Efficient mixture model for clustering of sparse high dimensional binary data

Clustering is one of the fundamental tools for preliminary analysis of data. While most of the clustering methods are designed for continuous data, sparse high-dimensional binary representations became very popular in various domains such as text mining or cheminformatics. The application of classical clustering tools to this type of data usually proves to be very inefficient, both in terms of computational complexity as well as in terms of the utility of the results. In this paper we propose a mixture model, SparseMix, for clustering of sparse high dimensional binary data, which connects model-based with centroid-based clustering. Every group is described by a representative and a probability distribution modeling dispersion from this representative. In contrast to classical mixture models based on the EM algorithm, SparseMix: is specially designed for the processing of sparse data; can be efficiently realized by an on-line Hartigan optimization algorithm; describes every cluster by the most representative vector. We have performed extensive experimental studies on various types of data, which confirmed that SparseMix builds partitions with a higher compatibility with reference grouping than related methods. Moreover, constructed representatives often better reveal the internal structure of data

Expression of alternatively spliced variants of the Dclk1 gene is regulated by psychotropic drugs

Abstract Background The long-term effects of psychotropic drugs are associated with the reversal of disease-related alterations through the reorganization and normalization of neuronal connections. Molecular factors that trigger drug-induced brain plasticity remain only partly understood. Doublecortin-like kinase 1 (Dclk1) possesses microtubule-polymerizing activity during synaptic plasticity and neurogenesis. However, the Dclk1 gene shows a complex profile of transcriptional regulation, with two alternative promoters and exon splicing patterns that suggest the expression of multiple isoforms with different kinase activities. Results Here, we applied next-generation sequencing to analyze changes in the expression of Dclk1 gene isoforms in the brain in response to several psychoactive drugs with diverse pharmacological mechanisms of action. We used bioinformatics tools to define the range and levels of Dclk1 transcriptional regulation in the mouse nucleus accumbens and prefrontal cortex. We also sought to investigate the presence of DCLK1-derived peptides using mass spectrometry. We detected 15 transcripts expressed from the Dclk1 locus (FPKM > 1), including 2 drug-regulated variants (fold change > 2). Drugs that act on serotonin receptors (5-HT2A/C) regulate a subset of Dclk1 isoforms in a brain-region-specific manner. The strongest influence was observed for the mianserin-induced expression of an isoform with intron retention. The drug-activated expression of novel alternative Dclk1 isoforms was validated using qPCR. The drug-regulated isoform contains genetic variants of DCLK1 that have been previously associated with schizophrenia and hyperactivity disorder in humans. We identified a short peptide that might originate from the novel DCLK1 protein product. Moreover, protein domains encoded by the regulated variant indicate their potential involvement in the negative regulation of the canonical DCLK1 protein. Conclusions In summary, we identified novel isoforms of the neuroplasticity-related gene Dclk1 that are expressed in the brain in response to psychotropic drug treatments

