How does the kinase Lck phosphorylate the T cell receptor? Spatial organization as a regulatory mechanism

T cell signaling begins with the ligation of the T cell antigen receptor (TCR) by a cognate peptide and the phosphorylation of the receptor’s immunoreceptor tyrosine-based activation motif domains by the kinase Lck. However, the canonical receptor model is insufficient to explain how the constitutively active kinase Lck can discriminate between non-ligated and ligated TCRs. Here, we discuss the factors that are thought to regulate the spatial distribution of the TCR and Lck, and therefore critically influence TCR signaling initiation

Buying drugs on a Darknet market: A better deal? Studying the online illicit drug market through the analysis of digital, physical and chemical data.

Darknet markets, also known as cryptomarkets, are websites located on the Darknet and designed to allow the trafficking of illicit products, mainly drugs. This study aims at presenting the added value of combining digital, chemical and physical information to reconstruct sellers' activities. In particular, this research focuses on Evolution, one of the most popular cryptomarkets active from January 2014 to March 2015. Evolution source code files were analysed using Python scripts based on regular expressions to extract information about listings (i.e., sales proposals) and sellers. The results revealed more than 48,000 listings and around 2700 vendors claiming to send illicit drug products from 70 countries. The most frequent categories of illicit drugs offered by vendors were cannabis-related products (around 25%) followed by ecstasy (MDA, MDMA) and stimulants (cocaine, speed). The cryptomarket was then especially studied from a Swiss point of view. Illicit drugs were purchased from three sellers located in Switzerland. The purchases were carried out to confront digital information (e.g., the type of drug, the purity, the shipping country and the concealment methods mentioned on listings) with the physical analysis of the shipment packaging and the chemical analysis of the received product (purity, cutting agents, chemical profile based on minor and major alkaloids, chemical class). The results show that digital information, such as concealment methods and shipping country, seems accurate. But the illicit drugs purity is found to be different from the information indicated on their respective listings. Moreover, chemical profiling highlighted links between cocaine sold online and specimens seized in Western Switzerland. This study highlights that (1) the forensic analysis of the received products allows the evaluation of the accuracy of digital data collected on the website, and (2) the information from digital and physical/chemical traces are complementary to evaluate the practices of the online selling of illicit drugs on cryptomarkets

A geographical analysis of trafficking on a popular darknet market

© 2017 Elsevier B.V. Cryptomarkets are online marketplaces, located on the darknet, that facilitate the trading of a variety of illegal goods, mostly drugs. While the literature essentially focus on drugs, various other goods and products related to financial or identity fraud, firearms, counterfeit goods, as well as doping products are also offered on these marketplaces. Through the analysis of relevant data collected on a popular marketplace in 2014–2015, Evolution, this research provides an analysis of the structure of trafficking (types and proportions of products, number of vendors and shipping countries). It also aims at highlighting geographical patterns in the trafficking of these products (e.g. trafficking flows, specialisation of vendors and assessment of their role in the distribution chain). The analysis of the flow of goods between countries emphasises the role of specific countries in the international and domestic trafficking, potentially informing law enforcement agencies to target domestic mails or international posts from specific countries. The research also highlights the large proportion of licit and illicit drug listings and vendors on Evolution, followed by various fraud issues (in particular, financial fraud), the sharing of knowledge (tutorials) and finally goods, currencies and precious metals (principally luxury goods). Looking at the shipping country, there seems to be a clear division between digital and physical products, with more specific information for physical goods. This reveals that the spatial analysis of trafficking is particularly meaningful in the case of physical products (such as illicit drugs) and to a lesser extent for digital products. Finally, the geographical analysis reveals that spatial patterns on Evolution tend to reflect the structure of the traditional illicit market. However, regarding illicit drugs, country-specificity has been observed and are presented in this article

