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Rare genetic variants in ARID2are responsible for a recently described neurodevelopmental condition called ARID2-related disorder (ARID2-RD). ARID2 belongs to PBAF, a unit of the SWI/SNF complex, which is a chromatin remodeling complex. This work aims to further delineate the phenotypic spectrum of ARID2-RD, providing clinicians with additional data for better care and aid in the future diagnosis of this condition. We obtained the genotypes and phenotypes of 27 previously unreported individuals with ARID2-RD and compared this series with findings in the literature. We also assessed peripheral blood DNA methylation profiles in individuals with ARID2-RD compared to episignatures of controls, unresolved cases, and other neurodevelopmental disorders. The main clinical features of ARID2-RD are developmental delay, speech disorders, intellectual disability (ID), behavior problems, short stature, and various dysmorphic and ectodermal features. Genome-wide differential methylation analysis revealed a global hypermethylated profile in ARID2-RD that could aid in reclassifying variants of uncertain significance. Our study doubles the number of reported individuals with ARID2pathogenic variants to 53. It confirms loss-of-function as a pathomechanism and shows the absence of a clear genotype-phenotype correlation. We provide evidence for a unique DNA methylation episignature for ARID2-RD and further delineate the ARID2-associated phenotype.

Abstract—In this interview, taped in 2001 during The Meteoritical Society meeting in Rome, Friedrich Begemann recalls that after he earned his doctorate in physics under the direction of Professor Friedrich G. Houtermans, first in Göttingen and then in Bern, Switzerland, he began his career as what he calls a low‐level gas counting man, specializing in tritium (3H). In 1954 he accepted an invitation from Professor Willard F. Libby to run his gas‐counting laboratory at the University of Chicago. Begemann spent 3 years there during which he traced the distribution in the world's atmosphere and waters of tritium from two sources, natural cosmic radiation and the detonation of the first thermonuclear device. During his time at Chicago he was drawn into Harold C. Urey's group of scientists studying meteorites. Begemann found that he could measure tritium in meteorites, and by coupling his values with those of 3He, he and his collaborators initiated a new branch of meteoritics by determining the first cosmic‐ray exposure age of a meteorite—Norton County, which fell in 1947. In 1957, Begemann joined the group led by Friedrich A. Paneth at the Max‐Planck‐Institut für Chemie at Mainz, Germany, where he continued his studies of gas isotopes for the remainder of his career. His research led to the discovery of primitive noble gases in the diamond—graphite aggregates in ureilites, where their presence in presumably deep‐seated igneous rocks still remains to be explained. With the advent of the Apollo missions, Begemann extended his studies to the lunar rocks and soils in an effort to learn as much as possible about the interaction of solids with the space environment. He also became heavily involved in measuring the s‐process isotope abundance patterns of medium‐heavy chemical elements as they occur in interstellar grains. In 1995 at the meeting in Washington, D.C., The Meteoritical Society presented Friedrich Begemann with the Leonard Medal for his contributions to our understanding of the radiation encountered by bodies as they orbit through space.

