Miracle-dz/UniFAR-FTUs huggingface dataset:
A Conserved Residue Cluster That Governs Kinetics of ATP-dependent Gating of Kir6.2 Potassium Channels*

Background: Kir6.2 potassium channels are regulated by ATP. Results: We measured Kir6.2 gating kinetics in response to rapid ATP concentration jumps. Mutations to Trp-68 and Lys-170 dramatically decelerate gating. Conclusion: Trp-68 and Lys-170 interact to form a cluster that enables rapid gating transitions. Significance: The Trp-68/Lys-170 cluster is highly conserved and may play a similar role in other Kir channels. ATP-sensitive potassium (KATP) channels are heteromultimeric complexes of an inwardly rectifying Kir channel (Kir6.x) and sulfonylurea receptors. Their regulation by intracellular ATP and ADP generates electrical signals in response to changes in cellular metabolism. We investigated channel elements that control the kinetics of ATP-dependent regulation of KATP (Kir6.2 + SUR1) channels using rapid concentration jumps. WT Kir6.2 channels re-open after rapid washout of ATP with a time constant of ∼60 ms. Extending similar kinetic measurements to numerous mutants revealed fairly modest effects on gating kinetics despite significant changes in ATP sensitivity and open probability. However, we identified a pair of highly conserved neighboring amino acids (Trp-68 and Lys-170) that control the rate of channel opening and inhibition in response to ATP. Paradoxically, mutations of Trp-68 or Lys-170 markedly slow the kinetics of channel opening (500 and 700 ms for W68L and K170N, respectively), while increasing channel open probability. Examining the functional effects of these residues using φ value analysis revealed a steep negative slope. This finding implies that these residues play a role in lowering the transition state energy barrier between open and closed channel states. Using unnatural amino acid incorporation, we demonstrate the requirement for a planar amino acid at Kir6.2 position 68 for normal channel gating, which is potentially necessary to localize the ϵ-amine of Lys-170 in the phosphatidylinositol 4,5-bisphosphate-binding site. Overall, our findings identify a discrete pair of highly conserved residues with an essential role for controlling gating kinetics of Kir channels.
Analysis of Virion-Incorporated Host Proteins Required for Herpes Simplex Virus Type 1 Infection through a RNA Interference Screen

Viruses are strictly dependent on cells to propagate and many incorporate host proteins in their viral particles, but the significance of this incorporation is poorly understood. Recently, we performed the first comprehensive characterization of the mature herpes simplex virus type 1 (HSV-1) in which up to 49 distinct cellular proteins were identified by mass spectrometry. In the present study, we sought to identify if these cellular factors are relevant for the HSV-1 life cycle. To this end, we performed a small interfering RNA functional screen and found that 15 of these host proteins altered HSV-1 proliferation in cell culture, without any significant effect on cell viability. Moreover, the siRNA used had no negative consequences for Adenovirus type 5 propagation (with one exception) indicating that the modulation was specific for HSV-1 and not merely due to unhealthy cells. The positive host proteins include several Rab GTPases and other intracellular transport components as well as proteins involved in signal transduction, gene regulation and immunity. Remarkably, in most cases when virions were depleted for one of the above proteins, they replicated more poorly in subsequent infections in wild type cells. This highlights for the first time that both the cellular and virion-associated pools of many of these proteins actively contribute to viral propagation. Altogether, these findings underscore the power and biological relevance of combining proteomics and RNA interference to identify novel host-pathogen interactions.
How Does the Life Settlement A ¤ ect the Primary Life Insurance Market ?

