Dr.Nod: computational framework for discovery of regulatory non-coding drivers in tissue-matched distal regulatory elements

The discovery of cancer driver mutations is a fundamental goal in cancer research. While many cancer driver mutations have been discovered in the protein-coding genome, research into potential cancer drivers in the non-coding regions showed limited success so far. Here, we present a novel comprehensive framework Dr.Nod for detection of non-coding cis-regulatory candidate driver mutations that are associated with dysregulated gene expression using tissue-matched enhancer-gene annotations. Applying the framework to data from over 1500 tumours across eight tissues revealed a 4.4-fold enrichment of candidate driver mutations in regulatory regions of known cancer driver genes. An overarching conclusion that emerges is that the non-coding driver mutations contribute to cancer by significantly altering transcription factor binding sites, leading to upregulation of tissue-matched oncogenes and down-regulation of tumour-suppressor genes. Interestingly, more than half of the detected cancer-promoting non-coding regulatory driver mutations are over 20 kb distant from the cancer-associated genes they regulate. Our results show the importance of tissue-matched enhancer-gene maps, functional impact of mutations, and complex background mutagenesis model for the prediction of non-coding regulatory drivers. In conclusion, our study demonstrates that non-coding mutations in enhancers play a previously underappreciated role in cancer and dysregulation of clinically relevant target genes

Characterization of the genetic determinants of context-specific DNA methylation in primary monocytes

To better understand inter-individual variation in sensitivity of DNA methylation (DNAm) to immune activity, we characterized effects of inflammatory stimuli on primary monocyte DNAm (n = 190). We find that monocyte DNAm is site-dependently sensitive to lipopolysaccharide (LPS), with LPS-induced demethylation occurring following hydroxymethylation. We identify 7,359 high-confidence immune-modulated CpGs (imCpGs) that differ in genomic localization and transcription factor usage according to whether they represent a gain or loss in DNAm. Demethylated imCpGs are profoundly enriched for enhancers and colocalize to genes enriched for disease associations, especially cancer. DNAm is age associated, and we find that 24-h LPS exposure triggers approximately 6 months of gain in epigenetic age, directly linking epigenetic aging with innate immune activity. By integrating LPS-induced changes in DNAm with genetic variation, we identify 234 imCpGs under local genetic control. Exploring shared causal loci between LPS-induced DNAm responses and human disease traits highlights examples of disease-associated loci that modulate imCpG formation

Expression of <i>Idh1</i>^R132H in the murine subventricular zone stem cell niche recapitulates features of early gliomagenesis

Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1(R132H) in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced α-ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased. Cells expressing SVZ markers infiltrated surrounding brain regions. SVZ cells also gave rise to proliferative subventricular nodules. DNA methylation was globally increased, while hydroxymethylation was decreased. Mutant SVZ cells overexpressed Wnt, cell-cycle and stem cell genes, and shared an expression signature with human gliomas. Idh1(R132H) mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis

The Schnitzler syndrome

The Schnitzler syndrome is a rare and underdiagnosed entity which is considered today as being a paradigm of an acquired/late onset auto-inflammatory disease. It associates a chronic urticarial skin rash, corresponding from the clinico-pathological viewpoint to a neutrophilic urticarial dermatosis, a monoclonal IgM component and at least 2 of the following signs: fever, joint and/or bone pain, enlarged lymph nodes, spleen and/or liver, increased ESR, increased neutrophil count, abnormal bone imaging findings. It is a chronic disease with only one known case of spontaneous remission. Except of the severe alteration of quality of life related mainly to the rash, fever and pain, complications include severe inflammatory anemia and AA amyloidosis. About 20% of patients will develop a lymphoproliferative disorder, mainly Waldenström disease and lymphoma, a percentage close to other patients with IgM MGUS. It was exceedingly difficult to treat patients with this syndrome until the IL-1 receptor antagonist anakinra became available. Anakinra allows a complete control of all signs within hours after the first injection, but patients need continuous treatment with daily injections

Meta-analysis of archived DNA microarrays identifies genes regulated by hypoxia and involved in a metastatic phenotype in cancer cells

