Search

This paper describes the rationale and the protocol of the first component of the third simulation round of the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP3a, www.isimip.org) and the associated set of climate-related and direct human forcing data (CRF and DHF, respectively). The observation-based climate-related forcings for the first time include high-resolution observational climate forcings derived by orographic downscaling, monthly to hourly coastal water levels, and wind fields associated with historical tropical cyclones. The DHFs include land use patterns, population densities, information about water and agricultural management, and fishing intensities. The ISIMIP3a impact model simulations driven by these observation-based climate-related and direct human forcings are designed to test to what degree the impact models can explain observed changes in natural and human systems. In a second set of ISIMIP3a experiments the participating impact models are forced by the same DHFs but a counterfactual set of atmospheric forcings and coastal water levels where observed trends have been removed. These experiments are designed to allow for the attribution of observed changes in natural, human and managed systems to climate change, rising CH4 and CO2 concentrations, and sea level rise according to the definition of the Working Group II contribution to the IPCC AR6.

Zusammenfassung Ziel der Studie Zielsetzung dieser Analyse war die Erfassung sozialepidemiologischer Merkmale einer spezifischen Probandenpopulation nebst der Identifizierung von Abhängigkeiten zwischen vormaligen öffentlich-rechtlichen Unterbringungen und nachfolgenden Beurteilungen der individuellen Fahreignung durch den ÖGD. Methodik Für die retrospektive Datenanalyse wurden Dokumente von 87 Personen ausgewertet, die in den Jahren 2015 bis 2019 in psychiatrischen Facheinrichtungen öffentlich-rechtlich untergebracht wurden. Unter Verwendung des Software Pakets SAS wurden Häufigkeitsverteilungen und mittels Chi-Quadrat-Test statistische Abhängigkeiten zwischen spezifischen Merkmalen der Unterbringung und der Beurteilung der Fahreignung identifiziert. Ergebnisse Innerhalb der Studienkohorte lag das Durchschnittsalter bei 43,5 Jahren (Spannbreite von 16 bis 82 Jahren), wobei 59% männlichen Geschlechtes (versus 41% weiblich) waren. Häufigster Unterbringungsanlass waren Suizidankündigungen durch die Betroffenen. In einem Drittel der Fälle waren diese Personen zum Zeitpunkt der Unterbringung alkoholisiert und in 3 von 87 Fällen war ein Drogenkonsum dokumentiert. Bei 74% erfolgte die Unterbringung ausschließlich aufgrund einer Eigengefährdung, bei 26% wurde (zusätzlich) eine Fremdgefährdung festgestellt und bei 20% der Betroffenen kam es zu einem verbalen und/oder körperlichen Widerstand gegen die Vollstreckung der Unterbringung. Die verkehrsmedizinische Begutachtung erbrachte bei 57% der Fälle Zweifel an der Fahreignung, sodass dieser Sachverhalt an die Fahrerlaubnisbehörde weitergeleitet wurde. Statistisch signifikante Abhängigkeiten zeigten sich zwischen dem Unterbringungsanlass, der Gefährdungsart und einem Widerstand gegen die Unterbringungsvollstreckung zum Ergebnis der Fahreignungsbeurteilung durch den ÖGD. Schlussfolgerung Die Datengrundlagen über öffentlich-rechtlich untergebrachte Personen in Verbindung mit verkehrsmedizinischen Fragestellungen sollten qualitativ optimiert werden, wozu das auf der Grundlage des Bayerischen Psychisch-Kranken-Hilfe-Gesetz (BayPsychKHG) eingeführte anonyme Melderegister einen Beitrag leisten kann. Ergänzend sind weitergehende Qualifizierungsmaßnahmen aller involvierten Akteure im Sinne eines effektiven Qualitätsmanagements notwendig.

