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Peptides play important roles in regulating biological processes and form the basis of a multiplicity of therapeutic drugs. To date, only about 300 peptides in human have confirmed bioactivity, although tens of thousands have been reported in the literature. The majority of these are inactive degradation products of endogenous proteins and peptides, presenting a needle-in-a-haystack problem of identifying the most promising candidate peptides from large-scale peptidomics experiments to test for bioactivity. To address this challenge, we conducted a comprehensive analysis of the mammalian peptidome across seven tissues in four different mouse strains and used the data to train a machine learning model that predicts hundreds of peptide candidates based on patterns in the mass spectrometry data. We provide in silico validation examples and experimental confirmation of bioactivity for two peptides, demonstrating the utility of this resource for discovering lead peptides for further characterization and therapeutic development. Bioactive peptides regulate many physiological functions but progress in discovering them has been slow. Here, the authors use a machine learning framework to predict mammalian peptide candidates from the global and local structure of large-scale tissue-specific mass spectrometry data.

We present and use the robotic building block concept to create playware. Playware is the use of intelligent technology to create the kinds of leisure activity we normally label play, i.e., intelligent hard- and software that aims at producing play and playful experiences among users. The technological concept of physical building blocks with processing, input, and output (including communication) is derived from embodied artificial intelligence that emphasizes the role of interplay between morphology and control. We exemplify the building block concept with the tangible tiles that we created as components for a new kind of playground on which children can experience immediate feedback on their motions. Hence, this kind of playground allows the implementation of games and plays that demand physical activity amongst the users, and thereby contribute as a new tool in the fight against obesity. The tangible tiles are homogenous building blocks, which gives assembly, substitution, and production advantages. However, we may also create a system of heterogeneous building blocks, e.g., by adding special-purpose tiles such as loud-speaker tiles. We performed tests with the tangible tiles placed at a school for 2 months' continuous use.

Based on the concepts of RoboMusic and modular playware, we developed a system composed of modular playware devices which allow any user to perform music in a simple, interactive manner. The key features exploited in the modular playware approach are modularity, flexibility, construction, immediate feedback to stimulate engagement, creative exploration of play activities, and in some cases activity design by end-users (e.g., DJs). We exemplify the approach with the development of 11 rock genres and 6 pop music pieces for modular I-BLOCKS, which are exhibited and in daily use at the Rock Me exhibition, and have been used at several international music events in Japan and the USA. A key finding is that professional music design is essential for the development of primitives in a musical behavior-based system, and this professional esthetics is necessary to engage the users in the activity of assembling and coordinating these “professional” musical primitives. This article describes, explores, and discusses this concept.

The aim of this paper is to describe the opportunities and challenges involved in designing educational scenarios for teaching with the computer game Minecraft in mother tongue education (MTE). The empirical data presented is based on an on-going research project, funded by the Danish Ministry of Education, which explores the use of a particular game map entitled \"The Mysterious Island\" in the context of MTE in five primary school classes (age 7-8) located at two different Danish schools. The Mysterious Island scenario is a loosely structured Robinsonade narrative that invites the students to \"survive\" on a deserted island. The empirical data mainly consist of classroom observations collected and analysed using an ethnographically inspired approach to discourse analysis. The data analysis is based on theoretical perspectives on scenario-based education, which assumes that the educational use of game scenarios can be understood as a dynamic interplay of different domains and knowledge practices. In this way, the educational use of The Mysterious Island is understood as socially negotiated translations between the knowledge practices of the Robinsonade-based game scenario, the knowledge practices of the disciplinary domain of MTE, the knowledge practices of the pedagogical domain of \"schooling\", and the knowledge practices of the everyday domain, especially in relation to the students' prior Minecraft experiences. In summary, the analysis presents preliminary findings on different teachers' educational redesign of The Mysterious Island and the students' reframing of the various domains and narratives involved. We conclude that the meaningful use of Minecraft in MTE depends largely on the pedagogical approaches of the teachers to redesigning meaningful game scenarios and opportunities for students to reframe their experiences across the domains and knowledge practices involved.

