Modal Interface Automata

De Alfaro and Henzinger's Interface Automata (IA) and Nyman et al.'s recent combination IOMTS of IA and Larsen's Modal Transition Systems (MTS) are established frameworks for specifying interfaces of system components. However, neither IA nor IOMTS consider conjunction that is needed in practice when a component shall satisfy multiple interfaces, while Larsen's MTS-conjunction is not closed and Bene\v{s} et al.'s conjunction on disjunctive MTS does not treat internal transitions. In addition, IOMTS-parallel composition exhibits a compositionality defect. This article defines conjunction (and also disjunction) on IA and disjunctive MTS and proves the operators to be 'correct', i.e., the greatest lower bounds (least upper bounds) wrt. IA- and resp. MTS-refinement. As its main contribution, a novel interface theory called Modal Interface Automata (MIA) is introduced: MIA is a rich subset of IOMTS featuring explicit output-must-transitions while input-transitions are always allowed implicitly, is equipped with compositional parallel, conjunction and disjunction operators, and allows a simpler embedding of IA than Nyman's. Thus, it fixes the shortcomings of related work, without restricting designers to deterministic interfaces as Raclet et al.'s modal interface theory does.Comment: 28 page

Robustness of a bisimulation-type faster-than preorder

TACS is an extension of CCS where upper time bounds for delays can be specified. Luettgen and Vogler defined three variants of bismulation-type faster-than relations and showed that they all three lead to the same preorder, demonstrating the robustness of their approach. In the present paper, the operational semantics of TACS is extended; it is shown that two of the variants still give the same preorder as before, underlining robustness. An explanation is given why this result fails for the third variant. It is also shown that another variant, which mixes old and new operational semantics, can lead to smaller relations that prove the same preorder.Comment: Express Worksho

Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors

Delta-9-tetrahydrocannabinol (THC), the main psychoactive compound of marijuana, induces numerous undesirable effects, including memory impairments, anxiety, and dependence. Conversely, THC also has potentially therapeutic effects, including analgesia, muscle relaxation, and neuroprotection. However, the mechanisms that dissociate these responses are still not known. Using mice lacking the serotonin receptor 5-HT2A, we revealed that the analgesic and amnesic effects of THC are independent of each other: while amnesia induced by THC disappears in the mutant mice, THC can still promote analgesia in these animals. In subsequent molecular studies, we showed that in specific brain regions involved in memory formation, the receptors for THC and the 5-HT2A receptors work together by physically interacting with each other. Experimentally interfering with this interaction prevented the memory deficits induced by THC, but not its analgesic properties. Our results highlight a novel mechanism by which the beneficial analgesic properties of THC can be dissociated from its cognitive side effects

Brain Abnormalities in Patients with Germline Variants in H3F3: Novel Imaging Findings and Neurologic Symptoms Beyond Somatic Variants and Brain Tumors

BACKGROUND AND PURPOSE: Pathogenic somatic variants affecting the genes Histone 3 Family 3A and 3B (H3F3) are extensively linked to the process of oncogenesis, in particular related to central nervous system tumors in children. Recently, H3F3 germline missense variants were described as the cause of a novel pediatric neurodevelopmental disorder. We aimed to investigate patterns of brain MR imaging of individuals carrying H3F3 germline variants. MATERIALS AND METHODS: In this retrospective study, we included individuals with proved H3F3 causative genetic variants and available brain MR imaging scans. Clinical and demographic data were retrieved from available medical records. Molecular genetic testing results were classified using the American College of Medical Genetics criteria for variant curation. Brain MR imaging abnormalities were analyzed according to their location, signal intensity, and associated clinical symptoms. Numeric variables were described according to their distribution, with median and interquartile range. RESULTS: Eighteen individuals (10 males, 56%) with H3F3 germline variants were included. Thirteen of 18 individuals (72%) presented with a small posterior fossa. Six individuals (33%) presented with reduced size and an internal rotational appearance of the heads of the caudate nuclei along with an enlarged and squared appearance of the frontal horns of the lateral ventricles. Five individuals (28%) presented with dysgenesis of the splenium of the corpus callosum. Cortical developmental abnormalities were noted in 8 individuals (44%), with dysgyria and hypoplastic temporal poles being the most frequent presentation. CONCLUSIONS: Imaging phenotypes in germline H3F3-affected individuals are related to brain features, including a small posterior fossa as well as dysgenesis of the corpus callosum, cortical developmental abnormalities, and deformity of lateral ventricles

A controlled study of supplementation with essential amino acids and α-keto acids in the conservative management of patients with chronic renal failure

