Miracle-dz/UniFAR-FTUs huggingface dataset:
Solving an Old Puzzle: Elucidation and Evaluation of the Binding Mode of Salvinorin A at the Kappa Opioid Receptor

The natural product Salvinorin A (SalA) was the first nitrogen-lacking agonist discovered for the opioid receptors and exhibits high selectivity for the kappa opioid receptor (KOR) turning SalA into a promising analgesic to overcome the current opioid crisis. Since SalA’s suffers from poor pharmacokinetic properties, particularly the absence of gastrointestinal bioavailability, fast metabolic inactivation, and subsequent short duration of action, the rational design of new tailored analogs with improved clinical usability is highly desired. Despite being known for decades, the binding mode of SalA within the KOR remains elusive as several conflicting binding modes of SalA were proposed hindering the rational design of new analgesics. In this study, we rationally determined the binding mode of SalA to the active state KOR by in silico experiments (docking, molecular dynamics simulations, dynophores) in the context of all available mutagenesis studies and structure-activity relationship (SAR) data. To the best of our knowledge, this is the first comprehensive evaluation of SalA’s binding mode since the determination of the active state KOR crystal structure. SalA binds above the morphinan binding site with its furan pointing toward the intracellular core while the C2-acetoxy group is oriented toward the extracellular loop 2 (ECL2). SalA is solely stabilized within the binding pocket by hydrogen bonds (C210ECL2, Y3127.35, Y3137.36) and hydrophobic contacts (V1182.63, I1393.33, I2946.55, I3167.39). With the disruption of this interaction pattern or the establishment of additional interactions within the binding site, we were able to rationalize the experimental data for selected analogs. We surmise the C2-substituent interactions as important for SalA and its analogs to be experimentally active, albeit with moderate frequency within MD simulations of SalA. We further identified the non-conserved residues 2.63, 7.35, and 7.36 responsible for the KOR subtype selectivity of SalA. We are confident that the elucidation of the SalA binding mode will promote the understanding of KOR activation and facilitate the development of novel analgesics that are urgently needed.
Grid approximation of a singularly perturbed elliptic convection–diffusion equation in an unbounded domain

We consider the Dirichlet problem for a singularly perturbed elliptic convection-diffusion equation in the quarter plane {(x 1, x 2) : x 1, x 2 ≥ 0}. The highest derivatives of the equation and the first derivative along the x 2-axis contain, respectively, the parameters ε 1 and ε 2, which take arbitrary values from the half-open interval (0,1] and the segment [–1,1]. For small values of the parameter ε 1, a boundary layer appears in the neighbourhood of the domain boundary. Depending on the ratio between the parameters ε 1 and ε 2, this layer may be regular, elliptic, parabolic, or hyperbolic. Beside the boundary layer scale controlled by the perturbation parameters, one can observe a resolution scale, which is specified by the 'width' of the domain in which the problem is to be solved on a computer. It turns out that for solutions of the boundary value problem and a formal difference scheme (i.e., a scheme on meshes with an infinite number of nodes) considered on bounded subdomains of interest (referred to as resolution subdomains), domains of essential dependence, i.e., domains outside which the finite variation of the solution causes relatively small perturbations of the solution on resolution subdomains, are bounded uniformly with respect to the vector parameter = (ε1, ε2). Using the concept of a 'domain of essential solution dependence', we develop a constructive finite difference scheme (i.e., a scheme on meshes with a finite number of nodes) that converges -uniformly on the bounded resolution subdomains.
A systematic review of observational studies of trifluridine/tipiracil (TAS-102) for metastatic colorectal cancer

