Planetary Probe Entry Models for Concurrent and Integrated Interplanetary Mission Design

There are many prospective mission opportunities involving atmospheric entry probes. The Planetary Science Deep Space SmallSat Studies (PSDS3) re-cently selected probe missions to Venus, Mars, and the outer planets as part of the 10 selected studies. Two of the six themes in the most recent New Fron-tiers call were a Saturn probe and a Venus in situ explorer. The 2013-2022 Planetary Science Decadal Survey includes probe missions at Venus, Mars, Saturn, Titan, Uranus, and Neptune. Across mission destinations and mission classes there is growing interest in planetary probes. While interplanetary trajectory specialists may like to use a broad sweep of low-fidelity solutions to find a wide array of trajectory options, probe specialists typically start off with mid- to high-fidelity point designs for the entry probe since the equations of motion for atmospheric probes require numerical integration and are so directly linked with some of the probe's subsystem design. Cur-rently, there are no alternatives to this design ap-proach as there are no tools capable of automatical-ly and concurrently designing interplanetary and atmospheric trajectories. Unfortunately, this makes us reliant on point designs in the early stages of the mission design process. The reliance on point de-signs for atmospheric probes hinders the flexibility of the design, making the design process cumber-some and restricting decision-making down the road. The research presented here addresses this problem by providing low-fidelity models for the automated, rapid design of atmospheric trajectories and probe's models which may be solved concur-rently with the interplanetary trajectory

Fourier transform ion cyclotron resonance mass spectrometric detection of small Ca2+-induced conformational changes in the regulatory domain of human cardiac troponin C

AbstractTroponin C (TnC), a calcium-binding protein of the thin filament of muscle, plays a regulatory role in skeletal and cardiac muscle contraction. NMR reveals a small conformational change in the cardiac regulatory N-terminal domain of TnC (cNTnC) on binding of Ca2+ such that the total exposed hydrophobic surface area increases very slightly from 3090 ± 86 Å2 for apo-cNTnC to 3108 ± 71 Å2 for Ca2+-cNTnC. Here, we show that measurement of solvent accessibility for backbone amide protons by means of solution-phase hydrogen/deuterium (H/D) exchange followed by pepsin digestion, high-performance liquid chromatography, and electrospray ionization high-field (9.4 T) Fourier transform Ion cyclotron resonance mass spectrometry is sufficiently sensitive to detect such small ligand binding-induced conformational changes of that protein. The extent of deuterium incorporation increases significantly on binding of Ca2+ for each of four proteolytic segments derived from pepsin digestion of the apo- and Ca2+-saturated forms of cNTnC. The present results demonstrate that H/D exchange monitored by mass spectrometry can be sufficiently sensitive to detect and identify even very small conformational changes in proteins, and should therefore be especially informative for proteins too large (or too insoluble or otherwise intractable) for NMR analysis

Matrix-assisted laser desorption ionization hydrogen/deuterium exchange studies to probe peptide conformational changes

AbstractHydrogen/deuterium (H/D) exchange chemistry monitored by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry is used to study solution phase conformational changes of bradykinin, α-melanocyte stimulating hormone, and melittin as water is added to methanol-d4, acetonitrile, and isopropanol-d8 solutions. The results are interpreted in terms of a preference for the peptides to acquire more compact conformations in organic solvents as compared to the random conformations. Our interpretation is supported by circular dichroism spectra of the peptides in the same solvent systems and by previously published structural data for the peptides. These results demonstrate the utility of MALDI-TOF as a method to monitor the H/D exchange chemistry of peptides and investigations of solution-phase conformations of biomolecules

Promiscuous Aggregate-Based Inhibitors Promote Enzyme Unfolding

One of the leading sources of false positives in early drug discovery is the formation of organic small molecule aggregates, which inhibit enzymes nonspecifically at micromolar concentrations in aqueous solution. The molecular basis for this widespread problem remains hazy. To investigate the mechanism of inhibition at a molecular level, we determined changes in solvent accessibility that occur when an enzyme binds to an aggregate using hydrogen-deuterium exchange mass spectrometry. For AmpC beta-lactamase, binding to aggregates of the small molecule rottlerin increased the deuterium exchange of all 10 reproducibly detectable peptides, which covered 41% of the sequence of beta-lactamase. This suggested a global increase in proton accessibility upon aggregate binding, consistent with denaturation. We then investigated whether enzyme-aggregate complexes were more susceptible to proteolysis than uninhibited enzyme. For five aggregators, trypsin degradation of beta-lactamase increased substantially when beta-lactamase was inhibited by aggregates, whereas uninhibited enzyme was generally stable to digestion. Combined, these results suggest that the mechanism of action of aggregate-based inhibitors proceeds via partial protein unfolding when bound to an aggregate particle

Longitudinal Assessment of Resident Performance Using Entrustable Professional Activities