Single-Carrier Frequency Division Multiple Access (SC-FDMA) is a promising technique for high data rate indoor Terahertz (THz) communications in future beyond 5G systems. In an indoor propagation scenario, the Line-Of-Sight (LOS) component may be blocked by the obstacles. Thus, efficient THz SC-FDMA communications require a fast and reliable Beam Alignment (BA) method for both LOS and Non-Line-Of-Sight (NLOS) scenarios. In this paper, we first adopt the hierarchical discrete Fourier transform codebook for LOS BA, and introduce the hierarchical k-means codebook for NLOS BA to improve the beamforming gain. Simulation results illustrate that the hierarchical DFT codebook and the hierarchical k-means codebook can achieve the beamforming gain close to that of the maximum ratio transmission in LOS and NLOS cases, respectively. Based on these two codebooks, we propose a Multi-Armed Bandit (MAB) algorithm named Hierarchical Beam Alignment (HBA) for single-user SC-FDMA THz systems to reduce the BA latency. HBA utilizes a hierarchical structure in the adopted codebook and prior knowledge regarding the noise power to speed up the BA process. Both theoretical analysis and simulation results indicate that the proposed BA method converges to the optimal beam with high probability for both the hierarchical DFT codebook and the hierarchical k-means codebook in the LOS and NLOS scenarios, respectively. The latency introduced by HBA is significantly lower when compared to an exhaustive search method and other MAB-based methods.

ZusammenfassungEpileptische Anfälle als Folge eines Schädel-Hirn-Traumas (SHT) werden entsprechend ihres zeitlichen Auftretens in Bezug zum ursächlichen Ereignis in Frühanfälle (bis zu 7 Tage nach Trauma) und Spätanfälle (> 7 Tage nach Trauma) unterteilt. Immediatanfälle werden als Untergruppe der Frühanfälle abgegrenzt und sind als akut symptomatische Anfälle, die innerhalb von 24 h nach dem SHT auftreten, definiert. Eine posttraumatische Epilepsie liegt bei ≥ 2 epileptischen Anfällen als Folge eines Traumas vor. Die meisten posttraumatischen Anfälle ereignen sich innerhalb der ersten 2 Jahre nach dem SHT. Schwere Traumen korrelieren mit einem deutlich erhöhten Risiko für Früh- und Spätanfälle, bedingt durch die direkten Folgen der Gewalteinwirkung und die sekundären pathophysiologischen Reaktionsmuster auf zellulärer Ebene einschließlich neuroinflammatorischer Prozesse. Der prophylaktische Einsatz von Antikonvulsiva wird generell nicht empfohlen. Diese können das Auftreten von Frühanfällen reduzieren, haben aber keinen relevanten Einfluss auf die durch das Trauma eingeleitete Epileptogenese bzw. das Auftreten von Spätanfällen oder einer posttraumatischen Epilepsie.

The decarbonization of India’s economy will affect economic actors differently. Here we study the distributional effects of climate policy in India, taking the specific role of structural economic change into account. We contrast distributional effects from climate policy with distributional effects from structural change and quantify how far carbon pricing supports structural change and economic development. We develop and apply a comprehensive model framework that combines long-term growth and medium-term trade dynamics related to structural change with detailed household income and expenditure data for India. Our results emphasize that distributional effects from structural change are stronger than from carbon pricing. Consequently, governments should not focus solely on the distributional effects of climate policy, but also consider the larger context of economic transformation processes when designing and implementing social policies.

ZusammenfassungDas Spektrum der Entwicklungsstörungen gehört zum Alltag des Facharztes für Kinder- und Jugendmedizin. Durch den zunehmenden Einsatz von „Next-generation sequencing“-Methoden in den letzten 10 Jahren werden die genetischen Hintergründe besser verstanden. Hiermit eröffnen sich Möglichkeiten in der Routinediagnostik und auch für pathomechanismusbasierte individuelle Therapieansätze („personalized precision medicine“). Dieser Beitrag beschreibt die patientenzentrierte Einbettung einer multidisziplinären Tagesklinik („Murmeltiersprechstunde“) zu zeit- und ressourcensparender Diagnostik und Behandlung von Entwicklungsstörungen. Bei 43 an der Murmeltiersprechstunde teilnehmenden Kindern (Durchschnittsalter 4,9 Jahre) mit einer Entwicklungsstörung konnte in 24 Fällen (56 %) eine pathogene Variante in einem bereits bekannten Krankheitsgen, in 4 weiteren Fällen (12 %) in einem Kandidatengen gefunden werden und somit eine Diagnose gestellt werden. Hierdurch konnte in 6 Fällen (14 %) eine pathomechanismusbasierte Therapie erfolgreich eingeleitet werden. Die durchschnittliche Dauer zwischen der Aufnahme in der Tagesklinik und der Befundmitteilung betrug 6 Monate. Die Murmeltiersprechstunde zeigt, wie „personalized precision medicine“ in den Alltag einer Kinderklinik eingebaut werden kann und direkten Einfluss auf die Behandlung hat.

