Automated generation of consistent models using qualitative abstractions and exploration strategies.

Automatically synthesizing consistent models is a key prerequisite for many testing scenarios in autonomous driving to ensure a designated coverage of critical corner cases. An inconsistent model is irrelevant as a test case (e.g., false positive); thus, each synthetic model needs to simultaneously satisfy various structural and attribute constraints, which includes complex geometric constraints for traffic scenarios. While different logic solvers or dedicated graph solvers have recently been developed, they fail to handle either structural or attribute constraints in a scalable way. In the current paper, we combine a structural graph solver that uses partial models with an SMT-solver and a quadratic solver to automatically derive models which simultaneously fulfill structural and numeric constraints, while key theoretical properties of model generation like completeness or diversity are still ensured. This necessitates a sophisticated bidirectional interaction between different solvers which carry out consistency checks, decision, unit propagation, concretization steps. Additionally, we introduce custom exploration strategies to speed up model generation. We evaluate the scalability and diversity of our approach, as well as the influence of customizations, in the context of four complex case studies.

Characterization of a Carbon Monoxide-Activated Soluble Guanylate Cyclase from Chlamydomonas reinhardtii.

Signaling pathways that involve diatomic gases in photosynthetic organisms are not well understood. Exposure to nitric oxide or carbon monoxide is known to elicit certain responses in some photosynthetic organisms. For example, Chlamydomonas reinhardtii grown in low-iron media responds to exogenous carbon monoxide by increasing cell growth and intracellular chlorophyll levels. Here, we characterize Cyg11, a gas-responsive soluble guanylate cyclase from the eukaryotic green alga C. reinhardtii that converts GTP to cGMP. Cyg11 transcription is upregulated when C. reinhardtii is grown in iron-limited media, suggesting its importance in nutrient-limited environments. Cyg11 is purified as a homodimer and is activated by nitric oxide (2.5-fold over basal activity) and carbon monoxide (6.3-fold). The heme binding stoichiometry of Cyg11 was found to be one heme per homodimer, an unexpected result based on the sequence and oligomerization state of the enzyme. Gas binding properties, the kinetics of gas binding, and the ligand-modulated activity of Cyg11 are consistent with CO as the relevant physiological ligand.

Longitudinal influence of microglial activation and amyloid on neuronal function in Alzheimer's disease.

Amyloid deposition, tangle formation, neuroinflammation and neuronal dysfunction are pathological processes involved in Alzheimer's disease. However, the relative role of these processes in driving disease progression is still unclear. The aim of this positron emission tomography study was to: (i) investigate longitudinal changes of microglial activation, amyloid and glucose metabolism; and (ii) assess the temporospatial relationship between these three processes in Alzheimer's disease. A group of eight patients with a diagnosis of Alzheimer's disease (66 ± 4.8 years) and 14 healthy controls (65 ± 5.5 years) underwent T1 and T2 magnetic resonance imaging, along with (11)C-(R)-PK11195, (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose positron emission tomography scans for microglial activation, amyloid deposition and glucose metabolism. All patients were followed-up with repeated magnetic resonance imaging and three positron emission tomography scans after 16 months. Parametric maps were interrogated using region of interest analysis, Statistical Parametric Mapping, and between-group correlation analysis at voxel-level using Biological Parametric Mapping. At baseline, patients with Alzheimer's disease showed significantly increased microglial activation compared to the control subjects. During follow-up, for the first time, we found that while there is a progressive reduction of glucose metabolism, there was a longitudinal increase of microglial activation in the majority of the patients with Alzheimer's disease. Voxel-wise correlation analysis revealed that microglial activation in patients with Alzheimer's disease was positively correlated with amyloid deposition and inversely correlated with regional cerebral metabolic rate at voxel level over time. Even though one of the limitations of this study is the lack of longitudinal follow-up of healthy control subjects, this study demonstrates that there is persistent neuroinflammation throughout the Alzheimer's disease process with associated synaptic dysfunction and reduced glucose metabolism. Voxel-wise correlation analysis suggests that neuroinflammation is associated with localized amyloid deposition and glucose metabolism over time, however, the level of inflammation could also occur independently of amyloid pathology, especially in the later stages of Alzheimer's disease.

Diversity and demography in Beringia: multilocus tests of paleodistribution models reveal the complex history of arctic ground squirrels.

