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Water-ethyl acetate-ethanol is widely used as “green” extractant system. We show that two different types of phase separation can be induced upon centrifugation in this ternary system using ethanol as a co-solvent of water and ethyl acetate (EA): centrifuge-induced criticality and centrifuge-induced emulsification. The expected composition profiles of samples after centrifugation can be represented by bent lines in a ternary phase diagram when gravitational energy is added to the free energy of mixing. The experimental equilibrium composition profiles behave qualitatively as expected and can be predicted using a phenomenological theory of mixing. The concentration gradients are small except near the critical point, as expected for small molecules. Nevertheless, they are usable when accompanied by temperature cycles. These findings open new possibilities of centrifugal separation, even if control is delicate during temperature cycles. These schemes are accessible even at relatively low centrifugation speed for molecules that float and sediment with apparent molar masses several hundred times larger than the molecular mass.

Background Delirium prevalence is high in critical care settings. We examined the incidence, risk factors, and outcome of delirium in a medical intensive care unit (MICU) with a particular focus on liver diseases. We analyzed this patient population in terms of delirium risk prediction and differentiation between delirium and hepatic encephalopathy. Methods We conducted an observational study and included 164 consecutive patients admitted to an MICU of a university hospital. Patients were assessed for delirium using the Confusion Assessment Method for ICUs and the Richmond Agitation-Sedation Scale (RASS). On admission and at the onset of delirium Sequential Organ Failure Assessment (SOFA) score was determined. A population of patients with liver disease was compared to a population with gastrointestinal diseases. In the population with liver diseases, hepatic encephalopathy was graded according to the West Haven classification. We analyzed the incidence, subtype, predisposing, precipitating, and health-care setting-related factors, treatment, outcome of delirium and the association between delirium and hepatic encephalopathy in patients with liver diseases. Results The incidence of delirium was 32.5% (n = 53). Univariable binary regression analyses adjusted by the Holm-Bonferroni method showed that the development of delirium was significantly determined by 10 risk factors: Alcohol abuse (p = 0.016), severity of disease (Simplified Acute Physiology Score (SAPS) II, p = 0.016), liver diseases (p = 0.030) and sepsis (p = 0.016) compared to the control group (gastrointestinal (GI) diseases and others), increased sodium (p = 0.016), creatinine (p = 0.030), urea (p = 0.032) or bilirubin (p = 0.042), decreased hemoglobin (p = 0.016), and mechanical ventilation (p = 0.016). Of note, we identified liver diseases as a novel and relevant risk factor for delirium. Hepatic encephalopathy was not a risk factor for delirium. Delirium and hepatic encephalopathy are both life-threatening but clearly distinct conditions. The median SOFA score for patients with delirium at delirium onset was significantly higher than the SOFA score of all patients at admission (p = 0.008). Patients with delirium had five times longer ICU stays (p = 0.004) and three times higher in-hospital mortality (p = 0.036). Patients with delirium were five times more likely to be transferred to an intensive medical rehabilitation unit for post-intensive care (p = 0.020). Treatment costs per case were more than five times higher in patients with delirium than in patients without delirium (p = 0.004). Conclusions The 10 risk factors identified in this study should be assessed upon admission to ICU for effective detection, prevention, and treatment of delirium. Liver diseases are a novel risk factor for delirium with a level of significance comparable to sepsis as an established risk factor. Of note, in patients with liver diseases delirium and hepatic encephalopathy should be recognized as distinct entities to initiate appropriate treatment. Therefore, we propose a new algorithm for efficient diagnosis, characterization, and treatment of altered mental status in the ICU. This algorithm integrates the 10 risk factor prediction-model for delirium and prompts grading of the severity of hepatic encephalopathy using the West Haven classification if liver disease is present or newly diagnosed.

Background The acute respiratory distress syndrome (ARDS) is a life-threatening condition with the risk of developing hypoxia and thus requires for invasive mechanical ventilation a long-term analgosedation. Yet, prolonged analgosedation may be a reason for declining health-related quality of life (HRQoL) and the development of psychiatric disorders. Methods We used data from the prospective observational nation‑wide ARDS study across Germany (DACAPO) to investigate the influence of sedation and analgesia on HRQoL and the risk of psychiatric symptoms in ARDS survivors 3, 6 and 12 months after their discharge from the intensive care unit (ICU). HRQoL was measured with the Physical and Mental Component Scale of the Short‑Form 12 Questionnaire (PCS‑12, MCS‑12). The prevalence of psychiatric symptoms (depression and post‑traumatic stress disorder [PTSD]) was assessed using the Patient Health Questionnaire‑9 and the Post‑Traumatic Stress Syndrome‑14. The associations of analgosedation with HRQoL and psychiatric symptoms were investigated by means of multivariable linear regression models. Results The data of 134 ARDS survivors (median age [IQR]: 55 [44–64], 67% men) did not show any significant association between analgosedation and physical or mental HRQoL up to 1 year after ICU discharge. Multivariable linear regression analysis (B [95%‑CI]) yielded a significant association between symptoms of psychiatric disorders and increased cumulative doses of ketamine up to 6 months after ICU discharge (after 3 months: depression: 0.15 [0.05, 0.25]; after 6 months: depression: 0.13 [0.03, 0.24] and PTSD: 0.42 [0.04, 0.80)]). Conclusions Up to 1 year after ICU discharge, analgosedation did not influence HRQoL of ARDS survivors. Prolonged administration of ketamine during ICU treatment, however, was positively associated with the risk of psychiatric symptoms. The administration of ketamine to ICU patients with ARDS should be with caution. Trial registration Clinicaltrials.gov: NCT02637011 (Registered 15 December 2015, retrospectively registered).