<p>Abstract</p> <p>Background</p> <p>Metastasis is a major cancer-related cause of death. Recent studies have described metastasis pathways. However, the exact contribution of each pathway remains unclear. Another key feature of a tumor is the presence of hypoxic areas caused by a lack of oxygen at the center of the tumor. Hypoxia leads to the expression of pro-metastatic genes as well as the repression of anti-metastatic genes. As many Affymetrix datasets about metastasis and hypoxia are publicly available and not fully exploited, this study proposes to re-analyze these datasets to extract new information about the metastatic phenotype induced by hypoxia in different cancer cell lines.</p> <p>Methods</p> <p>Affymetrix datasets about metastasis and/or hypoxia were downloaded from GEO and ArrayExpress. AffyProbeMiner and GCRMA packages were used for pre-processing and the Window Welch <it>t </it>test was used for processing. Three approaches of meta-analysis were eventually used for the selection of genes of interest.</p> <p>Results</p> <p>Three complementary approaches were used, that eventually selected 183 genes of interest. Out of these 183 genes, 99, among which the well known <it>JUNB</it>, <it>FOS </it>and <it>TP63</it>, have already been described in the literature to be involved in cancer. Moreover, 39 genes of those, such as <it>SERPINE1 </it>and <it>MMP7</it>, are known to regulate metastasis. Twenty-one genes including <it>VEGFA </it>and <it>ID2 </it>have also been described to be involved in the response to hypoxia. Lastly, DAVID classified those 183 genes in 24 different pathways, among which 8 are directly related to cancer while 5 others are related to proliferation and cell motility. A negative control composed of 183 random genes failed to provide such results. Interestingly, 6 pathways retrieved by DAVID with the 183 genes of interest concern pathogen recognition and phagocytosis.</p> <p>Conclusion</p> <p>The proposed methodology was able to find genes actually known to be involved in cancer, metastasis and hypoxia and, thus, we propose that the other genes selected based on the same methodology are of prime interest in the metastatic phenotype induced by hypoxia.</p

E-consultation and the quest for inclusive governance in Nigeria

Inclusive governance through public consultation is fundamental to sustainable development as reiterated in the SDG16. Citizens’ consultation in the policy planning and determination enhances the quality of policy outcomes and help to build public trust in political institutions. Traditional institutions for public consultation are however, often limited thus, policy decisions are in most cases, at variance with public aspirations. The consequence is a growing public cynicism of governmental institutions. To address this democratic decline, governments across the world are now utilizing ICT tools to better consult with citizens in the public policy process. This paper which adopts a mixture of descriptive and analytical research designs engages a systematic literature review for collecting and analysing data. The aim is to investigate the adoption of ICTs as tools for public consultation to enhance inclusive governance in Nigeria. Findings reveal among others that the increase in acceptance and usage of mobile technologies in the face of the challenges of infrastructure, energy instability and low level of ICT literacy among others, provide veritable platform for e-consultation. E-consultation brings to bear the equally important bottom-up approach in policy making by providing additional channel for greater public voice in the policy-making process. E-consultation thus poses to be cardinal to achieving sustainable development goal of just, peaceful and inclusive societies in Nigeria

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

Mutational signature distribution varies with DNA replication timing and strand asymmetry

Background: DNA replication plays an important role in mutagenesis, yet little is known about how it interacts with other mutagenic processes. Here, we use somatic mutation signatures – each representing a mutagenic process – derived from 3056 patients spanning 19 cancer types to quantify the strand asymmetry of mutational signatures around replication origins and between early and late replicating regions. Results: We observe that most of the detected mutational signatures are significantly correlated with the timing or direction of DNA replication. The properties of these associations are distinct for different signatures and shed new light on several mutagenic processes. For example our results suggest that oxidative damage to the nucleotide pool substantially contributes to the mutational landscape of esophageal adenocarcinoma. Conclusions: Together, our results indicate an interaction between DNA replication, the associated damage repair, and most mutagenic processes

Лідерство та Макіавеллівські прояви: інноваційний розвиток працівників та ефективність бізнесу