Hypoxia is more and more perceived as pivotal physiological driving force, allowing cells in the brain and elsewhere to acclimate to lowered oxygen (O2), and abridged metabolism. The mediating transcription program is induced by inspiratory hypoxia but also by intensive motor‐cognitive tasks, provoking a relative decrease in O2in relation to the acutely augmented requirement. We termed this fundamental, demand‐dependent drop in O2availability “functional hypoxia.” Major players in the hypoxia response are hypoxia‐inducible factors (HIFs) and associated prolyl‐hydroxylases. HIFs are transcription factors, stabilized by low O2accessibility, and control expression of a multitude of genes. Changes in oxygen, however, can also be sensed via other pathways, among them the thiol‐oxidase (2‐aminoethanethiol) dioxygenase. Considering the far‐reaching biological response to hypoxia, hitherto mostly observed in rodents, we initiated a translational project, combining mild to moderate inspiratory with functional hypoxia. We had identified this combination earlier to benefit motor‐cognitive attainment in mice. A total of 20 subjects were included: 13 healthy individuals and 7 patients with depression and/or autism spectrum disorder. Here, we show that motor‐cognitive training under inspiratory hypoxia (12% O2) for 3.5 h daily over 3 weeks is optimally tolerated. We present first signals of beneficial effects on general well‐being, cognitive performance, physical fitness and psychopathology. Erythropoietin in serum increases under hypoxia and flow cytometry analysis of blood reveals several immune cell types to be mildly modulated by hypoxia. To obtain reliable information regarding the “add‐on” value of inspiratory on top of functional hypoxia, induced by motor‐cognitive training, a single‐blind study—with versus without inspiratory hypoxia—is essential and outlined here. Motor‐cognitive training under inspiratory hypoxia (12% O2) for 3.5 h daily over 3 weeks is very well tolerated by healthy individuals as well as by patients with depression and/or autism spectrum disorder.We find first promising signals of beneficial effects on general well‐being, cognitive performance, physical fitness, and psychopathology.Our protocol of motor‐cognitive training under inspiratory hypoxia does not adversely affect the mononuclear cell composition in the blood of adults.To obtain reliable information regarding the “add‐on” value of mild to moderate inspiratory on top of functional hypoxia, induced by motor‐cognitive training, the planned single‐blind study—with versus without inspiratory hypoxia—is required. Motor‐cognitive training under inspiratory hypoxia (12% O2) for 3.5 h daily over 3 weeks is very well tolerated by healthy individuals as well as by patients with depression and/or autism spectrum disorder. We find first promising signals of beneficial effects on general well‐being, cognitive performance, physical fitness, and psychopathology. Our protocol of motor‐cognitive training under inspiratory hypoxia does not adversely affect the mononuclear cell composition in the blood of adults. To obtain reliable information regarding the “add‐on” value of mild to moderate inspiratory on top of functional hypoxia, induced by motor‐cognitive training, the planned single‐blind study—with versus without inspiratory hypoxia—is required.

Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 1:50,000. During the diagnostic process, 34 novel and 23 candidate genotype–phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams.

While mostly de novo truncating variants in SCAF4were recently identified in 18 individuals with variable neurodevelopmental phenotypes, knowledge on the molecular and clinical spectrum is still limited. We assembled data on 50 novel individuals with SCAF4variants ascertained via GeneMatcher and personal communication. With detailed evaluation of clinical data, in silico predictions and structural modeling, we further characterized the molecular and clinical spectrum of the autosomal dominant SCAF4-associated neurodevelopmental disorder. The molecular spectrum comprises 25 truncating, eight splice-site and five missense variants. While all other truncating variants were classified as pathogenic/likely pathogenic, significance of one C-terminal truncating variant, one splice-site variant and the missense variants remained unclear. Three missense variants in the CTD-interacting domain of SCAF4 were predicted to destabilize the domain. Twenty-three variants occurred de novo, and variants were inherited in 13 cases. Frequent clinical findings were mild developmental delay with speech impairment, seizures, and skeletal abnormalities such as clubfoot, scoliosis or hip dysplasia. Cognitive abilities ranged from normal IQ to severe intellectual disability (ID), with borderline to mild ID in the majority of individuals. Our study confirms the role of SCAF4variants in neurodevelopmental disorders and further delineates the associated clinical phenotype.

