Dairying, diseases and the evolution of lactase persistence in Europe.

In European and many African, Middle Eastern and southern Asian populations, lactase persistence (LP) is the most strongly selected monogenic trait to have evolved over the past 10,000 years1. Although the selection of LP and the consumption of prehistoric milk must be linked, considerable uncertainty remains concerning their spatiotemporal configuration and specific interactions2,3. Here we provide detailed distributions of milk exploitation across Europe over the past 9,000 years using around 7,000 pottery fat residues from more than 550 archaeological sites. European milk use was widespread from the Neolithic period onwards but varied spatially and temporally in intensity. Notably, LP selection varying with levels of prehistoric milk exploitation is no better at explaining LP allele frequency trajectories than uniform selection since the Neolithic period. In the UK Biobank4,5 cohort of 500,000 contemporary Europeans, LP genotype was only weakly associated with milk consumption and did not show consistent associations with improved fitness or health indicators. This suggests that other reasons for the beneficial effects of LP should be considered for its rapid frequency increase. We propose that lactase non-persistent individuals consumed milk when it became available but, under conditions of famine and/or increased pathogen exposure, this was disadvantageous, driving LP selection in prehistoric Europe. Comparison of model likelihoods indicates that population fluctuations, settlement density and wild animal exploitation-proxies for these drivers-provide better explanations of LP selection than the extent of milk exploitation. These findings offer new perspectives on prehistoric milk exploitation and LP evolution.

Cross-scanner and cross-protocol multi-shell diffusion MRI data harmonization: Algorithms and results.

Cross-scanner and cross-protocol variability of diffusion magnetic resonance imaging (dMRI) data are known to be major obstacles in multi-site clinical studies since they limit the ability to aggregate dMRI data and derived measures. Computational algorithms that harmonize the data and minimize such variability are critical to reliably combine datasets acquired from different scanners and/or protocols, thus improving the statistical power and sensitivity of multi-site studies. Different computational approaches have been proposed to harmonize diffusion MRI data or remove scanner-specific differences. To date, these methods have mostly been developed for or evaluated on single b-value diffusion MRI data. In this work, we present the evaluation results of 19 algorithms that are developed to harmonize the cross-scanner and cross-protocol variability of multi-shell diffusion MRI using a benchmark database. The proposed algorithms rely on various signal representation approaches and computational tools, such as rotational invariant spherical harmonics, deep neural networks and hybrid biophysical and statistical approaches. The benchmark database consists of data acquired from the same subjects on two scanners with different maximum gradient strength (80 and 300 â€‹mT/m) and with two protocols. We evaluated the performance of these algorithms for mapping multi-shell diffusion MRI data across scanners and across protocols using several state-of-the-art imaging measures. The results show that data harmonization algorithms can reduce the cross-scanner and cross-protocol variabilities to a similar level as scan-rescan variability using the same scanner and protocol. In particular, the LinearRISH algorithm based on adaptive linear mapping of rotational invariant spherical harmonics features yields the lowest variability for our data in predicting the fractional anisotropy (FA), mean diffusivity (MD), mean kurtosis (MK) and the rotationally invariant spherical harmonic (RISH) features. But other algorithms, such as DIAMOND, SHResNet, DIQT, CMResNet show further improvement in harmonizing the return-to-origin probability (RTOP). The performance of different approaches provides useful guidelines on data harmonization in future multi-site studies.

Stability and predictability in human control of complex objects.

Previous research on movement control suggested that humans exploit stability to reduce vulnerability to internal noise and external perturbations. For interactions with complex objects, predictive control based on an internal model of body and environment is needed to preempt perturbations and instabilities due to delays. We hypothesize that stability can serve as means to render the complex dynamics of the body and the task more predictable and thereby simplify control. However, the assessment of stability in complex interactions with nonlinear and underactuated objects is challenging, as for existent stability analyses the system needs to be close to a (known) attractor. After reviewing existing methods for stability analysis of human movement, we argue that contraction theory provides a suitable approach to quantify stability or convergence in complex transient behaviors. To test its usefulness, we examined the task of carrying a cup of coffee, an object with internal degrees of freedom. A simplified model of the task, a cart with a suspended pendulum, was implemented in a virtual environment to study human control strategies. The experimental task was to transport this cart-and-pendulum on a horizontal line from rest to a target position as fast as possible. Each block of trials presented a visible perturbation, which either could be in the direction of motion or opposite to it. To test the hypothesis that humans exploit stability to overcome perturbations, the dynamic model of the free, unforced system was analyzed using contraction theory. A contraction metric was obtained by numerically solving a partial differential equation, and the contraction regions with respect to that metric were computed. Experimental results showed that subjects indeed moved through the contraction regions of the free, unforced system. This strategy attenuated the perturbations, obviated error corrections, and made the dynamics more predictable. The advantages and shortcomings of contraction analysis are discussed in the context of other stability analyses.

The use of HIV post-exposure prophylaxis in forensic medicine following incidents of sexual violence in Hamburg, Germany: a retrospective study.

