The emergence of complex diseases resulting from abnormal cell-cell signaling and the spread of infectious diseases caused by pathogens are significant threats to humanity. Unraveling the dynamic... Show moreThe emergence of complex diseases resulting from abnormal cell-cell signaling and the spread of infectious diseases caused by pathogens are significant threats to humanity. Unraveling the dynamic mechanisms underlying cell-cell signaling and infectious disease spreading is crucial for effective disease prevention and treatment. As science and technology advance, the availability and diversity of observational and experimental data related to these biological processes continue to grow. In this thesis, we integrate multisource data with dynamic modeling to investigate the biological mechanisms of Notch signaling in biological development and to develop prevention and control strategies for infectious diseases. Show less
Cheng, S.; Jacobs, C.G.; Mogollón Pérez, E.A.; Chen, D.; Sanden, J.T. van de; Bretscher, K.M.; ... ; Zee, M. van der 2023
Developmental time is a key life-history trait with large effects on Darwinian fitness. In many insects, developmental time is currently under strong selection to minimize ecological mismatches in... Show moreDevelopmental time is a key life-history trait with large effects on Darwinian fitness. In many insects, developmental time is currently under strong selection to minimize ecological mismatches in seasonal timing induced by climate change. The genetic basis of responses to such selection, however, is poorly understood. To address this problem, we set up a long-term evolve-and-resequence experiment in the beetle Tribolium castaneum and selected replicate, outbred populations for fast or slow embryonic development. The response to this selection was substantial and embryonic developmental timing of the selection lines started to diverge during dorsal closure. Pooled whole-genome resequencing, gene expression analysis and an RNAi screen pinpoint a 222 bp deletion containing binding sites for Broad and Tramtrack upstream of the ecdysone degrading enzyme Cyp18a1 as a main target of selection. Using CRISPR/Cas9 to reconstruct this allele in the homogenous genetic background of a laboratory strain, we unravel how this single deletion advances the embryonic ecdysone peak inducing dorsal closure and show that this allele accelerates larval development but causes a trade-off with fecundity. Our study uncovers a life-history allele of large effect and reveals the evolvability of developmental time in a natural insect population. Show less
Zhao, Z.; Ding, X.; Behren, P.A.; Li, J.; He, M.; Gao, Y.; ... ; Chen, D. 2023
All tissue development and replenishment relies upon the breaking of symmetries leading to the morphological and operational differentiation of progenitor cells into more specialized cells. One of... Show moreAll tissue development and replenishment relies upon the breaking of symmetries leading to the morphological and operational differentiation of progenitor cells into more specialized cells. One of the main engines driving this process is the Notch signal transduction pathway, a ubiquitous signalling system found in the vast majority of metazoan cell types characterized to date. Broadly speaking, Notch receptor activity is governed by a balance between two processes: 1) intercellular Notch transactivation triggered via interactions between receptors and ligands expressed in neighbouring cells; 2) intracellular cis inhibition caused by ligands binding to receptors within the same cell. Additionally, recent reports have also unveiled evidence of cis activation. Whilst context-dependent Notch receptor clustering has been hypothesized, to date, Notch signalling has been assumed to involve an interplay between receptor and ligand monomers. In this study, we demonstrate biochemically, through a mutational analysis of DLL4, both in vitro and in tissue culture cells, that Notch ligands can efficiently self-associate. We found that the membrane proximal EGF-like repeat of DLL4 was necessary and sufficient to promote oligomerization/dimerization. Mechanistically, our experimental evidence supports the view that DLL4 ligand dimerization is specifically required for cis-inhibition of Notch receptor activity. To further