Background In a previous study, we had investigated the intensive care course of patients with coronavirus disease 2019 (COVID-19) in the first wave in Germany by calculating models for prognosticating in-hospital death with univariable and multivariable regression analysis. This study analyzed if these models were also applicable to patients with COVID-19 in the second wave. Methods This retrospective cohort study included 98 critical care patients with COVID-19, who had been treated at the University Medical Center Regensburg, Germany, between October 2020 and February 2021. Data collected for each patient included vital signs, dosage of catecholamines, analgosedation, anticoagulation, and antithrombotic medication, diagnostic blood tests, treatment with extracorporeal membrane oxygenation (ECMO), intensive care scores, ventilator therapy, and pulmonary gas exchange. Using these data, expected mortality was calculated by means of the originally developed mathematical models, thereby testing the models for their applicability to patients in the second wave. Results Mortality in the second-wave cohort did not significantly differ from that in the first-wave cohort (41.8% vs. 32.2%, p = 0.151). As in our previous study, individual parameters such as pH of blood or mean arterial pressure (MAP) differed significantly between survivors and non-survivors. In contrast to our previous study, however, survivors and non-survivors in this study showed significant or even highly significant differences in pulmonary gas exchange and ventilator therapy (e.g. mean and minimum values for oxygen saturation and partial pressure of oxygen, mean values for the fraction of inspired oxygen, positive expiratory pressure, tidal volume, and oxygenation ratio). ECMO therapy was more frequently administered than in the first-wave cohort. Calculations of expected mortality by means of the originally developed univariable and multivariable models showed that the use of simple cut-off values for pH, MAP, troponin, or combinations of these parameters resulted in correctly estimated outcome in approximately 75% of patients without ECMO therapy.

INTRODUCTION: Immunological memory is the basis for durable protective immunity after infections or vaccinations. Duration of immunological memory after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 is unclear. Immunological memory can consist of memory B cells, antibodies, memory CD4+ T cells, and/or memory CD8+ T cells. Knowledge of the kinetics and interrelationships among those four types of memory in humans is limited. Understanding immune memory to SARS-CoV-2 has implications for understanding protective immunity against COVID-19 and assessing the likely future course of the COVID-19 pandemic. RATIONALE: Assessing virus-specific immune memory over at least a 6-month period is likely necessary to ascertain the durability of immune memory to SARS-CoV-2. Given the evidence that antibodies, CD4+ T cells, and CD8+ T cells can all participate in protective immunity to SARS-CoV-2, we measured antigen-specific antibodies, memory B cells, CD4+ T cells, and CD8+ T cells in the blood from subjects who recovered from COVID-19, up to 8 months after infection. RESULTS: The study involved 254 samples from 188 COVID-19 cases, including 43 samples at 6 to 8 months after infection. Fifty-one subjects in the study provided longitudinal blood samples, allowing for both cross-sectional and longitudinal analyses of SARS-CoV-2–specific immune memory. Antibodies against SARS-CoV-2 spike and receptor binding domain (RBD) declined moderately over 8 months, comparable to several other reports. Memory B cells against SARS-CoV-2 spike actually increased between 1 month and 8 months after infection. Memory CD8+ T cells and memory CD4+ T cells declined with an initial half-life of 3 to 5 months. This is the largest antigen-specific study to date of the four major types of immune memory for any viral infection. Among the antibody responses, spike immunoglobulin G (IgG), RBD IgG, and neutralizing antibody titers exhibited similar kinetics. Spike IgA was still present in the large majority of subjects at 6 to 8 months after infection. Among the memory B cell responses, IgG was the dominant isotype, with a minor population of IgA memory B cells. IgM memory B cells appeared to be short-lived. CD8+ T cell and CD4+ T cell memory was measured for all SARS-CoV-2 proteins. Although ~70% of individuals possessed detectable CD8+ T cell memory at 1 month after infection, that proportion declined to ~50% by 6 to 8 months after infection. For CD4+ T cell memory, 93% of subjects had detectable SARS-CoV-2 memory at 1 month after infection, and the proportion of subjects positive for CD4+ T cells (92%) remained high at 6 to 8 months after infection. SARS-CoV-2 spike-specific memory CD4+ T cells with the specialized capacity to help B cells [T follicular helper (TFH) cells] were also maintained. The different types of immune memory each had distinct kinetics, resulting in complex interrelationships between the abundance of T cell, B cell, and antibody immune memory over time. Additionally, substantially heterogeneity in memory to SARS-CoV-2 was observed. CONCLUSION: Substantial immune memory is generated after COVID-19, involving all four major types of immune memory. About 95% of subjects retained immune memory at ~6 months after infection. Circulating antibody titers were not predictive of T cell memory. Thus, simple serological tests for SARS-CoV-2 antibodies do not reflect the richness and durability of immune memory to SARS-CoV-2. This work expands our understanding of immune memory in humans. These results have implications for protective immunity against SARS-CoV-2 and recurrent COVID-19.

Einleitung: Simulationstraining wird bereits seit Jahren zur praktischen Aus- und Weiterbildung von Personal im Gesundheitsbereich herangezogen. Dabei haben sich unzählige Möglichkeiten und Variationen entwickelt. Besonderer Fokus soll in dieser Arbeit auf die Verbesserung der Patient*innensicherheit durch Simulation gelegt werden. Methodik: Durch systematische Literaturrecherche wurden acht wissenschaftliche Studien zur Bearbeitung der Thematik herangezogen. Diese werden zunächst übersichtsmäßig dargestellt und anschließend zu einer Synthese zusammengeführt. Ergebnisse: Es existieren diverse effektive Methoden zur Verbesserung der Patient*innensicherheit durch Simulation. Als besonders wirkungsvoll zeigten sich Methoden zur Verbesserung der Kommunikation im multiprofessionellen Team als auch Methoden zur Identifikation und Vermeidung von potentiell patient*innenschädigenden Fehlern. Schlussfolgerung: Die Durchführung von Simulationstraining ist sinnvoll und ratsam um Personal speziell in Hochrisikobereichen des Gesundheitssystems zu Schulen und auf Notfallsituationen vorzubereiten. Dabei sollte nach Möglichkeit strukturiert vorgegangen werden. Introduction: Simulation has been used for years to train heath care professionals. This led to the development of various methods and variations. The aim of this publication is to highlight the improvement of patient safety using simulation training. Methodology: A systematic literature review accounted for eight studies that were considered to investigate this subject. These will at first be presented as a summary and afterwards merged into a synthesis. Results: There are different effective methods to increase patient safety by simulation. Great effects are shown by improving communication skills in the multidisciplinary team as well as identifying and avoiding compromising mistakes. Conclusio: The implementation of simulation training is useful and is recommended to training health care professionals, especially those who are working in high risk environments. This should be done in a structured manner.