Innere, sog. zirkadiane Uhren regulieren zahlreiche Körperfunktionen – darunter unseren Schlaf-Wach-Rhythmus – im 24-h-Takt. Während die Funktion des zirkadianen Systems in der Regulation der Phasenlage des Schlafs (Prozess C) lange bekannt war, zeigen neuere Studien eine weit engere Verknüpfung von Uhrensystem und Schlaffunktion auf mehreren Ebenen. Genetische Defekte im molekularen Uhrwerk haben Auswirkungen auf den Schlafhomöostat (Prozess S). Umgekehrt wirken Änderungen im natürlichen Schlafzyklus zurück auf die Funktion der zirkadianen Uhr – und das nicht nur im zentralen Nervensystem (ZNS), sondern insbesondere auch in peripheren Organen. Dieser Schlaf-Uhr-Crosstalk könnte viele der negativen Effekte von Rhythmus- und Schlafstörungen auf den Energiestoffwechsel erklären. Gleichzeitig bietet er neue Ansatzpunkte für die Prävention und Behandlung von schlafassoziierten pathologischen Effekten, z. B. bei Schichtarbeitern. Dieser Übersichtsartikel beschreibt die Interaktion von Uhrensystem und Schlaf-Regelkreisen im ZNS und deren Effekte auf periphere physiologische Prozesse, insbesondere den Energiestoffwechsel. Er skizziert ein Modell der engen Kopplung von Schlaf und Uhrenfunktion und deren Bedeutung als Angriffspunkt für die Behandlung von durch Schlafstörungen bedingte Erkrankungen.

Zusammenfassung: Der kleine, inzidentell entdeckte Nierentumor stellt ein häufiges Problem in der klinischen Routinediagnostik dar. Zwar werden kleine Nierentumoren durch die leistungsfähigen, modernen Schnittbildverfahren immer häufiger entdeckt, die eindeutige Zuordnung der Dignität dieser Läsionen ist anhand der Bildgebung jedoch nicht immer zu gewährleisten. In der Hoffnung, eine minimal-invasive, histologische Klärung zu erzielen und die Zahl unnötiger operativer Eingriffe zu minimieren, wird der Ruf nach der perkutanen Biopsie kleiner Nierentumoren in den letzten Jahren zunehmend lauter. Der vorliegende Beitrag erläutert den aktuellen Stellenwert der perkutanen Biopsie kleiner Nierenraumforderungen unter besonderer Berücksichtigung der Entwicklung neuer histopathologischer Analyseverfahren, technischer Aspekte der Stanzbiopsie und der Zuverlässigkeit der Diagnosefindung. Darüber hinaus werden die Indikationen zur Stanzbiopsie kleiner Nierentumoren vor dem Hintergrund der aktuellen Literatur erörtert.

Zusammenfassung: Einleitung: Die Sakroplastie stellt ein noch junges Verfahren zur perkutanen Zementapplikation bei schmerzhafter Insuffizienzfraktur oder tumoröser Läsion dar. Bislang liegen noch keine standardisierten Untersuchungen zu den Ergebnissen, insbesondere zur Zementaustrittsrate, vor. Zielsetzung der vorgelegten Studie war, in einem kontrollierten Experiment Praktikabilität und Ergebnisse der ballonassistierten, CT-gesteuerten Zementapplikation zu eruieren. Material und Methoden: Die Versuche wurden an fixierten Spenderleichen (n=6) vorgenommen. Die Zementapplikation erfolgte rechtsseitig unter Verwendung insufflierbarer Ballons (Kyphon), auf der Gegenseite in konventioneller Technik. Zur präoperativen Planung und postoperativen Auswertung wurde jeweils ein Spiral-CT (Philips Brilliance 64) durchgeführt. Intraoperativ wurde die Prozedur durch einzelne Durchleuchtungsbilder im „CT-Fluoro“-Modus gesteuert. Ergebnisse: Während der Prozeduren traten keine technischen Probleme auf. Die durchschnittliche Operationszeit betrug 36,9±2,4 min (Spannweite 33,1–38,9) pro Präparat. Mit dem gewählten CT-Protokoll resultierten folgende Effektivdosen: 0,99 mSv (weiblich) respektive 0,63 mSv (männlich) pro Scan sowie 0,33 mSv (weiblich) und 0,25 mSv (männlich) pro Durchleuchtungsbild. Ein extraossärer Zementaustritt wurde weder bei der ballonassistierten noch bei der konventionellen Applikation beobachtet. Schlussfolgerung: Die CT-gesteuerte Sakroplastie wies in unserer Studie eine gute Praktikabilität und hohe Präzision bei vertretbarer Strahlenexposition auf. Klinische Studien werden allerdings erst zeigen müssen, in wieweit das vorgestellte, ballonassistierte Verfahren der konventionellen Technik hinsichtlich der Zementaustrittsrate überlegen ist. Außerdem wird die analgetische Effizienz des Verfahrens zu prüfen sein.