We study the e¤ect of life settlement market on the structure of the long-term contracts o¤ered by the primary insurance market, as well as on the consumer welfare in a dynamic model of insurance with one-sided commitment as in Hendel and Lizzeri (2003) and Daily, Hendel and Lizzeri (2008). We show that the presence of the settlement market a¤ects the extent as well as the form of dynamic reclassi cation risk insurance in the equilibrium of the primary insurance market; and that the settlement market generally leads to lower consumer welfare. In the most extreme form, the presence of the settlement market can completely unravel the dynamic contracts to a sequence of spot short-term contracts. We also examine the primary insurersresponse to the settlement market when they can o¤er enriched contracts by specifying optimally chosen cash surrender values (CSVs). We show that the option of specifying CSVs is a useless option when there is no settlement rms; but facing the threat from the settlement rms, contracts with optimally chosen health-contingent CSVs will emerge in the equilibrium of the primary market, and such contracts improve consumer welfare, even though consumer welfare is still lower than that without the secondary market. In contrast, the option to endogenously specify non-health contingent CSVs is useless for the primary insurers. Keywords: Life insurance, dynamic insurance, secondary market JEL Classi cation Codes: G22, L11 Preliminary and incomplete; comments welcome. Please do not quote without permission. Many ideas in this paper originated when the rst author prepared a discussion of Daily, Hendel and Lizzeri (2008) in the American Economic Association Annual Meetings in New Orleans. We are grateful to Andrew Postlewaite for stimulating discussions. All remaining errors are our own. yDepartment of Economics, Duke University, 213 Social Sciences Building, P.O. Box 90097, Durham, NC 277080097. Email addresses are respectively: hanming.fang@duke.edu; edward.kung@duke.edu
Stochastic rigidity: image registration for nowhere-static scenes

We consider the registration of sequences of images where the observed scene is entirely non-rigid for example a camera flying over water, a panning shot of a field of sunflowers in the wind, or footage of a crowd applauding at a sports event. In these cases, it is not possible to impose the constraint that world points have similar colour in successive views, so existing registration techniques cannot be applied. Indeed the relationship between a point's colours in successive frames is essentially a random process. However by treating the sequence of images as a set of samples from a multidimensional stochastic time-series, we can learn a stochastic model (e.g. an AR model) of the random process which generated the sequence of images. With a static camera, this stochastic model can be used to extend the sequence arbitrarily in time. Driving the model with random noise results in an infinitely varying sequence of images which always looks like the short input sequence. In this way, we can create "videotextures" which can play forever without repetition. With a moving camera, the image generation process comprises two components-a stochastic component-generated by the videotexture, and a parametric component due to the camera motion.
Computer model for determining localized changes in ventricle wall thickness as a function of changing wall stress determined by Laplace's law

The ventricular myocardium remodels in an attempt to normalize local wall stress (σ) created by physical forces and optimize cardiac function. This σ is considered a major driving determinant of growth or regression of myocardial cells that in turn change the local ventricular myocardial wall thickness (h) and area stress. A computer model was developed that describes the magnitude and time course of changes in h in response to variations in physical factors (pressure, geometry). The model algorithm describes the driving changes in myocardial protein synthesis and h based on a stimulus of wall stress (Δs) outside of the normal range (σο). Changes in the segmental wall thickness (dh/dt) are considered directly related to the differential in σ integrated over time. As h changes, the actual wall stress (σα) also changes as defined by Laplace's Law. The iteratively determined σ drives the growth/atrophy of the ventricle wall until an equilibrium is reached and = 0. Model performance was compared to values from the literature that examine changes in σa during a clinical perturbation and was found to closely map changes in σa with an exponential approach to a maximum loss of about 35% of total h at 60 days with a k value of 0.0006. This model can serve as a driving algorithm for defining myocardial plasticity in a FEM of the heart and used to study cardiac remodeling.
Dominant Red Coat Color in Holstein Cattle Is Associated with a Missense Mutation in the Coatomer Protein Complex, Subunit Alpha (COPA) Gene

