imagine (Institute of molecular genetics and genetic engineering)
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New concept for treatment of glycogen storage disease Ib and diabetes mellitus type 2: small molecule compounds able to adjust glucose level through binding glucose-6-phospate translocase (GlucoAdjust)
Get PDFGlucoAdjust project aims to solve fast-growing health challenges important for the society,
namely it will focus on discovery of new treatments for one rare disease glycogen storage
disease type Ib (GSD Ib) and one common disease diabetes mellitus type 2 (DM type 2). We
propose a completely new concept based on the identification of small molecule (SM)
compounds able to directly bind to glucose-6-phospate translocase (G6PT) and thus fine-tune
glucose level. To tackle these challenges, an interdisciplinary international team will screen large
library of SMs combining in silico and in vitro approaches and identify SMs that directly bind to
G6PT. SMs able to stabilize G6PT and increase its function thus correcting hypoglycemia are
potential drugs for GSD Ib. On the other hand, SMs that inhibit G6PT may be used to induce
hypoglycemia in DM type 2 treatment. To obtain highly functional results of testing SMs in vitro,
human hepatocyte models for GSD Ib and DM type 2 as well as controls will be developed
(differentiated from human healthy and GSD Ib iPSC and diabetic adipose stem cells). For the
first time, whole transcriptome of human GSD Ib hepatocytes will be used to delineate molecular
processes disturbed due to G6PT deficiency. As a result, RNA hallmarks of GSD Ib phenotype will
be determined and used for evaluation of SMs’ effect in both models. To be efficient for GSD Ib,
SMs will have to revert GSD Ib phenotype into normal. The key to discover satisfactorily
effective, yet sufficiently mild inhibitor for DM type 2 will be to avoid hallmarks representing
GSD Ib phenotype. Thus, a revolutionary concept of using GSD Ib as a model of hypoglycemia to
better optimize DM type 2 treatment is proposed here. Results will be openly disseminated to
make a wide scientific, educational, social and economic impacts. GlucoAdjust anticipates
innovative results with a potential to be further translated into drugs able to improve lives of
people with GSD Ib and DM type 2 worldwide.Principal Investigator:Dr Maja Stojiljkovic, IMGGEDuration period: 2024-202
MOLECULAR BASIS OF PHENYLKETONURIA IN SERBIAN PAEDIATRIC COHORT
No full text32nd Meeting of the European Society of CLINICAL RESEARCH 24-25 May 2024 Opatija, Croatia PAEDIATRIC CLINICAL RESEARCH 24-25 May 2024 Opatija, Croati
Benchmarking of five NGS mapping tools for the reference alignment of bacterial outer membrane vesicles-associated small RNAs
No full textAdvances in small RNAs (sRNAs)-related studies have posed a challenge for NGS-related bioinformatics, especially regarding the correct mapping of sRNAs. Depending on the algorithms and scoring matrices on which they are based, aligners are influenced by the characteristics of the dataset and the reference genome. These influences have been studied mainly in eukaryotes and to some extent in prokaryotes. However, in bacteria, the selection of aligners depending on sRNA-seq data associated with outer membrane vesicles (OMVs) and the features of the corresponding bacterial reference genome has not yet been investigated. We selected five aligners: BBmap, Bowtie2, BWA, Minimap2 and Segemehl, known for their generally good performance, to test them in mapping OMV-associated sRNAs from Aliivibrio fischeri to the bacterial reference genome. Significant differences in the performance of the five aligners were observed, resulting in differential recognition of OMV-associated sRNA biotypes in A. fischeri. Our results suggest that aligner(s) should not be arbitrarily selected for this task, which is often done, as this can be detrimental to the biological interpretation of NGS analysis results. Since each aligner has specific advantages and disadvantages, these need to be considered depending on the characteristics of the input OMV sRNAs dataset and the corresponding bacterial reference genome to improve the detection of existing, biologically important OMV sRNAs. Until we learn more about these dependencies, we recommend using at least two, preferably three, aligners that have good metrics for the given dataset/bacterial reference genome. The overlapping results should be considered trustworthy, yet their differences should not be dismissed lightly, but treated carefully in order not to overlook any biologically important OMV sRNA. This can be achieved by applying the intersect-then-combine approach. For the mapping of OMV-associated sRNAs of A. fischeri to the reference genome organized into two circular chromosomes and one circular plasmid, containing copies of sequences with rRNA- and tRNA-related features and no copies of sequences with protein-encoding features, if the aligners are used with their default parameters, we advise avoiding Segemehl, and recommend using the intersect-then-combine approach with BBmap, BWA and Minimap2 to improve the potential for discovery of biologically important OMV-associated sRNAs
A NEW TOOL: VUS NOTIFIER
No full textThere are over 300 million people living with one of over 7,000 identified genetic rare diseases
(RD) around the world. Over 80% of RD are genetic, and nowadays comprehensive genetic tests
(such as whole-exome sequencing and whole-genome sequencing) become the first-tier test in the
process of reaching diagnosis. Accurate and timely diagnosis is necessary for specific and effective
treatment of affected people, and can enable their family members to perform prenatal diagnostics
and have healthy offspring.