substantiate these findings, we have adapted and extended existing ordinary differential equation-based models of Notch signalling to take account of the ligand dimerization-dependent cis-inhibition reported here. Our new model faithfully recapitulates our experimental data and improves predictions based upon published data. Collectively, our work favours a model in which net output following Notch receptor/ligand binding results from ligand monomer-driven Notch receptor transactivation (and cis activation) counterposed by ligand dimer-mediated cis-inhibition.Author summary The growth and maintenance of tissues is a fundamental characteristic of metazoan life, controlled by a highly conserved core of cell signal transduction networks. One such pathway, the Notch signalling system, plays a unique role in these phenomena by orchestrating the generation of the phenotypic and genetic asymmetries which underlie tissue development and remodeling. At the molecular level, it achieves this via two specific types of receptor/ligand interaction: intercellular binding of receptors and ligands expressed in neighbouring cells, which triggers receptor activation (transactivation); intracellular receptor/ligand binding within the same cell which blocks receptor activation (cis inhibition). Together, these counterposed mechanisms determine the strength, the direction and the specificity of Notch signalling output. Whilst, the basic mechanisms of receptor transactivation have been delineated in some detail, the precise nature of cis inhibition has remained enigmatic. Through a combination of experimental approaches and computational modelling, in this study, we present a new model of Notch signalling in which ligand monomers promote Notch receptor transactivation, whereas cis inhibition is induced optimally via ligand dimers. This is the first model to include a concrete molecular distinction, in terms of ligand configuration, between the main branches of Notch signalling. Our model faithfully recapitulates both our presented experimental results as well as the recently published work of others, and provides a novel perspective for understanding Notch-regulated biological processes such as embryo development and angiogenesis.Competing Interest StatementThe authors have declared no competing interest. Show less
IntroductionExcessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA) can impair vigilance/attention. Solriamfetol, a dopamine/norepinephrine reuptake inhibitor... Show moreIntroductionExcessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA) can impair vigilance/attention. Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved to treat EDS associated with narcolepsy (75-150 mg/day) or OSA (37.5-150 mg/day). The analysis reported here explored the use of the Sleep, Activity, Fatigue, and Task Effectiveness (SAFTE) model (used in transport industries to model performance based on accumulated sleep and circadian variability) as a substitute for healthy controls using psychomotor vigilance task (PVT) data collected during clinical studies. MethodsData were analyzed from two phase 2 studies of solriamfetol in adults with OSA (NCT02806895, EudraCT 2015-003930-28) or narcolepsy (NCT02806908, EudraCT 2015-003931-36). Participants were randomly assigned 1:1 to solriamfetol 150 mg/day (3 days) followed by 300 mg/day (4 days), or placebo (7 days), then crossed over to the other treatment. Actual task effectiveness scores were calculated from average PVT inverse reaction time (pre-dose; 2 h post-dose; 6 h post-dose). Actigraphy-derived sleep intervals were used in SAFTE to determine modeled healthy control task effectiveness scores. ResultsIn participants with OSA (N = 31) on placebo or solriamfetol, actual and modeled healthy control task effectiveness did not differ at any time point. In participants with narcolepsy (N = 20) on placebo, actual task effectiveness at 2 h post-dose was lower than modeled healthy control task effectiveness (nominal P = 0.03), a difference not present with solriamfetol. There was no main effect of solriamfetol on actual or modeled healthy control task effectiveness across time points. ConclusionThis study represents a novel application of the SAFTE biomathematical model to approximate healthy controls in sleep disorder research and provides valuable lessons that may optimize future research. Future studies should perform a priori power analyses for model-tested outcomes and use sleep measures that capture sleep fragmentation characteristic of sleep disorders for sleep input (e.g., total sleep time rather than time in bed). Show less