The role of glucagon-like peptide 1-receptor gene in type 2 diabetes

WSTĘP. Celem badania było poszukiwanie związku między polimorfizmami Gly168Ser i Leu260Phe genu receptora glukagonopodobnego peptydu-1 z cukrzycą typu 2 w populacji polskiej. MATERIAŁ I METODY. Analizowano materiał genetyczny 462 chorych na cukrzycę typu 2 i 428 zdrowych ochotników. Genotypowanie polimorfizmów wykonywano, namnażając odpowiednie fragmenty DNA za pomocą reakcji łańcuchowej polimerazy, tnąc namnożone fragmenty enzymami restrykcyjnymi i uwidaczniając produkty cięcia na żelu agarozowym z dodatkiem bromku etydyny. Analiza statystyczna obejmowała test c2 dla zbadania zależności genotypów z chorobą i regresję logistyczną dla zbadania zależności haplotypów z chorobą. WYNIKI. Częstość homozygot Ser/Ser była znamiennie wyższa w grupie chorych na cukrzycę (15,7%) niż w grupie kontrolnej (9,8%), p = 0,03. Iloraz szans rozwoju cukrzycy u tych pacjentów wskazywał na niemal 2-krotnie wyższe ryzyko niż u pacjentów niebędących homozygotami Ser/Ser. Polimorfizm w pozycji 260 oraz haplotypy utworzone przez dwa badane polimorfizmy nie były związane z występowaniem cukrzycy typu 2. WNIOSKI. Wyniki badania sugerują, że polimorfizm Gly168Ser jest potencjalnym czynnikiem ryzyka cukrzycy typu 2 w populacji polskiej. Obserwacja ta wymaga potwierdzenia w innych grupach etnicznych.INTRODUCTION. The aim of the study was to search for the association between Gly168Ser and Leu260Phe amino acid variants of the glucagon-like peptide 1 receptor gene and type 2 diabetes in a Polish population. METHODS. 462 patients with type 2 diabetes and 428 healthy volunteers were genotyped by restriction fragments length polymorphism method after amplification of examined genome fragment by polymerase chain reaction technique. The digestion products were separated and visualized by electrophoresis on agarose gel containing ethidium bromide. Statistical analysis involved chi-square test for genotype-phenotype association and logistic regression for association of phenotype with haplotypes. RESULTS. Ser/Ser homozygotes frequency in diabetic patients group was significantly higher than in control group (15.7% vs. 9.8%, p = 0,03). Odds ratio of having type 2 diabetes in Ser/Ser carriers group versus other genotype carriers showed almost two fold risk increase associated with this genotype. Polymorphism in 260 amino acid position and haplotypes of the analyzed polymorphisms were not associated with type 2 diabetes. CONCLUSIONS. The results of the study suggest that polymorphism Gly168Ser may be potentially a risk factor of the type 2 diabetes in Polish population. This observation should be evaluated in other ethnic groups

The role of glucagon-like peptide 1-receptor gene in type 2 diabetes

WSTĘP. Celem badania było poszukiwanie związku między polimorfizmami Gly168Ser i Leu260Phe genu receptora glukagonopodobnego peptydu-1 z cukrzycą typu 2 w populacji polskiej. MATERIAŁ I METODY. Analizowano materiał genetyczny 462 chorych na cukrzycę typu 2 i 428 zdrowych ochotników. Genotypowanie polimorfizmów wykonywano, namnażając odpowiednie fragmenty DNA za pomocą reakcji łańcuchowej polimerazy, tnąc namnożone fragmenty enzymami restrykcyjnymi i uwidaczniając produkty cięcia na żelu agarozowym z dodatkiem bromku etydyny. Analiza statystyczna obejmowała test χ2 dla zbadania zależności genotypów z chorobą i regresję logistyczną dla zbadania zależności haplotypów z chorobą. WYNIKI. Częstość homozygot Ser/Ser była znamiennie wyższa w grupie chorych na cukrzycę (15,7%) niż w grupie kontrolnej (9,8%), p = 0,03. Iloraz szans rozwoju cukrzycy u tych pacjentów wskazywał na niemal 2-krotnie wyższe ryzyko niż u pacjentów niebędących homozygotami Ser/Ser. Polimorfizm w popozycji 260 oraz haplotypy utworzone przez dwa badane polimorfizmy nie były związane z występowaniem cukrzycy typu 2. WNIOSKI. Wyniki badania sugerują, że polimorfizm Gly168Ser jest potencjalnym czynnikiem ryzyka cukrzycy typu 2 w populacji polskiej. Obserwacja ta wymaga potwierdzenia w innych grupach etnicznych.INTRODUCTION. The aim of the study was to search for the association between Gly168Ser and Leu260Phe amino acid variants of the glucagon-like peptide 1 receptor gene and type 2 diabetes in a Polish population. METHODS. 462 patients with type 2 diabetes and 428 healthy volunteers were genotyped by restriction fragments length polymorphism method after amplification of examined genome fragment by polymerase chain reaction technique. The digestion products were separated and visualized by electrophoresis on agarose gel containing ethidium bromide. Statistical analysis involved chi-square test for genotype-phenotype association and logistic regression for association of phenotype with haplotypes. RESULTS. Ser/Ser homozygotes frequency in diabetic patients group was significantly higher than in control group (15.7% vs. 9.8%, p = 0,03). Odds ratio of having type 2 diabetes in Ser/Ser carriers group versus other genotype carriers showed almost two fold risk increase associated with this genotype. Polymorphism in 260 amino acid position and haplotypes of the analyzed polymorphisms were not associated with type 2 diabetes. CONCLUSIONS. The results of the study suggest that polymorphism Gly168Ser may be potentially a risk factor of the type 2 diabetes in Polish population. This observation should be evaluated in other ethnic groups