However, interpretation of genetic test is limited by the currently available scientific data and for
substantial part of genetic variants detected by genetic test, there is just not enough data to be
classified as pathogenic or benign and therefore they are classified as variants of uncertain
significance (VUS). In time, new scientific evidence will be gathered and VUS will eventually be
re-classified as pathogenic or benign.
To aid in the process of providing latest information, we developed a VUS notifier application.
VUS notifier solves the problem of providing notifications regarding VUS. Now, an interested
party, whether a patient, family member, doctor, etc., can conveniently receive notifications when
new information relevant to a specific VUS appears in genetic databases or scientific publications.VII Congress of the Serbian Genetic Society Zlatibor; October 2 to 5, 2024
Craft Beer Produced by Immobilized Yeast Cells with the Addition of Grape Pomace Seed Powder: Physico-Chemical Characterization and Antioxidant Properties
No full textThe aim of this study was to produce and to characterize craft beer fermented by immobilized yeast cells with the addition of Prokupac grape pomace seed powder (2.5% and 5%), to obtain a beer enriched with phenolic compounds and improved sensory characteristics. The immobilization of the yeast cells was performed by electrostatic extrusion, while the obtained calcium alginate beads were characterized by light and scanning electron microscopy. Phenolic and hop-derived bitter compounds in beer with or without grape pomace seed powder (GS) phenolics were identified using UHPLC Q-ToF MS. The results indicated that GS adjunct significantly shortened the fermentation process of wort and increased the content of phenolic compounds, especially ellagic acid, flavan-3-ols and pro(antho)cyanidins in the final products compared to the control beer. A total of twenty (iso)-α-acids and one prenylflavonoid were identified, although their levels were significantly lower in beers with GS phenolics compared to the control beer. Beers with GS phenolics showed good antioxidant properties as measured by the reduction of ferric ions (FRP) and the scavenging of ABTS•+ and DPPH• radicals. The concentration of immobilized viable yeast cells was higher than 1 × 108 CFU/g wet mass after each fermentation without destroying the beads, indicating that they can be reused for the repeated fermentation of wort. Beers produced with 5% GS added to the wort exhibited the best sensory properties (acidity, astringency, bitterness intensity, mouthfeel, aftertaste and taste), and highest overall acceptability by the panelists. The results showed that grape pomace seed powder present a promising adjunct for the production of innovative craft beer with good sensory properties and improved functionality
Long-chain 4-aminoquinolines inhibit filamentation and increase efficacy of nystatin against Candida albicans infections in vivo
No full textIn exploring a growing demand for innovative approaches to tackle emerging and life threatening fungal diseases, we identified long-chain 4-aminoquinoline (4-AQ) derivatives as a new class of anti-virulence agents. For the first time, we demonstrated that 4-AQs effectively prevent filamentation of Candida albicans, a key virulence trait, under multiple triggering conditions. Selected 4-AQ derivatives inhibited filament formation in a zebrafish model of disseminated candidiasis at 1.56 µM, with no toxicity up to 50 µM. Combining nystatin with 4-AQs resulted in a 100% survival rate of infected embryos and complete eradication of C. albicans, compared to 65–75% survival with nystatin alone. The most potent 4-AQ derivatives also showed significant activity against C. albicans biofilms, with derivative 11 suppressing mixed C. albicans-Pseudomonas aeruginosa biofilms. This dual capability highlights the potential of 4-AQs as novel anti-virulence agents to enhance conventional antifungal therapies, marking a significant advance in treating complex fungal infections
Unveiling the 4-aminoquinoline derivatives as potent agents against pancreatic ductal adenocarcinoma (PDAC) cell lines