In this study, generalized predictive models were developed to estimate KOA of four kinds of aromatic pollutants based on the calculated solvation free energy and taking the dimer effect into... Show moreIn this study, generalized predictive models were developed to estimate KOA of four kinds of aromatic pollutants based on the calculated solvation free energy and taking the dimer effect into account. Uncorrected log KOA values, which were directly estimated from the calculated solvation free energy of individual molecules, underestimated experimental values, and the deviation increased with increasing log KOA. Dimers were found to greatly affect the apparent KOA values of these aromatic pollutants, which were driven by π-π interactions. London dispersion and exchange-repulsion terms were identified to be dominant components of the underlying π-π interactions. It is interesting to find that the π-π interactions of polybrominated diphenyl ethers correlate with not only the molecular polarizability but also the size of opposing aromatic surfaces, which leads to a different trend of π-π interactions from other aromatic pollutants. A universal quantitative structure-activity relationship model was developed to estimate the proportion of dimers based on five molecular structural descriptors relevant to the π-π interactions. After calibration with the dimer effect, estimations of log KOA were consistent with experimental values. Therefore, the dimer effect should be taken into consideration when investigating the partition behavior of aromatic pollutants, and the solvation free energy model could be an alternative method for the prediction of KOA. Show less
Objectives: This analysis characterized changes in weight in participants with obstructive sleep apnea (OSA) or narcolepsy treated with solriamfetol (SunosiTM) 37.5 (OSA only), 75, 150, or 300 mg/d... Show moreObjectives: This analysis characterized changes in weight in participants with obstructive sleep apnea (OSA) or narcolepsy treated with solriamfetol (SunosiTM) 37.5 (OSA only), 75, 150, or 300 mg/d. Methods: In two 12-week, randomized, placebo-controlled trials and one 1-year open-label extension study, changes in weight were evaluated from baseline to end of study (week 12 or week 40 of the open -label extension [after up to 52 weeks of solriamfetol treatment]) in participants with OSA or narcolepsy. Results: After 12 weeks of solriamfetol treatment, median percent change in weight from baseline across all solriamfetol doses was-0.84%, compared with 0.54% for placebo, in participants with OSA; and-0.07%, compared with 3.08% for placebo, in participants with narcolepsy. After up to 52 weeks of solriamfetol treatment, overall median percent change in weight from baseline was-1.76%, which showed a dose-dependent pattern (75 mg, 0.57%; 150 mg,-1.2%; 300 mg,-2.5%).Results were similar in subgroups of participants with OSA or narcolepsy, with overall median percent changes in weight of-2.2% and-1.1%, respectively. After up to 52 weeks of solriamfetol treatment, the percentage of participants with weight loss >= 5% relative to baseline was 25.7% overall and increased in a dose -dependent manner (75 mg, 4.5%; 150 mg, 17.3%; 300 mg, 32.4%). Results were similar among sub-groups of participants with OSA or narcolepsy, with 26.4% and 24.2% of participants experiencing weight loss >= 5%, respectively. No weight-related treatment-emergent adverse events were serious. Conclusions: Solriamfetol treatment was associated with decreases in body weight in a dose-related manner.(c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Show less
