Design and Implementation of Hierarchical Digital Twins in Industrial Production Environments

The increasing requirements for industrial production environments due to customer expectations, the implementation of batch size 1, and further automation of production processes are confronting companies with new challenges. In particular, the emergence of cyber-physical systems is influencing and complicating manufacturing processes by capturing an increasing amount of information within production facilities. Digital twins are an interdisciplinary technology that may solve these issues because they serve to monitor, control, and optimize cyber-physical systems by creating a digital representation of real-world objects. Existing concepts for digital twins usually consider specific and independent objects. This is of limited use for production environments due to a multitude of different machines and associated sensor types. Therefore, we propose a requirements catalog, concept, and prototypical implementation for the hierarchical structuring of digital twins in this paper

History and evolution of the afroalpine fora: in the footsteps of Olov Hedberg

The monumental work of Olov Hedberg provided deep insights into the spectacular and fragmented tropical alpine flora of the African sky islands. Here we review recent molecular and niche modelling studies and re-examine Hedberg’s hypotheses and conclusions. Colonisation started when mountain uplift established the harsh diurnal climate with nightly frosts, accelerated throughout the last 5 Myr (Plio-Pleistocene), and resulted in a flora rich in local endemics. Recruitment was dominated by long-distance dispersals (LDDs) from seasonally cold, remote areas, mainly in Eurasia. Colonisation was only rarely followed by substantial diversification. Instead, most of the larger genera and even species colonised the afroalpine habitat multiple times independently. Conspicuous parallel evolution occurred among mountains, e.g., of gigantism in Lobelia and Dendrosenecio and dwarf shrubs in Alchemilla. Although the alpine habitat was ~ 8 times larger and the treeline was ~ 1000 m lower than today during the Last Glacial Maximum, genetic data suggest that the flora was shaped by strong intermountain isolation interrupted by rare LDDs rather than ecological connectivity. The new evidence points to a much younger and more dynamic island scenario than envisioned by Hedberg: the afroalpine flora is unsaturated and fragile, it was repeatedly disrupted by the Pleistocene climate oscillations, and it harbours taxonomic and genetic diversity that is unique but severely depauperated by frequent bottlenecks and cycles of colonisation, extinction, and recolonisation. The level of intrapopulation genetic variation is alarmingly low, and many afroalpine species may be vulnerable to extinction because of climate warming and increasing human impact.publishedVersio

I Olov Hedbergs fotspor: Plantenes evolusjon i det afrikanske høyfjellet

Floraen i det tropiske afrikanske høyfjellet er spektakulær og rik på endemiske (stedegne) arter, og ikke minst er forekomstene av plantearter ekstremt fragmentert på grunn av lange avstander mellom de enkelte fjellene (fig. 1). Denne særegne floraen ble dyptpløyende analysert av Olov Hedberg i hans monumentale verk fra 1957 (Hedberg 1957) og i påfølgende arbeider (f.eks. Hedberg 1961, Hedberg 1969). Studier basert på molekylære data og nisjemodellering har senere gitt sterk støtte til flere av hans hypoteser, men også ledet til ny og overraskende innsikt. Plantenes innvandring til det afrikanske høyfjellet startet allerede da fjellhevingen skapte det spesielle tropisk-alpine døgnklimaet med frost hver natt og høye dagtemperaturer året rundt. Antallet arter økte deretter betydelig gjennom de siste 5 millioner år (plio-pleistocen) og faktisk helt fram til vår tid. En stor del av floraen oppstod etter langdistansespredning fra fjerne, kalde områder, hovedsakelig i Eurasia. Plantenes innvandring ble bare i noen få tilfeller fulgt av betydelig diversifisering (f.eks. hos marikåpe Alchemilla) – tvert imot har slekter som er artsrike i det afrikanske høyfjellet, ofte vist seg å ha spredt seg uavhengig dit gjentatte ganger (f.eks. starr Carex), noe til og med enkeltarter som vår egen fjellskrinneblom Arabis alpina har gjort. De nye studiene tyder på at den afrikanske høyfjellsfloraen har utvikletseg under et mye yngre og mer dynamisk øy-scenario enn det Hedberg så for seg: Den framstår som umettet og sårbar for framtidige klima- og arealendringer på grunn av katastrofale forstyrrelser under klimasvingningene gjennom de siste par millioner år. Den rommer artsmangfold og genetisk diversitet som er unikt, men sterkt svekket av genetiske «flaskehalser» og sykluser av innvandring, utdøing og gjeninnvandring. Det er usedvanlig lite genetisk variasjon i dagens populasjoner, noe som kan bety at mange arter står i fare for å dø ut på grunn av klimaoppvarming og økende menneskelig påvirkning

Of “raisins” and “yeast”: mobilisation and framing in the East German revolution of 1989

There is no shortage of literature on the social movements that arose in East Germany in 1989. Numerous studies have shed light upon the nature, scale and dynamics of the uprising of that year. But on certain issues questions remain. No consensus exists, for example, on the relationship between the “civic groups” (New Forum, Democratic Awakening, etc.) and the street protests of the autumn of 1989. Were these simply two facets of a single movement? Or are they better characterised as two distinct streams within the same movement delta? Did the street protests push the civic movement activists into the limelight? Or is it more accurate to say, with Reinfried Musch, that “the civic movement brought the people onto the streets”?1 This paper considers two contrasting interpretations of these issues, and finds both wanting. An alternative interpretation is offered, one that draws upon Marc Steinberg's “dialogical” development of frame theory

Increased plasma level of terminal complement complex in AMD patients: potential functional consequences for RPE cells

PurposePolymorphisms in complement genes are risk-associated for age-related macular degeneration (AMD). Functional analysis revealed a common deficiency to control the alternative complement pathway by risk-associated gene polymorphisms. Thus, we investigated the levels of terminal complement complex (TCC) in the plasma of wet AMD patients with defined genotypes and the impact of the complement activation of their plasma on second-messenger signaling, gene expression, and cytokine/chemokine secretion in retinal pigment epithelium (RPE) cells.DesignCollection of plasma from patients with wet AMD (n = 87: 62% female and 38% male; median age 77 years) and controls (n = 86: 39% female and 61% male; median age 58 years), grouped for risk factor smoking and genetic risk alleles CFH 402HH and ARMS2 rs3750846, determination of TCC levels in the plasma, in vitro analysis on RPE function during exposure to patients’ or control plasma as a complement source.MethodsGenotyping, measurement of TCC concentrations, ARPE-19 cell culture, Ca2+ imaging, gene expression by qPCR, secretion by multiplex bead analysis of cell culture supernatants.Main outcome measuresTCC concentration in plasma, intracellular free Ca2+, relative mRNA levels, cytokine secretion.ResultsTCC levels in the plasma of AMD patients were five times higher than in non-AMD controls but did not differ in plasma from carriers of the two risk alleles. Complement-evoked Ca2+ elevations in RPE cells differed between patients and controls with a significant correlation between TCC levels and peak amplitudes. Comparing the Ca2+ signals, only between the plasma of smokers and non-smokers, as well as heterozygous (CFH 402YH) and CFH 402HH patients, revealed differences in the late phase. Pre-stimulation with complement patients’ plasma led to sensitization for complement reactions by RPE cells. Gene expression for surface molecules protective against TCC and pro-inflammatory cytokines increased after exposure to patients’ plasma. Patients’ plasma stimulated the secretion of pro-inflammatory cytokines in the RPE.ConclusionTCC levels were higher in AMD patients but did not depend on genetic risk factors. The Ca2+ responses to patients’ plasma as second-messenger represent a shift of RPE cells to a pro-inflammatory phenotype and protection against TCC. We conclude a substantial role of high TCC plasma levels in AMD pathology

NT-proBNP or Self-Reported Functional Capacity in Estimating Risk of Cardiovascular Events After Noncardiac Surgery