No full textCommon antimalarials such as artemisinins, chloroquine and their derivatives also possess potent anti-inflamantory, antiviral and anticancer properties. In the search for new therapeutics to combat difficult-to-treat pancreatic carcinomas, we unveiled that 4-aminoquinoline derivatives, with significant antiplasmodial properties and a great safety profile in vivo, have remarkable anticancer activity against pancreatic ductal adenocarcinoma (PDAC) and considerable efficacy in the xenograft model in vivo. The aim of the present study was to further investigate anticancer properties of these compounds in a drug-repurposing manner. The compounds showed profound cytotoxic effects at nanomolar to low micromolar concentration in 2D cultured cells (in vitro) and in the zebrafish PDAC xenograft model (in vivo). A deeper insight into their mechanisms of cytotoxic action showed these compounds induce apoptosis while increasing reactive oxygen species levels along with autophagy inhibition. Additional investigation of the autophagy modulation proved that tested quinoline derivatives cause P62 and LC3-II accumulation in PDAC cells alongside lysosomal alkalinization. Further, in vivo toxicity studies in the zebrafish model showed low toxicity without developmental side effects of the investigated 4-aminoquinolines, while the applied compounds effectively inhibited tumor growth and prevented the metastasis of xenografted pancreatic cells. Taken together, these results highlight the 4-aminoquinolines as privileged structures that ought to be investigated further for potential application in pancreatic carcinoma treatment
NEW GATA3 VARIANT IN A PATIENT WITH BARAKAT SYNDROME
No full textGATA3 protein is a transcription factor involved in the embryonic development of
parathyroid glands, kidney, thymus, inner ear, and central nervous system. Pathogenic heterozygous
germline variants in the GATA3 gene impair protein activity by haploinsufficiency leading to
hypoparathyroidism, sensorineural deafness, and renal dysplasia- HDR or Barakat syndrome. So far,
about 200 patients have been reported in the literature worldwide. A novel variant in GATA3 gene was
detected. Next -generation sequencing analysis of DNA isolated from peripheral blood of a 17-year-old
patient with clinical diagnosis of bilateral sensorineural deafness, unilateral renal agenesis,
developmental delay and double uterus, is performed using TruSight One panel and NextSeq 550 system
(Illumina). A novel missense heterozygous variant c.989G>A p.(Arg330Lys) in GATA3 gene was
detected in a patient. This variant results in a replacement of amino acid arginine by lysine on position
330 in GATA3 transcription factor protein. It is in a highly conserved zinc-finger protein region and is
very likely to disrupt the function of the enzyme by haploinsufficiency. According to ACMG
classification, the detected variant is characterized as likely pathogenic. Barakat syndrome is a clinically
heterogenous autosomal dominant disorder caused by pathogenic variants in the GATA3 gene. So far, 93
GATA3 pathogenic variants have been reported in the literature. GATA3 variants show incomplete
penetrance, causing great clinical variability. We present the patient, a heterozygous carrier of novel
variant in GATA3 gene, with no typical presentation of HDR syndrome, since hypoparathyroidism was
clinically unapparent, and the patient had additional clinical manifestations – neurological developmental
delay and a double uterus. Since prenatal ultrasound and neonatal hearing screening can identify renal or
hearing defects, the presence of those symptoms should represent clinical indication for NGS testing
which will result in earlier diagnosis of HDR and detection of other symptoms, enabling early
intervention and genetic counseling.Book of abstracts: 2nd B&H Symposium of Laboratory Geneticists and Molecular Biologists (with International Participation) May, 202
FAIR Research Software as the catalyst for trustworthy AI in Life Sciences
No full textAs a result of many years of global efforts, ensuring that data are Findable, Accessible, Interoperable
and Reusable (also known as FAIR) is nowadays a clear expectation across all science domains. While
data and data management have been the primary focus across many activities, research software has
only recently started getting similar attention. As a result, a coordinated effort by the wider community
allowed to redefine and extend the FAIR principles to research software, with similar activities now in
progress aiming to enhance reproducibility, quality assurance, and long-term sustainability in software
development.