Objective: To evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on-the-road driving performance in participants with narcolepsy. Methods: In this randomised,... Show moreObjective: To evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on-the-road driving performance in participants with narcolepsy. Methods: In this randomised, double-blind, placebo-controlled, crossover study, driving performance during a 1 h on-road driving test was assessed at 2 and 6 h post-dose following 7 days of treatment with solriamfetol (150 mg/day for 3 days, followed by 300 mg/day for 4 days) or placebo. The primary endpoint was standard deviation of lateral position (SDLP) at 2 h post-dose. Results:The study included 24 participants (54% male; mean age, 40 years); 22 had evaluable SDLP data. At 2 h post-dose, median SDLP was significantly lower (improved) with solriamfetol compared with placebo (19.08 vs. 20.46 cm [median difference, -1.9 cm], p = 0.002). Four participants on solriamfetol and 7 on placebo had incomplete driving tests. At 6 h post-dose, median SDLP was not statistically significantly different with solriamfetol compared with placebo (19.59 vs. 19.78 cm [median difference, -1.1 cm], p = 0.125). Three participants on solriamfetol and 10 on placebo had incomplete driving tests. Common adverse events (>= 5%) included headache, decreased appetite, and somnolence. Conclusions: Solriamfetol 300 mg/day improved on-the-road driving performance, at 2 h post-administration in participants with narcolepsy. Show less
ObjectiveTo evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on-the-road driving performance in participants with narcolepsy.MethodsIn this randomised,... Show moreObjectiveTo evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on-the-road driving performance in participants with narcolepsy.MethodsIn this randomised, double-blind, placebo-controlled, crossover study, driving performance during a 1 h on-road driving test was assessed at 2 and 6 h post-dose following 7 days of treatment with solriamfetol (150 mg/day for 3 days, followed by 300 mg/day for 4 days) or placebo. The primary endpoint was standard deviation of lateral position (SDLP) at 2 h post-dose.ResultsThe study included 24 participants (54% male; mean age, 40 years); 22 had evaluable SDLP data. At 2 h post-dose, median SDLP was significantly lower (improved) with solriamfetol compared with placebo (19.08 vs. 20.46 cm [median difference, −1.9 cm], p = 0.002). Four participants on solriamfetol and 7 on placebo had incomplete driving tests. At 6 h post-dose, median SDLP was not statistically significantly different with solriamfetol compared with placebo (19.59 vs. 19.78 cm [median difference, −1.1 cm], p = 0.125). Three participants on solriamfetol and 10 on placebo had incomplete driving tests. Common adverse events (≥5%) included headache, decreased appetite, and somnolence.ConclusionsSolriamfetol 300 mg/day improved on-the-road driving performance, at 2 h post-administration in participants with narcolepsy. Show less
Objective: To evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on-the-road driving in participants with excessive daytime sleepiness (EDS) associated with... Show moreObjective: To evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on-the-road driving in participants with excessive daytime sleepiness (EDS) associated with obstructive sleep apnoea (OSA). Methods: Eligible participants were aged 21-75 years with OSA and EDS (Maintenance of Wakefulness Test mean sleep latency <30 minutes and Epworth Sleepiness Scale score >= 10). Participants were randomised 1:1 to solriamfetol (150 mg/day [3 days], then 300 mg/day [4 days]) or placebo for 7 days, before crossover to the other treatment paradigm. On Day 7 of each period, standardised on-road driving tests occurred (2 and 6 hours postdose). Standard deviation of lateral position (SDLP) was the primary endpoint. Results: Solriamfetol significantly reduced SDLP at 2 (n = 34; least squares mean difference, -1.1 cm; 95% CI, -1.85, -0.32; p = 0.006) and 6 hours postdose (n = 32; least squares mean difference, -0.8 cm; 95% CI, -1.58, -0.03; p = 0.043). Two hours postdose, 4 placebo-treated and 1 solriamfetol-treated participants had incomplete driving tests; 6 hours postdose, 7 and 3 participants, respectively, had incomplete tests. Common treatment-emergent adverse events included headache, nausea, and insomnia. Conclusions: Solriamfetol 300 mg/day significantly improved on-the-road driving performance in participants with EDS associated with OSA. Show less
Xu, B.; Zhang, J.; Egusquiza, M.; Chen, D.; Li, F.; Behrens, P.A.; Egusquiza, E. 2021