Abstract Background: The treatment options for patients with therapy refractory metastatic colorectal cancer (mCRC) are sparse. TAS-102 (FTD/TPI) is a new oral anti-tumour agent composed of a nucleoside analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil, indicated for patients with mCRC who are refractory to standard therapies. This study summarizes published and unpublished experience with FTD/TPI in clinical practice settings. Patients and methods: The Medline/PubMed, Embase and Cochrane Library databases were searched to identify observational studies on FTD/TPI monotherapy for mCRC. Papers describing use of FTD/TPI monotherapy outside clinical trials in series of patients evaluable for effectiveness were eligible. The outcomes of interest were median progression free survival (mPFS), median overall survival (mOS) as well as mean PFS time restricted to six months (PFS6m) and mean OS time restricted to one year (OS1y). Results of the pooled analyses of observational studies were compared to the results of the Japanese phase II trial and the two phase III trials, RECOURSE and TERRA. Results: Seven published and two unpublished studies with 1008 patients from 64 centres were included for analysis. The pooled mPFS was 2.2 months (95% CI 2.1 to 2.3 months), and the pooled mOS was 6.6 months (95% CI 6.1 to 7.1 months). PFS6m was 2.9 months (95% CI 2.6 to 3.1 months) and OS1y was 6.8 (95% CI 6.0 to 7.5) months. While these results all reflect RECOURSE, the pooled mOS is lower than in the phase II trial and the OS1y is inferior to both the phase II trial and TERRA. Conclusion: This systematic review and a meta-analysis indicates that in real life settings, the survival benefit of FTD/TPI monotherapy in patients with therapy refractory mCRC reflects the outcomes in RECOURSE but is inferior to outcomes in the two Asian efficacy trials. What is already known TAS 102 (Lonsurf) is an oral fixed dose combination of trifluridine (FTD) and tipiracil (TPI) indicated as salvage-line treatment in patients with therapy refractory metastatic colorectal cancer (mCRC). A Japanese phase II trial and two phase III trials, RECOURSE and TERRA, demonstrated that FTD/TPI prolonged overall survival. What this study adds This systematic review and meta-analysis of real life data from 64 sites indicates that the effectiveness in daily clinical practice settings of FTD/TPI monotherapy in late stage mCRC reflects the outcomes in RECOURCE but is inferior to the outcomes in the Japanese phase II trial and TERRA.
Study on Computer Screening and Drug Properties of Herbs Intervening in Copper Death

Objective The objective of this study was to explore the medicinal properties of herbal medicines that can interfere with the copper death pathway. Methods The Human Gene Database, Chemical Interactions in Comparative Toxicogenomics Database, Encyclopedia of Traditional Chinese Medicine, China Medical Information Platform, and Cytoscape software were used to find target and chemicals that interfere with copper death targets, as well as herbal medicines containing these chemicals and their four natures and five flavors (basic properties of herbal medicines). Results 27 copper death-related targets were finally retrieved, as well as 2143 chemicals that could interfere with them, including 180 herbal compounds. The compounds with the highest degree values (number of nodes connected to this node) were folic acid, resveratrol, and quercetin. The 180 compounds were related to 278 herbs; those with the highest degree values (number of nodes connected to this node) were Jujubae Fructus, Ginkgo biloba L, and Acanthopanax senticosus. The 27 copper death targets were indirectly associated with 278 herbs; those with the highest degree values (number of nodes connected to this node) were Achyranthis Bidentatae Radix, Polygonum cuspidatum Sieb. et Zucc, and Mori Folium. Among the 278 herbs, 6 had incomplete information. A pharmacological analysis showed that among the 272 Chinese herbs, the most frequent meridians were the liver (133), lung (104), and spleen (91). Of the four natures, the most frequent were cold (73), warm (68), and flat (45). Of the five flavors, the most frequent were bitter (165), pungent (116), and sweet (99). Conclusion This study preliminarily discussed the material basis and medicinal properties of herbs that can intervene in copper death, which can provide reference for the theoretical discussion, drug development, and clinical research of Chinese medicine regulating copper death.
Model selection and validation for yield trials with interaction