Das an der FH Münster angebotene Lehrprojekt "Ich sehe was, was Du nicht siehst - ungewohnte Perspektiven im Versorgungshandeln" schaut - im wahren Sinne des Wortes - auf nähe-kritische Versorgungssituationen, indem es den Fokus auf die visuelle Nähe lenkt und durch die Arbeit mit Fotografie einen Perspektivwechsel anstößt, um die Studierenden in ihrem Reflexionsprozess zu begleiten. Ziel ist es, für das Thema "Nähe und Distanz" zu sensibilisieren und interaktive Kompetenzen zu stärken. Zudem kommt das Projekt den Forderungen nach einer verstärkten Selbsterfahrung und Reflexion im Rahmen der Ausbildung von Pflegefachkräften nach.

In der Luftfahrt kommen hochfeste Schichtverbundwerkstoffe zum Einsatz, welche zumeist im Nietverfahren gefügt werden. Dies erfordert eine vorausgehende Bohrbearbeitung des Werkstoffverbunds. Da die beiden Einzelwerkstoffe meist gegensätzliche Bohrparameter erfordern (z. B. Titan und CFK) kommen derzeit Kompromissparameter zum Einsatz. Die Fertigungsqualität ist dadurch beschränkt und der Werkzeugverschleiß hoch. Dieser Beitrag stellt eine wirkleistungsbasierte Bohrprozesssteuerung vor, welche die materialspezifische Umschaltung der Prozessparameter ermöglicht. Die Detektionslogik basiert auf dem dynamischen Anteil der Spindelwirkleistung und erweist sich in mehreren Bohrserien als präzise und robust. Zudem ist eine erhöhte Fertigungsqualität zu verzeichnen.

IMPORTANCE: Psychotic symptoms greatly increase the burden of disease for people with neurodegenerative disorders and their caregivers. Cholinesterase inhibitors (ChEIs) may be effective treatment for psychotic symptoms in these disorders. Previous trials only evaluated neuropsychiatric symptoms as a secondary and an overall outcome, potentially blurring the outcomes noted with ChEI use specifically for psychotic symptoms. OBJECTIVE: To quantitatively assess the use of ChEIs for treatment of individual neuropsychiatric symptoms, specifically hallucinations and delusions, in patients with Alzheimer disease (AD), Parkinson disease (PD), and dementia with Lewy bodies (DLB). DATA SOURCES: A systematic search was performed in PubMed (MEDLINE), Embase, and PsychInfo, without year restrictions. Additional eligible studies were retrieved from reference lists. The final search cutoff date was April 21, 2022. STUDY SELECTION: Studies were selected if they presented the results of placebo-controlled randomized clinical trials, including at least 1 donepezil, rivastigmine, or galantamine treatment arm in patients with AD, PD, or DLB; if they applied at least 1 neuropsychiatric measure including hallucinations and/or delusions; and if a full-text version of the study was available in the English language. Study selection was performed and checked by multiple reviewers. DATA EXTRACTION AND SYNTHESIS: Original research data were requested on eligible studies. A 2-stage meta-analysis was then performed, using random-effects models. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed for extracting data and assessing the data quality and validity. Data extraction was checked by a second reviewer. MAIN OUTCOMES AND MEASURES: Primary outcomes were hallucinations and delusions; secondary outcomes included all other individual neuropsychiatric subdomains as well as the total neuropsychiatric score. RESULTS: In total, 34 eligible randomized clinical trials were selected. Individual participant data on 6649 individuals (3830 [62.6%] women; mean [SD] age, 75.0 [8.2] years) were obtained from 17 trials (AD: n = 12; PD: n = 5; individual participant data were not available for DLB). An association with ChEI treatment was shown in the AD subgroup for delusions (−0.08; 95% CI, −0.14 to −0.03; P = .006) and hallucinations (−0.09; 95% CI, −0.14 to −0.04; P = .003) and in the PD subgroup for delusions (−0.14; 95% CI, −0.26 to −0.01; P = .04) and hallucinations (−0.08, 95% CI −0.13 to −0.03; P = .01). CONCLUSIONS AND RELEVANCE: The results of this individual participant data meta-analysis suggest that ChEI treatment improves psychotic symptoms in patients with AD and PD with small effect sizes.