Einleitung: Die Parkinson-Krankheit führt durch die Kombination von motorischen und nicht-motorischen Funktionsstörungen nicht nur zu wesentlichen Beeinträchtigungen der Gesundheit und des Lebens von Betroffenen, sondern beeinflusst auch die betreuenden Personen und das psychosoziale Umfeld der Patient*innen. Eine erfolgreiche Therapie benötigt ein Team, bestehend aus kompetenten Expert*innen, welches gut vernetzt und interdisziplinär zusammenarbeiten muss. Speziell ausgebildete Pflegepersonen (Parkinsons`Disease specialists (PDNS) zählen zu diesem Team und sind essentiell für die Betreuung, Begleitung und Aufrechterhaltung der Lebensqualität betroffener Personen. Methodik: Zur Beantwortung der Forschungsfrage dieser Arbeit wurde eine systematische Literaturrecherche in den Datenbanken „Pubmed“, „Google Scholar“ und „ResearchGate“ im Zeitraum von Januar 2020 bis April 2020 durchgeführt. Mithilfe von zuvor festgelegten Ein- und Ausschlusskriterien sowie englischen und deutschen Schlüsselbegriffen wurden relevante Studien herangezogen und nach dem Beurteilungsinstrument von Brandenburg, Panfil und Mayer (2007) kritisch bewertet. Im Anschluss wurden aus den Ergebnissen der Studien konkrete Synthesen gebildet, welche miteinander in Zusammenhang gebracht wurden. Ergebnisse: In der Arbeit wurden zehn Studien (drei qualitative, drei Mixed Method Studien, und vier quantitative) eingeschlossen und ausgewertet. In den quantitativen Studien ist eine statistisch signifikante Verbesserung in mehreren Bereichen dokumentiert: Dies betrifft die Lebensqualität, den globalen Gesundheitszustand, motorische und nicht-motorische Störungen, Depressionen und psychosoziale Faktoren. Kein Einfluss einer PDNS-Betreuung ließ sich auf die Belastung der Angehörigen nachweisen, auch bei den Behandlungskosten ergaben sich keine Unterschiede. In den quantitativen Studien ist die komplexe Symptomatik der Parkinson’schen Erkrankung mit Beeinflussung der Betroffenen und deren Umgebung ausführlich geschildert, zudem die Notwendigkeit der Zusammenarbeit in einem gut vernetzten Team. Menschen mit Parkinson- Krankheit müssen im Mittelpunkt solcher Behandlungsteams stehen. Schlussfolgerung: Die Forschungsfrage konnte aufgrund der Ergebnisse von wenigen quantitativen Studien beantwortet werden. Die Notwendigkeit einer PDNS wird allgemein betont. Die wissenschaftliche Evidenz dafür ist, auch nach Angabe aller Autor*innen dazu nicht sehr ausgedehnt. Aus diesem Grund sind weitere Studien mit einem genauen Konzept betreffend Ausbildung und Aufgaben einer PDNS nötig. Auf längere Sicht müssen auch die Behandlungskosten evaluiert werden. Introduction: Parkinson`s disease has a broad spectrum of symptoms. Motor and non-motor symptoms may lead to substantial deterioration of the patient`s health and develop a negative influence on the caregivers and the environment of the patients. Successful therapy demands a full team of competent experts. Team members have to work together closely and well organized. In these teams Parkinsons`disease nurse specialists (PDNS) play a central role for patients and caregivers. Methodology: To answer the question, whether therapy including a PDNS compared to a regime without a PDNS would improve the quality of life of persons with Parkinson`s disease, a systematic search of the literature was performed. Databases „Pubmed“, „Google Scholar“ and „ResearchGate“ were screened between January 2020 to April 2020 using English and German keywords, as well as inclusion and exclusion criteria to find relevant studies. The studies found were then judged according to an assessment tool developed by Brandenburg, Panfil und Mayer (2007). From the content of the studies and the results respectively, syntheses were formed to answer the research question of this study. Results: Ten studies (three quantitative, three mixed method and four quantitative) were evaluated. Quantitative studies showed a significant improvement in the intervention group concerning quality of live, global health, motor and non-motor function depression and psychosocial factors. The intervention by a PDNS did not influence the stress of the caregivers. Only on study looked for health costs and did not find a difference between the two groups. In all other studies the broad and complex spectrum of symptoms and their consequences to diseased persons and their caregivers is stressed in an impressive way. In addition the necessarity of team work with the central role of a PDNS is emphasized. Conclusion: The research question was answered by the result of three quantitative studies. In the qualitative studies in general, the central role of a PDNS is accepted and appreciated widely in the literature. In contrary, the evidence for this practice could be better, according to researchers. Therefore, more studies with an exact concept concerning the education of a PDNS and for determining the role of a PDNS is necessary. In the long run health care costs of the PDNS implementation must be evaluated.

Here we describe a unique microbial biotechnology for simultaneous bioremediation and biomining of twelve ionic metals overcoming the obstacles of multimetal toxicity to microbes. After a thorough search of key microorganisms in microbiomes of many sulfidic springs in Bavaria (Germany) over an area of 200 km2, we found three new strains EH8, EH10 and EH11 of Mucor hiemalis physiologically compatible and capable of multimetal-remediation and enrichment. We combined the multimetal-resistance, hyper-accumulation and elicitation power of EH8, EH10 and EH11 to develop a novel biotechnology for simultaneous removal, fractionation and enrichment of metal ions. As a first step we showed the intracellular fixing and deposition of mercury as nanospheres in EH8’s sporangiospores. Scanning Electron Microscopy-Energy-Dispersive X-Ray analysis revealed binding and precipitation of other applied metal ions as spherical nano-particles (~50–100 nm) at the outer electro-negative cellwall-surface of EH8, EH10 and EH11 sporangiospores. Microbiomes, germinated spores and dead insoluble cellwalls of these strains removed >81–99% of applied Al, Cd, Co, Cr, Cu, Hg, Ni, Pb, U, and Zn simultaneously and furthermore enriched precious Ag, Au and Ti from water all within 48 h, demonstrating the potential of new biotechnologies for safe-guarding our environment from metal pollution and concentrating precious diluted, ionic metals.

Advances in precision molecular imaging promise to transform our ability to detect, diagnose and treat disease. Here, we describe the engineering and validation of a new cystine knot peptide (knottin) that selectively recognizes human integrin αvβ6 with single-digit nanomolar affinity. We solve its 3D structure by NMR and x-ray crystallography and validate leads with 3 different radiolabels in pre-clinical models of cancer. We evaluate the lead tracer’s safety, biodistribution and pharmacokinetics in healthy human volunteers, and show its ability to detect multiple cancers (pancreatic, cervical and lung) in patients at two study locations. Additionally, we demonstrate that the knottin PET tracers can also detect fibrotic lung disease in idiopathic pulmonary fibrosis patients. Our results indicate that these cystine knot PET tracers may have potential utility in multiple disease states that are associated with upregulation of integrin αvβ6., Knottin is a cystine knot peptide. Here, the authors develop a knottin-based tracer for positron emission tomography and demonstrate its ability to detect cancer and idiopathic pulmonary fibrosis through selective binding to integrin αvβ6.