ZusammenfassungGenetische Defekte werden vielfach noch als Schicksal empfunden, mit dem man sich Zeit seines Lebens abfinden muss. Es stimmt, dass vererbte Anlagen in vielen Fällen zu schweren Krankheiten führen, allerdings stimmt es auch, dass der Anteil von genetischen Defekten, bei denen eine Therapieoption besteht, stetig wächst und sich der Ausbruch von Krankheitssymptomen bei einigen davon bestenfalls gänzlich verhindern lässt. Die Kenntnis des genauen molekularen Krankheitsmechanismus liefert oft die Grundlage für einen Therapieansatz. Zum Auffinden des genetischen Defekts haben die Möglichkeiten der genomweiten Sequenzierung und ihr mittlerweile breiter Einsatz in der Diagnostik entscheidend beigetragen. Nach dem Nachweis einer genetischen Veränderung braucht es aber noch die Untersuchung der pathobiochemischen Konsequenzen auf zellulärer und systemischer Ebene. Dabei handelt es sich oft um einen längeren Prozess, da der volle Umfang von Funktionsausfällen nicht immer auf Anhieb erkennbar ist. Bei metabolischen Defekten kann die Therapie ein Auffüllen von fehlenden Produkten oder eine Reduktion von giftigen Substraten sein. Oft lässt sich auch die Restfunktion von betroffenen „pathways“ verbessern. Neuerdings haben Therapien mit direkter Korrektur des betroffenen Gendefekts Einzug in die therapeutische Anwendung gefunden. Da die ersten Krankheitssymptome in vielen Fällen früh im Leben auftreten, trifft die Kinderheilkunde eine Vorreiterrolle in der Entwicklung von Therapieansätzen.

Contains fulltext : 231549.pdf (Publisher’s version ) (Closed access) PURPOSE: The 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants provide a framework to standardize terminology in the classification of variants uncovered through genetic testing. We aimed to assess the validity of utilizing clinical response to therapies specifically targeted to a suspected disease in clarifying variant pathogenicity. METHODS: Five families with disparate clinical presentations and different genetic diseases evaluated and treated in multiple diagnostic settings are summarized. RESULTS: Extended evaluations indicated possible genetic diagnoses and assigned candidate causal variants, but the cumulative clinical, biochemical, and molecular information in each instance was not completely consistent with the identified disease. Initiation of treatment specific to the suspected diagnoses in the affected individuals led to clinical improvement in all five families. CONCLUSION: We propose that the effect of therapies that are specific and targeted to treatable genetic diseases embodies an in vivo physiological response and could be considered as additional criteria within the 2015 ACMG/AMP guidelines in determining genomic variant pathogenicity.

We report the characterization of amphiphilic aminoglycoside conjugates containing luminophores with aggregation‐induced emission properties as transfection reagents. These inherently luminescent transfection vectors are capable of binding plasmid DNA through electrostatic interactions; this binding results in an emission “on” signal due to restriction of intramolecular motion of the luminophore core. The luminescent cationic amphiphiles effectively transferred plasmid DNA into mammalian cells (HeLa, HEK 293T), as proven by expression of a red fluorescent protein marker. The morphologies of the aggregates were investigated by microscopy as well as ζ‐potential and dynamic light‐scattering measurements. The transfection efficiencies using luminescent cationic amphiphiles were similar to that of the gold‐standard transfection reagent Lipofectamine® 2000., Transfection tracker: Conjugates of luminophores with aggregation‐induced emission properties linked to the aminoglycoside tobramycin are reported. These compounds reveal an emission “on” behavior upon plasmid‐DNA binding and are able to transfect different mammalian cell lines. The cellular uptake was investigated using the emission properties of the formed plasmid DNA‐vector assemblies.