Art und Zusammensetzung einer optimalen eiweißarmen Ernährung für Patienten mit Niereninsuffizienz sind weiterhin umstritten. Die orale medikamentöse Behandlung mit essentiellen Aminosäuren oder α-Ketosäuren wird häufig empfohlen. Unsere Untersuchungen vergleichen nacheinander bei 15 ambulanten Patienten mit chronischem Nierenversagen (mittlere Kreatinin-Clearance 10,8 ml/min) unter einer eiweißarmen Ernährung von 0,57 g/kg Körpergewicht (40 g/70 kg) die Wirkung einer Substitution mit essentiellen Aminosäuren, danach die Substitution mit α-Ketosäuren gegenüber Plazebo. Der nachgewiesene Proteingehalt in der Nahrung betrug 0,55 g/kg, die Energiezufuhr 27 kcal/kg Körpergewicht, wie mehrfach Ernährungsprotokolle über jeweils 7 Tage bei den Patienten zeigen ließen. Nach einer Vorperiode von 6 Wochen nur unter diätetischen Maßnahmen erhielten alle Patienten zusätzlich 0,112 g essentielle Aminosäuren/kg Körpergewicht über 6 Wochen, danach in einer Doppelblinduntersuchung 0,105 g α-Ketosäuren/kg Körpergewicht im Vergleich gegenüber Plazebo, ebenfalls jeweils über 6 Wochen. Nüchtern-Blutuntersuchungen wurden für ein Standard-Laborwertprogramm, insbesondere für 15 Proteinmangelparameter, alle 3 Wochen durchgeführt, ferner anthropometrische und klinische Kontrollen. Die Laborwerte erbrachten keine Hinweise auf einen manifesten Proteinmangel. Die Therapie mit α-Ketosäuren erniedrigte die Phosphatspiegel signifikant (p<0,05). Dagegen konnten weder unter essentiellen Aminosäuren oder α-Ketosäuren andere für den Patienten wesentliche Effekte nachgewiesen werden. Deshalb erscheint uns eine Substitution mit essentiellen Aminosäuren oder Ketosäuren überflüssig bei Patienten mit einer chronischen Niereninsuffizienz, die sich in einem stabilen Stoffwechselgleichgewicht befinden und mit einer Eiweißzufuhr von 0,55 g/kg Körpergewicht behandelt werden. Oral therapy with essential amino acids (EAA) or α-keto acids (α-KA) has been recommended in patients with renal failure, but quality and quantity of optimal protein intake are still controversial. This study compares sequentially the effect of supplementation with EAA, and with α-KA versus placebo in 15 ambulatory patients with chronic renal failure (average creatinine clearance 10.8 ml/min), maintained on a protein diet of 0.57 g/kg body weight (40 g for a 70-kg patient). The actual dietary intake averaged 0.55 g protein/kg and 27 kcal/kg according to repeated 7-day dietary recordings. After a 6-week baseline period on this diet, all patients received additionally 0.112 g EAA/kg for 6 weeks followed by a double-blind cross-over study of 0.105 g α-KA/kg versus placebo supplementation for 6 weeks each. Fasting blood samples for multiple parameters, including 15 indicators for protein deficiency, as well as anthropometric and clinical data were evaluated every 3 weeks. Laboratory data revealed no indications of protein deficiency. Therapy with α-KA diminished serum phosphate concentration (p<0.05), however no other significant beneficial effects could be demonstrated during supplementation with either EAA or α-KA. Therefore, such supplementation to a 0.55-g/kg-protein diet appears superfluous in stable ambulatory patients with renal insufficiency.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41743/1/394_2005_Article_BF02020747.pd

Mutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy

Background Nephronophthisis associated ciliopathies (NPHP-AC) comprise a group of autosomal recessive cystic kidney diseases that includes nephronophthisis (NPHP), Senior-Loken syndrome (SLS), Joubert syndrome (JBTS), and Meckel-Gruber syndrome (MKS). To date, causative mutations in NPHP-AC have been described for 18 different genes, rendering mutation analysis tedious and expensive. To overcome the broad genetic locus heterogeneity, a strategy of DNA pooling with consecutive massively parallel resequencing (MPR) was devised.Methods In 120 patients with severe NPHP-AC phenotypes, five pools of genomic DNA with 24 patients each were prepared which were used as templates in order to PCR amplify all 376 exons of 18 NPHP-AC genes (NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, GLIS2, RPGRIP1L, NEK8, TMEM67, INPP5E, TMEM216, AHI1, ARL13B, CC2D2A, TTC21B, MKS1, and XPNPEP3). PCR products were then subjected to MPR on an Illumina Genome-Analyser and mutations were subsequently assigned to their respective mutation carrier via CEL I endonuclease based heteroduplex screening and confirmed by Sanger sequencing.Results For proof of principle, DNA from patients with known mutations was used and detection of 22 out of 24 different alleles (92% sensitivity) was demonstrated. MPR led to the molecular diagnosis in 30/120 patients (25%) and 54 pathogenic mutations (27 novel) were identified in seven different NPHP-AC genes. Additionally, in 24 patients only single heterozygous variants of unknown significance were found.Conclusions The combined approach of DNA pooling followed by MPR strongly facilitates mutation analysis in broadly heterogeneous single gene disorders. The lack of mutations in 75% of patients in this cohort indicates further extensive heterogeneity in NPHP-AC

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation