scholarly journals Molecular Determinants of Selectivity in Disordered Complexes May Shed Light on Specificity in Protein Condensates

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 92
Author(s):  
Alexander Miguel Monzon ◽  
Damiano Piovesan ◽  
Monika Fuxreiter
Keyword(s):  
High Resolution ◽  
Selective Recognition ◽  
Conformational Heterogeneity ◽  
Structural Studies ◽  
Sequence Motifs ◽  
Conformational Ensembles ◽  
Wide Range ◽  
Molecular Determinants ◽  
High Degree ◽  
Shed Light

Biomolecular condensates challenge the classical concepts of molecular recognition. The variable composition and heterogeneous conformations of liquid-like protein droplets are bottlenecks for high-resolution structural studies. To obtain atomistic insights into the organization of these assemblies, here we have characterized the conformational ensembles of specific disordered complexes, including those of droplet-driving proteins. First, we found that these specific complexes exhibit a high degree of conformational heterogeneity. Second, we found that residues forming contacts at the interface also sample many conformations. Third, we found that different patterns of contacting residues form the specific interface. In addition, we observed a wide range of sequence motifs mediating disordered interactions, including charged, hydrophobic and polar contacts. These results demonstrate that selective recognition can be realized by variable patterns of weakly defined interaction motifs in many different binding configurations. We propose that these principles also play roles in determining the selectivity of biomolecular condensates.

Machine Learning Steel Ms Temperature

SIMULATION ◽  
2021 ◽  
pp. 003754972199557
Author(s):  
Yun Zhang ◽  
Xiaojie Xu
Keyword(s):  
Low Cost ◽  
Network Modeling ◽  
Gaussian Process Regression ◽  
Alloying Elements ◽  
Neural Network Modeling ◽  
Wide Range ◽  
High Degree ◽  
The Relationship ◽  
Shed Light ◽  
Accuracy And Stability

Empirical equations, thermodynamics frameworks, and neural network modeling have been developed to predict steel martensite start temperature, [Formula: see text], but they might not tend to generalize well when composition includes a wide range of alloying elements. In this study, we develop the Gaussian process regression (GPR) model to shed light on the relationship between alloying elements and [Formula: see text] temperature for steels. A total of 1119 steels with [Formula: see text] ranging from 153 K to 938 K are examined. The model has a high degree of accuracy and stability, contributing to fast low-cost [Formula: see text] temperature estimations.

Practical Aspects of FIB Milling: Understanding Ion Beam/Material Interactions

2000 ◽  
Vol 6 (S2) ◽  
pp. 502-503
Author(s):  
B. I. Prenitzer ◽  
B. W. Kempshall ◽  
S. M. Schwarz ◽  
L. A. Giannuzzi ◽  
F. A. Stevie
Keyword(s):  
High Resolution ◽  
Focused Ion Beam ◽  
Ion Beam ◽  
Nanometer Scale ◽  
Specimen Preparation ◽  
Site Specific ◽  
Vertical Milling ◽  
Wide Range ◽  
Beam Currents ◽  
High Degree

Nanometer scale, high resolution Ga+ ion probes, attainable in commercially available focused ion beam (FIB) instruments, allow imaging, sputtering and deposition operations to be performed with a high degree of spatial precision. Of particular interest is how this precision milling/deposition capability has enabled a wide range of site specific micromachining and microfabrication operations (e.g., TEM, SEM, SIMS, and AUGER specimen preparation and circuit modification). The applications of FIB instruments frequently involve the creation of high aspect ratio features (i.e., deep narrow trenches). Ideally, the sidewalls of an FIB milled feature should be vertical; however, it has been generally observed that the trenches tend to exhibit a gradual sloping. The observed deviation from vertical milling has been attributed to the redeposition of sputtered material, and is especially pervasive at high beam currents and confining trench geometries. A hole milled with an FIB tends to be widest at the top surface and taper down to a point at the bottom.

scholarly journals Fragment Binding to the Nsp3 Macrodomain of SARS-CoV-2 Identified Through Crystallographic Screening and Computational Docking

