This paper presents a report on outcomes of the 10th Computational Modeling in Biology Network (COMBINE) meeting that was held in Heidelberg, Germany, in July of 2019. The annual event brings ...together researchers, biocurators and software engineers to present recent results and discuss future work in the area of standards for systems and synthetic biology. The COMBINE initiative coordinates the development of various community standards and formats for computational models in the life sciences. Over the past 10 years, COMBINE has brought together standard communities that have further developed and harmonized their standards for better interoperability of models and data. COMBINE 2019 was co-located with a stakeholder workshop of the European EU-STANDS4PM initiative that aims at harmonized data and model standardization for
models in the field of personalized medicine, as well as with the FAIRDOM PALs meeting to discuss findable, accessible, interoperable and reusable (FAIR) data sharing. This report briefly describes the work discussed in invited and contributed talks as well as during breakout sessions. It also highlights recent advancements in data, model, and annotation standardization efforts. Finally, this report concludes with some challenges and opportunities that this community will face during the next 10 years.
Three new unsymmetrical compartmental dinucleating ligands, 4‐bromo‐2‐(4‐methylpiperazin‐1‐ylmethyl)‐6‐{2‐(1‐piperidyl)ethyl}aminomethylphenol (HL1), ...4‐bromo‐2‐(4‐methylpiperazin‐1‐ylmethyl)‐6‐{2‐(morpholin‐4‐yl)ethyl}aminomethylphenol (HL2), and 4‐bromo‐2‐(4‐methylpiperazin‐1‐ylmethyl)‐6‐{2‐(thiomorpholin‐4‐yl)ethyl}aminomethylphenol (HL3), have been synthesized in order to model the active site of type 3 copper proteins. The dicopper(II) complexes of these ligands give first hints about the influence of a thioether group close to the metal site. The bromophenol‐based ligands have one piperazine arm and one other bidentate arm in positions 2 and 6 of the phenolic ring, respectively. With each ligand a dinuclear copper(II) complex was prepared and structurally characterized. The copper ions were found to have square pyramidal environments and a mixture of endogenous phenoxo and exogenous acetate bridging. The influence of a heteroatom in one arm of the ligand on catecholase activity and speciation in solution was studied by UV/Vis spectroscopy, ESI‐MS experiments and, DFT calculations.
Helpful heteroatoms: Model complexes for type 3 copper proteins that contain compartmental bischelating ligands have been prepared (see structure). Incorporation of heteroatoms into a side arm of a phenol‐based ligand, especially in the form of a thioether, was found to increase the turnover number for the oxidation of catechols.
Preclinical Alzheimer's disease (AD) is one possible cause of subjective cognitive decline (SCD). Normal task performance despite ongoing neurodegeneration is typically considered as neuronal ...compensation, which is reflected by greater neuronal activity. Compensatory brain activity has been observed in frontal as well as parietal regions in SCD, but data are scarce, especially outside the memory domain.
To investigate potential compensatory activity in SCD. Such compensatory activity is particularly expected in participants where blood-based biomarkers indicated amyloid positivity as this implies preclinical AD.
52 participants with SCD (mean age: 71.00±5.70) underwent structural and functional neuroimaging (fMRI), targeting episodic memory and spatial abilities, and a neuropsychological assessment. The estimation of amyloid positivity was based on plasma amyloid-β and phosphorylated tau (pTau181) measures.
Our fMRI analyses of the spatial abilities task did not indicate compensation, with only three voxels exceeding an uncorrected threshold at p < 0.001. This finding was not replicated in a subset of 23 biomarker positive individuals.
Our results do not provide conclusive evidence for compensatory brain activity in SCD. It is possible that neuronal compensation does not manifest at such an early stage as SCD. Alternatively, it is possible that our sample size was too small or that compensatory activity may be too heterogeneous to be detected by group-level statistics. Interventions based on the individual fMRI signal should therefore be explored.
Background
Neurorehabilitation in dementia becomes an increasingly relevant topic and requires early detection of signs of domain‐specific cognitive decline. To this end, neuropsychological testing ...is usually performed in specialized centers, which can be difficult to reach for people living in rural regions for example. These centers also usually have long waiting‐lists, which can defer proper diagnosis for long periods of time. Today, increasing attention is devoted to developing rapid cognitive screening batteries that are easy to administer remotely, and have a game‐like interface to reduce test anxiety, capture attention and increase motivation. In terms of treatment, “serious videogames” share the same stimulating, motivating and adaptive qualities, and are surfacing and showing real promise as a viable treatment option (Sokolov et al., 2020).
Method
Regarding assessment: We conducted an observational multi‐centric study, evaluating the reliability of the mobile and adaptive serious videogame ACE‐X in detecting cognitive deficits in patients with subjective cognitive decline and mild neurocognitive disorders consulting specialized memory clinics in Bern and Lausanne in Switzerland, and Nice in France.