To assess effects of historical climate change on northern species, we quantified the population history of the arctic ground squirrel (Spermophilus parryii), an arctic-adapted rodent that evolved in Beringia and was strongly influenced by climatic oscillations of the Quaternary. Competing hypotheses for the species' population history were derived from patterns of mitochondrial (mtDNA) structure and a bioclimatic envelope model (BEM). Hypotheses invoked (1) sequential isolation of regional populations beginning with the Arctic, (2) deep isolation only across central Alaska, and (3) widespread panmixia, and were tested using coalescent methods applied to eight nuclear (nDNA) loci. The data rejected strict interpretations of all three hypotheses, but perspectives underlying each encompassed aspects of the species' history. Concordance between mtDNA and nDNA geographic structure revealed three semi-independently evolving phylogroups, whereas signatures of gene flow at nDNA loci were consistent with a historical contact between certain populations as inferred by the BEM. Demographic growth was inferred for all regions despite expectations of postglacial habitat contraction for parts of Beringia. Our results highlight the complementary perspectives on species' histories that multiple lines of evidence provide, and underscore the utility of multilocus data for resolving complex population histories relevant to understanding effects of climate change.

Roles of matrix metalloproteinases in the etiology of inguinal hernia.

INTRODUCTION: The fascia transversalis is accepted as one of the anatomical structures that can prevent hernia formation. Degradation of collagen within the fascia transversalis is one of the known reasons for the development of inguinal hernia. In the present study, we investigated the roles of matrix metalloproteinases (MMPs), specifically MMP-1, MMP-2, and MMP-9 in the etiology of inguinal hernia. MATERIALS AND METHODS: This prospective study included 60 inguinal hernia patients: 30 patients had indirect inguinal hernia and 30 patients had direct inguinal hernia. An additional 30 patients operated for reasons other than hernia in the inguinal canal were included as a control group. All patients underwent operations at Istanbul Training and Research Hospital between 1 June 2009 and 1 December 2009. Tissue specimens were taken from the fascia transversalis from patient and control groups during the operation, and MMP-1, MMP-2, MMP-9 values were investigated using immunohistochemical methods. RESULTS: Significantly higher values of MMP-1, MMP-2, MMP-9, were found in inguinal hernia cases than in the control group (P = 0.0001, P = 0.007, P = 0.021, respectively). CONCLUSION: Increased MMP-1, MMP-2, MMP-9 values play a role in the etiology of inguinal hernia. Since weakening may also occur in other tissues in addition to the floor of inguinal canal in inguinal hernia patients, the association of arterial aneurisms and connective tissue diseases should also be investigated in these patients.

Carbon-11-Pittsburgh compound B positron emission tomography imaging of amyloid deposition in presenilin 1 mutation carriers.

(11)Carbon-Pittsburgh compound B positron emission tomography studies have suggested early and prominent amyloid deposition in the striatum in presenilin 1 mutation carriers. This cross-sectional study examines the (11)Carbon-Pittsburgh compound B positron emission tomography imaging profiles of presymptomatic and mildly affected (mini-mental state examination ≥ 20) carriers of seven presenilin 1 mutations, comparing them with groups of controls and symptomatic sporadic Alzheimer's disease cases. Parametric ratio images representing (11)Carbon-Pittsburgh compound B retention from 60 to 90 min were created using the pons as a reference region and nine regions of interest were studied. We confirmed that increased amyloid load may be detected in presymptomatic presenilin 1 mutation carriers with (11)Carbon-Pittsburgh compound B positron emission tomography and that the pattern of retention is heterogeneous. Comparison of presenilin 1 and sporadic Alzheimer's disease groups revealed significantly greater thalamic retention in the presenilin 1 group and significantly greater frontotemporal retention in the sporadic Alzheimer's disease group. A few individuals with presenilin 1 mutations showed increased cerebellar (11)Carbon-Pittsburgh compound B retention suggesting that this region may not be as suitable a reference region in familial Alzheimer's disease.

11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study.

