Miracle-dz/UniFAR-FTUs huggingface dataset:
A comparison of successful and failed protein interface designs highlights the challenges of designing buried hydrogen bonds

The accurate design of new protein–protein interactions is a longstanding goal of computational protein design. However, most computationally designed interfaces fail to form experimentally. This investigation compares five previously described successful de novo interface designs with 158 failures. Both sets of proteins were designed with the molecular modeling program Rosetta. Designs were considered a success if a high‐resolution crystal structure of the complex closely matched the design model and the equilibrium dissociation constant for binding was less than 10 μM. The successes and failures represent a wide variety of interface types and design goals including heterodimers, homodimers, peptide‐protein interactions, one‐sided designs (i.e., where only one of the proteins was mutated) and two‐sided designs. The most striking feature of the successful designs is that they have fewer polar atoms at their interfaces than many of the failed designs. Designs that attempted to create extensive sets of interface‐spanning hydrogen bonds resulted in no detectable binding. In contrast, polar atoms make up more than 40% of the interface area of many natural dimers, and native interfaces often contain extensive hydrogen bonding networks. These results suggest that Rosetta may not be accurately balancing hydrogen bonding and electrostatic energies against desolvation penalties and that design processes may not include sufficient sampling to identify side chains in preordered conformations that can fully satisfy the hydrogen bonding potential of the interface.
Wave-Packet Models for Jet Dynamics and Sound Radiation

Organized structures in turbulent jets can be modeled as wavepackets. These are characterized by spatial amplification and decay, both of which are related to stability mechanisms, and they are coherent over several jet diameters, thereby constituting a noncompact acoustic source that produces a distinctive directivity in the acoustic field. In this review, we use simplified model problems to discuss the salient features of turbulent-jet wavepackets and their modeling frameworks. Two classes of model are considered. The first, that we refer to as kinematic, is based on Lighthill's acoustic analogy, and allows an evaluation of the radiation properties of sound-source functions postulated following observation of jets. The second, referred to as dynamic, is based on the linearized, inhomogeneous Ginzburg–Landau equation, which we use as a surrogate for the linearized, inhomogeneous Navier–Stokes system. Both models are elaborated in the framework of resolvent analysis, which allows the dynamics to be viewed in terms of an input–ouput system, the input being either sound-source or nonlinear forcing term, and the output, correspondingly, either farfield acoustic pressure fluctuations or nearfield flow fluctuations. Emphasis is placed on the extension of resolvent analysis to stochastic systems, which allows for the treatment of wavepacket jitter, a feature known to be relevant for subsonic jet noise. Despite the simplicity of the models, they are found to qualitatively reproduce many of the features of turbulent jets observed in experiment and simulation. Sample scripts are provided and allow calculation of most of the presented results.
Reassessing the type I dehydroquinate dehydratase catalytic triad: Kinetic and structural studies of Glu86 mutants

Dehydroquinate dehydratase (DHQD) catalyzes the third reaction in the biosynthetic shikimate pathway. Type I DHQDs are members of the greater aldolase superfamily, a group of enzymes that contain an active site lysine that forms a Schiff base intermediate. Three residues (Glu86, His143, and Lys170 in the Salmonella enterica DHQD) have previously been proposed to form a triad vital for catalysis. While the roles of Lys170 and His143 are well defined—Lys170 forms the Schiff base with the substrate and His143 shuttles protons in multiple steps in the reaction—the role of Glu86 remains poorly characterized. To probe Glu86′s role, Glu86 mutants were generated and subjected to biochemical and structural study. The studies presented here demonstrate that mutant enzymes retain catalytic proficiency, calling into question the previously attributed role of Glu86 in catalysis and suggesting that His143 and Lys170 function as a catalytic dyad. Structures of the Glu86Ala (E86A) mutant in complex with covalently bound reaction intermediate reveal a conformational change of the His143 side chain. This indicates a predominant steric role for Glu86, to maintain the His143 side chain in position consistent with catalysis. The structures also explain why the E86A mutant is optimally active at more acidic conditions than the wild‐type enzyme. In addition, a complex with the reaction product reveals a novel, likely nonproductive, binding mode that suggests a mechanism of competitive product inhibition and a potential strategy for the design of therapeutics.
A Well-Defined Estelle Specification for the Automatic Test Generation

The characteristics of the Estelle specification language are analyzed and a well-defined specification, a restricted form of an Estelle specification, is proposed based on the analyzed results to enable a direct derivation of a single reduced finite state machine-which is called a CFG (control flow graph)-from the specification written in Estelle. The derived CFG provides a basis for the automatic test case generation. Algorithms to test whether the specification written in Estelle is well defined or not, and to generate the CFG from the well-defined specification, are developed. Finally, as an example, the proposed technique is applied to TP0 (transport protocol class 0) specification written in Estelle. In applying these algorithms to the Estelle specification, some guidelines are also suggested for the specification which is not well defined. >
Low Density Lipoprotein-Heterogenität als prognostischer Marker kardiovaskulärer Erkrankungen / Low density lipoprotein heterogeneity for risk evaluation of cardiovascular disease

