SGLT2 Inhibitors May Restore Endothelial Barrier Interrupted by 25-Hydroxycholesterol.

SGLT2 (Sodium-glucose Cotransporter-2) inhibitors are newer glucose-lowering drugs with many cardiovascular benefits that are not fully understood yet. Endothelial integrity plays a key role in cardiovascular homeostasis. 25-hydroxycholesterol (25-OHC), which is a proatherogenic stimuli that impairs endothelial barrier functions. VE-cadherin is an endothelial-specific protein crucial in maintaining endothelial integrity. The aim of this study was to assess the influence of SGLT2i on the integrity of endothelial cells interrupted by 25-OHC. We also aimed to evaluate whether this effect is associated with changes in the levels of VE-cadherin. We pre-incubated HUVECs with 10 µg/mL of 25-hydroxycholesterol (25-OHC) for 4 h and then removed it and incubated endothelial cells with 1 µM of empagliflozin, 1 µM canagliflozin, or 1 µM dapagliflozin for 24 h. The control group included HUVECs cultured with the medium or with 25-OHC 10 µg/mL. The integrity of endothelial cells was measured by the RTCA-DP xCELLigence system, and VE-cadherin was assessed in confocal microscopy. Our results show that SGLT2 inhibitors significantly increase endothelial integrity in comparison to medium controls, and they improve endothelial cell integrity interrupted by 25-OHC. This effect is associated with significant improvements in VE-cadherin levels. SGLT2i: empagliflozin, canagliflozin, and dapagliflozin have a beneficial effect on the endothelial cell integrity and VE-cadherin levels reduced by 25-OHC.

sSfS: Segmented Shape from Silhouette Reconstruction of the Human Body.

Three-dimensional (3D) shape estimation of the human body has a growing number of applications in medicine, anthropometry, special effects, and many other fields. Therefore, the demand for the high-quality acquisition of a complete and accurate body model is increasing. In this paper, a short survey of current state-of-the-art solutions is provided. One of the most commonly used approaches is the Shape-from-Silhouette (SfS) method. It is capable of the reconstruction of dynamic and challenging-to-capture objects. This paper proposes a novel approach that extends the conventional voxel-based SfS method with silhouette segmentation-segmented Shape from Silhouette (sSfS). It allows the 3D reconstruction of body segments separately, which provides significantly better human body shape estimation results, especially in concave areas. For validation, a dataset representing the human body in 20 complex poses was created and assessed based on the quality metrics in reference to the ground-truth photogrammetric reconstruction. It appeared that the number of invalid reconstruction voxels for the sSfS method was 1.7 times lower than for the state-of-the-art SfS approach. The root-mean-square (RMS) error of the distance to the reference surface was also 1.22 times lower.

Novel N7-Arylmethyl Substituted Dinucleotide mRNA 5' cap Analogs: Synthesis and Evaluation as Modulators of Translation.

Dinucleotide analogs of the messenger RNA cap (m7GpppN) are useful research tools and have potential applications as translational inhibitors or reagents for modification of in vitro transcribed mRNAs. It has been previously reported that replacing the methyl group at the N7-position with benzyl (Bn) produces a dinucleotide cap with superior properties. Here, we followed up on this finding by synthesizing 17 novel Bn7GpppG analogs and determining their structure-activity relationship regarding translation and translational inhibition. The compounds were prepared in two steps, including selective N7-alkylation of guanosine 5'-monophosphate by arylmethyl bromide followed by coupling with imidazole-activated GDP, with total yields varying from 22% to 62%. The compounds were then evaluated by determining their affinity for eukaryotic translation initiation factor 4E (eIF4E), testing their susceptibility to decapping pyrophosphatase, DcpS-which is most likely the major cellular enzyme targeting this type of compound-and determining their translation inhibitory properties in vitro. We also synthesized mRNAs capped with the evaluated compounds and tested their translational properties in A549 cells. Our studies identified N7-(4-halogenbenzyl) substituents as promising modifications in the contexts of either mRNA translation or translational inhibition. Finally, to gain more insight into the consequences at the molecular level of N7-benzylation of the mRNA cap, we determined the crystal structures of three compounds with eIF4E.