Regarding neurorehabilitation and serious games: We have tested a closed‐loop adaptive cognitive exergame in healthy older adults (Anguera et al., 2022), patients with stroke (NCT05169632) and multiple sclerosis (NCT03737825).
Results
Regarding assessment: The results indicate that ACE‐X can reveal deficits in working memory and multi‐tasking relevant for everyday life.
Regarding neurorehabilitation and serious games: The outcomes show sustained benefits in attention, working memory and everyday life. These findings pave the way for integrated, cognitive‐physical, closed‐loop adaptive training for the cognitive neurorehabilitation of people with dementia.
Conclusion
Detecting subclinical signs of cognitive decline in the aging population is crucial, as it allows to put in place early ‐ and thus more effective ‐ interventions. Closed‐loop adaptive assessment serious video games may be used to perform large‐scale screenings of elderly people at home, to identify those that may benefit from a referral to a medical practitioner. Subsequently, interventional serious video games may represent a promising tool for cognitive neurorehabilitation of cognitive decline due to neurodegeneration.
The presented study reports the synthesis and the vibrational spectroscopic characterization of different matrix-embedded model photocatalysts. The goal of the study is to investigate the interaction ...of a polymer matrix with photosensitizing dyes and metal complexes for potential future photocatalytic applications. The synthesis focuses on a new rhodamine B derivate and a Pt(II) terpyridine complex, which both contain a polymerizable methacrylate moiety and an acid labile acylhydrazone group. The methacrylate moieties are afterward utilized to synthesize functional model hydrogels mainly consisting of poly(ethylene glycol) methacrylate units. The pH-dependent and temperature-dependent behavior of the hydrogels is investigated by means of Raman and IR spectroscopy assisted by density functional theory calculations and two-dimensional correlation spectroscopy. The spectroscopic results reveal that the Pt(II) terpyridine complex can be released from the polymer matrix by cleaving the CN bond in an acid environment. The same behavior could not be observed in the case of the rhodamine B dye although it features a comparable CN bond. The temperature-dependent study shows that the water evaporation has a significant influence neither on the molecular structure of the hydrogel nor on the model photocatalytic moieties.
Summary
Tepotinib is a highly selective, potent, mesenchymal-epithelial transition factor (MET) inhibitor, approved for the treatment of non-small cell lung cancer harboring
MET
exon 14 skipping ...alterations. The aims of this work were to investigate the potential for drug-drug interactions via cytochrome P450 (CYP) 3A4/5 or P-glycoprotein (P-gp) inhibition. In vitro studies were conducted in human liver microsomes, human hepatocyte cultures and Caco-2 cell monolayers to investigate whether tepotinib or its major metabolite (MSC2571109A) inhibited or induced CYP3A4/5 or inhibited P-gp. Two clinical studies were conducted to investigate the effect of multiple dose tepotinib (500 mg once daily orally) on the single dose pharmacokinetics of a sensitive CYP3A4 substrate (midazolam 7.5 mg orally) and a P-gp substrate (dabigatran etexilate 75 mg orally) in healthy participants. Tepotinib and MSC2571109A showed little evidence of direct or time-dependent CYP3A4/5 inhibition (IC
50
> 15 μM) in vitro, although MSC2571109A did show mechanism-based CYP3A4/5 inhibition. Tepotinib did not induce CYP3A4/5 activity in vitro, although both tepotinib and MSC2571109A increased CYP3A4 mRNA. In clinical studies, tepotinib had no effect on the pharmacokinetics of midazolam or its metabolite 1’-hydroxymidazolam. Tepotinib increased dabigatran maximum concentration and area under the curve extrapolated to infinity by 38% and 51%, respectively. These changes were not considered to be clinically relevant. Tepotinib was considered safe and well tolerated in both studies. The potential of tepotinib to cause clinically relevant DDI with CYP3A4- or P-gp-dependent drugs at the clinical dose is considered low. Study 1 (midazolam): NCT03628339 (registered 14 August 2018). Study 2 (dabigatran): NCT03492437 (registered 10 April 2018).
Recent studies suggest that computerized puzzle games are enjoyable, easy to play, and engage attentional, visuospatial, and executive functions. They may help mediate impairments seen in cognitive ...decline in addition to being an assessment tool. Eye tracking provides a quantitative and qualitative analysis of gaze, which is highly useful in understanding visual search behavior.
The goal of the research was to test the feasibility of eye tracking during a puzzle game and develop adjunct markers for cognitive performance using eye-tracking metrics.