Zusammenfassung Zusammenfassung Generell ist die Bestimmung von Low Density Lipoprotein-Subfraktionen (LDL-Subfraktionen) zur Aufklärung pathophysiologischer Zusammenhänge im Bereich der vaskulären Medizin und für die Risikoabschätzung kardiovaskulärer Erkrankungen von Bedeutung. Es gibt verschiedene Methoden zur Bestimmung von LDL-Subfraktionen, welche sich unterschiedliche physiko-chemische Eigenschaften der LDL zu Nutze machen. So trennen Ultrazentrifugationsmethoden nach Dichte, die Gradientengelelektrophorese (GGE) und das Magnetresonanzverfahren (NMR) nach Größe auf. Für differentialdiagnostische Zwecke oder bei der routinemäßigen Abschätzung des kardiovaskulären Risikos ist die Analytik der LDL-Subfraktionen derzeit aber wenig sinnvoll. Dies liegt zum einen an den teilweise aufwändigen Techniken, zum anderen an der schlechten Standardisierung der Methoden und der noch offenen klinischen Relevanz der gewonnenen Ergebnisse.
Hematological Parameters as Predictors of Cardiovascular Disease in Obstructive Sleep Apnea Syndrome Patients

We investigated the role of the red cell distribution width (RDW) and other parameters including platelet (PLT) count, mean platelet volume (MPV), and platelet distribution width (PDW) in patients with obstructive sleep apnea syndrome (OSAS) having cardiovascular diseases (CVDs). Patients (n = 142) having sleep disorders and who applied for a night polysomnography were included in this study. For statistical analysis, chi-square test, bivarite correlation, and logistic and stepwise regression tests were used. A positive correlation between RDW MPV, RDW, and body mass index as well as PLT and apnea–hypopnea index were observed. A negative correlation between AHI and PDW (P = .041) and a positive correlation between AHI and PLT (P = .010) were found in the patients ≥40 years old with CVD. The RDW was higher in patients ≥40 years old who had CVD (P = .016), and 19% of them had RDW >14%. The PDW (odds ratio = 6.02 [95% confidence interval = 1.3-28.2], P = .023) appeared to be associated with increased risk of hyperlipidemia in patients with severe OSAS. If these results are confirmed, RDW could be used with other markers, especially PLT and PDW, in prediction of CVD in patients with severe OSAS.
Metal cation controls myosin and actomyosin kinetics

We have perturbed myosin nucleotide binding site with magnesium‐, manganese‐, or calcium‐nucleotide complexes, using metal cation as a probe to examine the pathways of myosin ATPase in the presence of actin. We have used transient time‐resolved FRET, myosin intrinsic fluorescence, fluorescence of pyrene labeled actin, combined with the steady state myosin ATPase activity measurements of previously characterized D.discoideum myosin construct A639C:K498C. We found that actin activation of myosin ATPase does not depend on metal cation, regardless of the cation‐specific kinetics of nucleotide binding and dissociation. The rate limiting step of myosin ATPase depends on the metal cation. The rate of the recovery stroke and the reverse recovery stroke is directly proportional to the ionic radius of the cation. The rate of nucleotide release from myosin and actomyosin, and ATP binding to actomyosin depends on the cation coordination number.
A study of user profile representation for personalized cross-language information retrieval

Purpose – With an increase in the amount of multilingual content on the World Wide Web, users are often striving to access information provided in a language of which they are non-native speakers. The purpose of this paper is to present a comprehensive study of user profile representation techniques and investigate their use in personalized cross-language information retrieval (CLIR) systems through the means of personalized query expansion. Design/methodology/approach – The user profiles consist of weighted terms computed by using frequency-based methods such as tf-idf and BM25, as well as various latent semantic models trained on monolingual documents and cross-lingual comparable documents. This paper also proposes an automatic evaluation method for comparing various user profile generation techniques and query expansion methods. Findings – Experimental results suggest that latent semantic-weighted user profile representation techniques are superior to frequency-based methods, and are particularly suita.
Influence of hydrophobic and electrostatic residues on SARS-coronavirus S2 protein stability: Insights into mechanisms of general viral fusion and inhibitor design