Cellular delivery of dinucleotides by conjugation with small molecules: targeting translation initiation for anticancer applications.

Targeting cap-dependent translation initiation is one of the experimental approaches that could lead to the development of novel anti-cancer therapies. Synthetic dinucleoside 5',5'-triphosphates cap analogs are potent antagonists of eukaryotic translation initiation factor 4E (eIF4E) in vitro and could counteract elevated levels of eIF4E in cancer cells; however, transformation of these compounds into therapeutic agents remains challenging - they do not easily penetrate into cells and are susceptible to enzymatic cleavage. Here, we tested the potential of several small molecule ligands - folic acid, biotin, glucose, and cholesterol - to deliver both hydrolyzable and cleavage-resistant cap analogs into cells. A broad structure-activity relationship (SAR) study using model fluorescent probes and cap-ligand conjugates showed that cholesterol greatly facilitates uptake of cap analogs without disturbing the interactions with eIF4E. The most potent cholesterol conjugate identified showed apoptosis-mediated cytotoxicity towards cancer cells.

Tricks and threats of RNA viruses - towards understanding the fate of viral RNA.

Human innate cellular defence pathways have evolved to sense and eliminate pathogens, of which, viruses are considered one of the most dangerous. Their relatively simple structure makes the identification of viral invasion a difficult task for cells. In the course of evolution, viral nucleic acids have become one of the strongest and most reliable early identifiers of infection. When considering RNA virus recognition, RNA sensing is the central mechanism in human innate immunity, and effectiveness of this sensing is crucial for triggering an appropriate antiviral response. Although human cells are armed with a variety of highly specialized receptors designed to respond only to pathogenic viral RNA, RNA viruses have developed an array of mechanisms to avoid being recognized by human interferon-mediated cellular defence systems. The repertoire of viral evasion strategies is extremely wide, ranging from masking pathogenic RNA through end modification, to utilizing sophisticated techniques to deceive host cellular RNA degrading enzymes, and hijacking the most basic metabolic pathways in host cells. In this review, we aim to dissect human RNA sensing mechanisms crucial for antiviral immune defences, as well as the strategies adopted by RNA viruses to avoid detection and degradation by host cells. We believe that understanding the fate of viral RNA upon infection, and detailing the molecular mechanisms behind virus-host interactions, may be helpful for developing more effective antiviral strategies; which are urgently needed to prevent the far-reaching consequences of widespread, highly pathogenic viral infections.

Xpo7 negatively regulates Hedgehog signaling by exporting Gli2 from the nucleus.

Dynamic bidirectional transport between the nucleus and the cytoplasm is critical for the regulation of many transcription factors, whose levels inside the nucleus must be tightly controlled. Efficient shuttling across the nuclear membrane is especially crucial with regard to the Hedgehog (Hh) pathway, where the transcriptional signal depends on the fine balance between the amounts of Gli protein activator and repressor forms in the nucleus. The nuclear export machinery prevents the unchecked nuclear accumulation of Gli proteins, but the mechanistic insight into this process is limited. We show that the atypical exportin Xpo7 functions as a major nuclear export receptor that actively excludes Gli2 from the nucleus and controls the outcome of Hh signaling. We show that Xpo7 interacts with several domains of Gli2 and that this interaction is modulated by SuFu, a key negative regulator of Hh signaling. Our data pave the way for a more complete understanding of the nuclear shuttling of Gli proteins and the regulation of their transcriptional activity.

Gli Proteins: Regulation in Development and Cancer.