Background Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, improved wakefulness and reduced excessive daytime sleepiness (EDS) in studies of participants with narcolepsy with and... Show moreBackground Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, improved wakefulness and reduced excessive daytime sleepiness (EDS) in studies of participants with narcolepsy with and without cataplexy. Objective Prespecified subgroup analyses of data from a 12-week randomized, double-blind, placebo-controlled, phase III trial of solriamfetol for EDS in narcolepsy evaluated the efficacy and safety of solriamfetol by cataplexy status. Methods Participants with narcolepsy received solriamfetol (75, 150, or 300 mg/day) or placebo and were stratified by cataplexy status. Coprimary endpoints were change from baseline on Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS); Patient Global Impression of Change (PGI-C) was the key secondary endpoint. Change in frequency of cataplexy attacks was evaluated in participants reporting cataplexy at baseline. Safety was evaluated. No adjustments were made for multiple comparisons; thereforepvalues are nominal. Results There were 117 participants in the cataplexy subgroup and 114 in the non-cataplexy subgroup. At week 12, least-squares (LS) mean (95% confidence interval [CI]) differences from placebo on change from baseline in MWT for solriamfetol 75, 150, and 300 mg in the cataplexy subgroup were 1.6 (- 3.6 to 6.9), 6.1 (0.7-11.4), and 8.9 (3.5-14.2) minutes, respectively (p < 0.05; 150 and 300 mg), and in the non-cataplexy subgroup were 3.4 (- 1.9 to 8.7), 9.1 (3.8-14.3), and 11.2 (5.8-16.6) minutes, respectively (p < 0.001; 150 and 300 mg). At week 12, LS mean (95% CI) differences from placebo on ESS change from baseline for solriamfetol 75, 150, and 300 mg in the cataplexy subgroup were - 1.3 (- 3.9 to 1.3), - 3.7 (- 6.4 to - 1.1), and - 4.5 (- 7.1 to - 1.9), respectively (p < 0.01; 150 and 300 mg), and in the non-cataplexy subgroup were - 3.0 (- 5.6 to - 0.4), - 3.7 (- 6.3 to - 1.2), and - 4.9 (- 7.6 to - 2.2), respectively (p < 0.05; all doses). For PGI-C at week 12, the mean percentage difference from placebo (95% CI) for solriamfetol 75, 150, and 300 mg in the cataplexy subgroup was 10% (- 15 to 35), 33% (9-57), and 39% (16-61), respectively (p < 0.05; 150 and 300 mg), and in the non-cataplexy subgroup was 48% (25-70), 44% (21-67), and 52% (30-73), respectively (p < 0.001; all doses), with somewhat differential treatment effects for 75 mg by cataplexy status. No changes in the number of cataplexy attacks were observed for solriamfetol compared with placebo (mean +/- standard deviation changes: - 3.6 +/- 13.3 [combined solriamfetol] and - 3.5 +/- 9.8 [placebo]). Common adverse events (headache, nausea, decreased appetite, and nasopharyngitis) were similar between cataplexy subgroups. Conclusions These data strongly indicate that solriamfetol was effective in treating EDS in participants with narcolepsy with or without cataplexy, as indicated by robust effects on MWT, ESS, and PGI-C. The safety profile was similar regardless of cataplexy status. Show less
An international interdisciplinary team of experts achieved consensus around primary methods and domains for assessing neurodevelopmental effects (i.e., benefits and/or difficulties) of pubertal... Show moreAn international interdisciplinary team of experts achieved consensus around primary methods and domains for assessing neurodevelopmental effects (i.e., benefits and/or difficulties) of pubertal suppression treatment in transgender youth. Show less
Objective: Solriamfetol (formerly JZP-110), a dopamine/norepinephrine reuptake inhibitor, is approved in the US to improve wakefulness in adults with excessive daytime sleepiness associated with... Show moreObjective: Solriamfetol (formerly JZP-110), a dopamine/norepinephrine reuptake inhibitor, is approved in the US to improve wakefulness in adults with excessive daytime sleepiness associated with narcolepsy (75-150 mg/d) or obstructive sleep apnea (37.5-150 mg/d). In a randomized, double-blind, placebocontrolled trial in participants with narcolepsy, effects of solriamfetol on functional status, health-related quality of life (HRQoL), and work productivity were evaluated.Methods: Participants with narcolepsy (N = 239) were randomized to solriamfetol 75, 150, or 300 