Severe acute respiratory syndrome (SARS) is an acute respiratory disease caused by the SARS‐coronavirus (SARS‐CoV). SARS‐CoV entry is facilitated by the spike protein (S), which consists of an N‐terminal domain (S1) responsible for cellular attachment and a C‐terminal domain (S2) that mediates viral and host cell membrane fusion. The SARS‐CoV S2 is a potential drug target, as peptidomimetics against S2 act as potent fusion inhibitors. In this study, site‐directed mutagenesis and thermal stability experiments on electrostatic, hydrophobic, and polar residues to dissect their roles in stabilizing the S2 postfusion conformation was performed. It was shown that unlike the pH‐independent retroviral fusion proteins, SARS‐CoV S2 is stable over a wide pH range, supporting its ability to fuse at both the plasma membrane and endosome. A comprehensive SARS‐CoV S2 analysis showed that specific hydrophobic positions at the C‐terminal end of the HR2, rather than electrostatics are critical for fusion protein stabilization. Disruption of the conserved C‐terminal hydrophobic residues destabilized the fusion core and reduced the melting temperature by 30°C. The importance of the C‐terminal hydrophobic residues led us to identify a 42‐residue substructure on the central core that is structurally conserved in all existing CoV S2 fusion proteins (root mean squared deviation = 0.4 Å). This is the first study to identify such a conserved substructure and likely represents a common foundation to facilitate viral fusion. We have discussed the role of key residues in the design of fusion inhibitors and the potential of the substructure as a general target for the development of novel therapeutics against CoV infections.
Drugs That Affect the Resting Heart Rate

We read with interest the article ‘‘The Relationship Between Resting Heart Rate and SYNTAX Score in Patients With Stable Coronary Artery Disease’’ by Yilmaz et al. Elevated resting heart rate is an independent marker of mortality within a wide spectrum of conditions. Yilmaz et al found that resting heart rate predicts the severity and complexity of coronary atherosclerosis. We have some comments about this article. In the study, the authors specified the medications for patients. We think that the dosage of drugs such as b-blockers or calcium channel blockers is important, because target dose of these medications can affect the heart rate. We think that the dosage of these medications should be similar in both the groups. It is necessary to note the time period the patient has been receiving these drugs before the resting heart rate was measured. Although ivabradine has been used for the symptomatic management of stable angina pectoris, there were no data about the usage of ivabradine. Also, digoxin is occasionally used in the treatment of various heart rhythms, such as atrial fibrillation, atrial flutter, and sometimes heart failure that cannot be controlled by other medication. Despite the exclusion criteria of the patients with heart failure and atrial fibrillation, there was no information about the usage of digoxin.
Auditory representations of acoustic signals

An analytically tractable framework is presented to describe mechanical and neural processing in the early stages of the auditory system. Algorithms are developed to assess the integrity of the acoustic spectrum at all processing stages. The algorithms employ wavelet representations, multiresolution processing, and the method of convex projections to construct a close replica of the input stimulus. Reconstructions using natural speech sounds demonstrate minimal loss of information along the auditory pathway. Close inspection of the final auditory patterns reveals spectral enhancements and noise suppression that have close perceptual correlates. The functional significance of the various auditory processing stages is discussed in light of the model, together with their potential applications in automatic speech recognition and low bit-rate data compression. >
Evaluating the innovation of the Internet of Things: Empirical evidence from the intellectual capital assessment

Purpose – The Internet of Things (IoT) represents the network connection of people, processes, data and things. Due to the relevant position that this intelligent infrastructure is acquiring, the purpose of this paper is to investigate the effects of IoT on the companies’ value, with specific reference to the intellectual capital value. Design/methodology/approach – The methodology is based on a single case study approach with an empirical analysis which aims to analyse whether and how the introduction of the IoT’ innovations influences the value of the intellectual capital owned by a company. The evaluation method used for the empirical analysis is the Economic Value Added. The application is carried out on the company “Cisco Systems Inc.” by analysing the company’s financial reports covering the period 2007-2014. Findings – The paper demonstrates the impact of the innovation of IoT on intellectual capital owned by a high intensity cognitive company by determining its economic value. The results demonstr.
Emerging applications of small angle solution scattering in structural biology

Small angle solution X‐ray and neutron scattering recently resurfaced as powerful tools to address an array of biological problems including folding, intrinsic disorder, conformational transitions, macromolecular crowding, and self or hetero‐assembling of biomacromolecules. In addition, small angle solution scattering complements crystallography, nuclear magnetic resonance spectroscopy, and other structural methods to aid in the structure determinations of multidomain or multicomponent proteins or nucleoprotein assemblies. Neutron scattering with hydrogen/deuterium contrast variation, or X‐ray scattering with sucrose contrast variation to a certain extent, is a convenient tool for characterizing the organizations of two‐component systems such as a nucleoprotein or a lipid‐protein assembly. Time‐resolved small and wide‐angle solution scattering to study biological processes in real time, and the use of localized heavy‐atom labeling and anomalous solution scattering for applications as FRET‐like molecular rulers, are amongst promising newer developments. Despite the challenges in data analysis and interpretation, these X‐ray/neutron solution scattering based approaches hold great promise for understanding a wide variety of complex processes prevalent in the biological milieu.
Role of membrane contact sites in protein import into mitochondria