2020 ◽  
Author(s):  
Marion Schuller ◽  
Galen J. Correy ◽  
Stefan Gahbauer ◽  
Daren Fearon ◽  
Taiasean Wu ◽  
...  
Keyword(s):  
High Resolution ◽  
Active Site ◽  
Conformational Heterogeneity ◽  
Structural Protein ◽  
Computational Docking ◽  
X Ray ◽  
Wide Range ◽  
Biophysical Techniques ◽  
Fragment Libraries ◽  
Chemical Matter

ABSTRACTThe SARS-CoV-2 macrodomain (Mac1) within the non-structural protein 3 (Nsp3) counteracts host-mediated antiviral ADP-ribosylation signalling. This enzyme is a promising antiviral target because catalytic mutations render viruses non-pathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of diverse fragment libraries resulted in 214 unique macrodomain-binding fragments, out of 2,683 screened. An additional 60 molecules were selected from docking over 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several crystallographic and docking fragment hits were validated for solution binding using three biophysical techniques (DSF, HTRF, ITC). Overall, the 234 fragment structures presented explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.

Development of a conical anode Fe-gun for low voltage SEM

1988 ◽  
Vol 46 ◽  
pp. 978-979
Author(s):  
T. Miyokawa ◽  
S. Norioka ◽  
S. Goto
Keyword(s):  
High Resolution ◽  
Field Emission ◽  
Low Voltage ◽  
Irradiation Damage ◽  
Cold Cathode ◽  
Virtual Source ◽  
Source Position ◽  
Electrostatic Lens ◽  
Electrostatic Lenses ◽  
Wide Range

Field emission SEMs (FE-SEMs) are becoming popular due to their high resolution needs. In the field of semiconductor product, it is demanded to use the low accelerating voltage FE-SEM to avoid the electron irradiation damage and the electron charging up on samples. However the accelerating voltage of usual SEM with FE-gun is limited until 1 kV, which is not enough small for the present demands, because the virtual source goes far from the tip in lower accelerating voltages. This virtual source position depends on the shape of the electrostatic lens. So, we investigated several types of electrostatic lenses to be applicable to the lower accelerating voltage. In the result, it is found a field emission gun with a conical anode is effectively applied for a wide range of low accelerating voltages.A field emission gun usually consists of a field emission tip (cold cathode) and the Butler type electrostatic lens.

Three-fold astigmatism: An important TEM aberration

1993 ◽  
Vol 51 ◽  
pp. 972-973 ◽  
Author(s):  
O.L. Krivanek ◽  
M.L. Leber
Keyword(s):  
High Resolution ◽  
Spatial Frequency ◽  
Field Emission ◽  
Azimuthal Angle ◽  
Hollow Cone ◽  
Small Probe ◽  
Wide Range ◽  
High Resolution Images ◽  
Image Position

Three-fold astigmatism resembles regular astigmatism, but it has 3-fold rather than 2-fold symmetry. Its contribution to the aberration function χ(q) can be written as:where A3 is the coefficient of 3-fold astigmatism, λ is the electron wavelength, q is the spatial frequency, ϕ the azimuthal angle (ϕ = tan-1 (qy/qx)), and ϕ3 the direction of the astigmatism.Three-fold astigmatism is responsible for the “star of Mercedes” aberration figure that one obtains from intermediate lenses once their two-fold astigmatism has been corrected. Its effects have been observed when the beam is tilted in a hollow cone over a wide range of angles, and there is evidence for it in high resolution images of a small probe obtained in a field emission gun TEM/STEM instrument. It was also expected to be a major aberration in sextupole-based Cs correctors, and ways were being developed for dealing with it on Cs-corrected STEMs.