Gli proteins are transcriptional effectors of the Hedgehog signaling pathway. They play key roles in the development of many organs and tissues, and are deregulated in birth defects and cancer. We review the molecular mechanisms of Gli protein regulation in mammals, with special emphasis on posttranslational modifications and intracellular transport. We also discuss how Gli proteins interact with co-activators and co-repressors to fine-tune the expression of Hedgehog target genes. Finally, we provide an overview of the regulation of developmental processes and tissue regeneration by Gli proteins and discuss how these proteins are involved in cancer progression, both through canonical regulation via the Hedgehog pathway and through cross-talk with other signaling pathways.

The dissolution of temporal distance increases risk-taking: experimental evidence.

Earlier research shows that delaying the realization of a lottery (temporal distance) increases risk tolerance. Presumably, this happens because temporal distance protects one from encountering the negative emotions produced when facing risk. However, no study has tested whether people that made a choice in the presence of temporal distance would actually change their decision later on (in the absence of temporal distance), towards the safer choice. To test this, 137 participants were subject to actual temporal distance, consisting of a four-week waiting period. To explore how each participant behaved "in the heat of the moment" (in the absence of temporal distance), we assessed their electrodermal activity and analysed self-description measures of susceptibility to affect. Participants had to choose between 40 lottery pairs (they could win up to the equivalent of about $400 US; the expected payout for each participant was about $12). Results showed that, contrary to expectations, participants tended to choose riskier lotteries after the waiting period. The results of an additional experiment suggest that this is not the result of prior exposure to the same set of lotteries, however, interestingly, an exploratory analysis showed that the main effect was driven by the behaviour of male participants. We discuss possible explanations for our surprising main finding and its implications for studies on temporal distance.

Nucleotide Excision Repair Capacity and XPC and XPD Gene Polymorphism Modulate Colorectal Cancer Risk.

BACKGROUND: Colorectal cancer (CRC) is leading malignant tumors to occur mainly in industrialized countries, where it exhibits one of the highest mortality rates. Up to 80% of all CRCs characterize a chromosomal instability (CIN) phenotype. The main challenge faced by scientist is to reveal the mechanism of CIN development. An often proposed model is defects in DNA repair in terms of efficiency and genetic variations that modulate the response to stimuli from the environment. The objectives of this research were to determine whether nucleotide excision repair (NER) might affect CRC risk. MATERIALS AND METHODS: The first part of the study concerns NER efficiency. In the second part we selected 2 common single nucleotide polymorphisms within genes involved in NER (Xeroderma pigmentosum group C (XPC) Lys939Gln, Xeroderma pigmentosum group D (XPD) Lys751Gln) to determine the relation between them and CRC risk. The restriction fragment length polymorphism-polymerase chain reaction method was used for genotyping of 221 CRC patients vs. 270 cancer-free individuals. The isotopic labeling in vitro assay was used to evaluate NER capacity in lymphocytes and tissue protein extracts. RESULTS: We observed a significantly decreased level of NER capacity (P = .025) in lymphocytes delivered from CRC patients compared with healthy ones. Polymorphism screening points to higher CRC risk for the Gln939Gln genotype (P = .02) and Gln allele (P = .002) of the XPC gene. CONCLUSION: Taken together, our findings suggest a potential role for NER in CRC.

Novel tetrahydroacridine and cyclopentaquinoline derivatives with fluorobenzoic acid moiety induce cell cycle arrest and apoptosis in lung cancer cells by activation of DNA damage signaling.

