Miracle-dz/UniFAR-FTUs huggingface dataset:
Hexahydroquinoline Derivatives Are Selective Agonists for the Adhesion G Protein-Coupled Receptor ADGRG1/GPR56

GPR56 is a widely expressed adhesion GPCR (AGPCR) that has pleotropic roles in brain development, platelet function, cancer, and more. Nearly all AGPCRs possess extracellular regions that bind protein ligands and conceal a cryptic tethered peptide agonist. AGPCR reception of mechanical or shear force is thought to release the tethered agonist permitting its binding to the AGPCR orthosteric site for consequent activation of G protein signaling. This multistep mechanism of AGPCR activation is difficult to target, emphasizing the need for tool compounds and potential therapeutics that modulate AGPCRs directly. We expanded our cell-based pilot screen for GPR56 small molecule activators to screen >200,000 compounds and identified two promising agonists: 2-(furan-2-yl)-1-[(4-phenylphenyl)carbonyl]pyrrolidine, or compound 4, and propan-2-yl-4-(2-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, or compound 36. Both compounds activated GPR56 receptors enginered to have impaired tethered agonists and/or be cleavage deficient. Compound 4 activated a subset of group VIII AGPCRs while compound 36 had exclusive specificity for GPR56 among the GPCRs tested. Compound 36 SAR analysis identified an analog with the isopropyl R group replaced with a cyclopentyl ring and the electrophilic bromine replaced with a CF3 group. Analog 36.40 had 40% increased potency over compound 36 and was 20-fold more potent than synthetic peptidomimetics designed from the GPR56 tethered agonist. The new GPCR56 tool compounds discovered in this screen may be used to further advance understanding of GPR56 function and aid development of AGPCR-targeted therapeutics. SIGNIFICANCE STATEMENT Adhesion G protein coupled receptors (AGPCRs) are a large, clinically relevant class of GPCRs with no available therapeutics, in part due to their unique mechanism of activation. GPR56 is a widely expressed model AGPCR involved in cancer metastasis, hemostasis, and neuron myelination. In the present study, we identified novel small molecule agonists for GPR56. These molecules are among the most potent identified thus far and may become useful leads in the development of a GPR56-targeted therapeutic.
Different epidemiological characteristics between patients with non-hospital-onset and hospital-onset candidemia: a retrospective cohort study

Abstract Candidemia is a life-threatening infectious disease that has varying incidences. Previous studies revealed the differences in clinical characteristics and outcomes between non-hospital-onset (NHO) and hospital-onset (HO) candidemia. This 4-year retrospective research included adult patients with candidemia in a tertiary medical centre in Taiwan, and cases were categorised as NHO and HO candidemia. Survival analysis and risk factors associated with in-hospital mortality were performed using the Kaplan–Meier method and multivariate Cox proportional-hazards models. The analysis included 339 patients, and the overall incidence was 1.50 per 1,000 admission person-year. Of the cases, 82 (24.18%) were NHO candidemia, and 57.52% (195/339) of patients were diagnosed with at least one malignancy. C. albicans was the most commonly isolated species, accounting for 52.21%. Patients with NHO candidemia had a higher proportion of C. glabrata but a lower ratio of C. tropicalis in comparison to the HO group. The all-cause in-hospital mortality rate was 55.75%. Multivariate Cox proportional-hazards models showed that NHO candidemia was a better outcome predictor (adjusted hazard ratio, 0.44). The administration of antifungal therapy within 2 days was a protective factor. In conclusion, NHO candidemia showed distinct microbiological characteristics and a better outcome than HO candidemia.
Diabetes treatment deintensification in Australians with dementia compared to the general population: A national cohort study.