The study of doping market: how to produce intelligence from Internet forums

Despite the predominant role played by Internet in the distribution of doping substances, little is currently known about the online offer of doping products. Therefore, the study focuses on the detection of doping substances and suppliers discussed in Internet forums. It aims at having a comprehensive understanding of products and sellers to lead an operational monitoring of the online doping market. Thirteen community forums on the Internet were investigated and one million topics were extracted with source code scrappers. Then, a semantic analysis was conducted with a semi-automatic process to classify the relevant words according to doping matters. Additionally, the ranking of doping products, active substances and suppliers in regards to the number of contributors to the forums were established and analyzed over time. Finally, promotion methods of suppliers were evaluated. The results show that anabolic androgenic steroids, used to enhance body image and performance, are the most discussed type of products. A temporal analysis illustrates the stability of the most popular products as well as the emergence of new products such as peptides (e.g. CJC-1295). 327 suppliers were detected, mostly with dedicated websites or direct sales by e-mail as selling methods. Globally, the implemented methodology shows its ability to detect products and suppliers as well as to follow their temporal trends. The intelligence will serve the definition of online monitoring strategies (e.g. the selection of appropriate keywords). Additionally, it also allows the adjustment of customs inspection strategies and anti-doping analysis by monitoring the popular and emerging substances

Sex differences and heritability of two indices of heart rate dynamics: A twin study.

We investigated whether women show larger heart rate variability (HRV) than men after controlling for a large number of health-related covariates, using two indices of HRV, namely respiratory sinus arrhythmia (RSA) and approximate entropy (ApEn). In a twin design, the heritability of both indices was examined. The covariation between RSA and ApEn, a measure of heart rate dynamics derived from nonlinear dynamical systems theory, was decomposed into genetic and environmental components. Subjects were 196 male and 210 female middle-aged twins. Females showed larger HRV than men before (ApEn: p <.001; RSA: p = .052) and after adjustment for covariates (ApEn: p <.001; RSA: p = .015). This sex difference was confirmed by significant intrapair differences in the opposite-sex twin pairs for both ApEn (p <.001) and RSA (p = .03). In addition to sex, only heart period and age (both p <.001) were found to be independent predictors of ApEn, whereas RSA was also influenced by respiration rate and smoking (both p <.001). Age explained 16% and 6% of the variance in FSA and ApEn, respectively. Oral contraceptive use and menopausal status had no effect on HRV. Genetic model fitting yielded moderate heritability estimates for RSA (30%) and ApEn (40%) for both males and females. The correlation between RSA and ApEn (r = .60) could be attributed to genetic factors (48%), environmental factors (36%) and age (16%). The present study found support for a gender difference in HRV with women having greater HRV than men even after controlling for a large number of potential confounders. Indices of heart rate dynamics derived from nonlinear dynamical systems theory are moderately heritable and may be more sensitive than traditional indices of HRV to reveal subtle sex differences with important implications for health and disease

Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination

Antigen recognition by the T-cell receptor (TCR) is a hallmark of the adaptive immune system. When the TCR engages a peptide bound to the restricting major histocompatibility complex molecule (pMHC), it transmits a signal via the associated CD3 complex. How the extracellular antigen recognition event leads to intracellular phosphorylation remains unclear. Here, we used single-molecule localization microscopy to quantify the organization of TCR–CD3 complexes into nanoscale clusters and to distinguish between triggered and nontriggered TCR–CD3 complexes. We found that only TCR–CD3 complexes in dense clusters were phosphorylated and associated with downstream signaling proteins, demonstrating that the molecular density within clusters dictates signal initiation. Moreover, both pMHC dose and TCR–pMHC affinity determined the density of TCR–CD3 clusters, which scaled with overall phosphorylation levels. Thus, TCR–CD3 clustering translates antigen recognition by the TCR into signal initiation by the CD3 complex, and the formation of dense signaling-competent clusters is a process of antigen discrimination

Eclogite or jadeitite: The two colours involved in the transfer of alpine axeheads in western Europe

During the 5th and 4th millennia BC, the Neolithic extraction of stone around Mont Viso and in the Mont Beigua massif in the north Italian Alps resulted in the production of large polished axeheads in ecologite, omphacitite, jadeitite and amphibolite - raw materials which were not only rare but which also have remarkable mechanical and aesthetic properties. These axeheads circulated around western Europe over great distances and in particular, between the Alps, the Atlantic and the North Sea. Among these Alpine jades, research suggests a tendency for different raw materials to be represented in different geographic areas. Axeheads and other items made from dark-coloured rocks from the family of eclogites and omphacitites tend to predominate in the Paris Basin, in Germany and in Great Britain and Ireland. This paper documents the manufacture, circulation and deposition of different types of Alpine axeheads over time. More specifically, it discusses observed trends in relation to variability in the supply of raw materials and finished objects, the nature of regional traditions and long-distance transfer, and ultimately, the changing significance of axeheads as socially valorized artefacts