Bacterial abortive-infection systems limit the spread of foreign invaders by shutting down or killing infected cells before the invaders can replicate1,2. Several RNA-targeting CRISPR–Cas systems (that is, types III and VI) cause abortive-infection phenotypes by activating indiscriminate nucleases3–5. However, a CRISPR-mediated abortive mechanism that leverages indiscriminate DNase activity of an RNA-guided single-effector nuclease has yet to be observed. Here we report that RNA targeting by the type V single-effector nuclease Cas12a2 drives abortive infection through non-specific cleavage of double-stranded DNA (dsDNA). After recognizing an RNA target with an activating protospacer-flanking sequence, Cas12a2 efficiently degrades single-stranded RNA (ssRNA), single-stranded DNA (ssDNA) and dsDNA. Within cells, the activation of Cas12a2 induces an SOS DNA-damage response and impairs growth, preventing the dissemination of the invader. Finally, we harnessed the collateral activity of Cas12a2 for direct RNA detection, demonstrating that Cas12a2 can be repurposed as an RNA-guided RNA-targeting tool. These findings expand the known defensive abilities of CRISPR–Cas systems and create additional opportunities for CRISPR technologies.

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2Aand transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies.

Heterozygous missense variants in the WD repeat domain 11(WDR11) gene are associated with hypogonadotropic hypogonadism in humans. In contrast, knockout of both alleles of Wdr11in mice results in a more severe phenotype with growth and developmental delay, features of holoprosencephaly, heart defects and reproductive disorders. Similar developmental defects known to be associated with aberrant hedgehog signaling and ciliogenesis have been found in zebrafish after Wdr11knockdown. We here report biallelic loss-of-function variants in the WDR11gene in six patients from three independent families with intellectual disability, microcephaly and short stature. The findings suggest that biallelic WDR11variants in humans result in an overlapping but milder phenotype compared to Wdr11-deficient animals. However, the observed human phenotype differs significantly from dominantly inherited variants leading to hypogonadotropic hypogonadism, suggesting that recessive WDR11variants result in a clinically distinct entity.

Considering the immense societal and personal costs and suffering associated with multiple drug use or “polytoxicomania”, better understanding of environmental and genetic causes is crucial. While previous studies focused on single risk factors and selected drugs, effects of early-accumulated environmental risks on polytoxicomania were never addressed. Similarly, evidence of genetic susceptibility to particular drugs is abundant, while genetic predisposition to polytoxicomania is unexplored. We exploited the GRAS data collection, comprising information on N~2000 deep-phenotyped schizophrenia patients, to investigate effects of early-life environmental risk accumulation on polytoxicomania and additionally provide first genetic insight. Preadult accumulation of environmental risks (physical or sexual abuse, urbanicity, migration, cannabis, alcohol) was strongly associated with lifetimepolytoxicomania (p= 1.5 × 10−45; OR = 31.4), preadultpolytoxicomania with OR = 226.6 (p= 1.0 × 10−33) and adultpolytoxicomania with OR = 17.5 (p= 3.4 × 10−24). Parallel accessibility of genetic data from GRAS patients and N~2100 controls for genome-wide association (GWAS) and phenotype-based genetic association studies (PGAS) permitted the creation of a novel multiple GWAS–PGAS approach. This approach yielded 41 intuitively interesting SNPs, potentially conferring liability to preadult polytoxicomania, which await replication upon availability of suitable deep-phenotyped cohorts anywhere world-wide. Concisely, juvenile environmental risk accumulation, including cannabis and alcohol as starter/gateway drugs, strongly predicts polytoxicomania during adolescence and adulthood. This pivotal message should launch more effective sociopolitical measures to prevent this deleterious psychiatric condition.

