scholarly journals The emerging role of physical modeling in the future of structure determination

2017 ◽  
Author(s):  
Kari Gaalswyk ◽  
Mir Ishruna Muniyat ◽  
Justin L. MacCallum
Keyword(s):  
Structure Determination ◽  
Physical Modeling ◽  
Physical Models ◽  
List Type ◽  
Biomolecular Structure ◽  
Conformational Ensembles ◽  
Making Sense ◽  
Physical Insight ◽  
Ambiguous Data

AbstractBiomolecular structure determination has long relied on heuristics based on physical insight; however, recent efforts to model conformational ensembles and to make sense of sparse, ambiguous, and noisy data have revealed the value of detailed, quantitative physical models in structure determination. We review these two key challenges, describe different approaches to physical modeling in structure determination, and illustrate several successes and emerging technologies enabled by physical modeling.HighlightsQuantitative physical modeling is emerging as a key tool in structure determinationThere are different approaches to incorporate physical modeling into structure determinationModeling conformational ensembles and making sense of sparse, noisy, and ambiguous data are two challenges where physical modeling can play a prominent role

scholarly journals Molecular basis of F-actin regulation and sarcomere assembly via myotilin

2020 ◽  
Author(s):  
Julius Kostan ◽  
Miha Pavšič ◽  
Vid Puž ◽  
Thomas C. Schwarz ◽  
Friedel Drepper ◽  
...  
Keyword(s):  
Structural Model ◽  
Structural Integrity ◽  
Striated Muscle ◽  
Actin Binding ◽  
List Type ◽  
Striated Muscles ◽  
Conformational Ensembles ◽  
Sarcomere Assembly ◽  
Flanking Regions

AbstractSarcomeres, the basic contractile units of striated muscle cells, contain arrays of thin (actin) and thick (myosin) filaments that slide past each other during contraction. The Ig-like domain containing protein myotilin provides structural integrity to Z-discs - the boundaries between adjacent sarcomeres. Myotilin binds to Z-disc components, including F-actin and α-actinin-2, but the molecular mechanism of binding and implications of these interactions on Z-disc integrity are still elusive. We used a combination of small angle X-ray scattering, cross-linking mass spectrometry, biochemical and molecular biophysics approaches. We discovered that myotilin displays conformational ensembles in solution. We generated a structural model of the F-actin:myotilin complex that revealed how myotilin interacts with and stabilizes F-actin via its Ig-like domains and flanking regions. Mutant myotilin designed with impaired F-actin binding showed increased dynamics in cells. Structural analyses and competition assays uncovered that myotilin displaces tropomyosin from F-actin. Our findings suggest a novel role of myotilin as a co-organizer of Z-disc assembly and advance our mechanistic understanding of myotilin’s structural role in Z-discs.Significance StatementSarcomeres are the primary structural and functional unit of striated muscles, conferring movement in all animals. The Z-disk is the boundary between adjacent sarcomeres, where actin filaments (F-actin) are anchored. Z-disc protein myotilin, is a scaffold protein, which provides structural integrity to the Z-disc by multiple interactions to its central components, including F-actin and α-actinin-2. Here we provide the structure of myotilin, revealing its structural plasticity in solution and the first integrative structural model of its complex with F-actin. We further show that myotilin displaces tropomyosin from F-actin, implying a novel role of myotilin in sarcomere biogenesis beyond being an interaction hub for Z-disk partners.Highlights፧Myotilin is structurally described as a dynamic ensemble፧Flanking regions enhance F-acting binding to tandem Ig domains፧Integrative structural model of myotilin bound to F-actin፧Myotilin displaces tropomyosin from F-actin, suggesting an organisational role in Z-disc

scholarly journals The emerging role of physical modeling in the future of structure determination

2018 ◽  
Vol 49 ◽  
pp. 145-153 ◽  
Author(s):  
Kari Gaalswyk ◽  
Mir Ishruna Muniyat ◽  
Justin L MacCallum
Keyword(s):  
Structure Determination ◽  
Physical Modeling ◽  
The Future

Design Fixation in Physical Modeling: An Investigation on the Role of Sunk Cost

2011 ◽  
Author(s):  
Vimal Viswanathan ◽  
Julie Linsey
Keyword(s):  
Mental Models ◽  
Physical Modeling ◽  
Idea Generation ◽  
Vital Role ◽  
Physical Models ◽  
Controlled Study ◽  
Sunk Cost ◽  
Subject Experiment ◽  
High Degree

Physical models are very commonly used as tools for engineering idea generation, yet the guidelines in literature about their implementation are conflicting. A prior study has shown that physical models have the potential to supplement designers’ erroneous mental models; whereas a few observational studies have shown that physical models can cause a high degree of fixation under certain circumstances. At the same time, a previous controlled study fails to show the presence of fixation in idea generation with physical models. This study hypothesizes that prior observed fixation in physical modeling is due to Sunk Cost Effect, which is the reluctance to choose a different path of action once significant money, time or effort is invested in present one. Consistent with the prior study, this study also hypothesizes that physical models supplement designers’ mental models. These hypotheses are investigated through a controlled between-subject experiment. The results show that cost of building plays a vital role in fixation and fixation is not likely inherent in physical representations. Results also show that physical models supplement designers’ mental models and lead them to higher quality ideas.

scholarly journals Cavitation Bubble Cloud Break-Off Mechanisms at Micro-Channels

Fluids ◽  
2021 ◽  
Vol 6 (6) ◽  
pp. 215
Author(s):  
Paul McGinn ◽  
Daniel Pearce ◽  
Yannis Hardalupas ◽  
Alex Taylor ◽  
Konstantina Vogiatzaki
Keyword(s):  
Cavitation Bubble ◽  
Cavitation Inception ◽  
Wave Dynamics ◽  
Bubble Cloud ◽  
Cloud Dynamics ◽  
Micro Channels ◽  
Physical Insight ◽  
Cloud Process ◽  
Good Agreement

This paper provides new physical insight into the coupling between flow dynamics and cavitation bubble cloud behaviour at conditions relevant to both cavitation inception and the more complex phenomenon of flow “choking” using a multiphase compressible framework. Understanding the cavitation bubble cloud process and the parameters that determine its break-off frequency is important for control of phenomena such as structure vibration and erosion. Initially, the role of the pressure waves in the flow development is investigated. We highlight the differences between “physical” and “artificial” numerical waves by comparing cases with different boundary and differencing schemes. We analyse in detail the prediction of the coupling of flow and cavitation dynamics in a micro-channel 20 m high containing Diesel at pressure differences 7 MPa and 8.5 MPa, corresponding to cavitation inception and "choking" conditions respectively. The results have a very good agreement with experimental data and demonstrate that pressure wave dynamics, rather than the “re-entrant jet dynamics” suggested by previous studies, determine the characteristics of the bubble cloud dynamics under “choking” conditions.

scholarly journals Early oxygen levels contribute to brain injury in extremely preterm infants

2021 ◽  
Author(s):  
Krista Rantakari ◽  
Olli-Pekka Rinta-Koski ◽  
Marjo Metsäranta ◽  
Jaakko Hollmén ◽  
Simo Särkkä ◽  
...  
Keyword(s):  
Preterm Infants ◽  
Brain Structures ◽  
High Oxygen ◽  
List Type ◽  
Neurodevelopmental Outcomes ◽  
Oxygen Levels ◽  
Arterial Blood ◽  
Extremely Preterm ◽  
Extremely Preterm Infants

Abstract Background Extremely low gestational age newborns (ELGANs) are at risk of neurodevelopmental impairments that may originate in early NICU care. We hypothesized that early oxygen saturations (SpO2), arterial pO2 levels, and supplemental oxygen (FiO2) would associate with later neuroanatomic changes. Methods SpO2, arterial blood gases, and FiO2 from 73 ELGANs (GA 26.4 ± 1.2; BW 867 ± 179 g) during the first 3 postnatal days were correlated with later white matter injury (WM, MRI, n = 69), secondary cortical somatosensory processing in magnetoencephalography (MEG-SII, n = 39), Hempel neurological examination (n = 66), and developmental quotients of Griffiths Mental Developmental Scales (GMDS, n = 58). Results The ELGANs with later WM abnormalities exhibited lower SpO2 and pO2 levels, and higher FiO2 need during the first 3 days than those with normal WM. They also had higher pCO2 values. The infants with abnormal MEG-SII showed opposite findings, i.e., displayed higher SpO2 and pO2 levels and lower FiO2 need, than those with better outcomes. Severe WM changes and abnormal MEG-SII were correlated with adverse neurodevelopment. Conclusions Low oxygen levels and high FiO2 need during the NICU care associate with WM abnormalities, whereas higher oxygen levels correlate with abnormal MEG-SII. The results may indicate certain brain structures being more vulnerable to hypoxia and others to hyperoxia, thus emphasizing the role of strict saturation targets. Impact This study indicates that both abnormally low and high oxygen levels during early NICU care are harmful for later neurodevelopmental outcomes in preterm neonates. Specific brain structures seem to be vulnerable to low and others to high oxygen levels. The findings may have clinical implications as oxygen is one of the most common therapies given in NICUs. The results emphasize the role of strict saturation targets during the early postnatal period in preterm infants.

scholarly journals 332 The diagnostic role of shunt series radiographs (SSR) in children presenting to the children’s emergency department (CED) with suspected ventriculoperitoneal (VP) shunt failure

2020 ◽  
Vol 37 (12) ◽  
pp. 852.3-853
Author(s):  
Angharad Griffiths ◽  
Ikechukwu Okafor ◽  
Thomas Beattie
Keyword(s):  
Clinical Outcome ◽  
Sensitivity And Specificity ◽  
Clinical Information ◽  
Flow Diagram ◽  
List Type ◽  
Shunt Failure ◽  
Vp Shunt ◽  
Wide Range ◽  
Diagnostic Role