Nach einer akuten schweren Schadigung des Zentralnervensystems soll sich unmittelbar an die Akutphase auf der Intensivstation die Fruhrehabilitation in einem spezialisierten Zentrum anschliesen. In dieser Krankheitsphase sind die Kinder weiter instabil. Es besteht ein hoher medizinischer und pflegerischer Betreuungsaufwand, der die Uberwachungs- und Behandlungsmoglichkeiten eines Akutkrankenhauses erfordert. Zentrale arztliche Aufgaben sind die Verantwortung der akutmedizinischen Behandlung und die Steuerung der Therapie im multiprofessionellen Team. Viele Kinder werden nicht mehr vollstandig gesund und mit oft schweren Behinderungen entlassen. Die Begleitung der Kinder und ihrer Familien in diese neuen Lebensumstande sowie die Vorbereitung der sozialen Integration und Teilhabe sind dann herausfordernde, zentrale Aufgaben.

The objective of this analysis was to record the social and epidemiological characteristics of a specific sample population, as well as to identify any associations between a previous commitment to a public facility on legal grounds and subsequent assessments of an individual's fitness to drive as per the National Health Service (or "ÖGD").For the retrospective data analysis, the documents of 87 subjects were evaluated who had been committed to public psychiatric institutions on legal grounds between 2015 and 2019. Using the SAS software package, frequency distributions and statistical relationships were identified between specific features of the commitment to accommodation and the assessment of fitness to drive by means of Chi-squared testing.The average age of the study cohort was 43.5 years (range: 16-82 years; male: 59%). The most frequent grounds for commitment to a facility were suicidal intentions expressed by the person in question. In one third of the cases, these individuals were under the influence of alcohol at the time of commitment to the facility, and drug use was documented in 3 of the 87 cases. In 74% of cases, confinement was solely due to an individual's risk to themselves; in 26% a risk to others was (additionally) identified; and in 20% of those affected, there was verbal and/or physical resistance to commitment to the accommodation facility. In 57% of cases, the medical evaluation raised doubts about the individual's fitness to drive, resulting in the matter being referred on to the driving license authority. Statistically significant associations were demonstrated between: a) the grounds for commitment to a facility; the type of risk; and resistance to commitment being enforced, and b) the results of a fitness-to-drive assessment carried out by the ÖGD.The data available on individuals committed to public facilities on legal grounds in connection with driving-related medical issues should be optimised to improve quality, whereby the anonymous registration system, introduced on the basis of the Bavarian Mental Health Act ("BayPsychoKHG"), can make a contribution in this regard. In addition, further qualification measures for effective quality management are necessary for all actors involved.Zielsetzung dieser Analyse war die Erfassung sozialepidemiologischer Merkmale einer spezifischen Probandenpopulation nebst der Identifizierung von Abhängigkeiten zwischen vormaligen öffentlich-rechtlichen Unterbringungen und nachfolgenden Beurteilungen der individuellen Fahreignung durch den ÖGD.Für die retrospektive Datenanalyse wurden Dokumente von 87 Personen ausgewertet, die in den Jahren 2015 bis 2019 in psychiatrischen Facheinrichtungen öffentlich-rechtlich untergebracht wurden. Unter Verwendung des Software Pakets SAS wurden Häufigkeitsverteilungen und mittels Chi-Quadrat-Test statistische Abhängigkeiten zwischen spezifischen Merkmalen der Unterbringung und der Beurteilung der Fahreignung identifiziert.Innerhalb der Studienkohorte lag das Durchschnittsalter bei 43,5 Jahren (Spannbreite von 16 bis 82 Jahren), wobei 59% männlichen Geschlechtes (versus 41% weiblich) waren. Häufigster Unterbringungsanlass waren Suizidankündigungen durch die Betroffenen. In einem Drittel der Fälle waren diese Personen zum Zeitpunkt der Unterbringung alkoholisiert und in 3 von 87 Fällen war ein Drogenkonsum dokumentiert. Bei 74% erfolgte die Unterbringung ausschließlich aufgrund einer Eigengefährdung, bei 26% wurde (zusätzlich) eine Fremdgefährdung festgestellt und bei 20% der Betroffenen kam es zu einem verbalen und/oder körperlichen Widerstand gegen die Vollstreckung der Unterbringung. Die verkehrsmedizinische Begutachtung erbrachte bei 57% der Fälle Zweifel an der Fahreignung, sodass dieser Sachverhalt an die Fahrerlaubnisbehörde weitergeleitet wurde. Statistisch signifikante Abhängigkeiten zeigten sich zwischen dem Unterbringungsanlass, der Gefährdungsart und einem Widerstand gegen die Unterbringungsvollstreckung zum Ergebnis der Fahreignungsbeurteilung durch den ÖGD.Die Datengrundlagen über öffentlich-rechtlich untergebrachte Personen in Verbindung mit verkehrsmedizinischen Fragestellungen sollten qualitativ optimiert werden, wozu das auf der Grundlage des Bayerischen Psychisch-Kranken-Hilfe-Gesetz (BayPsychKHG) eingeführte anonyme Melderegister einen Beitrag leisten kann. Ergänzend sind weitergehende Qualifizierungsmaßnahmen aller involvierten Akteure im Sinne eines effektiven Qualitätsmanagements notwendig.