BACKGROUND Diagnosis of dementia may change peoples' goals of care. In people with diabetes, this may lead to relaxing treatment targets and reducing the use of diabetes medications. The aim of this study was to examine changes in diabetes medication use before and after initiating medication for dementia. METHODS A national cohort of people aged 65-97 years, living with dementia and diabetes, and a general population cohort with diabetes matched for age, sex, and index date were extracted from the Australian national medication claims database. Trajectories of diabetes medication use, expressed as mean defined daily dose (DDD) each month for each individual from 24 months before to 24 months after the index date, were estimated using group-based trajectory modeling (GBTM). Cohorts were analyzed separately. RESULTS People with dementia (N = 1884) and the matched general population (N = 7067) had a median age of 80 years (interquartile range 76-84) and 55% were female. In both models, people exhibited one of five diabetes medication trajectories, with 16.5% of people with dementia and 24.0% of the general population assigned to trajectories that represented deintensification. In the general population model, those on deintensifying trajectories were older than those on stable trajectories (median 83 vs. 79 years). In the dementia cohort model, those on high or low deintensifying trajectories were slightly older (median age 81 or 82, respectively, vs. 80 years) and had at least 1 more comorbidity (median 8 or 7, respectively, vs. 6) than those on stable trajectories. CONCLUSIONS Initiating medication for dementia does not appear to be a trigger for deintensification of diabetes treatment regimens. Deintensification was more common in the general population; people living with dementia are potentially overtreated for diabetes.
Heart Rate Variability for Evaluating Psychological Stress Changes in Healthy Adults: A Scoping Review

The utility of heart rate variability (HRV) for characterizing psychological stress is primarily impacted by methodological considerations such as study populations, experienced versus induced stress, and method of stress assessment. Here, we review studies on the associations between HRV and psychological stress, examining the nature of stress, ways stress was assessed, and HRV metrics used. The review was performed according to the PRISMA guidelines on select databases. Studies that examined the HRV-stress relationship via repeated measurements and validated psychometric instruments were included (n = 15). Participant numbers and ages ranged between 10 and 403 subjects and 18 and 60 years, respectively. Both experimental (n = 9) and real-life stress (n = 6) have been explored. While RMSSD was the most reported HRV metric (n = 10) significantly associated with stress, other metrics, including LF/HF (n = 7) and HF power (n = 6) were also reported. Various linear and nonlinear HRV metrics have been utilized, with nonlinear metrics used less often. The most frequently used psychometric instrument was the State-Trait Anxiety Inventory (n = 10), though various other instruments have been reported. In conclusion, HRV is a valid measure of the psychological stress response. Standard stress induction and assessment protocols combined with validated HRV measures in different domains will improve the validity of findings.
Probabilistic Neural Network Based on Data Field

This paper proposed to decrease the structure of probabilistic neural network based on Gaussian potential of data field.Core idea is following:Introduce data field to estimate probabilistic density of training set of each class and select their maximum to construct the network;iteratively train the initial network by appending the maximum density sample unrecognized of each class to pattern layer and modify the weight of samples until satisfying desired accuracy.Incremental computing density ensures faster iteration and higher possible convergence.And introduce resampling technique to boost the generalization accuracy.Experiments show that the proposed algorithms have concise explanation,moderate fitness and effective calculation.
Modified Centroid Selection Method of K-Means Clustering

Clustering is a process of classifying object into groups which have similarity. The result of clustering will show that objects in one cluster will be more homogeneous than others. There are two methods in classic clustering analysis i.e. hierarchical cluster method and non-hierarchical cluster method. Determination of the member of clusters which formed by them is done subjectively. K-means is one of the algorithms that solve the well known clustering problem. The algorithm classifies object to a predefined number of clusters, which is given by the user. The idea is to choose random cluster centers, one for each other. The centroid initialization plays an important role in determining the cluster assignment in effective ways. This paper presents results of the simulated data of different datasets using original k-means and other modified algorithms implemented using MATLAB R2010a. This results are calculated on some performance measures such as no. iterations, and accuracy.
Oximetry at admission as a predictor of tomographic and functional impairment after 3–6 months in hospitalized patients with COVID-19

Objective To investigate characteristics that may be associated with radiologic and functional findings following discharge in patients with severe coronavirus disease 2019 (COVID-19). Methods This single-center, prospective, observational cohort study comprised patients aged >18 years who were hospitalized with COVID-19 pneumonia, between May and October 2020. After 3 to 6 months of discharge, patients were clinically evaluated and underwent spirometry, a 6-minute walk test (6MWT), and chest computed tomography (CT). Statistical analysis was performed using association and correlation tests. Results A total of 134 patients were included (25/114 [22%] were admitted with severe hypoxemia). On the follow-up chest CT, 29/92 (32%) had no abnormalities, regardless of the severity of the initial involvement, and the mean 6MWT distance was 447 m. Patients with desaturation on admission had an increased risk of remaining CT abnormalities: patients with SpO2 between 88 and 92% had a 4.0-fold risk, and those with SpO2 < 88% had a 6.2-fold risk. The group with SpO2 < 88% also walked shorter distances than patients with SpO2 between 88 and 92%. Conclusion Initial hypoxemia was found to be a good predictor of persistent radiological abnormalities in follow-up and was associated with low performance in 6MWT.
Effect of compression ratio in a slow-acting compression hearing aid: paired-comparison judgments of quality.