The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H2O2 or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.

Background Men who have sex with men (MSM) are disproportionally affected by sexually transmitted infections (STI). STI are often extragenital and asymptomatic. Both can delay diagnosis and treatment. Approval of HIV pre-exposure prophylaxis (PrEP) might have influenced sexual behaviour and STI-prevalence of HIV- MSM. We estimated STI-prevalence and risk factors amongst HIV- and HIV+ MSM in Germany to plan effective interventions. Methods We conducted a nationwide, cross-sectional study between February and July 2018. Thirteen MSM-friendly STI-practices screened MSM for Chlamydia trachomatis (CT) , Mycoplasma genitalium (MG), Neisseria gonorrhea (NG) , and Trichomonas vaginalis (TV) using self-collected rectal and pharyngeal swabs, and urine samples. APTIMA™ STI-assays (Hologic™ Inc., San Diego, USA) were used for diagnostics, and samples were not pooled. We collected information on socio-demographics, HIV-status, clinical symptoms, sexual behaviour within the last 6 months, and PrEP use. We combined HIV status and PrEP use for defining risk groups, and used directed acyclic graphs and multivariable logistic regression to identify risk factors for STI. Results Two thousand three hundred three MSM were included: 50.5% HIV+, median age 39 [18–79] years. Median number of male sex partners within the last 6 months was five. Sex without condom was reported by 73.6%, use of party drugs by 44.6%. 80.3% had a STI history, 32.2% of STI+ MSM reported STI-related symptoms. 27.6% of HIV- MSM used PrEP. Overall STI-prevalence was 30.1, 25.0% in HIV−/PrEP- MSM (CT:7.2%; MG:14.2%; NG:7.4%; TV:0%), 40.3% in HIV−/PrEP+ MSM (CT:13.8%; MG:19.4%; NG:14.8%; TV:0.4%), and 30.8% in HIV+ MSM (CT:10.1%; MG:18.4%; NG:8.6%; TV:0.1%). Being HIV+ (OR 1.7, 95%-CI 1.3–2.2), using PrEP (OR 2.0, 95%-CI 1.5–2.7), having > 5 sex partners (OR:1.65; 95%-CI:1.32–2.01.9), having condomless sex (OR:2.11.9; 95%-CI:1.65–2.86), and using party drugs (OR:1.65; 95%-CI:1.32–2.0) were independent risk factors for being tested positive for at least one STI. Conclusions We found a high STI-prevalence in MSM in Germany, especially in PrEP users, frequently being asymptomatic. As a relevant proportion of PrEP users will not use a condom, counselling and comprehensive STI screening is essential and should be low threshold and preferably free of cost. Counselling of PrEP users should also address use of party drugs.

Inositol pyrophosphates, such as diphospho-myo-inositol pentakisphosphates (InsP 7 ), are an important family of signalling molecules, implicated in many cellular processes and therapeutic indications including insulin secretion, glucose homeostasis and weight gain. To understand their cellular functions, chemical tools such as photocaged analogues for their real-time modulation in cells are required. Here we describe a concise, modular synthesis of InsP 7 and caged InsP 7 . The caged molecule is stable and releases InsP 7 only on irradiation. While photocaged InsP 7 does not enter cells, its cellular uptake is achieved using nanoparticles formed by association with a guanidinium-rich molecular transporter. This novel synthesis and unprecedented polyphosphate delivery strategy enable the first studies required to understand InsP 7 signalling in cells with controlled spatiotemporal resolution. It is shown herein that cytoplasmic photouncaging of InsP 7 leads to translocation of the PH-domain of Akt, an important signalling-node kinase involved in glucose homeostasis, from the membrane into the cytoplasm. Photocaged inositol-pyrophosphates offer a tool to study cellular signalling, but their challenging synthesis has precluded any biological studies so far. Here, the authors report the synthesis and cellular delivery of a photocaged analogue, and show that it mediates protein translocation in cellulo .