Scanning tunneling microscopy of polymers: A status report

1989 ◽  
Vol 47 ◽  
pp. 330-331
Author(s):  
P.E. Russell ◽  
I.H. Musselman
Keyword(s):  
High Resolution ◽  
Scanning Tunneling Microscopy ◽  
Sample Surface ◽  
Atomic Scale ◽  
Constant Current ◽  
Scanning Tunneling ◽  
Status Report ◽  
Tunneling Microscopy ◽  
Research Issues ◽  
Wide Range

Scanning tunneling microscopy (STM) has evolved rapidly in the past few years. Major developments have occurred in instrumentation, theory, and in a wide range of applications. In this paper, an overview of the application of STM and related techniques to polymers will be given, followed by a discussion of current research issues and prospects for future developments. The application of STM to polymers can be conveniently divided into the following subject areas: atomic scale imaging of uncoated polymer structures; topographic imaging and metrology of man-made polymer structures; and modification of polymer structures. Since many polymers are poor electrical conductors and hence unsuitable for use as a tunneling electrode, the related atomic force microscopy (AFM) technique which is capable of imaging both conductors and insulators has also been applied to polymers.The STM is well known for its high resolution capabilities in the x, y and z axes (Å in x andy and sub-Å in z). In addition to high resolution capabilities, the STM technique provides true three dimensional information in the constant current mode. In this mode, the STM tip is held at a fixed tunneling current (and a fixed bias voltage) and hence a fixed height above the sample surface while scanning across the sample surface.

Sentence-Based Experience Logging in New Hearing Aid Users

2020 ◽  
Vol 29 (3S) ◽  
pp. 631-637
Author(s):  
Katja Lund ◽  
Rodrigo Ordoñez ◽  
Jens Bo Nielsen ◽  
Dorte Hammershøi
Keyword(s):  
Hearing Aid ◽  
Patient Experiences ◽  
Online Tool ◽  
Rehabilitation Process ◽  
Hearing Rehabilitation ◽  
Clinical Observations ◽  
Hearing Aid Use ◽  
Wide Range ◽  
Insight Into ◽  
Shed Light

Purpose The aim of this study was to develop a tool to gain insight into the daily experiences of new hearing aid users and to shed light on aspects of aided performance that may not be unveiled through standard questionnaires. Method The tool is developed based on clinical observations, patient experiences, expert involvement, and existing validated hearing rehabilitation questionnaires. Results An online tool for collecting data related to hearing aid use was developed. The tool is based on 453 prefabricated sentences representing experiences within 13 categories related to hearing aid use. Conclusions The tool has the potential to reflect a wide range of individual experiences with hearing aid use, including auditory and nonauditory aspects. These experiences may hold important knowledge for both the patient and the professional in the hearing rehabilitation process.

Understanding Conformational Entropy in Small Molecules

2020 ◽  
Author(s):  
Lucian Chan ◽  
Garrett Morris ◽  
Geoffrey Hutchison
Keyword(s):  
Small Molecules ◽  
Degrees Of Freedom ◽  
Absolute Error ◽  
Low Energy ◽  
Standard Entropy ◽  
Free Energies ◽  
Conformational Entropy ◽  
Wide Range ◽  
High Degree ◽  
Empirical Corrections

The calculation of the entropy of flexible molecules can be challenging, since the number of possible conformers grows exponentially with molecule size and many low-energy conformers may be thermally accessible. Different methods have been proposed to approximate the contribution of conformational entropy to the molecular standard entropy, including performing thermochemistry calculations with all possible stable conformations, and developing empirical corrections from experimental data. We have performed conformer sampling on over 120,000 small molecules generating some 12 million conformers, to develop models to predict conformational entropy across a wide range of molecules. Using insight into the nature of conformational disorder, our cross-validated physically-motivated statistical model can outperform common machine learning and deep learning methods, with a mean absolute error ≈4.8 J/mol•K, or under 0.4 kcal/mol at 300 K. Beyond predicting molecular entropies and free energies, the model implies a high degree of correlation between torsions in most molecules, often as- sumed to be independent. While individual dihedral rotations may have low energetic barriers, the shape and chemical functionality of most molecules necessarily correlate their torsional degrees of freedom, and hence restrict the number of low-energy conformations immensely. Our simple models capture these correlations, and advance our understanding of small molecule conformational entropy.