SUMMARY The additive main effects and multiplicative interaction (AMMI) model first applies the additive analysis of variance (ANOVA) model to two-way data, and then applies the multiplicative principal components analysis (PCA) model to the residual from the additive model, that is, to the interaction. AMMI analysis of yield trial data is a useful extension of the more familiar ANOVA, PCA, and linear regression procedures, particularly given a large genotype-by-environment interaction. Model selection and validation are considered from both predictive and postdictive perspectives, using data splitting and F-tests, respectively. A New York soybean yield trial serves as an example. Yield trials generate observations of yield, ordinarily replicated, for a number of genotypes grown in a number of environments (site-year combinations). Often the data are rather noisy, with a standard deviation for plot yields in excess of 25 % of the mean. An additional challenging feature of these data is the frequent presence of important and complex genotype-by-environment (GE) interactions. Plant breeders use yield trials to identify promising genotypes, and agronomists use them to make recommendations for farmers. The level of success in meeting these goals depends critically on two factors: (i) the accuracy of yield estimates, and (ii) the magnitudes of genotype-by-site, genotype-by-year, and genotype-by-site-by-year interactions (Talbot, 1984). In essence, these two factors reflect within-trial accuracy and between-trial predictability. This paper addresses only the first concern. Nothing is said regarding between-trial predictability, or agrotechnology transfer, other than to observe that success with withintrial accuracy is a necessary prelude to success with between-trial predictability. The within-trial accuracy of a statistical model may be assessed by two fundamentally different criteria: Postdictive success concerns a model's fit to its own data, whereas predictive success concerns the fit between a model constructed using part of the data and validation data not used in modelling. In either case, the statistical setting is that of an incompletely specified model, where empirical considerations enter into the decision to include a given' potential source in the model, or alternatively to relegate it to the model's residual (Bancroft, 1964). Whenever the data are noisy, postdiction and prediction are different tasks, and in general the model chosen by predictive criteria will be different and simpler than the model chosen by postdictive criteria. Because the several replicates of a yield trial constitute a noisy sample, a model chosen by predictive criteria may be expected to provide yield estimates that are closer to the true means (and to validation observations) than will a model chosen by postdictive criteria. This claim is readily subjected to experimental test. In what follows, the relative performances of statistical models chosen
Discovery and Characterization of Novel Bat Coronavirus Lineages from Kazakhstan

Coronaviruses are positive-stranded RNA viruses that infect a variety of hosts, resulting in a range of symptoms from gastrointestinal illness to respiratory distress. Bats are reservoirs for a high diversity of coronaviruses, and focused surveillance detected several strains genetically similar to MERS-coronavirus, SARS-coronavirus, and the human coronaviruses 229E and NL63. The bat fauna of central Asia, which link China to eastern Europe, are relatively less studied than other regions of the world. Kazakhstan is the world’s ninth largest country; however, little is understood about the prevalence and diversity of bat-borne viruses. In this study, bat guano was collected from bat caves in three different sites of southern Kazakhstan that tested positive for coronaviruses. Our phylogenetic reconstruction indicates these are novel bat coronaviruses that belong to the genus Alphacoronavirus. In addition, two distinct lineages of Kazakhstan bat coronaviruses were detected. Both lineages are closely related to bat coronaviruses from China, France, Spain, and South Africa, suggesting that co-circulation of coronaviruses is common in multiple bat species with overlapping geographical distributions. Our study highlights the need for collaborative efforts in understudied countries to increase integrated surveillance capabilities toward better monitoring and detection of infectious diseases.
Transmission and absorption properties of two-dimensional metallic photonic-band-gap materials

Using the multiple-scattering method, we study systematically the transmission and absorption properties of two-dimensional (2D) metallic photonic-band-gap (PBG) materials for a wide range of frequency and structure scales by adopting a realistic dielectric constant for metal cylinders. For both S and P waves, analytic expressions for the absorption power of a single metal cylinder under an arbitrary external field have been derived to explain the absorption behaviors of metallic PBG materials in a coherent way. The discussions and conclusions presented here can be generalized to 3D systems as well.
Cell‐free synthesis of silver nanoparticles in spent media of different Aspergillus species