Background and ObjectiveThe spectrum of myelin oligodendrocyte glycoprotein (MOG) antibody–associated disorder (MOGAD) comprises monophasic diseases such as acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), and transverse myelitis and relapsing courses of these presentations. Persistently high MOG antibodies (MOG immunoglobulin G [IgG]) are found in patients with a relapsing disease course. Prognostic factors to determine the clinical course of children with a first MOGAD are still lacking. The objective of the study is to assess the clinical and laboratory prognostic parameters for a risk of relapse and the temporal dynamics of MOG‐IgG titers in children with MOGAD in correlation with clinical presentation and disease course.MethodsIn this prospective multicenter hospital-based study, children with a first demyelinating attack and complete data set comprising clinical and radiologic findings, MOG-IgG titer at onset, and clinical and serologic follow-up data were included. Serum samples were analyzed by live cell-based assay, and a titer level of ≥1:160 was classified as MOG-IgG–positive.ResultsOne hundred sixteen children (f:m = 57:59) with MOGAD were included and initially diagnosed with ADEM (n = 59), unilateral ON (n = 12), bilateral ON (n = 16), myelitis (n = 6), neuromyelitis optica spectrum disorder (n = 8) or encephalitis (n = 6). The median follow-up time was 3 years in monophasic and 5 years in relapsing patients. There was no significant association between disease course and MOG-IgG titers at onset, sex, age at presentation, or clinical phenotype. Seroconversion to MOG-IgG–negative within 2 years of the initial event showed a significant risk reduction for a relapsing disease course. Forty-two/one hundred sixteen patients (monophasic n = 26, relapsing n = 16) had serial MOG-IgG testing in years 1 and 2 after the initial event. In contrast to relapsing patients, monophasic patients showed a significant decrease of MOG-IgG titers during the first and second years, often with seroconversion to negative titers. During the follow-up, MOG-IgG titers were persistently higher in relapsing than in monophasic patients. Decrease in MOG-IgG of ≥3 dilution steps after the first and second years was shown to be associated with a decreased risk of relapses. In our cohort, no patient experienced a relapse after seroconversion to MOG-IgG–negative.DiscussionIn this study, patients with declining MOG-IgG titers, particularly those with seroconversion to MOG-IgG–negative, are shown to have a significantly reduced relapse risk.

Contains fulltext : 248231.pdf (Publisher’s version ) (Open Access) OBJECTIVE: ATP synthase (ATPase) is responsible for the majority of ATP production. Nevertheless, disease phenotypes associated with mutations in ATPase subunits are extremely rare. We aimed at expanding the spectrum of ATPase-related diseases. METHODS: Whole-exome sequencing in cohorts with 2,962 patients diagnosed with mitochondrial disease and/or dystonia and international collaboration were used to identify deleterious variants in ATPase-encoding genes. Findings were complemented by transcriptional and proteomic profiling of patient fibroblasts. ATPase integrity and activity were assayed using cells and tissues from 5 patients. RESULTS: We present 10 total individuals with biallelic or de novo monoallelic variants in nuclear ATPase subunit genes. Three unrelated patients showed the same homozygous missense ATP5F1E mutation (including one published case). An intronic splice-disrupting alteration in compound heterozygosity with a nonsense variant in ATP5PO was found in one patient. Three patients had de novo heterozygous missense variants in ATP5F1A, whereas another 3 were heterozygous for ATP5MC3 de novo missense changes. Bioinformatics methods and populational data supported the variants' pathogenicity. Immunohistochemistry, proteomics, and/or immunoblotting revealed significantly reduced ATPase amounts in association to ATP5F1E and ATP5PO mutations. Diminished activity and/or defective assembly of ATPase was demonstrated by enzymatic assays and/or immunoblotting in patient samples bearing ATP5F1A-p.Arg207His, ATP5MC3-p.Gly79Val, and ATP5MC3-p.Asn106Lys. The associated clinical profiles were heterogeneous, ranging from hypotonia with spontaneous resolution (1/10) to epilepsy with early death (1/10) or variable persistent abnormalities, including movement disorders, developmental delay, intellectual disability, hyperlactatemia, and other neurologic and systemic features. Although potentially reflecting an ascertainment bias, dystonia was common (7/10). INTERPRETATION: Our results establish evidence for a previously unrecognized role of ATPase nuclear-gene defects in phenotypes characterized by neurodevelopmental and neurodegenerative features. ANN NEUROL 2022;91:225-237.