Cerebellotrigeminal Dermal Dysplasia (Gómez-López-Hernández Syndrome)

2018 ◽  
Vol 16 (05) ◽  
pp. 362-368 ◽  
Author(s):  
Federica Sullo ◽  
Agata Polizzi ◽  
Stefano Catanzaro ◽  
Selene Mantegna ◽  
Francesco Lacarrubba ◽  
...  
Keyword(s):  
De Novo ◽  
Chromosomal Rearrangements ◽  
Number Of Patients ◽  
Wide Range ◽  
Visual Problems ◽  
Neurodevelopmental Abnormalities ◽  
Clinical Triad ◽  
High Degree ◽  
Motor Handicap

Cerebellotrigeminal dermal (CTD) dysplasia is a rare neurocutaneous disorder characterized by a triad of symptoms: bilateral parieto-occipital alopecia, facial anesthesia in the trigeminal area, and rhombencephalosynapsis (RES), confirmed by cranial magnetic resonance imaging. CTD dysplasia is also known as Gómez-López-Hernández syndrome. So far, only 35 cases have been described with varying symptomatology. The etiology remains unknown. Either spontaneous dominant mutations or de novo chromosomal rearrangements have been proposed as possible explanations. In addition to its clinical triad of RES, parietal alopecia, and trigeminal anesthesia, CTD dysplasia is associated with a wide range of phenotypic and neurodevelopmental abnormalities.Treatment is symptomatic and includes physical rehabilitation, special education, dental care, and ocular protection against self-induced corneal trauma that causes ulcers and, later, corneal opacification. The prognosis is correlated to the mental development, motor handicap, corneal–facial anesthesia, and visual problems. Follow-up on a large number of patients with CTD dysplasia has never been reported and experience is limited to few cases to date. High degree of suspicion in a child presenting with characteristic alopecia and RES has a great importance in diagnosis of this syndrome.

scholarly journals Dissecting the Molecular Determinants of GABAA Receptors Current Rundown, a Hallmark of Refractory Human Epilepsy

2021 ◽  
Vol 11 (4) ◽  
pp. 441
Author(s):  
Pierangelo Cifelli ◽  
Silvia Di Angelantonio ◽  
Veronica Alfano ◽  
Alessandra Morano ◽  
Eleonora De Felice ◽  
...  
Keyword(s):  
Gabaa Receptors ◽  
Drug Resistant ◽  
Human Embryonic Kidney Cells ◽  
Inhibitory Function ◽  
Human Epilepsy ◽  
Wide Range ◽  
Molecular Determinants ◽  
The Central Nervous System ◽  
Heterologous Expression Systems ◽  
Important Therapeutic Target

GABAA receptors-(Rs) are fundamental for the maintenance of an efficient inhibitory function in the central nervous system (CNS). Their dysfunction is associated with a wide range of CNS disorders, many of which characterized by seizures and epilepsy. Recently, an increased use-dependent desensitization due to a repetitive GABA stimulation (GABAA current rundown) of GABAARs has been associated with drug-resistant temporal lobe epilepsy (TLE). Here, we aimed to investigate the molecular determinants of GABAA current rundown with two different heterologous expression systems (Xenopus oocytes and human embryonic kidney cells; HEK) which allowed us to manipulate receptor stoichiometry and to study the GABAA current rundown on different GABAAR configurations. To this purpose, we performed electrophysiology experiments using two-electrode voltage clamp in oocytes and confirming part of our results in HEK. We found that different degrees of GABAA current rundown can be associated with the expression of different GABAAR β-subunits reaching the maximum current decrease when functional α1β2 receptors are expressed. Furthermore, the blockade of phosphatases can prevent the current rundown observed in α1β2 GABAARs. Since GABAAR represents one important therapeutic target in the treatment of human epilepsy, our results could open new perspectives on the therapeutic management of drug-resistant patients showing a GABAergic impairment.

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