Obesity is a progressive, chronic disease, which can be caused by long-term miscommunication between organs. It remains challenging to understand how chronic dysfunction in a particular tissue remotely impairs other organs to eventually imbalance organismal energy homeostasis. Here we introduce RNAi Pulse Induction (RiPI) mediated by short hairpin RNA (shRiPI) or double-stranded RNA (dsRiPI) to generate chronic, organ-specific gene knockdown in the adult Drosophila fat tissue. We show that organ-restricted RiPI targeting Stromal interaction molecule (Stim), an essential factor of store-operated calcium entry (SOCE), results in progressive fat accumulation in fly adipose tissue. Chronic SOCE-dependent adipose tissue dysfunction manifests in considerable changes of the fat cell transcriptome profile, and in resistance to the glucagon-like Adipokinetic hormone (Akh) signaling. Remotely, the adipose tissue dysfunction promotes hyperphagia likely via increased secretion of Akh from the neuroendocrine system. Collectively, our study presents a novel in vivo paradigm in the fly, which is widely applicable to model and functionally analyze inter-organ communication processes in chronic diseases.

Aging promotes lung function decline and susceptibility to chronic lung diseases, which are the third leading cause of death worldwide. Here, we use single cell transcriptomics and mass spectrometry-based proteomics to quantify changes in cellular activity states across 30 cell types and chart the lung proteome of young and old mice. We show that aging leads to increased transcriptional noise, indicating deregulated epigenetic control. We observe cell type-specific effects of aging, uncovering increased cholesterol biosynthesis in type-2 pneumocytes and lipofibroblasts and altered relative frequency of airway epithelial cells as hallmarks of lung aging. Proteomic profiling reveals extracellular matrix remodeling in old mice, including increased collagen IV and XVI and decreased Fraser syndrome complex proteins and collagen XIV. Computational integration of the aging proteome with the single cell transcriptomes predicts the cellular source of regulated proteins and creates an unbiased reference map of the aging lung., Aging impacts lung functionality and makes it more susceptible to chronic diseases. Combining proteomics and single cell transcriptomics, the authors chart molecular and cellular changes in the aging mouse lung, discover aging hallmarks, and predict the cellular sources of regulated proteins.

The functionality of most secreted proteins depends on their assembly into a defined quaternary structure. Despite this, it remains unclear how cells discriminate unassembled proteins en route to the native state from misfolded ones that need to be degraded. Here we show how chaperones can regulate and control assembly of heterodimeric proteins, using interleukin 23 (IL-23) as a model. We find that the IL-23 α-subunit remains partially unstructured until assembly with its β-subunit occurs and identify a major site of incomplete folding. Incomplete folding is recognized by different chaperones along the secretory pathway, realizing reliable assembly control by sequential checkpoints. Structural optimization of the chaperone recognition site allows it to bypass quality control checkpoints and provides a secretion-competent IL-23α subunit, which can still form functional heterodimeric IL-23. Thus, locally-restricted incomplete folding within single-domain proteins can be used to regulate and control their assembly., It is unclear how unassembled secretory pathway proteins are discriminated from misfolded ones. Here the authors combine biophysical and cellular experiments to study the folding of heterodimeric interleukin 23 and describe how ER chaperones recognize unassembled proteins and aid their assembly into protein complexes while preventing the premature degradation of unassembled units.

The inner structure of a material is called microstructure. It stores the genesis of a material and determines all its physical and chemical properties. While microstructural characterization is widely spread and well known, the microstructural classification is mostly done manually by human experts, which gives rise to uncertainties due to subjectivity. Since the microstructure could be a combination of different phases or constituents with complex substructures its automatic classification is very challenging and only a few prior studies exist. Prior works focused on designed and engineered features by experts and classified microstructures separately from the feature extraction step. Recently, Deep Learning methods have shown strong performance in vision applications by learning the features from data together with the classification step. In this work, we propose a Deep Learning method for microstructural classification in the examples of certain microstructural constituents of low carbon steel. This novel method employs pixel-wise segmentation via Fully Convolutional Neural Networks (FCNN) accompanied by a max-voting scheme. Our system achieves 93.94% classification accuracy, drastically outperforming the state-of-the-art method of 48.89% accuracy. Beyond the strong performance of our method, this line of research offers a more robust and first of all objective way for the difficult task of steel quality appreciation., Published in Nature - Scientific Reports Journal

Medienimpulse, Bd. 55 Nr. 4 (2017): 4/2017 - Kreativität/Ko-Kreativität

In almost all eukaryotes mitochondria maintain their own genome. Despite the discovery more than 50 years ago still very little is known about how the genome is properly segregated during cell division. The protozoan parasite Trypanosoma brucei contains a single mitochondrion with a singular genome the kinetoplast DNA (kDNA). Electron microscopy studies revealed the tripartite attachment complex (TAC) to physically connect the kDNA to the basal body of the flagellum and to ensure proper segregation of the mitochondrial genome via the basal bodies movement, during cell cycle. Using super-resolution microscopy we precisely localize each of the currently known unique TAC components. We demonstrate that the TAC is assembled in a hierarchical order from the base of the flagellum towards the mitochondrial genome and that the assembly is not dependent on the kDNA itself. Based on biochemical analysis the TAC consists of several non-overlapping subcomplexes suggesting an overall size of the TAC exceeding 2.8 mDa. We furthermore demonstrate that the TAC has an impact on mitochondrial organelle positioning however is not required for proper organelle biogenesis or segregation.