IMPORTANCE Entrustable professional activities (EPAs) are an emerging workplace-based, patient-oriented assessment approach with limited empirical evidence. OBJECTIVE To measure the development of pediatric trainees’ clinical skills over time using EPA-based assessment data. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of categorical pediatric residents over 3 academic years (2015-2016, 2016-2017, and 2017-2018) assessed on 17 American Board of Pediatrics EPAs. Residents in training at 23 pediatric residency programs in the Association of Pediatric Program Directors Longitudinal Educational Assessment Research Network were included. Assessment was conducted by clinical competency committee members, who made summative assessment decisions regarding levels of supervision required for each resident and each EPA. Data were collected from May 2016 to November 2018 and analyzed from November to December 2018. INTERVENTIONS Longitudinal, prospective assessment using EPAs. MAIN OUTCOMES AND MEASURES Trajectories of supervision levels by EPA during residency training and how often graduating residents were deemed ready for unsupervised practice in each EPA. RESULTS Across the 5 data collection cycles, 1987 residents from all 3 postgraduate years in 23 residency programs were assigned 25 503 supervision level reports for the 17 general pediatrics EPAs. The 4 EPAs that required the most supervision across training were EPA 14 (quality improvement) on the 5-level scale (estimated mean level at graduation, 3.7; 95% CI, 3.6-3.7) and EPAs 8 (transition to adult care; mean, 7.0; 95% CI, 7.0-7.1), 9 (behavioral and mental health; mean, 6.6; 95% CI, 6.5-6.6), and 10 (resuscitate and stabilize; mean, 6.9; 95% CI, 6.8-7.0) on the expanded 5-level scale. At the time of graduation (36 months), the percentage of trainees who were rated at a supervision level corresponding to “unsupervised practice” varied by EPA from 53% to 98%. If performance standards were set to align with 90% of trainees achieving the level of unsupervised practice, this standard would be met for only 8 of the 17 EPAs (although 89% met this standard for EPA 17, performing the common procedures of the general pediatrician). CONCLUSIONS AND RELEVANCE This study presents initial evidence for empirically derived practice readiness and sets the stage for identifying curricular gaps that contribute to discrepancy between observed practice readiness and standards needed to produce physicians able to meet the health needs of the patient populations they serve. Future work should compare these findings with post-graduation outcomes data as a means of seeking validity evidence

Functional polymorphisms of the brain serotonin synthesizing enzyme tryptophan hydroxylase-2

Many neuropsychiatric disorders are considered to be related to the dysregulation of brain serotonergic neurotransmission. Tryptophan hydroxylase-2 (TPH2) is the neuronal-specific enzyme that controls brain serotonin synthesis. There is growing genetic evidence for the possible involvement of TPH2 in serotonin-related neuropsychiatric disorders; however, the degree of genetic variation in TPH2 and, in particular, its possible functional consequences remain unknown. In this short review, we will summarize some recent findings with respect to the functional analysis of TPH2

From risk factors to detection and intervention: a practical proposal for future work on cyberbullying

While there is an increasing flow of media stories reporting cases of cyberbullying, particularly within online social media, research efforts in the academic community are scattered over different topics across the social science and computer science academic disciplines. In this work, we explored research pertaining to cyberbullying, conducted across disciplines. We mainly sought to understand scholarly activity on intelligence techniques for the detection of cyberbullying when it occurs. Our findings suggest that the vast majority of academic contributions on cyberbullying focus on understanding the phenomenon, risk factors, and threats, with the prospect of suggesting possible protection strategies. There is less work on intelligence techniques for the detection of cyberbullying when it occurs, while currently deployed algorithms seem to detect the problem only up to some degree of success. The article summarises the current trends aiming to encourage discussion and research with a new scope; we call for more research tackling the problem by leveraging statistical models and computational mechanisms geared to detect, intervene, and prevent cyberbullying. Coupling intelligence techniques with specific web technology problems can help combat this social menace. We argue that a multidisciplinary approach is needed, with expertise from human–computer interaction, psychology, computer science, and sociology, for current challenges to be addressed and significant progress to be made

(In)formalization and the civilizing process : applying the work of Norbert Elias to housing-based anti-social behaviour interventions in the UK

This paper uses Norbert Elias's theory of the civilizing process to examine trends in social conduct in the UK and to identify how problematic “anti‐social” behaviour is conceptualized and governed through housing‐based mechanisms of intervention. The paper describes how Elias's concepts of the formalization and informalization of conduct and the construction of established and outsider groups provide an analytical framework for understanding social relations. It continues by discussing how de‐civilizing processes are also evident in contemporary society, and are applied to current policy discourse around Respect and anti‐social behaviour. The paper uses the governance of “anti‐social” conduct through housing mechanisms in the UK to critique the work of Elias and concludes by arguing that a revised concept of the civilizing process provides a useful analytical framework for future studies