At the same time, we see the emergence of the field of artificial intelligence (AI) and machine learning
(ML) as a key technology impacting all sciences. As AI algorithms and models become increasingly
integrated into scientific workflows, there is an urgent need to maintain high standards for research
software, with the reliability and quality of the underlying software being of primary concern.
High-quality research software is definitely a key catalyst in that direction. In this context, “quality”
involves not only creating robust and efficient algorithms, but also implementing rigorous quality
control processes throughout the software lifecycle. There are several initiatives (such as ReSA, Turing
Way and SSI) that are making available best practices, guidelines and recommendations on research
software, from design and coding to testing and deployment, as well as major funded projects (such
as EVERSE).
Another key aspect is around benchmarking, as it serves as a critical tool for evaluating performance,
scalability, and generalizability of AI solutions across diverse datasets and use cases. In order to
effectively run a benchmarking process, it is essential to establish standardized benchmarks and
evaluations protocols, as well as the respective underlying services and infrastructure to facilitate
this. In both cases, input and direct involvement of the respective community is essential, in order to
fostering transparency and comparability in AI research.
Finally, beyond the technical aspects, there is a clear need for a coherent effort towards the interpretation
of the actual FAIR principles for ML. Some efforts already exist, such as the RDA FAIR4ML interest
group, as well as the efforts under the AI4EOSC project and the ELIXIR infrastructure. However, we still
have some way to go, and direct community involvement is critical to ensure both wide adoption and
ultimately uptake of these practices.Book of abstracts: 5th Belgrade Bioinformatics Conference, Serbia, Belgrade,17-20 june 2024
Evidence of widespread hemizygosity and gene presence/absence variation in invertebrate pangenomes: are we overlooking the impact of genomic structural variation in metazoans?
No full textRecent advancements in genome sequencing technologies have unveiled unprecedented
insights into the genomic makeup of non-model metazoans, whose distinct traits have been
long overshadowed by the emphasis placed on monoploid reference assemblies. While
the phenotypic effects of structural variation (SV) are well-documented in plants, their
significance in the animal kingdom has only recently come to light. Bivalve mollusks, with
their complex genomes, present an intriguing model for investigating these phenomena.
Our research on the Mediterranean mussel and on the Pacific oyster uncovered an
unexpected pangenomic organization, characterized by a plethora of dispensable genes
exhibiting Presence/Absence Variation (PAV) and linked to hemizygous regions. Notably,
these genes were disproportionately associated with immune response and survival
functions, hinting at their role in local adaptation. Subsequent examinations revealed that
widespread hemizygosity is a common feature among various bivalve species, indicating
an underappreciated functional impact of SV and PAV in these organisms. Interestingly,
preliminary analyses suggest that gene PAV is prevalent to varying degrees in aquatic
environments, underscoring the necessity for a shift in genomic research focus in nonmodel
metazoans, from monoploid reference assemblies to pan-genomesBook of abstracts: 5th Belgrade Bioinformatics Conference, Serbia, Belgrade,17-20 june 2024