mg, or placebo for 12 weeks. Outcome measures included the Functional Outcomes of Sleep Questionnaire short version (FOSQ-10), 36-Item Short Form Health Survey version 2 (SF-36v2), and Work Productivity and Activity Impairment questionnaire for Specific Health Problem (WPAI:SHP). A mixed-effects model with repeated measures was used for comparisons vs placebo.Results: At week 12, solriamfetol increased FOSQ-10 total score, with greatest mean difference from placebo (95% CI) at 300 mg (1.45 [0.31, 2.59]). On SF-36v2, improvements vs placebo were observed in physical component summary scores (300 mg: 2.22 [0.04, 4.41]) and subscales of role physical, general health, and vitality. On WPAI:SHP, solriamfetol 150 mg reduced overall work impairment vs placebo (-15.5 [-29.52, -1.47]), and 150 and 300 mg reduced activity impairment vs placebo (-10.05 [-19.48, -0.62] and -13.49 [-23.19, -3.78], respectively). Most treatment-emergent adverse events (TEAEs) were mild or moderate in severity. Common TEAEs were headache, nausea, decreased appetite, nasopharyngitis, dry mouth, and anxiety.Conclusions: Solriamfetol improved measures of functional status, HRQoL, and work productivity, particularly at the 150- and 300-mg doses. Most TEAEs were mild to moderate. (C) 2019 Elsevier B.V. All rights reserved. Show less
Jiang, M.; Behrens, P.A.; Wang, T.; Tang, Z.; Yu, Y.; Chen, D.; ... ; Zhu, B. 2019
China has undergone unprecedented increases in material development and by 2010 drove 30% of the global material footprint (MF). Understanding China’s MF distribution and development is critical... Show moreChina has undergone unprecedented increases in material development and by 2010 drove 30% of the global material footprint (MF). Understanding China’s MF distribution and development is critical for resource efficiency and circular economy ambitions globally. We combine a provincial input–output table (IOT), province-specific import–export statistics, a global IOT, and detailed extraction data to assess sector-specific and province-specific MFs in China. Capital investment—crucial to China’s development—is up to 4 times more resource-intensive than consumption and comprises 49 to 86% of provincial MF. We find large differences in MF per capita across provinces, even among those with similar development characteristics. Findings indicate the need for improved understanding of material developments in other emerging countries in the 21st century. Show less
A key enabling step in leveraging the properties of nanoparticles (NPs) is to explore new, simple, controllable, and scalable nanotechnologies for their syntheses. Among “wet” methods, cathodic... Show moreA key enabling step in leveraging the properties of nanoparticles (NPs) is to explore new, simple, controllable, and scalable nanotechnologies for their syntheses. Among “wet” methods, cathodic corrosion has been used to synthesize catalytic aggregates with some control over their size and preferential faceting. Here, we report on a modification of the cathodic corrosion method for producing a range of nonaggregated nanocrystals (Pt, Pd, Au, Ag, Cu, Rh, Ir, and Ni) and nanoalloys (Pt50Au50, Pd50Au50, and AgxAu100–x) with potential for scaling up the production rate. The method employs poly(vinylpyrrolidone) (PVP) as a stabilizer in an electrolyte solution containing nonreducible cations (Na+, Ca2+), and cathodic corrosion of the corresponding wires takes place in the electrolyte under ultrasonication. The ultrasonication not only promotes particle–PVP interactions (enhancing NP dispersion and diluting locally high NP concentration) but also increases the production rate by a factor of ca. 5. Further increase in the production rate can be achieved through parallelization of electrodes to construct comb electrodes. With respect to applications, carbon-supported Pt NPs prepared by the new method exhibit catalytic activity and durability for methanol oxidation comparable or better than the commercial benchmark catalyst. A variety of AgxAu100–x nanoalloys are characterized by ultraviolet–visible absorption spectroscopy and high-resolution transmission electron microscopy. The protocol for NP synthesis by cathodic corrosion should be a step toward its further use in academic research as well as in its practical upscaling. Show less