Impaired self-awareness of cognitive deficits (ISAcog) has rarely been investigated in Parkinson's disease (PD). ISAcog is associated with poorer long-term outcome in other diseases. This study examines ISAcog in PD with and without mild cognitive impairment (PD-MCI), compared to healthy controls, and its clinical-behavioral and neuroimaging correlates. We examined 63 PD patients and 30 age- and education-matched healthy controls. Cognitive state was examined following the Movement Disorder Society Level II criteria. ISAcog was determined by subtracting -scores (based on controls' scores) of objective tests and subjective questionnaires. Neural correlates were assessed by structural magnetic resonance imaging (MRI) and 2-[fluorine-18]fluoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET) in 47 patients (43 with MRI) and 11 controls. We analyzed whole-brain glucose metabolism and cortical thickness in regions where FDG-uptake correlated with ISAcog. PD-MCI patients ( = 23) showed significantly more ISAcog than controls and patients without MCI ( = 40). When all patients who underwent FDG-PET were examined, metabolism in the bilateral superior medial frontal gyrus, anterior and midcingulate cortex negatively correlated with ISAcog (FWE-corrected p < 0.001). In PD-MCI, ISAcog was related to decreased metabolism in the right superior temporal lobe and insula ( = 13; FWE-corrected = 0.023) as well as the midcingulate cortex (FWE-corrected = 0.002). Cortical thickness was not associated with ISAcog in these regions. No significant correlations were found between ISAcog and glucose metabolism in controls and patients without MCI. Similar to Alzheimer's disease, the cingulate cortex seems to be relevant in ISAcog in PD. In PD-MCI patients, ISAcog might result from a disrupted network that regulates awareness of cognition and error processes.

The relative affinity of T cell receptors for different peptide–MHCs is measured at high throughput, revealing T cell cross-reactivity. The promiscuous nature of T-cell receptors (TCRs) allows T cells to recognize a large variety of pathogens, but makes it challenging to understand and control T-cell recognition 1 . Existing technologies provide limited information about the key requirements for T-cell recognition and the ability of TCRs to cross-recognize structurally related elements 2 , 3 . Here we present a 'one-pot' strategy for determining the interactions that govern TCR recognition of peptide–major histocompatibility complex (pMHC). We measured the relative affinities of TCRs to libraries of barcoded peptide–MHC variants and applied this knowledge to understand the recognition motif, here termed the TCR fingerprint. The TCR fingerprints of 16 different TCRs were identified and used to predict and validate cross-recognized peptides from the human proteome. The identified fingerprints differed among TCRs recognizing the same epitope, demonstrating the value of this strategy for understanding T-cell interactions and assessing potential cross-recognition before selection of TCRs for clinical development.

YAP activation in cancer is linked to poor outcomes, making it an attractive therapeutic target. Previous research focused on blocking the interaction of YAP with TEAD transcription factors. Here, we took a different approach by disrupting YAP’s binding to the transcription factor B-MYB using MY-COMP, a fragment of B-MYB containing the YAP binding domain fused to a nuclear localization signal. MY-COMP induced cell cycle defects, nuclear abnormalities, and polyploidization. In an AKT and YAP-driven liver cancer model, MY-COMP significantly reduced liver tumorigenesis, highlighting the importance of the YAP-B-MYB interaction in tumor development. MY-COMP also perturbed the cell cycle progression of YAP-dependent uveal melanoma cells but not of YAP-independent cutaneous melanoma cell lines. It counteracted YAP-dependent expression of MMB-regulated cell cycle genes, explaining the observed effects. We also identified NIMA-related kinase (NEK2) as a downstream target of YAP and B-MYB, promoting YAP-driven transformation by facilitating centrosome clustering and inhibiting multipolar mitosis.