A desktop version of the Match-3 puzzle game with 15 difficulty levels was developed using Unity 3D (Unity Technologies). The goal of the Match-3 puzzle was to find configurations (target patterns) that could be turned into a row of 3 identical game objects (tiles) by swapping 2 adjacent tiles. Difficulty levels were created by manipulating the puzzle board size (all combinations of width and height from 4 to 8) and the number of unique tiles on the puzzle board (from 4 to 8). Each level consisted of 4 boards (ie, target patterns to match) with one target pattern each. In this study, the desktop version was presented on a laptop computer setup with eye tracking. Healthy older subjects were recruited to play a full set of 15 puzzle levels. A paper-pencil-based assessment battery was administered prior to the Match-3 game. The gaze behavior of all participants was recorded during the game. Correlation analyses were performed on eye-tracking data correcting for age to examine if gaze behavior pertains to target patterns and distractor patterns and changes with puzzle board size (set size). Additionally, correlations between cognitive performance and eye movement metrics were calculated.
A total of 13 healthy older subjects (mean age 70.67 SD 4.75 years; range 63 to 80 years) participated in this study. In total, 3 training and 12 test levels were played by the participants. Eye tracking recorded 672 fixations in total, 525 fixations on distractor patterns and 99 fixations on target patterns. Significant correlations were found between executive functions (Trail Making Test B) and number of fixations on distractor patterns (P=.01) and average fixations (P=.005).
Overall, this study shows that eye tracking in puzzle games can act as a supplemental source of data for cognitive performance. The relationship between a paper-pencil test for executive functions and fixations confirms that both are related to the same cognitive processes. Therefore, eye movement metrics might be used as an adjunct marker for cognitive abilities like executive functions. However, further research is needed to evaluate the potential of the various eye movement metrics in combination with puzzle games as visual search and attentional marker.
The resorption of magnesium-based alloy bioabsorbable screws results in the release of hydrogen gas, which can mimic infection and enter the growth plate. The screw itself and the released gas may ...also affect image quality.
The evaluation of magnetic resonance imaging (MRI) findings during the most active phase of screw resorption is the objective, with particular focus on the growth plate and to assess for the presence of metal-induced artifacts.
In total, 30 prospectively acquired MRIs from 17 pediatric patients with fractures treated with magnesium screws were assessed for the presence and distribution of intraosseous, extraosseous, and intra-articular gas; gas within the growth plate; osteolysis along the screw; joint effusion; bone marrow edema; periosteal reaction; soft tissue edema; and metal-induced artifacts.
Gas locules were found in the bone and soft tissues in 100% of the examinations, intra-articular in 40%, and in 37% of unfused growth plates. Osteolysis and the periosteal reaction were present in 87%, bone marrow edema in 100%, soft tissue edema in 100%, and joint effusion in 50% of examinations. Pile-up artifacts were present in 100%, and geometric distortion in 0% of examinations. Fat suppression was not significantly impaired in any examination.
Gas and edema in the bone and soft tissues are normal findings during the resorption of magnesium screws and should not be misinterpreted as infection. Gas can also be detected within growth plates. MRI examinations can be performed without metal artifact reduction sequences. Standard fat suppression techniques are not significantly affected.
Introduction
The objective was to investigate the association between chorionicity‐specific intertwin birthweight discordance and adverse outcomes including long‐term follow up at 6, 18, and 48–60 ...months after term via Ages and Stages Questionnaire.
Material and methods
In this secondary analysis of a cohort study (Oldenburg et al., n = 1688) and a randomized controlled trial (PREDICT study, n = 1045) twin pairs were divided into three groups according to chorionicity‐specific birthweight discordance: <75th percentile, 75th–90th percentile and >90th percentile. Information on infant mortality, admittance to neonatal intensive care units, and gestational age at delivery was available for all pairs. Detailed neonatal outcomes were available for 656 pairs from PREDICT, of which 567 pairs had at least one Ages and Stages Questionnair follow‐up. Logistic regression models were used for dichotomous outcomes. Ages and Stages Questionnair scores were compared using the method of generalized estimating equation to account for the correlation within twins.
Results
The 75th and 90th percentiles for birthweight discordance were 14.8 and 21.4% for monochorionic and 16.0 and 23.8% for dichorionic twins. After adjustment for small for gestational age and gender, birthweight discordance >75th and >90th percentile was associated with induced delivery <34 weeks odds ratio 1.71 (95% confidence interval 1.11–2.65) and odds ratio 2.83 (95% confidence interval 1.73–4.64), respectively. Discordance >75th‐percentile was associated with an increased risk of infant mortality after 28 days odds ratio 4.69 (95% confidence interval 1.07–20.45) but not with major neonatal complications or with low mean Ages and Stages Questionnair scores at 6, 18, and 48–60 months after term.
Conclusion
Chorionicity‐specific intertwin birthweight discordance is a risk factor for induced preterm delivery and infant mortality, but not for lower scores for neurophysiological development at 6, 18, and 48–60 months.
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