This paper presents the new and now open-source version 2.1 of the REgional Model of INvestments and Development (REMIND). REMIND, as an integrated assessment model (IAM), provides an integrated view of the global energy–economy–emissions system and explores self-consistent transformation pathways. It describes a broad range of possible futures and their relation to technical and socio-economic developments as well as policy choices. REMIND is a multiregional model incorporating the economy and a detailed representation of the energy sector implemented in the General Algebraic Modeling System (GAMS). It uses non-linear optimization to derive welfare-optimal regional transformation pathways of the energy-economic system subject to climate and sustainability constraints for the time horizon from 2005 to 2100. The resulting solution corresponds to the decentralized market outcome under the assumptions of perfect foresight of agents and internalization of external effects. REMIND enables the analyses of technology options and policy approaches for climate change mitigation with particular strength in representing the scale-up of new technologies, including renewables and their integration in power markets. The REMIND code is organized into modules that gather code relevant for specific topics. Interaction between different modules is made explicit via clearly defined sets of input and output variables. Each module can be represented by different realizations, enabling flexible configuration and extension. The spatial resolution of REMIND is flexible and depends on the resolution of the input data. Thus, the framework can be used for a variety of applications in a customized form, balancing requirements for detail and overall runtime and complexity.

The erythrocyte sedimentation rate (ESR) is one of the oldest medical diagnostic tools. However, currently there is some debate on the structure formed by the cells during the sedimentation process. While the conventional view is that erythrocytes sediment as separate aggregates, others have suggested that they form a percolating gel, similar to other colloidal suspensions. A direct probing of the structures formed by erythrocytes in blood at stasis is then required to settle these discrepancies. Here, we report observations performed with three different optical imaging techniques: direct light transmission through thin samples, two-photon microscopy and light-sheet microscopy. All techniques revealed a dynamic structure of a channeling gel but with differences in the resolved details. A quantitative analysis of the erythrocyte related processes and interactions during the sedimentation need a further refinement of the experimental set-ups.

Single-carrier frequency division multiple access (SC-FDMA) is a promising technique for high data rate Terahertz (THz) communications in future beyond 5G systems. Beam alignment (BA) is considered as a mandatory solution to establish a reliable communication link in SC-FDMA THz communication. However, existing BA methods introduce a large latency in searching for the optimal beam. In this paper, we propose a multi-armed bandit algorithm referred to as hierarchical beam alignment (HBA) for single-user SC-FDMA THz systems to reduce the beam alignment latency. HBA utilizes a hierarchical structure in the adopted codebook and the prior knowledge regarding the frequency-selective fading of the channel to speed up the BA process. Both theoretical analysis and simulation results illustrate that HBA converges to the optimal beam with high probability. The latency introduced by HBA is significantly lower compared to an exhaustive search method.

Melanoidins are formed in foods during processing through the Maillard reaction between carbohydrates and amino compounds. The aim of this study was to draw conclusions about the formation mechanism and the structure of melanoidins formed at low water contents and low temperatures. In the Maillard reaction of d-glucose and γ-aminobutyric acid at low water contents 3-deoxyglucosone is the most important intermediate. Therefore, we used the reaction of 3-deoxyglucosone with γ-aminobutyric acid or β-alanine as a simplified model system. The degradation of 3-deoxyglucosone and the color formation of the formed melanoidins were determined. In addition, the reaction mixture was analyzed with high-resolution mass spectrometry and a Kendrick analysis was applied. Oligomers consisting of up to four molecules of 3-deoxyglucosone and three amino acids and their respective dehydration products with furanoidic structure were detected. The melanoidin structure of C-C linked monomeric units postulated by Kroh et al. could be confirmed.