Conventional ubiquitination regulates key cellular processes by catalysing the ATP-dependent formation of an isopeptide bond between ubiquitin (Ub) and primary amines in substrate proteins 1 . Recently, the SidE family of bacterial effector proteins (SdeA, SdeB, SdeC and SidE) from pathogenic Legionella pneumophila were shown to use NAD+ to mediate phosphoribosyl-linked ubiquitination of serine residues in host proteins2, 3. However, the molecular architecture of the catalytic platform that enables this complex multistep process remains unknown. Here we describe the structure of the catalytic core of SdeA, comprising mono-ADP-ribosyltransferase (mART) and phosphodiesterase (PDE) domains, and shed light on the activity of two distinct catalytic sites for serine ubiquitination. The mART catalytic site is composed of an α-helical lobe (AHL) that, together with the mART core, creates a chamber for NAD+ binding and ADP-ribosylation of ubiquitin. The catalytic site in the PDE domain cleaves ADP-ribosylated ubiquitin to phosphoribosyl ubiquitin (PR-Ub) and mediates a two-step PR-Ub transfer reaction: first to a catalytic histidine 277 (forming a transient SdeA H277–PR-Ub intermediate) and subsequently to a serine residue in host proteins. Structural analysis revealed a substrate binding cleft in the PDE domain, juxtaposed with the catalytic site, that is essential for positioning serines for ubiquitination. Using degenerate substrate peptides and newly identified ubiquitination sites in RTN4B, we show that disordered polypeptides with hydrophobic residues surrounding the target serine residues are preferred substrates for SdeA ubiquitination. Infection studies with L. pneumophila expressing substrate-binding mutants of SdeA revealed that substrate ubiquitination, rather than modification of the cellular ubiquitin pool, determines the pathophysiological effect of SdeA during acute bacterial infection. Structural and functional investigations demonstrate how bacterial enzymes ubiquitinate host proteins.

Background The aim of our study was to determine the relation of alcohol consumption and cigarette smoking on continuous-measured hepatic fat fraction (HFF) in a population free of cardiovascular disease. We suggested a direct correlation of alcohol consumption with HFF and increased HFF in former smokers compared to current smokers. Methods Data from 384 subjects (mean age: 56 years, 58% men) of a population-based cohort study (KORA) were included in a cross-sectional design. Liver fat was assessed by 3 Tesla magnetic resonance imaging (MRI) using a multi-echo Dixon sequence and T2-corrected single voxel multi-echo spectroscopy (H-1-MRS). Smoking status was classified as never, former or current smoker and alcohol consumption as non-, moderate (0.1-39.9 g/day for men and 0.1-19.9 g/day for women), or heavy drinker (>= 40 g/day for men and >= 20 g/day for women). Fatty liver disease was defined as HFF >= 5.56%. Results Average HFF was 8.8% by H-1-MRS and 8.5% by MRI. Former smokers showed a higher HFF (MRI: beta = 2.64; p = 0.006) and a higher FLD prevalence (MRI: OR = 1.91; p = 0.006) compared to never smokers. Current smokers showed decreased odds for FLD measured by H-1-MRS after multivariable adjustment (OR = 0.37; p = 0.007) with never smoker as reference. Heavy drinking was positively associated with HFF (H-1-MRS: beta = 2.99; p = 0.003) and showed highest odds for FLD (H-1-MRS: OR = 3.05; p = 0.008) with non-drinker as reference. Moderate drinking showed a positive association with HFF (H-1-MRS: beta = 1.54; p = 0.061 and MRI: beta = 1.75; p = 0.050). Conclusions Our data revealed lowest odds for FLD in current smokers, moderate drinkers showing higher HFF than non-drinkers and heavy drinkers showing highest HFF and odds for FLD. These findings partly conflict with former literature and underline the importance of further studies to investigate the complex effects on liver metabolism.

Background Chronic obstructive pulmonary disease (COPD) has a high prevalence rate in Germany and a further increase is expected within the next years. Although risk factors on an individual level are widely understood, only little is known about the spatial heterogeneity and population-based risk factors of COPD. Background knowledge about broader, population-based processes could help to plan the future provision of healthcare and prevention strategies more aligned to the expected demand. The aim of this study is to analyze how the prevalence of COPD varies across northeastern Germany on the smallest spatial-scale possible and to identify the location-specific population-based risk factors using health insurance claims of the AOK Nordost. Methods To visualize the spatial distribution of COPD prevalence at the level of municipalities and urban districts, we used the conditional autoregressive Besag–York–Mollie (BYM) model. Geographically weighted regression modelling (GWR) was applied to analyze the location-specific ecological risk factors for COPD. Results The sex- and age-adjusted prevalence of COPD was 6.5% in 2012 and varied widely across northeastern Germany. Population-based risk factors consist of the proportions of insurants aged 65 and older, insurants with migration background, household size and area deprivation. The results of the GWR model revealed that the population at risk for COPD varies considerably across northeastern Germany. Conclusion Area deprivation has a direct and an indirect influence on the prevalence of COPD. Persons ageing in socially disadvantaged areas have a higher chance of developing COPD, even when they are not necessarily directly affected by deprivation on an individual level. This underlines the importance of considering the impact of area deprivation on health for planning of healthcare. Additionally, our results reveal that in some parts of the study area, insurants with migration background and persons living in multi-persons households are at elevated risk of COPD.

Genetic divergence by environment is a process whereby selection causes the formation of gene flow barriers between populations adapting to contrasting environments and is often considered to be the onset of speciation. Nevertheless, the extent to which genetic differentiation by environment on small spatial scales can be detected by means of neutral markers is still subject to debate. Previous research on the perennial herb Primula veris has shown that plants from grassland and forest habitats showed pronounced differences in phenology and flower morphology, suggesting limited gene flow between habitats. To test this hypothesis, we sampled 33 populations of P. veris consisting of forest and grassland patches and used clustering techniques and network analyses to identify sets of populations that are more connected to each other than to other sets of populations and estimated the timing of divergence. Our results showed that spatial genetic variation had a significantly modular structure and consisted of four well-defined modules that almost perfectly coincided with habitat features. Genetic divergence was estimated to have occurred about 114 generations ago, coinciding with historic major changes in the landscape. Overall, these results illustrate how populations adapting to different environments become structured genetically within landscapes on small spatial scales.

Technik und technischer Wandel zählen zu jenen Faktoren, die unser (all-)tägliches Leben entscheidend prägen. Dieser Sachverhalt dürfte in unserem technischen Zeitalter kaum einer besonderen Begründung bedürfen. Es liegt auf der Hand, dass die Menschheit von Technik und technischem Fortschritt abhängig geworden ist, und dies nicht erst in unserer Zeit. Seit jeher war es der Technik entwickelnde und zielgerichtet einsetzende Mensch, der vermittels ,seiner‘ Technik Lebensräume gestaltete, veränderte, revolutionierte, oder auch zerstörte. Unglaublicher Wohlstand auf der einen, aber auch bitterste Armut auf der anderen Seite waren dabei mögliche Konsequenzen, die der technische Wandel hervorzubringen vermochte. Die Einsicht, dass technischer Wandel als gesellschaftliches Phänomen zu interpretieren sei, uns technische Zukunftsentwürfe gerade auch gesellschaftliche Zukunftsentwürfe darstellten, vermochte sich hingegen erst langsam Bahn zu brechen.