In Hamburg, Germany, the initiation of HIV post-exposure prophylaxis (HIV PEP) in cases of sexual violence is often carried out by forensic medical specialists (FMS) using the city's unique Hamburg Model. FMS-provided three-day HIV PEP starter packs include a combination of raltegravir and emtricitabine/tenofovir. This study aimed to investigate the practice of offering HIV PEP, reasons for discontinuing treatment, patient compliance, and whether or not potential perpetrators were tested for HIV. We conducted a retrospective study of forensic clinical examinations carried out by the Hamburg Department of Legal Medicine following incidents of sexual violence from 2009 to 2016. One thousand two hundred eighteen incidents of sexual violence were reviewed. In 18% of these cases, HIV PEP was initially prescribed by the FMS. HIV PEP indication depended on the examination occurring within 24 h after the incident, no/unknown condom use, the occurrence of ejaculation, the presence of any injury, and the perpetrator being from population at high risk for HIV. Half of the HIV PEP recipients returned for a reevaluation of the HIV PEP indication by an infectious disease specialist, and just 16% completed the full month of treatment. Only 131 potential perpetrators were tested for HIV, with one found to be HIV positive. No HIV seroconversion was registered among the study sample. Provision of HIV PEP by an FMS after sexual assault ensures appropriate and prompt care for victims. However, patient compliance and completion rates are low. HIV testing of perpetrators must be carried out much more rigorously.

Paraoxonase-2 regulates coagulation activation through endothelial tissue factor.

Oxidative stress and inflammation of the vessel wall contribute to prothrombotic states. The antioxidative protein paraoxonase-2 (PON2) shows reduced expression in human atherosclerotic plaques and endothelial cells in particular. Supporting a direct role for PON2 in cardiovascular diseases, Pon2 deficiency in mice promotes atherogenesis through incompletely understood mechanisms. Here, we show that deregulated redox regulation in Pon2 deficiency causes vascular inflammation and abnormalities in blood coagulation. In unchallenged Pon2-/- mice, we find increased oxidative stress and endothelial dysfunction. Bone marrow transplantation experiments and studies with endothelial cells provide evidence that increased inflammation, indicated by circulating interleukin-6 levels, originates from Pon2 deficiency in the vasculature. Isolated endothelial cells from Pon2-/- mice display increased tissue factor (TF) activity in vitro. Coagulation times were shortened and platelet procoagulant activity increased in Pon2-/- mice relative to wild-type controls. Coagulation abnormalities of Pon2-/- mice were normalized by anti-TF treatment, demonstrating directly that TF increases coagulation. PON2 reexpression in endothelial cells by conditional reversal of the knockout Pon2 cassette, restoration in the vessel wall using bone marrow chimeras, or treatment with the antioxidant N-acetylcysteine normalized the procoagulant state. These experiments delineate a PON2 redox-dependent mechanism that regulates endothelial cell TF activity and prevents systemic coagulation activation and inflammation.

Stability and Predictability in Dynamically Complex Physical Interactions.

This study examines human control of physical interaction with objects that exhibit complex (nonlinear, chaotic, underactuated) dynamics. We hypothesized that humans exploited stability properties of the human-object interaction. Using a simplified 2D model for carrying a "cup of coffee", we developed a virtual implementation to identify human control strategies. Transporting a cup of coffee was modeled as a cart with a suspended pendulum, where humans moved the cart on a horizontal line via a robotic manipulandum. The specific task was to transport the cart-pendulum system to a target, as fast as possible, while accommodating assistive and resistive perturbations. To assess trajectory stability, we applied contraction analysis. We showed that when the perturbation was assistive, humans absorbed the perturbation by controlling cart trajectories into a contraction region prior to the perturbation. When the perturbation was resistive, subjects passed through a contraction region following the perturbation. Entering a contraction region stabilizes performance and makes the dynamics more predictable. This human control strategy could inspire more robust control strategies for physical interaction in robots.

The anti-apoptotic PON2 protein is Wnt/ß-catenin-regulated and correlates with radiotherapy resistance in OSCC patients.

Aberrant Wnt signaling and control of anti-apoptotic mechanisms are pivotal features in different types of cancer to undergo cell death programs. The intracellular human enzyme Paraoxonase-2 (PON2) is known to have anti-apoptotic properties in leukemia and oral squamous cell cancer (OSCC) cells. However, the distinct regulating pathways are poorly understood. First, we present a so far unknown regulation of PON2 protein expression through the Wnt/GSK3ß/ß-catenin pathway in leukemia and OSCC cells. This was confirmed via in silico analysis, promoter reporter studies and treatment of multiple cell lines (K562, SCC-4, PCI-13) with different Wnt ligands/inhibitors in vitro. Ex vivo analysis of OSCC patients revealed a correlation between PON2 and ß-catenin expression in tumor tissue. Higher PON2 expression in OSCC is associated with relapse independently of treatment (e.g. surgery/radio-/chemotherapy). These results emphasize the clinical impact of the newly described regulation of PON2 through Wnt/GSK3ß/ß-catenin. More importantly, the study revealed the fundamental finding of an overall Wnt/GSK3ß/ß-catenin dependent regulation of PON2 in different cancers, which was confirmed by systematic and multimethodological approaches. Thus, the herein presented mechanistic insight contributes to a better understanding of tumor specific escape from cell death strategies and suggests PON2 as a new potential biomarker for therapy resistance or as a prognostic tumor marker.