Coat color in Holstein dairy cattle is primarily controlled by the melanocortin 1 receptor (MC1R) gene, a central determinant of black (eumelanin) vs. red/brown pheomelanin synthesis across animal species. The major MC1R alleles in Holsteins are Dominant Black (MC1RD) and Recessive Red (MC1Re). A novel form of dominant red coat color was first observed in an animal born in 1980. The mutation underlying this phenotype was named Dominant Red and is epistatic to the constitutively activated MC1RD. Here we show that a missense mutation in the coatomer protein complex, subunit alpha (COPA), a gene with previously no known role in pigmentation synthesis, is completely associated with Dominant Red in Holstein dairy cattle. The mutation results in an arginine to cysteine substitution at an amino acid residue completely conserved across eukaryotes. Despite this high level of conservation we show that both heterozygotes and homozygotes are healthy and viable. Analysis of hair pigment composition shows that the Dominant Red phenotype is similar to the MC1R Recessive Red phenotype, although less effective at reducing eumelanin synthesis. RNA-seq data similarly show that Dominant Red animals achieve predominantly pheomelanin synthesis by downregulating genes normally required for eumelanin synthesis. COPA is a component of the coat protein I seven subunit complex that is involved with retrograde and cis-Golgi intracellular coated vesicle transport of both protein and RNA cargo. This suggests that Dominant Red may be caused by aberrant MC1R protein or mRNA trafficking within the highly compartmentalized melanocyte, mimicking the effect of the Recessive Red loss of function MC1R allele.
Clues to meaning: exploring potential effects of paired, congruent cues on toddlers' word learning

meanings’ of the words themselves but . to understand what their social partner wants to call their attention to” (p. 116). The mapping puzzle, then, according to these theorists, is not so daunting as Quine suggested; children solve it through socialpragmatic knowledge. One type of social cue available to children at a very early age is eye gaze. Research suggests that children as young as six months of age respond to the joint attention bids of their parents by matching their direction of gaze (Morales, Mundy, & Rojas, 1998; Morales et al., 2000) and this ability expands over the first year and a half of life (Morales et al., 2000). By 18-months-of age, toddlers are able to recruit this ability for word learning purposes; they can use a speaker’s direction of gaze to map words to meanings (Baldwin, 1991; 1993a; 1993b; Dunham, Dunham, & Curwin, 1993). In
Precision and accuracy of diffusion kurtosis estimation and the influence of b‐value selection

Diffusion kurtosis imaging (DKI) is an extension of diffusion tensor imaging that accounts for leading non‐Gaussian diffusion effects. In DKI studies, a wide range of different gradient strengths (b‐values) is used, which is known to affect the estimated diffusivity and kurtosis parameters. Hence there is a need to assess the accuracy and precision of the estimated parameters as a function of b‐value. This work examines the error in the estimation of mean of the kurtosis tensor (MKT) with respect to the ground truth, using simulations based on a biophysical model for both gray (GM) and white (WM) matter. Model parameters are derived from densely sampled experimental data acquired in ex vivo rat brain and in vivo human brain. Additionally, the variability of MKT is studied using the experimental data. Prevalent fitting protocols are implemented and investigated. The results show strong dependence on the maximum b‐value of both net relative error and standard deviation of error for all of the employed fitting protocols. The choice of b‐values with minimum MKT estimation error and standard deviation of error was found to depend on the protocol type and the tissue. Protocols that utilize two terms of the cumulant expansion (DKI) were found to achieve minimum error in GM at b‐values less than 1 ms/μm2, whereas maximal b‐values of about 2.5 ms/μm2 were found to be optimal in WM. Protocols including additional higher order terms of the cumulant expansion were found to provide higher accuracy for the more commonly used b‐value regime in GM, but were associated with higher error in WM. Averaged over multiple voxels, a net average error of around 15% for both WM and GM was observed for the optimal b‐value choice. These results suggest caution when using DKI generated metrics for microstructural modeling and when comparing results obtained using different fitting techniques and b‐values.
Numerical study of flow past a square cylinder with corner curvature at incidence