Mitochondria import more than 1,000 different proteins from the cytosol. The proteins are synthesized as precursors on cytosolic ribosomes and are translocated by protein transport machineries of the mitochondrial membranes. Five main pathways for protein import into mitochondria have been identified. Most pathways use the translocase of the outer mitochondrial membrane (TOM) as the entry gate into mitochondria. Depending on specific signals contained in the precursors, the proteins are subsequently transferred to different intramitochondrial translocases. In this article, we discuss the connection between protein import and mitochondrial membrane architecture. Mitochondria possess two membranes. It is a long‐standing question how contact sites between outer and inner membranes are formed and which role the contact sites play in the translocation of precursor proteins. A major translocation contact site is formed between the TOM complex and the presequence translocase of the inner membrane (TIM23 complex), promoting transfer of presequence‐carrying preproteins to the mitochondrial inner membrane and matrix. Recent findings led to the identification of contact sites that involve the mitochondrial contact site and cristae organizing system (MICOS) of the inner membrane. MICOS plays a dual role. It is crucial for maintaining the inner membrane cristae architecture and forms contacts sites to the outer membrane that promote translocation of precursor proteins into the intermembrane space and outer membrane of mitochondria. The view is emerging that the mitochondrial protein translocases do not function as independent units, but are embedded in a network of interactions with machineries that control mitochondrial activity and architecture.
The delayed fatigue effect in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating, long-term condition characterised by extreme fatigue (worsened by exertion), muscle and joint pain, and sleep disturbance. Post-exertional fatigue has been demonstrated previously following physical exercise, but not from mental exertion alone. Purpose: The aim of this exploratory study was to assess the ‘delayed fatigue effect,’ in this instance fatigue two days post-challenge, following a cognitively fatiguing task. Methods: Thirty-two participants (23 women; mean age 44, SD = 11.24; mean illness duration nine years, SD = 7.32) completed the Cambridge Neuropsychological Test Automated Battery, which acted as the cognitive challenge. Self-report measures were also completed that assessed fatigue (Multidimensional Fatigue Inventory; MFI), and anxiety and depression (Hospital Anxiety and Depression Scale; HADS) pre- and two days post-testing. Results: Significant differences were found between pre- and post-test measures in three MFI sub-scales of fatigue (general, mental, and physical) and on the depression scale of the HADS. However, there were no significant changes in motivation, activity level, or self-reported anxiety scores. Conclusions: These findings are suggestive of post-exertional symptom exacerbation following mental effort. This may have implications for working environments that present cognitive demands to individuals with ME/CFS.
Female Sex Trade Workers, Condoms, and the Public-Private Divide

Abstract This qualitative study explored the ways in which social relations within the public (work) as opposed to the private (home) contexts shape variable condom use among female sex trade workers. Semi-structured interviews were conducted with 68 female sex workers working in various settings in an urban center in Eastern Canada. The findings suggest that work-related social relations, and the meanings associated with condoms at work, create a strong confidence in condom use. Within the private setting, such confidence was also evident but most women reported either not using condoms or only using “sometimes. ” Nevertheless, many women do engage in risk management within the private setting, and take active steps to decrease their risks of Human Immunodeficiency Syndrome (HIV)/Sexually Transmitted Infections (STIs).
Free energy landscape of a minimalist salt bridge model

Salt bridges are essential to protein stability and dynamics. Despite the importance, there has been scarce of detailed discussion on how salt bridge partners interact with each other in distinct solvent exposed environments. In this study, employing a recent generalized orthogonal space tempering (gOST) method, we enabled efficient molecular dynamics simulation of repetitive breaking and reforming of salt bridge structures within a minimalist salt‐bridge model, the Asp‐Arg dipeptide and thereby were able to map its detailed free energy landscape in aqueous solution. Free energy surface analysis shows that although individually‐solvated states are more favorable, salt‐bridge states still occupy a noticeable portion of the overall population. Notably, the competing forces, e.g. intercharge attractions that drive the formation of salt bridges and solvation forces that pull the charged groups away from each other, are energetically comparable. As the result, the salt bridge stability is highly tunable by local environments; for instance when local water molecules are perturbed to interact more strongly with each other, the population of the salt‐bridge states is likely to increase. Our results reveal the critical role of local solvent structures in modulating salt‐bridge partner interactions and imply the importance of water fluctuations on conformational dynamics that involves solvent accessible salt bridge formations.