Rooting Formal Methods Within Higher Education Curricula for Computer Science and Software Engineering — A White Paper

This white paper argues that formal methods need to be better rooted in higher education curricula for computer science and software engineering programmes of study. To this end, it advocates improved teaching of formal methods;systematic highlighting of formal methods within existing, ‘classical’ computer science courses; andthe inclusion of a compulsory formal methods course in computer science and software engineering curricula. These recommendations are based on the observations that formal methods are an essential and cost-effective means to increase software quality; howevercomputer science and software engineering programmes typically fail to provide adequate training in formal methods; and thusthere is a lack of computer science graduates who are qualified to apply formal methods in industry. This white paper is the result of a collective effort by authors and participants of the 1st International Workshop on Formal Methods – Fun for Everybody which was held in Bergen, Norway, 2–3 December 2019. As such, it represents insights based on learning and teaching computer science and software engineering (with or without formal methods) at various universities across Europe.</p

Schizosaccharomyces pombe Ofd2 Is a Nuclear 2-Oxoglutarate and Iron Dependent Dioxygenase Interacting with Histones

2-oxoglutarate (2OG) dependent dioxygenases are ubiquitous iron containing enzymes that couple substrate oxidation to the conversion of 2OG to succinate and carbon dioxide. They participate in a wide range of biological processes including collagen biosynthesis, fatty acid metabolism, hypoxic sensing and demethylation of nucleic acids and histones. Although substantial progress has been made in elucidating their function, the role of many 2OG dioxygenases remains enigmatic. Here we have studied the 2OG and iron (Fe(II)) dependent dioxygenase Ofd2 in Schizosaccharomyces pombe, a member of the AlkB subfamily of dioxygenases. We show that decarboxylation of 2OG by recombinant Ofd2 is dependent on Fe(II) and a histidine residue predicted to be involved in Fe(II) coordination. The decarboxylase activity of Ofd2 is stimulated by histones, and H2A has the strongest effect. Ofd2 interacts with all four core histones, however, only very weakly with H4. Our results define a new subclass of AlkB proteins interacting with histones, which also might comprise some of the human AlkB homologs with unknown function

Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy

Objective:To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology.Methods:We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes.Results:We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families.Conclusions:De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders.Johannes R. Lemke (32EP30_136042/1) and Peter De Jonghe (G.A.136.11.N and FWO/ESF-ECRP) received financial support within the EuroEPINOMICS-RES network (www.euroepinomics.org) within the Eurocores framework of the European Science Foundation (ESF). Saskia Biskup and Henrike Heyne received financial support from the German Federal Ministry for Education and Research (BMBF IonNeurONet: 01 GM1105A and FKZ: 01EO1501). Katia Hardies is a PhD fellow of the Institute for Science and Technology (IWT) Flanders. Ingo Helbig was supported by intramural funds of the University of Kiel, by a grant from the German Research Foundation (HE5415/3-1) within the EuroEPINOMICS framework of the European Science Foundation, and additional grants of the German Research Foundation (DFG, HE5415/5-1, HE 5415/6-1), German Ministry for Education and Research (01DH12033, MAR 10/012), and grant by the German chapter of the International League against Epilepsy (DGfE). The project also received infrastructural support through the Institute of Clinical Molecular Biology in Kiel, supported in part by DFG Cluster of Excellence "Inflammation at Interfaces" and "Future Ocean." The project was also supported by the popgen 2.0 network (P2N) through a grant from the German Ministry for Education and Research (01EY1103) and by the International Coordination Action (ICA) grant G0E8614N. Christel Depienne, Caroline Nava, and Delphine Heron received financial support for exome analyses by the Centre National de Genotypage (CNG, Evry, France)

ECMO for COVID-19 patients in Europe and Israel

Since March 15th, 2020, 177 centres from Europe and Israel have joined the study, routinely reporting on the ECMO support they provide to COVID-19 patients. The mean annual number of cases treated with ECMO in the participating centres before the pandemic (2019) was 55. The number of COVID-19 patients has increased rapidly each week reaching 1531 treated patients as of September 14th. The greatest number of cases has been reported from France (n = 385), UK (n = 193), Germany (n = 176), Spain (n = 166), and Italy (n = 136) .The mean age of treated patients was 52.6 years (range 16–80), 79% were male. The ECMO configuration used was VV in 91% of cases, VA in 5% and other in 4%. The mean PaO2 before ECMO implantation was 65 mmHg. The mean duration of ECMO support thus far has been 18 days and the mean ICU length of stay of these patients was 33 days. As of the 14th September, overall 841 patients have been weaned from ECMO support, 601 died during ECMO support, 71 died after withdrawal of ECMO, 79 are still receiving ECMO support and for 10 patients status n.a. . Our preliminary data suggest that patients placed on ECMO with severe refractory respiratory or cardiac failure secondary to COVID-19 have a reasonable (55%) chance of survival. Further extensive data analysis is expected to provide invaluable information on the demographics, severity of illness, indications and different ECMO management strategies in these patients

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

Subcortical brain volume, regional cortical thickness, and cortical surface area across disorders: findings from the ENIGMA ADHD, ASD, and OCD Working Groups