Circularity measures - overview, properties and applications

Miarą kolistości jest funkcja, która kształtom przypisuje pewną liczbę wskazującą na ich stopień podobieństwa do koła. W literaturze dostępnych jest wiele prac definiujących różne miary kolistości. Niniejsza praca stanowi próbę zebrania znanych miar kolistości ich opisanie, zbadanie własności oraz ocenę praktycznego wykorzystania.A measure of circularity is a function that assigns a number to a shape. The number indicate degree of similarity to a circle. There are many available papers that define different measures of circularity. This paper is an attempt to collect known measures of circularity, to describe them, to examine their properties and to evaluate their practical application

Quaternions and their properties

Praca przedstawia podstawowe zagadnienia związane z ciałem kwaternionów. W pierwszej części zostały zaprezentowane podstawowe pojęcia i twierdzenia niezbędne do formalnego zdefiniowania ciała kwaternionów. W drugiej części zostały omówione inne sposoby reprezentacji kwaternionów, ich własności oraz wykorzystanie w obrotach w przestrzeni trójwymiarowej. Praca kończy się wspomnieniem o niektórych zastosowaniach kwaternionów w praktyce.The thesis introduces elementary issues in reference to the quaternions. The main part presents basic definitions and theorems needed to define the skew field of the quaternions formally. The second part discusses other representations of the quaternions, their properties and use in spatial rotations. In the summary several applications of quaternions were presented

Impact of the DRD2 Polymorphisms on the Effectiveness of the Training Program

Dopamine receptor D2 gene (DRD2) polymorphisms have been associated with cognitive abilities, obesity, addictions, and physical-activity-related behaviors, which may underlie differences in the effectiveness of training programs. What is not yet clear is the impact of DRD2 polymorphisms on the effectiveness of exercise programs. Thus, the aim of this study was to investigate the association between the DRD2 polymorphic sites (rs1076560, rs12364283, rs1799732, rs1800497, and rs1800498) and the body’s response to regular physical activity. We studied genotypes and haplotypes distribution in a group of 165 females measured for body mass and body composition measurements, lipid profile, and glucose levels before and after realization of a 12-week training program. When tested individually, statistical analyses revealed one significant genotype by training interaction under the general model (for the basal metabolic rate, BMR, p = 0.033). Carriers of the rs1076560 CC genotype exhibited a decrease in BMR in response to training (p = 0.006). Haplotype analyses also showed that (i) the CACCC and CACTT haplotypes were associated with a post-training decrease in glucose level (β = −4.11, p = 0.032; β = −6.86, p = 0.020, respectively); (ii) the CGCCT with an increase in BMR (β = 0.65, p = 0.003) and fat free mass (FFM, β = 1.20, p = 0.009); (iii) the CA-CT with a decrease in low-density lipoprotein cholesterol (LDL, β = −17.26, p = 0.046). These results provide some evidence that the DRD2 polymorphisms may play a role in post-training changes in lipid and carbohydrate metabolism, and, as a consequence, in the effectiveness of training programs

MicroRNA Let-7e in the Mouse Prefrontal Cortex Differentiates Restraint-Stress-Resilient Genotypes from Susceptible Genotype

Three strains of mice with various susceptibilities to restraint stress (RS), i.e., mice with a knocked out norepinephrine transporter gene (NET-KO), SWR/J and C57BL/6J (WT) mice were shown to serve as a good model to study the molecular mechanisms underlying different stress-coping strategies. We identified 14 miRNAs that were altered by RS in the PFC of these mice in a genotype-dependent manner, where the most interesting was let-7e. Further in silico analysis of its potential targets allowed us to identify five mRNAs (Bcl2l11, Foxo1, Pik3r1, Gab1 and Map2k4), and their level alterations were experimentally confirmed. A next-generation sequencing (NGS) approach, which was employed to find transcripts differentially expressed in the PFC of NET-KO and WT mice, showed that, among others, two additional mRNAs were regulated by mmu-let-7e, i.e., mRNAs that encode Kmt2d and Inf2. Since an increase in Bcl2l11 and Pik3r1 mRNAs upon RS in the PFC of WT mice resulted from the decrease in mmu-let-7e and mmu-miR-484 regulations, we postulated that MAPK, FoxO and PI3K-Akt signaling pathways were associated with stress resilience, although via different, genotype-dependent regulation of various mRNAs by let-7e and miR-484. However, a higher level of Kmt2d mRNA (regulated by let-7e) that was found with NGS analysis in the PFC of NET-KO mice indicated that histone methylation was also important for stress resilience