Метою статті є оцінювання рівня маніпулювання керівників та проявів макіавеллізму в трудовому колективі залежно від його соціально-демографічних характеристик. На основі теоретичного аналізу визначено три гіпотези щодо вивчення відмінностей між маніпуляціями та проявами макіавеллізму з точки зору місця проживання працівників (міських чи сільських), форми власності організації (приватної чи державної) та віку працівників. Вихідні дані дослідження сформовано на основі результатів опитування 123 респондентів. Для перевірки висунутих гіпотез застосовано методологічний інструментарій CASADI (розсудливість, самоствердження, дипломатичність) та шкалу макіавеллізму особистості (MPS). Використання CASADI дозволило визначити прояви макіавеллізму в бізнесі та управлінській поведінці на основі результатів оцінювання думки респондентів щодо маніпуляцій між людьми. Методологія MPS дозволила оцінити рівень маніпуляцій керівників. Практичну реалізацію усіх етапів дослідження здійснено за допомогою t-тесту та коефіцієнта кореляції Пірсона. Емпіричні розрахунки підтвердили наявність відмінностей у рівнях самоствердження, бажання контролю та недовіри залежно від місця проживання респондентів. У ході дослідження встановлено статистичну значущість між віковою різницею та проявом дипломатії відповідно до макіавеллізму, а також прагненні до соціального статусу при маніпуляціях керівників. Встановлено статистичну значущість для рівнів самоствердження та розсудливості (які є атрибутами прояву макіавеллізму), а також атрибутів маніпуляцій лідерів (аморальності, бажання контролювати та недовіри до інших) залежно від форми власності організації (приватної чи державної). Авторами наголошено, що працівники, які проживають у місті, мають вищий рівень макіавеллізму, про що свідчать мотивація до отримання прибутку, необхідність контролювати інших та недовіра. При цьому рівень макіавеллізму є обернено пропорційним до віку. Отримані результати засвідчили, що у працівників приватних організацій більш виражені прояви макіавеллізму.This research aims to assess the level of manipulation of leaders and Machiavellian manifestations in the work process within selected socio-demographic characteristics of employees. Based on the described theoretical basis, three hypotheses were established. The hypotheses concern is examining the differences between manipulation and Machiavellian manifestations regarding employees' residence (urban or rural), the sphere of the organization (private or public) in which they work, and the age of employees. The data were obtained through a questionnaire survey in which 123 respondents participated. The study involved methodological tools such as CASADI (Calculativness, Self-Assertion, Diplomacy) and MPS (Machiavellian Personality Scale). The new CASADI methodology identifies Machiavellian manifestations in business and managerial behavior. It contains statements that relate to the respondent's opinion on manipulation between people. The MPS methodology was created for leaders in determining the level of their manipulation through four factors determining Machiavellianism. The survey results were evaluated through a t-test and Pearson's correlation coefficient. The findings confirmed the differences in SelfAssertion, Desire for Control, and Distrust regarding respondents' residence. The study of age differences recorded the statistical significance for the attribute of Diplomacy within Machiavellian manifestations and the attribute of Desire for social status within the manipulation of leaders. Within the differences between the private and public spheres, statistical significance was recorded for the attributes of Machiavellian manifestations of Computation and SelfEnforcement, and for the attributes of the manipulation of leaders Amorality, Desire for Control and Distrust of others. The research results indicated that employees living in the city might have a higher degree of Machiavellianism. It is reflected in their motivation for for-profit and the need to control others and not trust them. Research suggested that the rate of Machiavellianism decreases with age. In the case of the organization activity where the employee works, it was found that Machiavellian tendencies were more pronounced in employees of the private sphere

Metronidazole-resistant strains of Trichomonas vaginalis display increased susceptibility to oxygen

Susceptibility to oxygen and properties relative to oxygen metabolism were compared in metronidazole-resistant and susceptible strains of Trichomonas vaginalis. The study involved clinical isolates displaying the aerobic type of resistance, as well as resistant strains developed in vitro, both with aerobic (MR-3) and anaerobic (MR-5, MR-100) resistance. Elevated sensitivity to oxygen of the resistant clinical isolates was observed. Progressive increase of susceptibility to oxygen also accompanied in vitro development of resistance. No correlation was found between the activity of NADH oxidase and aerobic resistance, while the in vitro derivative with fully developed anaerobic resistance (MR-100) showed about 50 % decrease of NADH oxidase activity. The superoxide dismutase (SOD) activity was elevated in both resistant clinical isolates and in in vitro-developed resistant strains. The changes in levels of ferredoxin were insufficient to support ferredoxin deficiency as a cause of aerobic metronidazole resistance. Western blot analysis and electron paramagnetic resonance spectroscopy of purified hydrogenosomes showed that ferredoxin is expressed in aerobically resistant strains and has intact iron-sulfur clusters. Down-regulation of ferredoxin was demonstrated only in the late phase of development of the anaerobic resistance (MR-100). The results support a link between aerobic resistance and defective oxygen scavenging. The increased levels of intracellular oxygen, beneficial to resistant parasites when they interact with the drug, may have adverse effects on their fitness as shown by their increased sensitivity to oxidative stress