Lung cancer is still the leading cause of cancer-related death worldwide, indicating a necessity to develop more effective therapy. Acridine derivatives are potential anticancer agents due to their ability to intercalate DNA as well as inhibit enzymes involved in replication and transcription. Recently, we have evaluated anticancer activity of 32 novel acridine-based compounds. We found that the most effective were tetrahydroacridine and cyclopentaquinoline derivatives with fluorobenzoic acid containing eight and nine carbon atoms in the aliphatic chain. The aim of this study was to determine the molecular mechanisms of compounds-induced cell cycle arrest and apoptosis in human lung adenocarcinoma cells. All compounds activated Ataxia telangiectasia mutated kinase and phosphorylated histone H2A.X at Ser139 indicating DNA damage. Treatment of cells with the compounds increased phosphorylation and accumulation of p53 that regulate cell cycle as well as apoptosis. All compounds induced G0/1 cell cycle arrest by phosphorylation of cyclin-dependent kinase 2 at Tyr15 resulting in attenuation of the kinase activity. In addition, cyclopentaquinoline derivatives induced expression of cyclin-dependent kinase 2 inhibitor, p21; however, tetrahydroacridine derivatives had no significant effect on p21. Moreover, all compounds decreased the mitochondrial membrane potential accompanied by increased expression of Bax and down-regulation of Bcl-2, suggesting activation of the mitochondrial pathway. All compounds also significantly attenuated the migration rates of lung cancer cells. Collectively, our findings suggest a central role of activation of DNA damage signaling in response to new acridine derivatives treatment to induce cell cycle arrest and apoptosis in cancer cells and provide support for their further development as potential drug candidates.

Potential of redox therapies in neurodegenerative disorders.

Recently significant advances have been made to understand the pathophysiological mechanisms of neurodegenerative disorders to provide real therapeutic benefits. There is evidence that persistent inflammation and oxidative stress are the crucial factors of ongoing cell damage in neurodegenerative complex etiology. The variety of reactive oxygen and nitrogen species are the cause of both axonal and neuronal destruction, which is pathological hallmark of neurodegeneration. Therefore, the reduction of oxidative stress is currently one of the main neuroprotective strategies. The World Health Organization (WHO) estimates that, by 2040, neurodegenerative diseases will be the main cause of death in industrialized countries ahead of the cancers. The redox therapeutic approch can target: degnerative component, inflammatory/autoimmune component and neurodegenerative component. Redox therapy should not be applied uniformly, and must be develop to target specific mechanisms. This review focus on the main antitoxidative therapies that are used in many countries as a supplements or even as a standart treatment. Aditionally, clinical synmptoms of most common neurodegenerative disordes and centralnervous system structures involved in oxidative/nitrosative stress are showed.

The role of base excision repair in pathogenesis of breast cancer in the Polish population.

Breast cancer (BC) is leading type of cancer among group of women, which determines almost 23% of invasive cancers. It has been reported repeatedly that the level of oxidative stress is higher for BC in comparison to cancer-free woman. The goal of the present study was to evaluate the role of base excision repair (BER) pathway in the development of BC. One-hundred seventy-one women with confirmed BC and 222 healthy controls were enrolled in presented study. The level of oxidative DNA damage and the kinetic of their repair were analyzed by the modified alkaline comet assay. The efficiency of BER pathway was evaluated by BER assay. The presence of the 326Cys/Cys genotype and 326Cys allele of OGG1 gene and the 324His/His of MUTYH gene are associated with increased risk of BC development. Moreover, correlation between clinical parameter with selected genes has shown increased risk of BC progression. The survival analysis has shown a significant lower DFS for individuals with the 762Ala/Ala genotype compared to 762Val/Vla carriers and the 762Val/Ala genotype in relation to concomitant chemotherapy and radiotherapy. In subgroup of patients with alone chemotherapy and alone radiotherapy, the 762Val/Val genotype was significantly associated with lower overall survival. Furthermore, we also elevated the level of basal and oxidative DNA damage in a group of patients with BC in relation to healthy controls. We also observed the difference in effectiveness of DNA damage repair. The results of present studies suggested the important role of BER pathway in BC development. © 2015 Wiley Periodicals, Inc.

You Cannot be Partially Pregnant: A Comparison of Divisible and Nondivisible Outcomes in Delay and Probability Discounting Studies.