Paired-comparison judgments of quality were obtained from 20 hearing-impaired listeners (half with a small dynamic range and half with a large dynamic range) for speech-in-noise (vent, apartment, and cafeteria) processed through a slow-acting compression hearing aid. Compression ratio was varied (1, 1.5, 2, 3, 5, and 10:1). Compression threshold, attack time, and release time were fixed. Sound quality judgments were significantly affected by compression ratio, noise, and dynamic range. Preference decreased with increasing compression ratio. The selection of compression ratio. The selection of compression ratios < or = 2:1 was significantly higher than of compression ratios > 3:1. Less compression (no compression or 1.5:1) was preferred with the highest level noise (cafeteria noise) than with the lower level noises (vent or apartment). In particular, the small dynamic range group preferred compression with the vent and apartment noises (noise below the compression threshold), but preferred a linear hearing aid with the cafeteria noise (above the compression threshold). The large dynamic range group showed a slightly greater preference for the linear hearing aid for all three noises.
Research on the spatial point pattern of geo-hazard——A case of Ningqiang county

By using the two point pattern analysis method of ecology(Nearest Neighbor Analysis and Ripley K function method),we calculated the pattern of spatial distribution of geo-hazards.The results showed that:1) The output result of Nearest Neighbor Analysis was that Z score value-12.44(P0.05). It indicated that the points of geo-hazards in Ningqiang county showed aggregated distribution characteristics.2) The method of Ripley K function overcame the shortcomings that the traditional methods which can only analyze single scale spatial distribution pattern,so the new method can try the best to use the information of space points,and describe different scales of spatial pattern information.The calculation results showed that the spatial distribution of geo hazards points were aggregated at 0-20km spatial scale.3) By calculating with the two method,it was found that the geo-hazards points showed aggregated distribution characteristics.They usually performed a lot of landslide group in small regions.Because of the aggregation effect of geo-hazards,there were most susceptibility section. ,which led to different risk zoning.
Inferences for Varying-Coefficient Partially Linear Models with Serially Correlated Errors

Varying-coefficient partially linear (VCPL) model provides a useful tool for statistical modeling. In this paper we focus on inference for the VCPL model when the errors are serially correlated and modeled as an AR process. A penalized spline least squares (PSLS) estimation is proposed based on the penalized spline technique. This approach is then improved by a weighted PSLS estimation. We investigate the asymptotics under the assumption that the number of knots is fixed, though potentially large. The weighted PSLS estimators of all parameters are shown to be √ n-consistent, asymptotically normal and asymptotically more efficient than the un-weighted ones. The proposed method can be used to make simultaneous inference for the parametric and nonparametric components by virtue of the sandwich formula for the joint covariance matrix. Simulations are conducted to demonstrate the finite sample performance of the proposed estimations. A real data analysis is used to illustrate the application of the proposed method. Abbreviated Tittle: Inference for Partially Linear Models
Factors influencing functioning after volar locking plate fixation of distal radius fractures: a scoping review of 148 studies

Background and purpose A better understanding of factors that influence functioning may improve the identification of patients with distal radius fractures (DRFs) who need hand therapy. The purpose of this scoping review was to provide a comprehensive overview of factors that have been evaluated for their influence on hand functioning following volar plate fixation of DRFs. Material and methods 6 databases were searched from 2005 to 2021 for publications regarding surgical treatment for a DRF with a volar locking plate. Included studies evaluated demographic, perioperative, and postoperative factors within the 6 weeks post-surgery for their influence on functioning at least 3 months post-surgery. Functioning was assessed with patient-reported outcome measures. The factors were categorized into themes and mapped to the International Classification of Functioning, Disability and Health (ICF). Results 148 studies were included. 708 factors were categorized into 39 themes (e.g. pain) and mapped to the ICF components. The themes were primarily mapped to “body functions and structures” (n = 26) and rarely to “activities and participation” (n = 5). Fracture type (n = 40), age (n = 38), and sex (n = 22) were the most frequently evaluated factors. Conclusion This scoping review identified an extensive number of factors evaluated within 6 weeks after surgery for their influence on functioning at least 3 months after volar plate fixa tion of a DRF and the existing research has primarily evaluated factors related to “body functions and structures,” with limited focus on factors related to “activities and participation. ”
Band gap of InAs 1 − x Sb x with native lattice constant