The recovery and valorization of metals and rare earth metals from wastewater are of great importance to prevent environmental pollution and recover valuable resources. Certain bacterial and fungal species are capable of removing metal ions from the environment by facilitating their reduction and precipitation. Even though the phenomenon is well documented, little is known about the mechanism. Therefore, we systematically investigated the influence of nitrogen sources, cultivation time, biomass, and protein concentration on silver reduction capacities of cell‐free cultivation media (spent media) of Aspergillus niger, A. terreus, and A. oryzae. The spent medium of A. niger showed the highest silver reduction capacities with up to 15 μmol per milliliter spent medium when ammonium was used as the sole N‐source. Silver ion reduction in the spent medium was not driven by enzymes and did not correlate with biomass concentration. Nearly full reduction capacity was reached after 2 days of incubation, long before the cessation of growth and onset of the stationary phase. The size of silver nanoparticles formed in the spent medium of A. niger was influenced by the nitrogen source, with silver nanoparticles formed in nitrate or ammonium‐containing medium having an average diameter of 32 and 6 nm, respectively.
ALA‐A2 Is a Novel Anticancer Peptide Inspired by Alpha‐Lactalbumin: A Discovery from a Computational Peptide Library, In Silico Anticancer Peptide Screening and In Vitro Experimental Validation

Anticancer peptides (ACPs) are rising as a new strategy for cancer therapy. However, traditional laboratory screening to find and identify novel ACPs from hundreds to thousands of peptides is costly and time consuming. Here, a sequential procedure is applied to identify candidate ACPs from a computer‐generated peptide library inspired by alpha‐lactalbumin, a milk protein with known anticancer properties. A total of 2688 distinct peptides, 5–25 amino acids in length, are generated from alpha‐lactalbumin. In silico ACP screening using the physicochemical and structural filters and three machine learning models lead to the top candidate peptides ALA‐A1 and ALA‐A2. In vitro screening against five human cancer cell lines supports ALA‐A2 as the positive hit. ALA‐A2 selectively kills A549 lung cancer cells in a dose‐dependent manner, with no hemolytic side effects, and acts as a cell penetrating peptide without membranolytic effects. Sequential window acquisition of all theorical fragment ions‐proteomics and functional validation reveal that ALA‐A2 induces autophagy to mediate lung cancer cell death. This approach to identify ALA‐A2 is time and cost‐effective. Further investigations are warranted to elucidate the exact intracellular targets of ALA‐A2. Moreover, these findings support the use of larger computational peptide libraries built upon multiple proteins to further advance ACP research and development.
Estimating Historical Heights

Abstract Historical samples of military, naval, and merchant marine heights suffer from undercounts of short people, undercounts highly irregular compared to the truncated distributions for which standard methods are available. Our knowledge is too imprecise for parametric models of the undercount process but it suffices for intuitive description of the deviations from normality with which estimators should cope. Two new estimators are developed. The first adapts maximum likelihood for truncated normals to height histograms with gradual lower-tail shortfall. The second exploits bends in quantile-quantile plots. Standard error estimates based on Efron's bootstrap appear reliable. The estimators show average heights from British Royal Marine samples much shorter than their American opponents in the Revolutionary War and reveal a statistically significant increase by the 1820's in the British heights.
The Total Least Squares Method in Individual Bioequivalence Evaluation

We propose a simple method for comparison of series of matched observations. While in all our examples we address “individual bioequivalence” (IBE), which is the subject of much discussion in pharmaceutical statistics, the methodology can be applied to a wide class of cross-over experiments, including cross-over imaging. From the statistical point of view the considered models belong to the class of the “error-in-variables” models. In computational statistics the corresponding optimization method is referred to as the “least squares distance” and the “total least squares” method. The derived confidence regions for both intercept and slope provide the basis for formulation of the IBE criteria and methods for its assessing. Simple simulations show that the proposed approach is very intuitive and transparent, and, at the same time, has a solid statistical and computational background.
Content-based image retrieval using the combination of the fast wavelet transformation and the colour histogram