ImportanceNearly 16 million surgical procedures are conducted in North America yearly, and postoperative cardiovascular events are frequent. Guidelines suggest functional capacity or B-type natriuretic peptides (BNP) to guide perioperative management. Data comparing the performance of these approaches are scarce.ObjectiveTo compare the addition of either N-terminal pro-BNP (NT-proBNP) or self-reported functional capacity to clinical scores to estimate the risk of major adverse cardiac events (MACE).Design, Setting, and ParticipantsThis cohort study included patients undergoing inpatient, elective, noncardiac surgery at 25 tertiary care hospitals in Europe between June 2017 and April 2020. Analysis was conducted in January 2023. Eligible patients were either aged 45 years or older with a Revised Cardiac Risk Index (RCRI) of 2 or higher or a National Surgical Quality Improvement Program, Risk Calculator for Myocardial Infarction and Cardiac (NSQIP MICA) above 1%, or they were aged 65 years or older and underwent intermediate or high-risk procedures.ExposuresPreoperative NT-proBNP and the following self-reported measures of functional capacity were the exposures: (1) questionnaire-estimated metabolic equivalents (METs), (2) ability to climb 1 floor, and (3) level of regular physical activity.Main Outcome and MeasuresMACE was defined as a composite end point of in-hospital cardiovascular mortality, cardiac arrest, myocardial infarction, stroke, and congestive heart failure requiring transfer to a higher unit of care.ResultsA total of 3731 eligible patients undergoing noncardiac surgery were analyzed; 3597 patients had complete data (1258 women [35.0%]; 1463 (40.7%) aged 75 years or older; 86 [2.4%] experienced a MACE). Discrimination of NT-proBNP or functional capacity measures added to clinical scores did not significantly differ (Area under the receiver operating curve: RCRI, age, and 4MET, 0.704; 95% CI, 0.646-0.763; RCRI, age, and 4MET plus floor climbing, 0.702; 95% CI, 0.645-0.760; RCRI, age, and 4MET plus physical activity, 0.724; 95% CI, 0.672-0.775; RCRI, age, and 4MET plus NT-proBNP, 0.736; 95% CI, 0.682-0.790). Benefit analysis favored NT-proBNP at a threshold of 5% or below, ie, if true positives were valued 20 times or more compared with false positives. The findings were similar for NSQIP MICA as baseline clinical scores.Conclusions and relevanceIn this cohort study of nearly 3600 patients with elevated cardiovascular risk undergoing noncardiac surgery, there was no conclusive evidence of a difference between a NT-proBNP–based and a self-reported functional capacity–based estimate of MACE risk.Trial RegistrationClinicalTrials.gov Identifier: NCT0301693

LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset Parkinson's disease (PD), but the underlying pathophysiological mechanisms and the normal function of this large multidomain protein remain speculative. To address the role of this protein in vivo, we generated three different LRRK2 mutant mouse lines. Mice completely lacking the LRRK2 protein (knock-out, KO) showed an early-onset (age 6 weeks) marked increase in number and size of secondary lysosomes in kidney proximal tubule cells and lamellar bodies in lung type II cells. Mice expressing a LRRK2 kinase-dead (KD) mutant from the endogenous locus displayed similar early-onset pathophysiological changes in kidney but not lung. KD mutants had dramatically reduced full-length LRRK2 protein levels in the kidney and this genetic effect was mimicked pharmacologically in wild-type mice treated with a LRRK2-selective kinase inhibitor. Knock-in (KI) mice expressing the G2019S PD-associated mutation that increases LRRK2 kinase activity showed none of the LRRK2 protein level and histopathological changes observed in KD and KO mice. The autophagy marker LC3 remained unchanged but kidney mTOR and TCS2 protein levels decreased in KD and increased in KO and KI mice. Unexpectedly, KO and KI mice suffered from diastolic hypertension opposed to normal blood pressure in KD mice. Our findings demonstrate a role for LRRK2 in kidney and lung physiology and further show that LRRK2 kinase function affects LRRK2 protein steady-state levels thereby altering putative scaffold/GTPase activity. These novel aspects of peripheral LRRK2 biology critically impact ongoing attempts to develop LRRK2 selective kinase inhibitors as therapeutics for PD

Capturing sequence diversity in metagenomes with comprehensive and scalable probe design.

Metagenomic sequencing has the potential to transform microbial detection and characterization, but new tools are needed to improve its sensitivity. Here we present CATCH, a computational method to enhance nucleic acid capture for enrichment of diverse microbial taxa. CATCH designs optimal probe sets, with a specified number of oligonucleotides, that achieve full coverage of, and scale well with, known sequence diversity. We focus on applying CATCH to capture viral genomes in complex metagenomic samples. We design, synthesize, and validate multiple probe sets, including one that targets the whole genomes of the 356 viral species known to infect humans. Capture with these probe sets enriches unique viral content on average 18-fold, allowing us to assemble genomes that could not be recovered without enrichment, and accurately preserves within-sample diversity. We also use these probe sets to recover genomes from the 2018 Lassa fever outbreak in Nigeria and to improve detection of uncharacterized viral infections in human and mosquito samples. The results demonstrate that CATCH enables more sensitive and cost-effective metagenomic sequencing