imagine (Institute of molecular genetics and genetic engineering)
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High-risk population screening for fabry disease in patients with chronic renal failure of unknown etiology
Get PDFFabry disease (FD) is a rare X-linked disorder caused by variants in the GLA gene leading to the
deficiency of lysosomal α-galactosidase-A and progressive accumulation of globotriaosylceramide
affecting the heart, nervous system, and kidneys. FD has overlapping phenotypes and often remains
undiagnosed. Therefore, a precise molecular-genetic diagnosis and the earliest possible treatment are
essential to avoid significant disease progression. The study aimed to determine the strategy for
establishing routine molecular genetic diagnostics of FD in Serbia to provide an early application of
appropriate therapy and genetic advice to families with a high risk for the birth of a child with FD. We
analyzed 95 (34 female and 61 male) hemodialysis patients with clinical suspicion of FD using Sanger
sequencing of all coding exons (7) and flanking intron regions of the GLA gene and measured the
relative expression of the GLA gene in available samples. The genetic analysis revealed 3 patients with
a missense variant (p.Asp313Tyr), and 10 patients with combinations of non-coding variants, described
as complex intronic haplotypes (CIHs). CIH1 (c.-10C>T, c.370-81_370-77delCAGCC, c.640-16A>G,
c.1000-22C>T), the most frequent haplotype, was detected in 7 (7.4%) patients. Lyso-Gb3 biomarker
levels were within the normal range in each tested patient. However, RT-qPCR analysis revealed
decreased relative expression of the GLA gene in PBMC of 2 female patients with CIH1 and one
female patient carrying only c.-10C>T variant by 9,1%, 7,4%, 46,3%, respectively, pointing out that
further analyses are needed to confirm/exclude FD in these patients. Because the effects of CIHs are not
yet fully understood, our work highlights the importance of analyzing intronic regions of the GLA gene
as genetic modifiers and the need to include expression analysis in the diagnostic algorithm.Book of abstracts: International Conference of Biochemists and Molecular Biologists in Bosnia and Herzegovina - ABMBBIH May, 202
Micronutrients, genetics and COVID-19
No full textPurpose of review Marked inter-individual differences in the clinical manifestation of coronavirus disease 2019 (COVID-19) disease has initiated studies in the field of genetics. This review evaluates recent genetic evidence (predominantly in the last 18 months) related to micronutrients (vitamins and trace elements) and COVID-19. Recent findings AQ5 In patients infected with SARS-CoV-2 virus, altered circulating levels of micronutrients may serve as prognostic markers of disease severity. Mendelian randomization (MR) studies did not find significant effect of variable genetically predicted levels of micronutrients on COVID-19 phenotypes, however, recent clinical studies on COVID-19 point out to vitamin D and zinc supplementation as a nutritional strategy to reduce disease severity and mortality. Recent evidence also points to variants in vitamin D receptor (VDR) gene, most notably rs2228570 (FokI) ‘‘f’’ allele and rs7975232 (ApaI) ‘‘aa’’ genotype as poor prognostic markers. Summary Since several micronutrients were included in the COVID-19 therapy protocols, research in the field of nutrigenetics of micronutrients is in progress. Recent findings from MR studies prioritize genes involved in biological effect, such as the VDR gene, rather than micronutrient status in future research. Emerging evidence on nutrigenetic markers may improve patient stratification and inform nutritional strategies against severe COVID-19
Preclinical validation of rilmenidine for repurposing in pancreatic ductal adenocarcinoma
Get PDFIntroduction: Pancreatic ductal adenocarcinoma (PDAC) has dismal
prognosis, as there are no screening tests available, most
often is diagnosed in the metastatic phase of the disease
and is refractory to conventional, targeted and
immunotherapy. We have examined the expression and
role of the novel tumor suppressor nischarin (NISCH) in
PDAC and the effects of treatment with the agonist
rilmenidine (approved for treatment of hypertension) in
order to determine the potential of nischarin agonists for
repurposing in this deadly disease.EACR 2023: Innovative Cancer Science, 12-15 June 2023, Torino, Ital
Privacy-preserving Systems Medicine
Get PDFArtificial intelligence (AI) offers game-changing opportunities to healthcare. However, it
also harbors risks to patient privacy in particular when dealing with sensitive clinical data
stored in critical healthcare IT infrastructure. Specifically, data exchange over the internet
is perceived insurmountable, posing a roadblock hampering big-data-based medical
innovations.
We created a novel AI platform, the FeatureCloud AI app store that is based on the idea of
federated learning where only model parameters are communicated. To maximize privacy,
sensitive datasets remain stored locally and are analysed behind safe firewalls to assure
the high standards in data privacy in order to (by design) comply with the strict GDPR.
We will exemplarly investigate the power of FeatureCloud apps for decentralized (1)
genome-wide association studies (GWAS), (2) gene expression data mining, and (3) timeto-
event data analytics to demonstrate how FeatureCloud may enhance worldwide
collaboration, accelerate innovation, and democratize scientific data usage. We show
that apps developed in FeatureCloud can produce highly similar results compared to
centralized approaches and scale well for an increasing number of participating sites.
