Assessing the impact of laws controlling the online availability of 25I-NBOMe, AH-7921, MDPV and MXE – outcomes of a semi-automated e-shop monitoring

Aims: The indicator of availability has been used in the risk assessment (RA) of new psychoactive substances (NPS). This paper aims to examine the pre- and post-control availability of 25INBOMe, AH-7921, MDPV and MXE, which were assessed by the EMCDDA. Methods: Data were collected by a semi-automated software tool (I-TREND SASF) on e-shops in national languages (Czech, French, Dutch, Polish and English) that offered shipping of these compounds into the respective countries; frequency analysis was used. Findings: The number of e-shops selling these substances decreased between III/2014 and XII/2015 (except for AH-7921). Both increases and decreases were found on the country-level for all the compounds (except for an overall decrease for MXE). In one instance an NPS disappeared from this market in 2015 (25I-NBOMe in NL); 25I-NBOMe and AH-7921 in France and AH-7921 in Poland appeared for the first time in 2015 after they were put under control. The e-shops listing AH-7921, 25I-NBOMe and MDPV in XII/2015 ranked higher in terms of ‘‘popularity’’ than in III/2014. The IP addresses were more likely to be outside the EU in 2015 than in 2014. Conclusions: We found no evidence that national-level compound bans contributed to the changes in online NPS markets. Indicators of the accessibility, availability, popularity, and IP origin should be considered in RA. Data triangulation with street markets and the darknet is needed as well as more research into the ‘‘displacement’’ and ‘‘replacement’’ effects of control laws

Quercetin abrogates chemoresistance in melanoma cells by modulating ΔNp73

<p>Abstract</p> <p>Background</p> <p>The alkylating agent Dacarbazine (DTIC) has been used in the treatment of melanoma for decades, but when used as a monotherapy for cancer only moderate response rates are achieved. Recently, the clinical use of Temozolomide (TMZ) has become the more commonly used analog of DTIC-related oral agents because of its greater bioavailability and ability to cross the blood brain barrier. The response rates achieved by TMZ are also unsatisfactory, so there is great interest in identifying compounds that could be used in combination therapy. We have previously demonstrated that the bioflavonoid quercetin (Qct) promoted a p53-mediated response and sensitized melanoma to DTIC. Here we demonstrate that Qct also sensitizes cells to TMZ and propose a mechanism that involves the modulation of a truncated p53 family member, ΔNp73.</p> <p>Methods</p> <p>DB-1 melanoma (p53 wildtype), and SK Mel 28 (p53 mutant) cell lines were treated with TMZ (400 μM) for 48 hrs followed by Qct (75 μM) for 24 hrs. Cell death was determined by Annexin V-FITC staining and immunocytochemical analysis was carried out to determine protein translocation.</p> <p>Results</p> <p>After treatment with TMZ, DB-1 cells demonstrated increased phosphorylation of Ataxia telangiectasia mutated (ATM) and p53. However, the cells were resistant to TMZ-induced apoptosis and the resistance was associated with an increase in nuclear localization of ΔNp73. Qct treatment in combination with TMZ abolished drug insensitivity and caused a more than additive induction of apoptosis compared to either treatment alone. Treatment with Qct, caused redistribution of ΔNp73 into the cytoplasm and nucleus, which has been associated with increased p53 transcriptional activity. Knockdown of ΔNp73 restored PARP cleavage in the TMZ treated cells, confirming its anti-apoptotic role. The response to treatment was predominantly p53 mediated as the p53 mutant SK Mel 28 cells showed no significant enhancement of apoptosis.</p> <p>Conclusion</p> <p>This study demonstrates that Qct can sensitize cells to TMZ and that the mechanisms of sensitization involve modulation of p53 family members.</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

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

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

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

Determinants of heritable gene silencing for KRAB-dCas9&nbsp;+&nbsp;DNMT3 and Ezh2-dCas9&nbsp;+&nbsp;DNMT3 hit-and-run epigenome editing.

Precision epigenome editing has gained significant attention as a method to modulate gene expression without altering genetic information. However, a major limiting factor has been that the gene expression changes are often transient, unlike the life-long epigenetic changes that occur frequently in nature. Here, we systematically interrogate the ability of CRISPR/dCas9-based epigenome editors (Epi-dCas9) to engineer persistent epigenetic silencing. We elucidated cis regulatory features that contribute to the differential stability of epigenetic reprogramming, such as the active transcription histone marks H3K36me3 and H3K27ac strongly correlating with resistance to short-term repression and resistance to long-term silencing, respectively. H3K27ac inversely correlates with increased DNA methylation. Interestingly, the dependance on H3K27ac was only observed when a combination of KRAB-dCas9 and targetable DNA methyltransferases (DNMT3A-dCas9&nbsp;+&nbsp;DNMT3L) was used, but not when KRAB was replaced with the targetable H3K27 histone methyltransferase Ezh2. In addition, programmable Ezh2/DNMT3A&nbsp;+&nbsp;L treatment demonstrated enhanced engineering of localized DNA methylation and was not sensitive to a divergent chromatin state. Our results highlight the importance of local chromatin features for heritability of programmable silencing and the differential response to KRAB- and Ezh2-based epigenetic editing platforms. The information gained in this study provides fundamental insights into understanding contextual cues to more predictably engineer persistent silencing