Research by The Psychological Record, 64(3), 433-440. doi:10.1007/s40732-014-0052-9, (2014) demonstrated the novel finding that the magnitude effect for medical outcomes does not reverse across delay and probability discounting as it does for monetary outcomes. We suggest that a possible reason for the lack of a reverse magnitude effect in nonmonetary outcomes is incomparable divisibility of discounted alternatives. To test whether the lack of a reverse magnitude effect in probability discounting of medical outcomes is due to incomparable divisibility of treatment effects, 4 studies were conducted. In the replication study, the effect observed by The Psychological Record, 64(3), 433-440. doi:10.1007/s40732-014-0052-9, (2014) was marginally not significant, although it was directionally consistent with their prediction of steeper discounting of small medical outcomes (as compared to large, defined as brain cancer) both in time and probability discounting. Our manipulation by substituting a divisible outcome (body paralysis) for an indivisible one (brain cancer) did not, however, bring expected results. We discuss the explanations and possible implications of introduced division for divisible and nondivisible medical outcomes.

Information Use Differences in Hot and Cold Risk Processing: When Does Information About Probability Count in the Columbia Card Task?

OBJECTIVE: This paper aims to provide insight into information processing differences between hot and cold risk taking decision tasks within a single domain. Decision theory defines risky situations using at least three parameters: outcome one (often a gain) with its probability and outcome two (often a loss) with a complementary probability. Although a rational agent should consider all of the parameters, s/he could potentially narrow their focus to only some of them, particularly when explicit Type 2 processes do not have the resources to override implicit Type 1 processes. Here we investigate differences in risky situation parameters' influence on hot and cold decisions. Although previous studies show lower information use in hot than in cold processes, they do not provide decision weight changes and therefore do not explain whether this difference results from worse concentration on each parameter of a risky situation (probability, gain amount, and loss amount) or from ignoring some parameters. METHODS: Two studies were conducted, with participants performing the Columbia Card Task (CCT) in either its Cold or Hot version. In the first study, participants also performed the Cognitive Reflection Test (CRT) to monitor their ability to override Type 1 processing cues (implicit processes) with Type 2 explicit processes. Because hypothesis testing required comparison of the relative importance of risky situation decision weights (gain, loss, probability), we developed a novel way of measuring information use in the CCT by employing a conjoint analysis methodology. RESULTS: Across the two studies, results indicated that in the CCT Cold condition decision makers concentrate on each information type (gain, loss, probability), but in the CCT Hot condition they concentrate mostly on a single parameter: probability of gain/loss. We also show that an individual's CRT score correlates with information use propensity in cold but not hot tasks. Thus, the affective dimension of hot tasks inhibits correct information processing, probably because it is difficult to engage Type 2 processes in such circumstances. Individuals' Type 2 processing abilities (measured by the CRT) assist greater use of information in cold tasks but do not help in hot tasks.

Confounding dynamic risk taking propensity with a momentum prognostic strategy: the case of the Columbia Card Task (CCT).

Figner et al. (2009) developed the Columbia Card Task (CCT) to measure risk-taking attitudes. This tool consists of two versions: in the COLD version the decision maker needs to state in advance how many cards (out of 32) they want to turn over (so called static risk taking), in the HOT version they have the possibility of turning over all 32 cards one-by-one until they decide to finish (dynamic risk taking). We argue that the HOT version confounds an individual's willingness to accept risk with their beliefs in trend continuation vs. trend reversal in a prognostic task. In two experimental studies we show that people believing in trend continuation (momentum subjects) turn over more cards than those believing in trend reversal (contrarians) in the HOT version of the task. However, this is not the case in the COLD version. Thus, we provide evidence that, when considered as a dynamic risk propensity measure, the number of turned over cards in the HOT version of the CCT is a contaminated measure and reflects two phenomena: (1) risk preference and (2) the decision-maker's belief in trend continuation. We speculate that other dynamic risk taking measures can also be biased by a momentum strategy.