FeatureCloud is a no-code platform for federated learning apps having the potential to
vastly increase the accessibility of privacy-preserving and distributed data analysis in
biomedicine and beyond.Book of abstract: 4th Belgrade Bioinformatics Conference, June 19-23, 202
Using whole exome sequencing to explore genetic basis of unicuspid aortic valve disease
Get PDFNormal aortic valve consists of three cusps that develop in the embryonic stage. Unicuspid
aortic valve (UAV) is a rare congenital anomaly resulting in only one cusp with estimated
prevalence of 0.02% in general population. Aim of this study was to identify genetic
variants possibly associated with development of UAV. The study included 17 subjects,
namely 5 UAV patients and their healthy family members without UAV disorder. Total
DNA was isolated from venous blood samples and whole exomes sequencing (WES) was
performed using BGI’s WES protocol. Adapter-trimmed and quality-filtered reads (fastp)
were mapped to hg38 reference genome using BWA/SAMtools. VCF files were generated
using GATK (BaseRecalibrator, HaplotypeCaller) and annotated with InterVar and AnnoVar
tools. Rare heterozygous variants present in UAV patients were found in NOTCH1, TGFB2,
MYH6, EGFR, FBN2, C1R, ROBO4 and TBX5, genes associated with development of aortic
valves. Among these, most were missense mutations with damaging effects as predicted
using in silico tools (SIFT and/or Polyphen). Only mutation in MYH6 p.Ala1130Ser was
found in at least two different UAV patients. Also, rare homozygous missense mutation
p.Gly577Ser with high damaging potential was found in ADAMTS5 gene. Besides, highly
damaging heterozygous missense mutations were detected in gene interacting functional
partners (STRING) of genes associated with development of aortic valves: DVL1, THBS1,
NOTCH4, ADAMTS3, FBN1, NOTCH2, ADAM17, LRP5, WWTR1, C1S, ANKRD6 and TNNI1,
as well as homozygous in ACAN and KNG1. Taken together, malfunctions in ADAMTS5,
ACTA2, MYH6, FBN2, AXIN1, CELSR1 or TBX5 networks were found to be common in at
least two UAV patients, suggesting existence of genetic basis in UAV disorder, possibly as
a result of combined effects of multiple variants.Book of abstract: 4th Belgrade Bioinformatics Conference, June 19-23, 202
Integration of differential transcriptomic and proteomic data in hydrated and desiccated leaves of Ramonda serbica Panc.
Get PDFThe resurrection plant Ramonda serbica Panc. survives long desiccation periods and fully
recovers metabolic functions within one day upon watering. We aimed to identify key
candidates and pathways involved in desiccation tolerance in R. serbica by employing a
systems biology approach, combining transcriptomics and proteomics.
A total of 68,694 differentially expressed genes (DEGs; p-value<0.005 and abs(log2FC)≥2) were
obtained in R. serbica leaves upon desiccation. Among them, 23,935 and 26,169 genes were
upregulated and downregulated in desiccated leaves (DL) and hydrated leaves (HL), respectively.
By differential TMT-based proteomic analysis 1192 different protein groups were identified
after filtering with at least two unique peptides per protein. In total, 229 protein groups
were more abundant in HL and 179 in DL (p-value<0.05 and abs(FC)≥1.3). The majority
of the DAPs and DEGs involved in photosynthesis, transport, secondary metabolism, and
signaling, were less abundant in DL. On the other hand, proteins and transcripts associated
with fermentation, N-metabolism, heme, protein synthesis, folding and assembly, C1-
metabolism, and late embryogenesis abundant proteins, were more accumulated in DL.
A poor correlation between proteomic and transcriptomic results was detected for mitochondrial
electron transport and ATP production, gluconeogenesis, glycolysis, tricarboxylic
acid cycle, and enzymatic H2O2 scavengers due to different mRNA half-life, protein turnover,
dynamic posttranscriptional and posttranslational modifications. Finally, desiccation tolerance
in R. serbica is a species-specific process orchestrated by several metabolic pathways
that are temporally and compartmentally regulated at several levels.Book of abstract: 4th Belgrade Bioinformatics Conference, June 19-23, 202
Energy and information exchange between “donor” and “molecular bridge” structures: non adiabatic polaron model
Get PDFMolecular chains (such as protein chains with alpha-helical secondary structure, DNA and
RNA molecules) can play the role of “bridges” for the highly efficient transfer of various
types of submolecular excitations (vibron excitations or electrons) over very long distances
(comparable to the length of the molecular chain itself). In the case when this process
takes place in living cells, the biomolecule is placed in an environment where it is usually
in thermodynamic equilibrium with the “heat bath”. As a result, the structural elements of
the molecular chain perform mechanical oscillations. In the general case, such mechanical
oscillations disrupt the ability of the molecular bridge to transfer the excitation over a
longer distance.
On the other side, by interacting with the thermal oscillations of the structure, excitations
injected into the molecule may be trapped and can form a stable self-trapped (polaronlike)
state. Such quasiparticles can move through the structure with minimal energy
loss. In this way, the high efficiency of energy and charge transport in living cells can be
explained. However, the properties of the possibly formed polaron quasiparticle must also
be affected by the presence of the donor molecule.