Organ transplantation remains the most effective treatment for patients with late stage organ failure. Transgenic pigs provide an alternative organ donor source to the limited availability of human organs. However, cellular rejection still remains to be the obstacle for xenotransplantation. Superior to other methods, antigen-specific regulatory T cells (Treg) alleviate cellular rejection with fewer side effects. Here we demonstrate the use of a fast method to provide tolerogenic dendritic cells (tolDC) that can be used to generate effective porcine-specific Treg cells (PSTreg). TolDC were produced within three days from human monocytes in medium supplemented with anti-inflammatory cytokines. Treg were generated from naïve CD4+ T cells and induced to become PSTreg by cocultivation with porcine-antigen-loaded tolDC. Results showed that PSTreg exhibited the expected phenotype, CD4+CD25+CD127low/− Foxp3+, and a more activated phenotype. The specificity of PSTreg was demonstrated by suppression of effector T cell (Teff) activation markers of different stages and inhibition of Teff cell proliferation. TolDC and PSTreg exhibited high expression of IL-10 and TGF-β1 at both protein and RNA levels, and PSTreg also highly expressed IL-35 at RNA levels. Upon restimulation, PSTreg retained the activated phenotype and specificity. Taken together, the newly developed procedure allows efficient generation of highly suppressive PSTreg.

BACKGROUND: Because of unreliable self-report, accelerometry is increasingly used to objectively monitor physical activity (PA). However, results of accelerometric studies vary depending on the chosen cutpoints between activity intensities. Population-specific activity patterns likely affect the size of these differences. To establish their size and stability we apply three sets of cutpoints, including two calibrated to a single reference, to our accelerometric data and compare PA estimates. METHODS: 1402 German adolescents from the GINIplus and LISAplus cohorts wore triaxial accelerometers (Actigraph GT3x) for one week (mean 6.23 days, 14.7 hours per day) at the hip. After validation of wear, we applied three sets of cutpoints for youth, including the most common standard (Freedson, 2005) and two calibrated to a single reference, (Romanzini uni- and triaxial, from Romanzini, 2014) to these data, estimating daily sedentary, light, moderate, vigorous and moderate-to-vigorous PA (MPA, VPA, MVPA). Stability of differences was assessed by comparing Romanzini's two sets of cutpoints. RESULTS: Relative agreement between cutpoints was closer for activity of lower intensities (largest difference for sedentary behaviour 9%) but increased for higher intensities (largest difference for light activity 40%, MPA 102%, VPA 88%; all p

Early after entry into monocytes, macrophages, dendritic cells, and resting CD4 T cells, HIV encounters a block, limiting reverse transcription (RT) of the incoming viral RNA genome. In this context, dNTP triphosphohydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) has been identified as a restriction factor, lowering the concentration of dNTP substrates to limit RT. The accessory lentiviral protein X (Vpx) proteins from the major simian immunodeficiency virus of rhesus macaque, sooty mangabey, and HIV-2 (SIVsmm/SIVmac/HIV-2) lineage packaged into virions target SAMHD1 for proteasomal degradation, increase intracellular dNTP pools, and facilitate HIV cDNA synthesis. We find that virion-packaged Vpx proteins from a second SIV lineage, SIV of red-capped mangabeys or mandrills (SIVrcm/mnd-2), increased HIV infection in resting CD4 T cells, but not in macrophages, and, unexpectedly, acted in the absence of SAMHD1 degradation, dNTP pool elevation, or changes in SAMHD1 phosphorylation. Vpx rcm/mnd-2 virion incorporation resulted in a dramatic increase of HIV-1 RT intermediates and viral cDNA in infected resting CD4 T cells. These analyses also revealed a barrier limiting HIV-1 infection of resting CD4 T cells at the level of nuclear import. Single amino acid changes in the SAMHD1-degrading Vpx mac239 allowed it to enhance early postentry steps in a Vpx rcm/mnd-2-like fashion. Moreover, Vpx enhanced HIV-1 infection of SAMHD1-deficient resting CD4 T cells of a patient with Aicardi-Goutières syndrome. These results indicate that Vpx, in addition to SAMHD1, overcomes a previously unappreciated restriction for lentiviruses at the level of RT that acts independently of dNTP concentrations and is specific to resting CD4 T cells.

Collective low-frequency molecular motions have large impact on chemical reactions and structural relaxation in liquids. So far, these modes have mostly been accessed indirectly by off-resonant optical pulses. Here, we provide evidence that intense terahertz (THz) pulses can resonantly excite reorientational-librational modes of aprotic and strongly polar liquids through coupling to the permanent molecular dipole moments. We observe a significantly enhanced response because the transient optical birefringence is up to an order of magnitude higher than obtained with optical excitation. Frequency-dependent measurements and a simple analytical model indicate that the enhancement arises from resonantly driven librations and their coupling to reorientational motion, assisted by the pump field and/or a cage translational mode. Our results open up the path to applications such as efficient molecular alignment, enhanced transient Kerr signals and systematic resonant nonlinear THz spectroscopy of the coupling between intermolecular modes in liquids.

In the learning process which aim is developing original creativity, has its central role complex thinking. This is important for the sensibilisation and intensification of the individual creative abilities. Multidisciplinary approach, various mind strategies and techniques of creating and resolving problems encourage by the individual and the group creativity, innovation, teamwork and critical thinking. The article represents four examples of the process in which new creative ideas, translated into complex graphical compositions representing the combination of architectural and fine arts contents, experience, ethical and esthetical sensitivity, existential self-awareness and the holistic personal development, are born.