Numerical Investigation is performed for flow past a square cylinder with different corner radius placed at an angle to the incoming flow. The focus of study is on the variation of wake structures and aerodynamic forces according to change in cylinder corner radius and orientation. In the present study, corner curvature ratio R/D=0 (square cylinder), 0.1, 0.2, 0.3, 0.4 and 0.5 (circular cylinder), (where R is the corner radius and D is the characteristic dimension of the body) and angle of incidence in the range α=0°-45° are considered at Reynolds number 500. The numerical model is validated by comparing the present results and found in good agreement with the available literatures. The corner radius and angle of incidence is found to significantly influence the flow characteristics around the cylinder which includes drag and lift coefficients, instantaneous velocity and vorticity and Strouhal number. The minimum mean drag coefficient (CD) for incidence angle α=0° is observed at R/D =0.2, while for other Incidence angle α=15°, 30°, 45° the drag reduces with the increase of R/D ratio. The variation of wake width with R/D and angle of Incidence shows a trend similar to that of CD.
Bootstrap misspecification tests for ARCH based on the empirical process of squared residuals

We propose and study by means of simulations and graphical tools a class of goodness-of-fit tests for ARCH models. The tests are based on the empirical distribution function of squared residuals and smooth (parametric) bootstrap. We examine empirical size and power by means of a simulation study. While the tests have overall correct size, their power strongly depends on the type of alternative and is particularly high when the assumption of Gaussian innovations is violated. As an example, the tests are applied to returns on Foreign Exchange rates. E-mail: gilles@ehess.cnrs-mrs.fr/gteyssiere@nbg-france.com E-mail: horvath@math.utah. edu
Successful treatment of thyroidectomy scar with a pneumatic needleless injector and silicone gel

Dear Editors, Thyroidectomy is the most frequently used method when performing surgery for thyroid cancer. A transverse incision on the neck is typically used to approach the thyroid; scar formation in highly visible areas of the neck is a consequence of using this method. The mean score of the Dermatology Life Quality Index for persons who have a thyroidectomy scar is similar to the mean score of patients with psoriasis and severe atopic dermatitis (1). In this study, we report the effects of a pneumatic needleless injector and silicone gel on scar remodelling in the case of a male patient with a thyroidectomy scar. A 41-year-old male patient visited our hospital to lessen the conspicuousness of a thyroidectomy scar (Figure 1). He underwent a total thyroidectomy and bilateral central node dissection 2 weeks prior to his visit. He had an erythematous protruding scar, with a length of 6 cm and a thickness of 3 mm. The Vancouver Scar Scale (VSS), including pigmentation, vascularity, pliability and height, was used for clinical assessment. The first time the patient presented, his VSS score was 7 points. We had him apply a silicone gel sheet (Scar-ClinicTM; Hans Biomed / Ildong Pharmaceutical Co, Ltd, Seoul, Korea) to only the left side of
Comparison of several BHT correction methods: a case study on an Australian data set

Bottom-hole temperatures (BHT) from oil exploration provide useful constraints on the subsurface thermal regime, but they need to be corrected to obtain the equilibrium temperature. In this work we introduce several BHT correction methods and compare them using a large Australian data set of more than 650 groups of multiple BHT measurements in about 300 oil exploration boreholes. Existing and suggested corrections are classified within a coherent framework, in which methods are divided into: line/cylinder source; instantaneous/continuous heat extraction; one/two component(s). Comparisons with reservoir test temperatures show that most of the corrections lead to reliable estimates of the formation equilibrium temperature within ± 10±C, but too few data exist to perform an inter-comparison of the models based on this criterion. As expected, the Horner method diverges from its parent models for small elapsed times (or equivalently large radii). The mathematical expression of line source models suffers from an unphysical delay time that also restrains their domain of applicability. The model that takes into account the difference of thermal properties between circulating mud and surrounding rocks – that is the two-component model – is delicate to use because of its high complexity. For these reasons, our preferred correction methods are the cylindrical source models. We show that mud circulation time below 10 hours has a negligible effect. The cylindrical source models rely on one parameter depending on the thermal diffusivity and the borehole radius, which are poorly constrained, but the induced uncertainty on the extrapolations remains reasonably low.
Mandatory notification of impaired doctors