In this study, an attempt has been made to study an image retrieval technique based on the combination of Haar wavelet transformation using lifting scheme and the colour histogram (CH) called lifting wavelet-based colour histogram. The colour feature is described by the CH, which is translation and rotation invariant. The Haar wavelet transformation is used to extract the texture features and the local characteristics of an image, to increase the accuracy of the retrieval system. The lifting scheme reduces the processing time to retrieve images. The experimental results indicate that the proposed technique outperforms the other schemes, in terms of the average precision, the average recall and the total average precision/recall.
Intra- and Inter-Subject Common Spatial Pattern for Reducing Calibration Effort in MI-Based BCI

One major problem limiting the practicality of a brain-computer interface (BCI) is the need for large amount of labeled data to calibrate its classification model. Although the effectiveness of transfer learning (TL) for conquering this problem has been evidenced by many studies, a highly recognized approach has not yet been established. In this paper, we propose a Euclidean alignment (EA)-based intra- and inter-subject common spatial pattern (EA-IISCSP) algorithm for estimating four spatial filters, which aim at exploiting intra- and inter-subject similarities and variability to enhance the robustness of feature signals. Based on the algorithm, a TL-based classification framework was developed for enhancing the performance of motor imagery (MI) BCIs, in which the feature vector extracted by each filter is dimensionally reduced by linear discriminant analysis (LDA) and a support vector machine (SVM) is used for classification. The performance of the proposed algorithm was evaluated on two MI data sets and compared with that of three state-of-the-art TL algorithms. Experimental results showed that the proposed algorithm significantly outperforms these competing algorithms for training trials per class from 15 to 50 and can reduce the amount of training data while maintaining an acceptable accuracy, thus facilitating the practical application of MI-based BCIs.
A factorization theorem for matrices

It is shown that a nonscalar invertible square matrix can be written as a product of two square matrices with prescribed eigenvalues subject only to the obvious determinant condition. As corollaries, we give short proofs of some known results such as Ballantine's characterization of products of four or five positive definite matrices, the commutator theorem of Shoda-Thompson for fields with sufficiently many elements and other results.
A Miniaturized Arc Shaped Near Isotropic Self-Complementary Antenna for Spectrum Sensing Applications

This paper presents the design of an arc-shaped near-isotropic self-complementary antenna for spectrum sensing application. An arc-shaped dipole with horizontal and vertical arms is used to achieve a near isotropic radiation pattern. The radiation pattern improved by adjusting the horizontal and vertical arm lengths. Simulated and experimental results show that the proposed antenna has an impedance bandwidth of 146% (2.4–18.4 GHz) for VSWR ≤ 2 with a good radiation pattern. In order to quantify the antenna performance, antenna gain variation, bandwidth, efficiency, and size have been compared with previously reported designs. It is shown that the proposed arc-shaped antenna can achieve nearly isotropic radiation patterns with a maximum radiation efficiency of 92%. The isotropic performance of the antenna has been characterized by observing the radiation pattern and solid angle. The FR4 substrate is used as a dielectric with relative permittivity 4.4 and loss tangent of 0.02. (εr = 4.4, h = 1.6 mm) The simulated and measured results are in good comparison, and the proposed design is a suitable candidate for spectrum sensing.
Temperature dependence of (111) and (110) ceria surface energy

High temperature properties of ceria surfaces are important for many applications. Here we report the temperature dependences of surface energy for the (111) and (110) CeO 2 obtained in the framework of the extended two-stage up-sampled thermodynamic integration using Langevin dynamics (TU-TILD). The method was used together with machine-learning potentials called moment tensor potentials (MTPs), which were fitted to the results of the ab initio MD calculations for (111) and (110) CeO 2 at different temperatures. The parameters of MTPs training and fitting were tested and the optimal algorithm for the ceria systems was proposed. We found that the temperature increases from 0 K to 2100 K led to the decrease of the Helmholtz free energy of (111) CeO 2 from 0.78 J/m 2 to 0.64 J/m 2 . The energy of (110) CeO 2 dropped from 1.19 J/m 2 at 0 K to 0.92 J/m 2 at 1800 K. We show that it is important to take anharmonicity into account as simple consideration of volume expansion gives wrong temperature dependences of the surface energies.