BACKGROUND: Inflammatory Bowel Disease (IBD) patients are confronted with needs and concerns related to their disease. AIM: To explore information expectations of patients included in a national bilingual IBD cohort in Switzerland (SIBDC). METHODS: This is a mixed-methods study, comprising 1) a semi-narrative survey sent to 1506 patients from the SIBDC and 2) two focus groups conducted with 14 patients to explore and assess the relevance of the survey's findings. Data collected within the framework of the SIBDC was used to characterize survey's responders. RESULTS: 728 patients (48%) replied to the survey: 52.5% females, 56% Crohn's disease (CD), 87% secondary/tertiary level educated, 70% full/part-time employed. On average, 47% of patients sought for information, regardless of the disease stage; 27% of them were dissatisfied with information received at the time of first symptoms. During flares, 43% were concerned about drugs and therapies; in remission, 57% had concerns on research and developments; 27% searched for information linked to daily disease management. Information-seeking increased when active disease, for CD with high levels of perceived stress (OR = 2.47; p = 0.003), and for all with higher posttraumatic stress symptoms. The focus groups confirmed a perceived lack of information about general functioning, disease course, treatments and their risks, extra-intestinal symptoms and manifestations. CONCLUSIONS: Information remains insufficient for IBD patients. Lack of information in specific domains can potentially cause stress and hinder detection of symptoms. Better information should be considered as a potentially important component in improving patients' outcomes in IBD.

Background Cardiomyopathies represent a rare group of disorders often of genetic origin. While approximately 50% of genetic causes are known for other types of cardiomyopathies, the genetic spectrum of restrictive cardiomyopathy (RCM) is largely unknown. The aim of the present study was to identify the genetic background of idiopathic RCM and to compile the obtained genetic variants to the novel signalling pathways using in silico protein network analysis. Patients and Methods We used Illumina MiSeq setup to screen for 108 cardiomyopathy and arrhythmia-associated genes in 24 patients with idiopathic RCM. Pathogenicity of genetic variants was classified according to American College of Medical Genetics and Genomics classification. Results Pathogenic and likely-pathogenic variants were detected in 13 of 24 patients resulting in an overall genotype-positive rate of 54%. Half of the genotype-positive patients carried a combination of pathogenic, likely-pathogenic variants and variants of unknown significance. The most frequent combination included mutations in sarcomeric and cytoskeletal genes (38%). A bioinformatics approach underlined the mechanotransducing protein networks important for RCM pathogenesis. Conclusions Multiple gene mutations were detected in half of the RCM cases, with a combination of sarcomeric and cytoskeletal gene mutations being the most common. Mutations of genes encoding sarcomeric, cytoskeletal, and Z-line-associated proteins appear to have a predominant role in the development of RCM.

The severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging, highly pathogenic bunyavirus against which neither antivirals nor vaccines are available. The SFTSV glycoproteins, Gn and Gc, facilitate viral entry into host cells. Gn and Gc are generated from a precursor protein, Gn/Gc, but it is currently unknown how the precursor is converted into the single proteins and whether this process is required for viral infectivity. Employing a rhabdoviral pseudotyping system, we demonstrate that a predicted signal sequence at the N-terminus of Gc is required for Gn/Gc processing and viral infectivity while potential proprotein convertase cleavage sites in Gc are dispensable. Moreover, we show that expression of Gn or Gc alone is not sufficient for host cell entry while particles bearing both proteins are infectious, and we provide evidence that Gn facilitates Golgi transport and virion incorporation of Gc. Collectively, these results suggest that signal peptidase liberates mature Gc from the Gn/Gc precursor and that this process is essential for viral infectivity and thus constitutes a potential target for antiviral intervention. peerReviewed

Analysis of observations and model projections provides large-scale emergent constraints on the extent of CO2 fertilization, with estimated increases in gross primary productivity for both high-latitude and extratropical ecosystems under elevated atmospheric CO2 concentrations. Climate–carbon cycle models generally assume that elevated atmospheric CO2 concentrations will enhance terrestrial plant productivity. But the magnitude of this so-called CO2 fertilization effect remains uncertain—with implications for future climate change projections. This study provides large-scale constraints on the extent of CO2 fertilization with an estimated increase in gross primary productivity of 37 ± 9 per cent for high-latitude ecosystems and 32 ± 9 per cent for extratropical ecosystems for a doubling of atmospheric CO2 concentrations. Uncertainties in the response of vegetation to rising atmospheric CO2 concentrations1,2 contribute to the large spread in projections of future climate change3,4. Climate–carbon cycle models generally agree that elevated atmospheric CO2 concentrations will enhance terrestrial gross primary productivity (GPP). However, the magnitude of this CO2 fertilization effect varies from a 20 per cent to a 60 per cent increase in GPP for a doubling of atmospheric CO2 concentrations in model studies5,6,7. Here we demonstrate emergent constraints8,9,10,11 on large-scale CO2 fertilization using observed changes in the amplitude of the atmospheric CO2 seasonal cycle that are thought to be the result of increasing terrestrial GPP12,13,14. Our comparison of atmospheric CO2 measurements from Point Barrow in Alaska and Cape Kumukahi in Hawaii with historical simulations of the latest climate–carbon cycle models demonstrates that the increase in the amplitude of the CO2 seasonal cycle at both measurement sites is consistent with increasing annual mean GPP, driven in part by climate warming, but with differences in CO2 fertilization controlling the spread among the model trends. As a result, the relationship between the amplitude of the CO2 seasonal cycle and the magnitude of CO2 fertilization of GPP is almost linear across the entire ensemble of models. When combined with the observed trends in the seasonal CO2 amplitude, these relationships lead to consistent emergent constraints on the CO2 fertilization of GPP. Overall, we estimate a GPP increase of 37 ± 9 per cent for high-latitude ecosystems and 32 ± 9 per cent for extratropical ecosystems under a doubling of atmospheric CO2 concentrations on the basis of the Point Barrow and Cape Kumukahi records, respectively.