Mandatory reporting of impaired doctors is compulsory in Australasia. Australian Health Practitioner Regulation Agency guidelines for notification claim high benchmark though the Royal Australasian College of Surgeons and the Royal Australasian College of Physicians suggest they still obstruct doctors seeking help. Western Australia excludes mandatory reporting of practitioner‐patients. This study examines reporting, consequences and international experiences with notification. Depressed doctors avoid diagnosis and treatment, fearing consequences, yet are more prone to marital problems, substance dependence and needing psychotherapy. South African research confirms isolation of impaired doctors and delayed seeking help with definable characteristics of those at risk. New Zealand data acknowledge: errors occur; questionable contribution from mandatory reporting; issues concerning competence assessment; favouring reporting to senior colleagues or self‐intervention to compliance with mandatory reporting. UK found an anaesthetist guilty of professional misconduct for not reporting and sanctioned doctors regarding Harold Shipman. Australians are reluctant to report, fearing legalistic intrusion into care. Australian research confirmed definable characteristics for doctors with psychiatric illness or alcohol abuse. Exposure to legal medicine evokes personal disenchantment for doctors involved. Medicine poses barriers for impaired doctors. Spanish and UK doctors do not use general practitioners and may have suboptimal care. US and European doctors self‐medicate using samples. US drug‐dependent doctors also prescribe for spouses. Junior doctors are losing empathy with the profession. UK doctors favour private care, avoiding public scrutiny. NZ and Brazil created specific services for doctors, which appear effective. Mandatory reporting may be counterproductive requiring reappraisal.
Classification in the KL-ONE Knowledge Representation System

KL-ONE lets one define and use a class of descriptive terms called Concepts, where each Concept denotes a set of objects A subsumption relation between Concepts is defined which is related to set inclusion by way of a semantics for Concepts. This subsumption relation defines a partial order on Concepts, and KL-ONE organizes all Concepts into a taxonomy that reflects this partial order. Classification is a process that takes a new Concept and determines other Concepts that either subsume it or that it subsumes, thereby determining the location for the new Concept within a given taxonomy. We discuss these issues and demonstrate some uses of the classification algorithm.
MR Imaging in Spinocerebellar Ataxias: A Systematic Review

BACKGROUND AND PURPOSE: Polyglutamine expansion spinocerebellar ataxias are autosomal dominant slowly progressive neurodegenerative diseases with no current treatment. MR imaging is the best-studied surrogate biomarker candidate for polyglutamine expansion spinocerebellar ataxias, though with conflicting results. We aimed to review quantitative central nervous system MR imaging technique findings in patients with polyglutamine expansion spinocerebellar ataxias and correlations with well-established clinical and molecular disease markers. MATERIALS AND METHODS: We searched MEDLINE, LILACS, and Cochrane data bases of clinical trials between January 1995 and January 2016, for quantitative MR imaging volumetric approaches, MR spectroscopy, diffusion tensor imaging, or other quantitative techniques, comparing patients with polyglutamine expansion spinocerebellar ataxias (SCAs) with controls. Pertinent details for each study regarding participants, imaging methods, and results were extracted. RESULTS: After reviewing the 706 results, 18 studies were suitable for inclusion: 2 studies in SCA1, 1 in SCA2, 15 in SCA3, 1 in SCA7, 1 in SCA1 and SCA6 presymptomatic carriers, and none in SCA17 and dentatorubropallidoluysian atrophy. Cerebellar hemispheres and vermis, whole brain stem, midbrain, pons, medulla oblongata, cervical spine, striatum, and thalamus presented significant atrophy in SCA3. The caudate, putamen and whole brain stem presented similar sensitivity to change compared with ataxia scales after 2 years of follow-up in a single prospective study in SCA3. MR spectroscopy and DTI showed abnormalities only in cross-sectional studies in SCA3. Results from single studies in other polyglutamine expansion spinocerebellar ataxias should be replicated in different cohorts. CONCLUSIONS: Additional cross-sectional and prospective volumetric analysis, MR spectroscopy, and DTI studies are necessary in polyglutamine expansion spinocerebellar ataxias. The properties of preclinical disease biomarkers (presymptomatic) of MR imaging should be targeted in future studies.