BackgroundImmune-stimulatory agents, like agonists of the innate immune receptor RIG-I, are currently tested in clinical trials as an intratumoral treatment option for patients with unresectable melanoma, aiming to enhance anti-tumor T cell responses. Switching of melanoma toward a dedifferentiated cell state has recently been linked to T cell and therapy resistance. It remains to be determined whether RIG-I agonists affect melanoma differentiation, potentially leading to T cell resistance.MethodsPatient metastases-derived melanoma cell lines were treated with the synthetic RIG-I agonist 3pRNA, and effects on tumor cell survival, phenotype and differentiation were determined. Transcriptomic data sets from cell lines and metastases were analyzed for associations between RIG-I (DDX58) and melanoma differentiation markers and used to define signaling pathways involved in RIG-I-driven dedifferentiation. The impact of 3pRNA-induced melanoma dedifferentiation on CD8 T cell activation was studied in autologous tumor T cell models.ResultsRIG-I activation by 3pRNA induced apoptosis in a subpopulation of melanoma cells, while the majority of tumor cells switched into a non-proliferative cell state. Those persisters displayed a dedifferentiated cell phenotype, marked by downregulation of the melanocytic lineage transcription factor MITF and its target genes, including melanoma differentiation antigens (MDA). Transition into the MITFlow/MDAlow cell state was JAK-dependent, with some cells acquiring nerve growth factor receptor expression. MITFlow/MDAlow persisters switched back to the proliferative differentiated cell state when RIG-I signaling declined. Consistent with our in vitro findings, an association between melanoma dedifferentiation and high RIG-I (DDX58) levels was detected in transcriptomic data from patient metastases. Notably, despite their dedifferentiated cell phenotype, 3pRNA-induced MITFlow/MDAlow persisters were still efficiently targeted by autologous CD8 tumor-infiltrating T lymphocytes (TILs).ConclusionsOur results demonstrate that RIG-I signaling in melanoma cells drives a transient phenotypic switch toward a non-proliferative dedifferentiated persister cell state. Despite their dedifferentiation, those persisters are highly immunogenic and sensitive toward autologous TILs, challenging the concept of melanoma dedifferentiation as a general indicator of T cell resistance. In sum, our findings support the application of RIG-I agonists as a therapeutic tool for the generation of long-term clinical benefit in non-resectable melanoma.

Background Mr-proANP is a biomarker produced in atrial and left ventricular myocardium. We investigated the effect of combined measurement of mr-proANP and high-sensitive cardiac Troponin I assay of the penultimate generation (s-cTnI) for an early type-1 and type-2 NSTE-ACS rule-out with emphasis on the very early presenters' subgroup with symptom onset time (SOT) ≤ 2 h. Methods This was a prospective cohort study of 311 consecutive patients admitted to ER with symptoms suggestive of an acute coronary syndrome (ACS). All patients had baseline mr-proANP and s-cTnI measurements. Results Of the total cohort, 17.6% (n = 55) had final diagnosis of NSTE-ACS: 9.6% (n = 30) had an angiographically-confirmed type-1 infarction and 8.0% (n = 25) had type-2 infarction. In the subgroup of very early presenters (SOT ≤ 2 h) the negative predictive value (NPV) of s-cTnI for type-1 NSTE-ACS was 96.7% (95%-CI: 87.5–99.4) and the NPV of mr-proANP was 100% (95%-CI: 87.1–100). The dual biomarker strategy yielded an NPV of 100% (95%-CI: 86.7–100). In the same time-related subgroup, the NPV of s-cTnI alone for type-2 was 98.3% (95%-CI: 89.8–99.9) and the NPV of mr-proANP was 97.0% (95%-CI: 82.5–100). The combination of biomarker increased the NPV to 100% (95%-CI: 86.7–100). Conclusions Our study demonstrated an immediate release pattern of mr-proANP in NSTE-ACS that may bridge the silent troponin time phenomenon when highest-sensitivity cardiac troponin assays are not used. This concept performed best in the very early presenters' subgroup with an excellent NPV of 100% and might result in an early rule-out of NSTE-ACS thus accelerating the diagnostic work-up.