Ablation of the dystrophin Dp71f alternative C-terminal variant increases sarcoma tumour cell aggressiveness

Alterations in Dp71 expression, the most ubiquitous dystrophin isoform, have been associated with patient survival across tumours. Intriguingly, in certain malignancies, Dp71 acts as a tumour suppressor, while manifesting oncogenic properties in others. This diversity could be explained by the expression of two Dp71 splice variants encoding proteins with distinct C-termini, each with specific properties. Expression of these variants has impeded the exploration of their unique roles. Using CRISPR/Cas9, we ablated the Dp71f variant with the alternative C-terminus in a sarcoma cell line not expressing the canonical C-terminal variant, and conducted molecular (RNAseq) and functional characterisation of the knockout cells. Dp71f ablation induced major transcriptomic alterations, particularly affecting the expression of genes involved in calcium signalling and ECM-receptor interaction pathways. The genome-scale metabolic analysis identified significant downregulation of glucose transport via membrane vesicle reaction (GLCter) and downregulated glycolysis/gluconeogenesis pathway. Functionally, these molecular changes corresponded with, increased calcium responses, cell adhesion, proliferation, survival under serum starvation and chemotherapeutic resistance. Knockout cells showed reduced GLUT1 protein expression, survival without attachment and their migration and invasion in vitro and in vivo were unaltered, despite increased matrix metalloproteinases release. Our findings emphasise the importance of alternative splicing of dystrophin transcripts and underscore the role of the Dp71f variant, which appears to govern distinct cellular processes frequently dysregulated in tumour cells. The loss of this regulatory mechanism promotes sarcoma cell survival and treatment resistance. Thus, Dp71f is a target for future investigations exploring the intricate functions of specific DMD transcripts in physiology and across malignancies.</p

Ablation of the dystrophin Dp71f alternative C-terminal variant increases sarcoma tumour cell aggressiveness

Alterations in Dp71 expression, the most ubiquitous dystrophin isoform, have been associated with patient survival across tumours. Intriguingly, in certain malignancies, Dp71 acts as a tumour suppressor, while manifesting oncogenic properties in others. This diversity could be explained by the expression of two Dp71 splice variants encoding proteins with distinct C-termini, each with specific properties. Expression of these variants has impeded the exploration of their unique roles. Using CRISPR/Cas9, we ablated the Dp71f variant with the alternative C-terminus in a sarcoma cell line not expressing the canonical C-terminal variant, and conducted molecular (RNAseq) and functional characterisation of the knockout cells. Dp71f ablation induced major transcriptomic alterations, particularly affecting the expression of genes involved in calcium signalling and ECM-receptor interaction pathways. The genome-scale metabolic analysis identified significant downregulation of glucose transport via membrane vesicle reaction (GLCter) and downregulated glycolysis/gluconeogenesis pathway. Functionally, these molecular changes corresponded with, increased calcium responses, cell adhesion, proliferation, survival under serum starvation and chemotherapeutic resistance. Knockout cells showed reduced GLUT1 protein expression, survival without attachment and their migration and invasion in vitro and in vivo were unaltered, despite increased matrix metalloproteinases release. Our findings emphasise the importance of alternative splicing of dystrophin transcripts and underscore the role of the Dp71f variant, which appears to govern distinct cellular processes frequently dysregulated in tumour cells. The loss of this regulatory mechanism promotes sarcoma cell survival and treatment resistance. Thus, Dp71f is a target for future investigations exploring the intricate functions of specific DMD transcripts in physiology and across malignancies.</p