapy. Bacteriophages (phages)
are viruses that naturally exploit bacteria as
their hosts for replication and can cause cell lysis,
which makes them promising candidates for
treating the infections that do not respond to
conventional antibiotic therapies. In this study,
we screened wastewater samples from four
different collectors in Belgrade urban area for
bacteriophages active against clinically isolated
strains of two biofilm-producing bacteria that
readily persist in hospital environment - Klebsiella
pneumoniae (6 strains) and Pseudomonas aeruginosa
(2 strains). Wastewaters were screened
for phage presence through phage enrichment
process, in which bacteria were grown in a mixture
of water samples and nutrient-rich broth.
Obtained cultures were screened for antimicrobial
activity against the respective host strains,
and candidates were subjected to a first-round
plaque assay to detect the phages. Finally, the
activity of all the candidates was tested against
all strains of the same species to gain the first insight
into their host range. We discovered 20 potentially
distinct bacteriophages active against
K. pneumoniae strains and two potentially different
candidates targeting P. aeruginosa. Notably,
one phage exhibited activity against all tested K.
pneumoniae strains, and four were active against
5 out of 6 tested strains. Among 22 candidates in
total, five showed depolymerizing activity, indicating
promise in combating biofilm formation.
Currently, isolation of new phages, as well as purification
and host range analysis is underway for
several candidates targeting K. pneumoniae and
two targeting P. aeruginosa strains.Book of abstract: From biotechnology to human and planetary health XIII congress of microbiologists of Serbia with international participation Mikromed regio 5, ums series 24: 4th – 6th april 2024, Mona Plaza hotel, Belgrade, Serbi