INTRODUCTION: Physical activity (PA) protects against most noncommunicable diseases and has been associated with decreased risk of allergic phenotype, which is increasing worldwide. However, the association is not always present; furthermore it is not clear whether it is strongest for asthma, rhinitis, symptoms of these, or atopic sensitization; which sex is most affected; or whether it can be explained by either avoidance of sport or exacerbation of symptoms by exercise. Interventions are thus difficult to target. METHODS: PA was measured by one-week accelerometry in 1137 Germans (mean age 15.6 years, 47% boys) from the GINIplus and LISAplus birth cohorts, and modeled as a correlate of allergic symptoms, sensitization, or reported doctor-diagnosed asthma or rhinitis. RESULTS: 8.3% of children had asthma, of the remainder 7.9% had rhinitis, and of the remainder 32% were sensitized to aero-allergens (atopic). 52% were lung-healthy controls. Lung-healthy boys and girls averaged 46.4 min and 37.8 min moderate-to-vigorous PA per day, of which 14.6 and 11.4 min was vigorous. PA in allergic girls was not altered, but boys with asthma got 13% less moderate and 29% less vigorous PA, and those with rhinitis with 13% less moderate PA, than lung-healthy boys. Both sexes participated comparably in sport (70 to 84%). Adolescents with wheezing (up to 68%, in asthma) and/or nose/eye symptoms (up to 88%, in rhinitis) were no less active. CONCLUSIONS: We found that asthma and rhinitis, but not atopy, were independently associated with low PA in boys, but not in girls. These results indicate that allergic boys remain a high-risk group for physical inactivity even if they participate comparably in sport. Research into the link between PA and allergy should consider population-specific and sex-specific effects, and clinicians, parents, and designers of PA interventions should specifically address PA in allergic boys to ensure full participation.

Circulating trimethylamine N-Oxide (TMAO) levels predict cardiovascular disease (CVD), possibly by impacting on cholesterol metabolism and oxidative stress. Because hepatic TMAO production is regulated by insulin signalling and it is unclear whether and to what extent circulating TMAO levels associate with CVD risk, independently of insulin resistance and its important determinants fatty liver and visceral obesity, we have now addressed this question in 220 subjects who participated in the Tübingen Lifestyle Intervention Program. Visceral fat mass (r = 0.40, p 20%). We provide novel information that increased serum TMAO levels associate with increased cIMT, independently of established cardiovascular risk markers, including insulin resistance, visceral obesity and fatty liver. Furthermore, the decrease of cIMT during a lifestyle intervention may be related to the decrease of TMAO levels.

Metabolic syndrome is characterized by insulin resistance, obesity, and dyslipidemia. It is the consequence of an imbalance between caloric intake and energy consumption. Adiponectin protects against metabolic syndrome. Insulin-induced signaling includes activation of PI3 kinase and protein kinase B (PKB)/Akt. PKB/Akt in turn inactivates glycogen synthase kinase (GSK) 3, a major regulator of metabolism. Here, we studied the significance of PI3K-dependent GSK3 inactivation for adiponectin formation in diet-induced metabolic syndrome. Mice expressing PI3K-insensitive GSK3 (gsk3(KI)) and wild-type mice (gsk3(WT)) were fed a high-fat diet. Compared with gsk3(WT) mice, gsk3(KI) mice were protected against the development of metabolic syndrome as evident from a markedly lower weight gain, lower total body and liver fat accumulation, better glucose tolerance, stronger hepatic insulin-dependent PKB/Akt phosphorylation, lower serum insulin, cholesterol, and triglyceride levels, as well as higher energy expenditure. Serum adiponectin concentration and the activity of transcription factor C/EBPα controlling the expression of adiponectin in adipose tissue was significantly higher in gsk3(KI) mice than in gsk3(WT) mice. Treatment with GSK3 inhibitor lithium significantly decreased the serum adiponectin concentration of gsk3(KI) mice and abrogated the difference in C/EBPα activity between the genotypes. Taken together, our data demonstrate that the expression of PI3K-insensitive GSK3 stimulates the production of adiponectin and protects from diet-induced metabolic syndrome.

The outer subventricular zone (OSVZ) is a germinal layer playing key roles in the development of the neocortex, with particular relevance in gyrencephalic species such as human and ferret, where it contains abundant basal radial glia cells (bRGCs) that promote cortical expansion. Here we identify a brief period in ferret embryonic development when apical RGCs generate a burst of bRGCs that become founders of the OSVZ. After this period, bRGCs in the OSVZ proliferate and self-renew exclusively locally, thereby forming a self-sustained lineage independent from the other germinal layers. The time window for the brief period of OSVZ bRGC production is delineated by the coincident downregulation of Cdh1 and Trnp1, and their upregulation reduces bRGC production and prevents OSVZ seeding. This mechanism in cortical development may have key relevance in brain evolution and disease., Funded by the German Research Foundation for vector production. The Spanish Ministry of Economy and Competitivity (MINECO) provided support to M.A.M-M. (Consolider fellowship), A.C. and V.F. (FPI fellowships), and in part to C.D.J.R. (Juan de la Cierva contract). The research leading to a part of these results received funding from the European Union Seventh Framework Programme FP7/2007–2013 under the project DESIRE (grant agreement no. 602531), European Research Council (309633) and MINECO (SAF2009-07367, BFU2012-33473 and CSD2007-00023) to V.B. and European Research Council grant (340793) to M.G. The Instituto de Neurociencias is a “Centre of Excellence Severo Ochoa”.

Determination of ovarian status and follicle monitoring are common methods of diagnosing female infertility. We evaluated the suitability of selective plane illumination microscopy (SPIM) for the study of ovarian follicles. The large field of view and fast acquisition speed of our SPIM system enables rendering of volumetric image stacks from intact whole porcine ovarian follicles, clearly visualizing follicular features including follicle volume and average diameter (70 μm–2.5 mm), their spherical asymmetry parameters, size of developing cumulus oophorus complexes (40 μm–110 μm), and follicular wall thickness (90 μm–120 μm). Follicles at all developmental stages were identified. A distribution of the theca thickness was measured for each follicle, and a relationship between these distributions and the stages of follicular development was discerned. The ability of the system to non-destructively generate sub-cellular resolution 3D images of developing follicles, with excellent image contrast and high throughput capacity compared to conventional histology, suggests that it can be used to monitor follicular development and identify structural abnormalities indicative of ovarian ailments. Accurate folliculometric measurements provided by SPIM images can immensely help the understanding of ovarian physiology and provide important information for the proper management of ovarian diseases.

The identification of tumor subpopulations that adversely affect patient outcomes is essential for a more targeted investigation into how tumors develop detrimental phenotypes, as well as for personalized therapy. Mass spectrometry imaging has demonstrated the ability to uncover molecular intratumor heterogeneity. The challenge has been to conduct an objective analysis of the resulting data to identify those tumor subpopulations that affect patient outcome. Here we introduce spatially mapped t-distributed stochastic neighbor embedding (t-SNE), a nonlinear visualization of the data that is able to better resolve the biomolecular intratumor heterogeneity. In an unbiased manner, t-SNE can uncover tumor subpopulations that are statistically linked to patient survival in gastric cancer and metastasis status in primary tumors of breast cancer.