Ідентифікація сенсорної репрезентативної системи у нейролінгвістичному програмуванні

У статті систематизовано аргументи та контраргументи у рамках наукової дискусії щодо проблеми нейролінгвістичного програмування. Автори зазначили, що нейролінгвістичне програмування це набір підходів та інструментів комунікації, технік і точок зору, які визначають хід думок та методи спілкування за допомогою мови. Нейролінгвістичне програмування використовується для розпізнавання та зміни моделей людської поведінки. Сенсорна репрезентативна система, або метод розпізнавання репрезентативних систем, який складається з п'яти основних органів чуття, впливає на цей процес. Систематизація літературних джерел та підходів до означеного питання вказує на те, що підхід нейролінгвістичного програмування включає три типи сенсорних репрезентативних систем (візуальну, аудіальну та кінестетичну). Наголошено, що домінуючий тип сенсорної репрезентативної системи індивіда може пояснити особливості його поведінки в управлінській та маркетинговій сферах. Головною метою дослідження є визначення бажаного типу сенсорної репрезентативної системи індивіду. Відповідно до мети дослідження авторами застосовано методику PRSS-VAK, яка складається із дев'яти тверджень, що оцінюються за шкалою від 1 (найменш характерно) до 4 (найбільш характерно). Вибір методології PRSS-VAK грунтується на можливості зрозуміти моделі поведінки індивіда та пов'язані з ним когнітивні чи емоційні процеси. У ході дослідження застосовано дослідницький факторний аналіз з ротацією Varimax для перевірки основних взаємозв’язків між вимірюваними змінними на вибірці з 214 респондентів зі Словацької Республіки. До того, було проведено підтверджуючий факторний аналіз для валідації відповідності даних гіпотетичній моделі на вибірці з 268 респондентів зі Словацької Республіки. Отримані результати мають практичне та теоретичне значення та можуть бути корисними широкому колу зацікавлених сторін. За результатами дослідження емпірично та теоретично підтверджено, що одна з бажаних сенсорних репрезентативних систем може бути домінантною та змінюватись відповідно до поточних умов (стимул, імпульс). При цьому кількісне дослідження не дозволяє встановити точну приналежність особи до певного типу сенсорної репрезентативної системи (візуальної, аудіальної чи кінестетичної). Результати дослідження дають підстави стверджувати, що ідентифікація бажаної сенсорної репрезентативної системи може покращити управлінські та маркетингові комунікації.The paper highlights the scientific debate on the Neurolinguistic programming (NLP) issue. NLP is a collection of approaches, communication tools, techniques, and perspectives that determine how individuals think and communicate through language. NLP is used to recognize and modify patterns of human behavior. The sensory representational system, or the method for recognizing representational systems, which is made up of five main senses, influences this process. Systematization literary sources and approaches to this issue indicate that three sensory representational systems exist in the NLP approach: visual, auditory, and kinesthetic (VAK), and that the individual's preferred representational sensory system could explain manifested behavior and characteristics in the managerial and marketing sphere. The central purpose of the research and the significance of choice made about this area of interest is to determine each individual's preferred representational sensory system (VAK) utilizing the original PRSS-VAK methodology. The methodological research tool was the PRSS-VAK methodology which contains nine statements, which are assessed on a scale from 1 (the least describes me) to 4 (the most describes me). The PRSS-VAK methodology would help to comprehend patterns of an individual's behavior and allied cognitive or emotional processes. EFA (Exploratory Factor Analysis) with Varimax rotation was used to verify the methodology on a sample of 214 respondents from the Slovak Republic, and CFA (Confirmatory Factor Analysis) was used to validate the structure on a sample of 268 respondents from the Slovak Republic. This research empirically and theoretically confirms that one of the preferred representational sensory systems may be dominant. However, this may change regarding the current situation (stimulus, impulse). The research results could be beneficial as a springboard not only for researchers concerning this issue. It also indicates that quantitative research does not determine exactly to which category (visual, auditory, or kinesthetic) a certain individual belongs. Using the identification of a preferred representational sensory system could help to facilitate both management and marketing communications