Ambitious climate policies, as well as economic development, education, technological progress and less resource-intensive lifestyles, are crucial elements for progress towards the UN Sustainable Development Goals (SDGs). However, using an integrated modelling framework covering 56 indicators or proxies across all 17 SDGs, we show that they are insufficient to reach the targets. An additional sustainable development package, including international climate finance, progressive redistribution of carbon pricing revenues, sufficient and healthy nutrition and improved access to modern energy, enables a more comprehensive sustainable development pathway. We quantify climate and SDG outcomes, showing that these interventions substantially boost progress towards many aspects of the UN Agenda 2030 and simultaneously facilitate reaching ambitious climate targets. Nonetheless, several important gaps remain; for example, with respect to the eradication of extreme poverty (180 million people remaining in 2030). These gaps can be closed by 2050 for many SDGs while also respecting the 1.5 °C target and several other planetary boundaries. Current action is insufficient to meet both the Paris Agreement and the Sustainable Development Goals. Integrated model-based analysis shows that strong interventions across many dimensions, together with ambitious lifestyle change, are needed to enable real progress towards the UN Agenda 2030.

Summary Local cell contraction pulses play important roles in tissue and cell morphogenesis. Here, we improve a chemo-optogenetic approach and apply it to investigate the signal network that generates these pulses. We use these measurements to derive and parameterize a system of ordinary differential equations describing temporal signal network dynamics. Bifurcation analysis and numerical simulations predict a strong dependence of oscillatory system dynamics on the concentration of GEF-H1, an Lbc-type RhoGEF, which mediates the positive feedback amplification of Rho activity. This prediction is confirmed experimentally via optogenetic tuning of the effective GEF-H1 concentration in individual living cells. Numerical simulations show that pulse amplitude is most sensitive to external inputs into the myosin component at low GEF-H1 concentrations and that the spatial pulse width is dependent on GEF-H1 diffusion. Our study offers a theoretical framework to explain the emergence of local cell contraction pulses and their modulation by biochemical and mechanical signals., Graphical Abstract, Highlights • Cell contraction dynamics are investigated via acute chemo-optogenetic perturbations • A theoretical model predicts GEF-H1-dependent switches in pulsatile Rho dynamics • Experimental manipulations of cytosolic GEF-H1 levels confirm model predictions • Local pulsatile dynamics are generated by coupling feedback regulation and diffusion, Kamps et al. derive a reaction-diffusion system that generates subcellular activity pulses of the cell contraction regulator Rho. System parameters are obtained by combining perturbation-response analyses with theoretical investigations. Multiple switches in activity dynamics, which are dependent on the positive feedback mediator GEF-H1, are predicted by theory and confirmed experimentally.

Purpose BiallelicCADvariants underlie CAD deficiency (or early infantile epileptic encephalopathy-50, [EIEE-50]), an error of pyrimidine de novo biosynthesis amenable to treatment via the uridine salvage pathway. We further define the genotype and phenotype with a focus on treatment. Methods Retrospective case series of 20 patients. Results Our study confirms CAD deficiency as a progressive EIEE with recurrent status epilepticus, loss of skills, and dyserythropoietic anemia. We further refine the phenotype by reporting a movement disorder as a frequent feature, and add that milder courses with isolated developmental delay/intellectual disability can occur as well as onset with neonatal seizures. With no biomarker available, the diagnosis relies on genetic testing and functional validation in patient-derived fibroblasts. Underlying pathogenic variants are often rated as variants of unknown significance, which could lead to underrecognition of this treatable disorder. Supplementation with uridine, uridine monophosphate, or uridine triacetate in ten patients was safe and led to significant clinical improvement in most patients. Conclusion We advise a trial with uridine (monophosphate) in all patients with developmental delay/intellectual disability, epilepsy, and anemia; all patients with status epilepticus; and all patients with neonatal seizures until (genetically) proven otherwise or proven unsuccessful after 6 months. CAD deficiency might represent a condition for genetic newborn screening.