Aims/Objectives/BackgroundVP shunts are used to drain CSF from the cranial vault because of a wide range of pathologies and, like any piece of hardware, can fail. Traditionally investigations include SSR and CT. This project examines the role of SSR in evaluating children with suspected VP shunt failure.Primary outcome: Sensitivity and specificity of SSR in children presenting to the CED with concern for shunt failure.Methods/DesignConducted in a single centre, tertiary CED of the national Irish Neurosurgical(NS) referral centre (ED attendance:>50,000 patients/year). 100 sequential SSR requested by the CED were reviewed. Clinical information was extracted from electronic requests. Shunt failure was defined by the need for NS intervention(Revision).Abstract 332 Figure 1Abstract 332 Figure 2Results/ConclusionsSensitivity and specificity is presented in figure 1 (two by two table).100 radiographs performed in 84 children.22% shunts revised (see flow diagram).7 SSR’s were abnormal.85% (n=6) shunts revised. [5 following abnormal CT].Of the normal SSR’s; 16 had abnormal CT and revised.85/100 received CT.64 of 85 CT’s (75%) were normal.□6 of the 64 had focal shunt concern.SSR’s shouldn’t be used in isolation. NPV&PPV, Sensitivity&Specificity is low.SSR’s are beneficial where there’s concern over focal shunt problems (injury/pain/swelling) or following abnormal CT.VP shunt failure is not well investigated with SSR alone.SSR’s could be omitted where there is no focal shunt concern/after normal CT (without impacting clinical outcome) reducing radiation exposure and reduce impact on CED’s.59 SSR’s could have been avoided without adverse clinical outcome.

Seven Canons of ICC Treaty Interpretation: Making Sense of Article 25's Rorschach Blot

2014 ◽  
Vol 27 (3) ◽  
pp. 755-788 ◽  
Author(s):  
LEILA NADYA SADAT ◽  
JARROD M. JOLLY
Keyword(s):  
Rome Statute ◽  
Correct Interpretation ◽  
International Treaty ◽  
Making Sense ◽  
Treaty Interpretation ◽  
Substantive Law ◽  
Interpretative Framework

AbstractThis article draws on well-established understandings of international treaty interpretation and the role of the judicial function to propose seven canons of treaty construction that may serve as the basis of a principled interpretation of the substantive law of the Rome Statute. This interpretative framework is then applied to the seemingly intractable debate within the Court and among scholars over the correct interpretation of Article 25, on modes of liability. The seven canons provide guidelines that may enable the ‘Rorschach blot’ of Article 25, capable of many divergent interpretations, to become uniformly and consistently understood and interpreted.

Abstract 5858: Role of Oxygen Tension and Oxidative Stress in Human Saphenous Vein Remodeling

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Binata Joddar ◽  
Rashmeet K Reen ◽  
Michael Firstenberg ◽  
Keith J Gooch
Keyword(s):  
Oxidative Stress ◽  
Oxygen Tension ◽  
Ex Vivo ◽  
Neointimal Hyperplasia ◽  
Fold Increase ◽  
List Type ◽  
Saphenous Veins ◽  
Arterial Po2 ◽  
And Oxidative Stress

Vessels cultured ex vivo maintain viability and vasoactivity for weeks and can remodel in response to mechanical cues. When cultured in the presence of 5% CO2/balance air veins develop neointimal hyperplasia (IH) while arteries do not suggesting that exposure to significant increases in pO2 levels might stimulate IH. Neointimal hyperplasia (IH) is a known mechanism by which saphenous veins have a decreased patency compared to arterial conduits when used for coronary artery bypass. We sought to explore the role of oxygen tension and oxidative stress in IH. Test the hypothesis that exposure of human saphenous veins (HSV) to arterial pO2 stimulates IH via ROS-mediated pathways. Almost 40 HSV remnants acquired following CABG were cultured ex vivo with arterial (~95mmHg) pO2 or venous (~40mmHg) pO2 for 14 days. All differences reported have a p<0.05 via Student’s t-test. Results: HSV cultured at arterial pO2 exhibited significant IH as evidenced by disruption of the IEL, invasion of cells from the media, and a 2.8-fold greater intimal area than fresh HSV, a 5.8-fold increase in cell proliferation compared to fresh HSV, increased ROS levels and oxidative stress as evidenced by 4-fold increase in 4-HNE level (a marker of oxidative stress), increased DHE staining (indicative of superoxide generation), and a progressive increase in total ROS levels with time as assessed by DCF fluorescence, and a 3-fold increase in phosphorylated p38-MAPK, which is implicated in SMC proliferation. In stark contrast vessels culture at arterial pO2, HSV cultured with venous pO2 did not develop increased IH and were indistinguishable from fresh vessels with respect to proliferation, markers of oxidative stress, and MAPK expression levels. Supplementing culture medium with antioxidants including Tiron or NAC blocked the pO2-induced changes. These data indicate that exposure to arterial pO2 increases cellular proliferation and stimulates IH, potentially via oxidative stress or ROS signaling and also suggest that exposure to elevated arterial pO2 might stimulate pathological remodeling of veins grafted into the arterial circulation. This research has received full or partial funding support from the American Heart Association, AHA Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).

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