Unfolded Protein Response and PERK Kinase as a New Therapeutic Target in the Pathogenesis of Alzheimer's Disease.

Recent evidence suggests that the development of Alzheimer's disease (AD) and related cognitive loss is due to mutations in the Amyloid Precursor Protein (APP) gene on chromosome 21 and increased activation of eukaryotic translation initiation factor-2α (eIF2α) phosphorylation. The high level of misfolded and unfolded proteins loading in Endoplasmic Reticulum (ER) lumen triggers ER stress and as a result Unfolded Protein Response (UPR) pathways are activated. Stress-dependent activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) leads to the significant elevation of phospho-eIF2α. That attenuates general translation and, on the other hand, promotes the preferential synthesis of Activating Transcription Factor 4 (ATF4) and secretase ß (BACE1) - a pivotal enzyme responsible for the initiation of the amyloidogenic pathway resulting in the generation of the amyloid ß (Aß) variant with high ability to form toxic senile plaques in AD brains. Moreover, excessive, long-term stress conditions may contribute to inducing neuronal death by apoptosis as a result of the overactivated expression of pro-apoptotic proteins via ATF4. These findings allow to infer that dysregulated translation, increased expression of BACE1 and ATF4, as a result of eIF2α phosphorylation, may be a major contributor to structural and functional neuronal loss resulting in memory impairment. Thus, blocking PERK-dependent eIF2α phosphorylation through specific, small-molecule PERK branch inhibitors seems to be a potential treatment strategy for AD individuals. That may contribute to the restoration of global translation rates and reduction of expression of ATF4 and BACE1. Hence, the treatment strategy can block accelerated ß -amyloidogenesis by reduction in APP cleaving via the BACE1-dependent amyloidogenic pathway.

Altered Expression Levels of MMP1, MMP9, MMP12, TIMP1, and IL-1ß as a Risk Factor for the Elevated IOP and Optic Nerve Head Damage in the Primary Open-Angle Glaucoma Patients.

The aim of presented work was to analyze the impact of particular polymorphic changes in the promoter regions of the -1607 1G/2G MMP1, -1562 C/T MMP9, -82 A/G MMP12, -511 C/T IL-1ß, and 372 T/C TIMP1 genes on their expression level in POAG patients. Blood and aqueous humor samples acquired from 50 patients with POAG and 50 control subjects were used for QPCR and protein levels analysis by ELISA. In vivo promoter activity assays were carried on HTM cells using dual luciferase assay. All studied subjects underwent ophthalmic examination, including BCVA, intraocular pressure, slit-lamp examination, gonioscopy, HRT, and OCT scans. Patients with POAG are characterized by an increased mRNA expression of MMP1, MMP9, MMP12, and IL-1ß genes as compared to the control group (P < 0.001). Aqueous humor acquired from patients with POAG displayed increased protein expression of MMP1, MMP9, MMP12, and IL-1ß compared to the control group (P < 0.001). Allele -1607 1G of MMP1 gene possesses only 42,91% of the -1607 2G allele transcriptional activity and allele -1562 C of MMP9 gene possesses only 21,86% of the -1562 T allele. Increased expression levels of metalloproteinases can be considered as a risk factor for the development of POAG.

The role of base excision repair in the development of primary open angle glaucoma in the Polish population.