BACKGROUND: Carbon-11-labelled Pittsburgh compound B ((11)C-PiB) PET is a marker of cortical fibrillar amyloid-beta load in vivo. We used (11)C-PiB PET to investigate whether bapineuzumab, a humanised anti-amyloid-beta monoclonal antibody, would reduce cortical fibrillar amyloid-beta load in patients with Alzheimer's disease. METHODS: Patients with mild-to-moderate Alzheimer's disease were randomly assigned to receive intravenous bapineuzumab or placebo in a ratio of seven to three in three ascending dose groups (0.5, 1.0, or 2.0 mg/kg). Each dose group was enrolled after safety review of the previous group. Randomisation was by interactive voice response system; masking was achieved with numbered kit allocation. Patients, investigators, study site personnel, sponsor staff, and carers were masked to treatment. Patients received up to six infusions, 13 weeks apart, and had (11)C-PiB PET scans at baseline and at weeks 20, 45, and 78. The primary outcome was the difference between the pooled bapineuzumab group and the pooled placebo group in mean change from screening to week 78 in (11)C-PiB cortical to cerebellar retention ratio averaged across six cortical regions of interest. Analysis was by modified intention to treat. This study is registered with EudraCT, number 2004-004120-12; ISRCTN17517446. FINDINGS: 28 patients were assigned to bapineuzumab (n=20) or placebo (n=8). 19 patients in the bapineuzumab group and seven in the placebo group were included in the modified intention-to-treat analysis. Estimated mean (11)C-PiB retention ratio change from baseline to week 78 was -0.09 (95% CI -0.16 to -0.02; p=0.014) in the bapineuzumab group and 0.15 (95% CI 0.02 to 0.28; p=0.022) in the placebo group. Estimated mean difference in (11)C-PiB retention ratio change from baseline to week 78 between the bapineuzumab group and the placebo group was -0.24 (95% CI -0.39 to -0.09; p=0.003). Differences between the bapineuzumab group and the placebo group in the individual regions of interest were similar to the overall mean difference. Adverse events were typically mild to moderate in severity and transient. Two patients in the 2.0 mg/kg bapineuzumab group had transient cerebral vasogenic oedema. INTERPRETATION: Treatment with bapineuzumab for 78 weeks reduced cortical (11)C-PiB retention compared with both baseline and placebo. (11)C-PiB PET seems to be useful in assessing the effects of potential Alzheimer's disease treatments on cortical fibrillar amyloid-beta load in vivo. FUNDING: Elan Pharmaceuticals and Wyeth Research.

Multiple intestinal intussusceptions in Peutz-Jeghers' syndrome: a case report.

Peutz-Jeghers' syndrome (PJS) is an autosomal dominant inherited disease, which is characterized by mucocutaneus pigmentation and hamartomatous gastro-intestinal polyps. Intussusceptions can easily occur in patients with PJS. Repeated laparotomy with resections and eventual short bowel syndrome is a major problem in these patients. We present a 20-year-old woman with multiple intestinal intussusceptions. Multiple enterotomies and intestinal resections were performed to achieve a longer symptom-free period.

Duodenal ulcer perforation and pneumothorax: a case report.

Pneumothorax and pneumomediastinum are rarely observed as a complication of perforated peptic ulcer, which is a common cause of acute abdomen. We report a case of a 30-year-old male patient with abdominal pain and respiratory distress. Resulting from physical examination and laboratory data of the patient, acute abdomen and pneumothorax were diagnosed simultaneously. Laparotomy revealed duodenal ulcer perforation and a simple patch closure was performed. No complications were observed during the postoperative course of the patient.

The effect of diaphragmatic peritoneal lymphatics on peritoneal adhesions: an experimental study.

In this study, we examined the effect of diaphragmatic peritoneal lymphatic function on the formation of peritoneal adhesions. A two phased design was used in fifty-two Wistar albino female rats. In the first phase (n = 12), the effects of diaphragmatic peritoneum damage model on the cecum and the terminal ileum were evaluated. In the second phase, the rats (n = 40) were divided into two equal groups. The adhesion model was created only in the cecum and the terminal ileum in the first group, whereas the diaphragmatic peritoneal damage model was created in the second group together with the same adhesion model. The rats were sacrificed on day 10 postoperatively and the adhesions formed were graded. In the first group, adhesions were formed at grade 1 in 5 rats (25%), grade 2 in 11 rats (55%) and grade 3 in 4 rats (20%), whereas adhesions were formed at grade 1 in 2 rats (10%), grade 2 in 8 rats (40%) and grade 3 in 10 rats (50%) in the second group (X2: 21.65, p < 0.0001). Diaphragmatic peritoneal lymphatic function reduced the number of adhesions and severity of the adhesions which occurred among intraabdominal organs after laparotomy. These findings suggest that special care should be undertaken to avoid damaging the diaphragmatic peritoneum during abdominal surgery so as to reduce the incidence of peritoneal adhesions.