Circulating autoantibodies (AB) of different immunoglobulin classes (IgM, IgA, and IgG), directed against the obligatory N-methyl-d-aspartate-receptor subunit NR1 (NMDAR1-AB), belong to the mammalian autoimmune repertoire, and appear with age-dependently high seroprevalence across health and disease. Upon access to the brain, they can exert NMDAR-antagonistic/ketamine-like actions. Still unanswered key questions, addressed here, are conditions of NMDAR1-AB formation/boosting, intraindividual persistence/course in serum over time, and (patho)physiological significance of NMDAR1-AB in modulating neuropsychiatric phenotypes. We demonstrate in a translational fashion from mouse to human that (1) serum NMDAR1-AB fluctuate upon long-term observation, independent of blood–brain barrier (BBB) perturbation; (2) a standardized small brain lesion in juvenile mice leads to increased NMDAR1-AB seroprevalence (IgM + IgG), together with enhanced Ig-class diversity; (3) CTLA4(immune-checkpoint) genotypes, previously found associated with autoimmune disease, predispose to serum NMDAR1-AB in humans; (4) finally, pursuing our prior findings of an early increase in NMDAR1-AB seroprevalence in human migrants, which implicated chronic life stress as inducer, we independently replicate these results with prospectively recruited refugee minors. Most importantly, we here provide the first experimental evidence in mice of chronic life stress promoting serum NMDAR1-AB (IgA). Strikingly, stress-induced depressive-like behavior in mice and depression/anxiety in humans are reduced in NMDAR1-AB carriers with compromised BBB where NMDAR1-AB can readily reach the brain. To conclude, NMDAR1-AB may have a role as endogenous NMDAR antagonists, formed or boosted under various circumstances, ranging from genetic predisposition to, e.g., tumors, infection, brain injury, and stress, altogether increasing over lifetime, and exerting a spectrum of possible effects, also including beneficial functions.

The term multilocus imprinting disturbance (MLID) describes the aberrant methylation of multiple imprinted loci in the genome, and MLID occurs in patients suffering from imprinting disorder carrying methylation defects. First data indicate that functional variants in factors expressed from both the fetal as well as the maternal genome cause MLID. Molecular changes in such genes of the maternal genome are called maternal effect variants, they affect members of the subcortical maternal complex (SCMC) in the oocyte which plays an important role during early embryonic development. Whereas the contribution of variants in the SCMC genes NLRP2, NLRP5, NLRP7, and KHDC3Lto the etiology of reproductive failure and aberrant imprinting is widely accepted, the involvement of PADI6variants in the formation of MLID is in discussion. We now report on the identification of biallelic variants in a woman suffering from different miscarriages and giving birth to two children with MLID. Thereby the role of PADI6 in maintaining the proper imprinting status during early development is confirmed. Thus, PADI6variants do not only cause (early) pregnancy losses, but maternal effect variants in this gene cause the same spectrum of pregnancy outcomes as variants in other SCMC encoding genes, including chromosomal aberrations and disturbed imprinting. The identification of maternal effect variants requires genetic and reproductive counseling as carriers of these variants are at high risks for reproductive failure.