Here, we have discussed the mechanism of excitation transfer from a molecular structure
(donor molecule) to the molecular chain. The presence of the donor structure and the
temperature influence on the energy of the self-trapped excitation were considered in the
dependence of the basic energy parameters of the molecular bridge. The obtained results
indicate the possibility of the formation of two types of self-trapped states: a quasi-free
excitation, which can easily move through the molecular bridge, and a localized, practically
immobile excitation, which is similar to a non-adiabatic polaron quasiparticle.Book of abstract: 4th Belgrade Bioinformatics Conference, June 19-23, 202
Methodology, performance and retrainability survey of intrinsic disorder predictors
Get PDFIntrinsically disordered proteins and regions are widely distributed within most proteomes.
Recent studies show that they are associated with many essential biological processes
and a broad range of human diseases. Given the prevalence of disordered proteins and
the growing acknowledgement of their functional relevance, considerable effort has been
made by the bioinformatics community to provide computational tools to predict protein
disorder. To date, based on various characteristics of protein disorder, along with variety of
diverse computational approaches, numerous disorder predictors have been developed.
Over the past decade several review papers examining intrinsic disorder predictors have
been published. All these papers have played a significant role in stimulating and greatly
facilitating the development of this actively growing field by pinpointing the potential
room for improvement. Inspired by these, in this work we aim to integrate the relevant
information regarding the existing intrinsic disorder predictors from the corresponding
research papers in a novel review, including latest prediction tools. In addition, for each
disorder predictor, we examined the possibility of their retraining using different datasets.
Here, we present an overview of 23 protein disorder prediction methods, including the
thorough analysis of their advantages and weaknesses which derive from their different
computational approaches. Regarding this, we precisely describe the methodology used
for building the models and categorize them by different classification schemes. The
performance of these models is presented by their scores from the most recent CAID
competition. Additional contribution of this work is the models’ retraining availability
analysis. We describe in detail the predictors’ implementation source code (if available) and
propose a way around to overcome the obstacles with retraining procedure (if possible).
This insight might be very useful, since older models were trained on significantly
smaller datasets compared to the newer ones, due to the increase in the number of
experimentally annotated disorder proteins with time. With respect to this, we discuss
in detail the possibility of retraining the models on a different (bigger, novel) dataset in
order to perform full-scale comparison of their expression power in delineating disorder
in proteins.Book of abstract: 4th Belgrade Bioinformatics Conference, June 19-23, 202
Analysis of nucleotide sequence repeats in coronaviruses
Get PDFRepeats in nucleotide sequences are connected with various genome characteristics.
RNA secondary structures are related to repeats at the primary structure level. Four
different types of nucleotide repeats may be identified: direct non-complementary,
direct complementary, inverse non-complementary and inverse complementary. Reverse
complementary tandem repeats, for example, may form hairpin secondary structures,
while reverse non-complementary may be recognized by proteins. On the other side,
direct complementary and/or non-complementary repeats may be reflected in protein
sequence repeats, if found in the same reading frame, within the protein-coding sequence.
Here we analyzed (determined and compared) all four types of nucleotide repeats in
referent sequences of SARS-CoV-1, SARS-CoV-2 and MERS-COV viruses. In addition
to the complete repeat set, we analyze different repeat subsets: repeats with the left
component within the 5’ end, repeats with the right component within the 3’ end, and
repeats with at least one component within the surface glycoprotein coding sequence.
We found significant differences in repeat sets corresponding to analyzed sequences
in all analyzed repeat sets. In this moment we can only speculate what are the real
consequences of the discovered differencesBook of abstract: 4th Belgrade Bioinformatics Conference, June 19-23, 202
Microbial live interactions with textiles
Get PDFMicroorganisms, especially soil-dwelling Streptomyces, have the potential to both degrade
and colour a variety of textiles. Pigments from Streptomycetes could serve as colouring
agents for different natural and synthetic fabrics. Apart from pigments, Streptomyces can
produce a variety of enzymes. Several of these enzymes show favourable application in the
depolymerization of synthetic materials such as polyamide and polyurethane.
The aim of this study was the assessment of live interactions of pigmented Streptomyces
strains from the lab collection using polyamide (PA) and Polyamide/Elastane (PA/EA) knits
as substrates.
Cultivation of pigment-producing Streptomyces strains was done following the standard
microbiological protocols, using two different growth media with the addition of PA and
PA/EA knits into flasks. Cultures were incubated at 30°C for 7 and 14 days under static and
dynamic conditions. Materials were recovered and their colour coordinates, colour difference
(ΔE), and fastness were determined, and their surface changes were examined by Scanning
Electron Microscopy (SEM).
The incubation of knits with living bacterial cultures resulted in both live dyeing and
degradation, depending on the strain used. The intensity of color yield was larger under
dynamic culture conditions. Therefore, Streptomyces strains could be successfully applied in
the development of greener dyeing and degradation bioprocesses.10th FEMS Congress of European Microbiologists, Hamburg, Germany from July 9 -13th, 2023