[A case of primary intestinal lymphoma associated with intestinal perforation]. / Primer intestinal lenfomaya bagli intestinal perforasyon olgusu.

A 17 year old male with symptoms of acute abdomen was operated upon. The preoperative diagnosis was peptic ulcus perforation but at the operation there were multiple perforations throughout the small bowels, multiple lymphadenopathies in the mesentery of the jejunum. 60 cm small bowel resection-end to end anastomosis, raphe omentoplasty, primary repair with suture were performed. The patient got well after the operation and was discharged postoperative 14th day. The pathological diagnosis was diffuse grand cell lymphoma. We conclude that, this rare condition which we could be able to find only one case in the literature must be thought among the reasons of acute abdomen.

[Laparotomy indications in pelvic fractures]. / Laparotomieindikationen bei Beckenbrüchen.

Infra-umbilical abdominal section concomitant with peritoneal lavage was applied to 74 patients with pelvic fracture and has proved to be helpful in early diagnosis of intra-abdominal organ injuries. However, the percentage of falsely positive results was found to be as high as 17.3 per cent, in the context of pelvic fractures. This has been attributable to the fact that the pelvic floor is likely to be elevated by the haematoma caused by a pelvic fracture, and the syringe may thus get accidentally into the haematoma.

[Aspartase activity and the stability of Escherichia coli cells immobilized in different carrageenan samples]. / Aspartaznaia aktivnost' i stabil'nost' kletok Escherichia coli, immobilizovannykh v razlichnye obraztsy karraginana.

The cells of Escherichia coli 85 immobilized in carrageenan from various sources were being studied for the aspartase activity and stability. These properties of the resultant preparations which display a relatively high and stable biocatalytic activity were shown to be almost independent of the raw material from which carrageenan was obtained and of the degree of its purification.

[Comparison of the aspartase activity and its stability in Escherichia coli cells immobilized on polyacrylamide gel and carrageenan]. / Sravnenie aspartaznoi aktivinosti i ee stabil'nosti u kletok Escherichia coli, immobilizovannykh v poliakrilamidnyi gel' i karraginan.

The conditions for immobilization of Escherichia coli cells (Soviet strain 85) on the natural polysaccharide carrier carrageenan (Soviet-made) were investigated and kinetic regularities of the aspartase reaction catalysed by immobilized in carrageenan cells of E. coli 85 were established. The conditions for retaining a high aspartase activity and stability of biocatalysts based on the E. coli 85 cells immobilized in PAAG and carrageenan were determined using full-loaded tanks for continuous synthesis of L-aspartic acid. The time-stable aspartase activity of the biocatalyst can be increased by treating the beads of the catalyst with bifunctional reagents (hexamethylenediamine, glutaraldehyde), the most active catalyst for the biotechnological synthesis of L-aspartic acid being obtained when carrageenan is used.

[Purification of lipase of microbial origin by silochrome chromatography]. / Ochistka lipazy mikrobnogo proiskhozhdeniia khromatografiei na silokhrome.

The possibility of purifying lipase from Geotrichum asteroides by chromatography with a modified silochrome used as sorbent has been explored. The paper presents a scheme of adsorption and subsequent desorption of lipase from octylsilochrome which requires that ethylene glycol, Na-deoxycholate and Triton X-100 be used as eluents. Triton, the last in the sequence, eluates the major portion of the enzyme. This eluent can be removed from the lipase solution by means of ultrafiltration through the Ripore-4 membrane in the presence of glycerol.

[Method of measuring activity of amino acid acylase]. / Metod opredeleniia aktivnosti atsilaz aminokislot.

The paper describes a method to follow acylase activity. The method is based on spectrophotometry of the amino acid released, using o-phthalic aldehyde and mercaptoethanol. The major advantage of the method are its high sensitivity and speed. With the aid of the method kinetic parameters of hydrolysis of N-acetyl-L-methionine and N-acetyl-D,L-methionine catalyzed by pig kidney acylase were determined. Michaelis constants at pH 7.5 were estimated to be 5 +/- 1 and 10 +/- 2, respectively; this being in consistency with the data in the literature. It was shown that N-acetyl-D-methionine, acetate ion and methionine at the concentrations tested (0.01-0.05 M) did not inhibit acylase from a pig kidney.