Objective Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders. Methods Structural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures). Results We found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed. Conclusion Our findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders

Spontaneous discharge rhythms and social signalling in the weakly electric fish Pollimyrus isidori (Cuvier et Valenciennes) (Mormyridae, Teleostei)

The electric organ discharge (EOD) signalling of isolated and of socially interacting Pollimyrus isidori was analyzed. 1. EOD interval histograms of resting animals showed wide ranges with three modes of 12 to 15 ms, of around 92 ms, and of 220 to 230 ms (Fig. 4a). In number and/or position of modes, the P. isidori histograms were clearly different from those shown by four other mormyrid species: Gnathonemus petersii, Mormyrus rume, Brienomyrus niger, Brienomyrus brachyistius. 2. The EOD interval histograms of swimming P. isidori (Fig. 4a) displayed only one mode of around 50 ms and closely resembled the EOD activity exhibited by G. petersii, B. niger, and B. brachyistius. 3. During overt attack (Figs. 4b, 6, 7a), P. isidori displayed high discharge rates as do G. petersii, B. niger, and M. rume. The EOD time patterns of the displays were clearly distinct from the other species' displays. 4. These data suggest the possibility that mormyrids might recognize conspecifics from their resting- or attack-associated EOD time patterns, not, however, by monitoring EOD swimming activity. During this behavior, species identification would seem possible only by the analysis of spectral cues from the properties of the individual EOD pulses (cf. Fig. 3). Compared with the other species mentioned above, the extremely short EOD of P. isidori contains much more energy in a high frequency band (peak: 10 kHz with energy beyond 30 kHz). 5. Different individuals of P. isidori displayed either a Preferred Latency Response of approx. 12 to 14 ms or a response consisting in avoiding a 10 to 20 ms discharge latency to foreign electrical stimuli (Figs. 8–10). While the avoidance response may be considered a jamming avoidance behaviour, reducing the probability of coincidences with a conspecific's EODs, the Prefered Latency Response in P. isidori would have the opposite effect and lsquojamrsquo a conspecific's signals when the latter displays high discharge rates occurring during attack behaviour. Whether these alternative types of latency behaviour are sex, age, or rank correlated remains to be investigated

Electric and Motor responses of the Weakly electric fish, Gnathonemus petersii (Mormyridae), to play-back of social signals

1. Seven isolated G. petersii resting in their daytime hiding-places were stimulated via a dipole model (Fig. 1a) with previously tape-recorded electric organ discharge (EOD) patterns in an attempt to determine whether G. petersii distinguishes two different intraspecific EOD patterns, rest and attack. 2. Rest pattern A was characterized by a broad distribution of EOD intervals, a low mean discharge rate (8 Hz, Fig. 3), and a long period of significantly positive autocorrelation (2 s, Fig. 4a). Accordingly, the spectrum of EOD rate fluctuations showed a low frequency range (0.005 to 0.12 Hz, Fig. 5a). Attack pattern B was a considerably different EOD interval distribution of high mean discharge rate (25 Hz, Fig. 3), showing a short period of significantly positive autocorrelation (0.8 s, Fig. 4b), only. Here, the spectrum of EOD rate fluctuations was at a considerably higher frequency range (0.09 to 0.47 Hz, Fig. 5b). 3. Play-back of attack pattern B elicited significantly more bodily startle responses from the experimental fish (Fig. 6) than did the rest pattern A (Table 1). Also the number of attacks directed at the dipolemodel was significantly greater during stimulation with attack pattern B (Table 2, Fig. 6). 4. The EOD responses of the experimental fish differed in several respects depending on which stimulation pattern was used. The modes of the pulse rate histograms as well as their spans were lower during play-back of rest pattern A than during stimulation with attack pattern B (average 12.3 vs 16.2 Hz, and average 47 vs 56 Hz, respectively; Fig. 11). Shortterm (0.2 s) EOD rate correlations were stronger when the fish were stimulated with rest pattern A than when they were stimulated with attack pattern B (average correlations 0.67 and 0.61, respectively; Figs. 10 and 11). Significant positive correlations were maintained for longer periods of time during rest pattern stimulation than during attack pattern stimulation (average 1.94 and 1.24 s, respectively; Figs. 10 and 11). The spectra of EOD rate fluctuations of the stimulated fish were at lower frequency ranges during rest pattern stimulation than during attack pattern stimulation (average amplitude-spectrum peak frequencies 0.02 and 0.07 Hz, respectively; Figs. 12 and 13). 5. Although maximal cross-correlations from the EOD rates to the stimulus pulse rates were weaker during rest pattern stimulation (average 0.2) than during attack pattern stimulation (average 0.33), significant cross-correlations were maintained for longer periods of time during rest pattern stimulation than during attack pattern stimulation (average 1.78 and 0.92 s, respectively). The lags of maximal cross-correlations were greater during rest pattern stimulation than during attack pattern stimulation (average 2.6 and 0.8 s, respectively; Figs. 14 and 15). 6. The results clearly showed that at least two specific EOD time patterns encode different lsquomessagesrsquo in the intraspecific communication system of G. petersii