Glaucoma is a leading cause of irreversible blindness in developing countries. Previous data have shown that progressive loss of human TM cells may be connected with chronic exposure to oxidative stress. This hypothesis may suggest a role of the base excision repair (BER) pathway of oxidative DNA damage in primary open angle glaucoma (POAG) patients. The aim of our study was to evaluate an association of BER gene polymorphism with a risk of POAG. Moreover, an association of clinical parameters was examined including cup disk ratio (c/d), rim area (RA) and retinal nerve fiber layer (RNFL) with glaucoma progression according to BER gene polymorphisms. Our research included 412 patients with POAG and 454 healthy controls. Gene polymorphisms were analyzed by PCR-RFLP. Heidelberg Retinal Tomography (HRT) clinical parameters were also analyzed. The 399 Arg/Gln genotype of the XRCC1 gene (OR 1.38; 95% CI 1.02-1.89 p = 0.03) was associated with an increased risk of POAG occurrence. It was indicated that the 399 Gln/Gln XRCC1 genotype might increase the risk of POAG progression according to the c/d ratio (OR 1.67; 95% CI 1.07-2.61 P = 0.02) clinical parameter. Moreover, the association of VF factor with 148 Asp/Glu of APE1 genotype distribution and POAG progression (OR 2.25; 95% CI 1.30-3.89) was also found. Additionally, the analysis of the 324 Gln/His MUTYH polymorphism gene distribution in the patient group according to RNFL factor showed that it might decrease the progression of POAG (OR 0.47; 95% CI 0.30-0.82 P = 0.005). We suggest that the 399 Arg/Gln polymorphism of the XRCC1 gene may serve as a predictive risk factor of POAG.

Analysis of oxidative DNA damage and its repair in Polish patients with diabetes mellitus type 2: Role in pathogenesis of diabetic neuropathy.

PURPOSE: Distal symmetric polyneuropathy (DSPN) is common complication of type 2 diabetes (T2DM). In this work we investigated the role of oxidative damage in connection with particular polymorphisms of DNA repair genes and their repair capacity. MATERIAL/METHODS: Materials constitute the peripheral blood of patients with T2DM with and without DSPN and control subjects without disturbance of the carbohydrate fraction. The study of gene polymorphisms which products take part in base excision repair (BER) pathway: 726 Val/Ala adenosine diphosphate ribosyl transferase (ADPRT), 324 His/Glu MutYhomolog (MUTYH) and 148 Asp/Glu human apurinic/apyrimidinic endonuclease (APE) was carried out using restriction fragment length polymorphism polymerase chain reaction (PCR-RFLP) method. The study of DNA damage induced by hydrogen peroxide and the efficiency of their repair was carried out using comet assay. RESULTS: None of the 3 polymorphisms were associated with the risk of DSPN. However, in group of patients together with T2DM and T2DM/DSPN 726 Ala ADPRT allele was significantly susceptible to increased risk of T2DM (OR=1.59; 95% CI: 1.08-2.36). Investigation of DNA damage and repair revealed that T2DM patients have decreased ability to DNA repair. This capacity even drops down in the group of T2DM/DSPN patients compared to subjects with diabetes alone. ADPRT and APE polymorphisms were significantly associated with higher DNA damages (P<0.05) in heterozygous and mutant homozygous in correlation to homozygous wild type, but for MUTYH polymorphism relation was not confirmed. CONCLUSIONS: Pathogenesis of T2DM and development of DSPN may be related to oxidative stress connected with BER gene polymorphisms.

Introducing conjoint analysis method into delayed lotteries studies: its validity and time stability are higher than in adjusting.

The delayed lotteries are much more common in everyday life than are pure lotteries. Usually, we need to wait to find out the outcome of the risky decision (e.g., investing in a stock market, engaging in a relationship). However, most research has studied the time discounting and probability discounting in isolation using the methodologies designed specifically to track changes in one parameter. Most commonly used method is adjusting, but its reported validity and time stability in research on discounting are suboptimal. The goal of this study was to introduce the novel method for analyzing delayed lotteries-conjoint analysis-which hypothetically is more suitable for analyzing individual preferences in this area. A set of two studies compared the conjoint analysis with adjusting. The results suggest that individual parameters of discounting strength estimated with conjoint have higher predictive value (Study 1 and 2), and they are more stable over time (Study 2) compared to adjusting. We discuss these findings, despite the exploratory character of reported studies, by suggesting that future research on delayed lotteries should be cross-validated using both methods.