The band gap energy of the alloy InAsSb has been studied as a function of composition with special emphasis on minimization of strain-induced artifacts. The films were grown by molecular beam epitaxy on GaSb substrates with compositionally graded buffer layers that were designed to produce strain-free films. The compositions were precisely determined by high-resolution x-ray diffraction. Evidence for weak, long-range, group-V ordering was detected in materials exhibiting residual strain and relaxation. In contrast, unstrained films having the nondistorted cubic form showed no evidence of group-V ordering. The photoluminescence (PL) peak positions therefore corresponds to the inherent band gap of unstrained, unrelaxed, InAsSb. PL peaks were recorded for compositions up to 46$%$ Sb, reaching a peak wavelength of 10.3 \ensuremath{\mu}m, observed under low excitation at $T=13$ K. The alloy band gap energies determined from PL maxima are described with a bowing parameter of 0.87 eV, which is significantly larger than measured for InAsSb in earlier work. The sufficiently large bowing parameter and the ability to grow the alloys without ordering allows direct band gap InAsSb to be a candidate material for low-temperature long-wavelength infrared detector applications.
TD‐DFT study of BIPS spiropyran: Effects of functionals and high‐polarity solvent on CspiroO bond dissociation and recovery

We performed a theoretical analysis of the BIPS photochemical cycle using an extensive set of forty hybrid functionals and taking into account a highly polar solvent (methanol). The functionals with a small fraction of the exact Hartree‐Fock exchange (%HF) showed the predominant S0 → S2 transition with the strengthening of the CspiroO bond. At the same time, functionals with medium and high %HF (including those with long‐range correction) gave a dominant S0 → S1 transition with weakening or breaking of the CspiroO bond, which corresponds to the experimental results. The influence of a highly polar solvent on the photochemical electrocyclic transformations of BIPS turned out to be significant. The number of functionals causing dissociation of the CspiroO bond decreased from 10 to 7 compared to the gas phase. The magnitude of the oscillator strength has increased by approximately one and a half times. Structural distortions of the BIPS molecule during excitation (both with and without CspiroO bond cleavage) significantly decreased in methanol compared to the gas phase. The two strong hydrogen bonds of methanol molecules with the oxygen and nitrogen atoms of spiropyran also have a significant effect on its excitation. They lead to a change in the predominant transition from S0 → S2 to S0 → S1 for five functionals. The number of functionals giving dissociation of the CspiroO bond decreased from seven to four (M08HX, M052X, CAM‐B3LYP, and M11). After the opening of the excited BIPS molecule, both of its strong H‐bonds with methanol are preserved. Of this set of four functionals, only M052X and CAM‐B3LYP exhibited the dominant HOMO‐1 → LUMO configuration observed in high‐level computations by other authors. Therefore, both of these functionals are recommended for modeling the photochemical cycle of this spiropyran. The photochemical cycle of BIPS was theoretically analyzed. The redistribution of the electron density in this cycle was quantitatively described using the differences in NPA of the atomic charges. The most important result of this analysis was the electrostatic mechanism of the approach of Cspiro and oxygen atoms at the fourth stage, which causes further reduction of the CspiroO bond.
Elementary Theory Of Electric And Magnetic Fields

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A randomized clinical trial of on-demand oral pre-exposure prophylaxis does not modulate lymphoid/myeloid HIV target cell density in the foreskin

Objectives: As topical pre-exposure prophylaxis (PrEP) has been shown to cause immune modulation in rectal or cervical tissue, our aim was to examine the impact of oral PrEP on lymphoid and myeloid changes in the foreskin in response to dosing and timing of drug administration. Design: HIV-negative male individuals (n = 144) were recruited in South Africa and Uganda into an open-label randomized controlled trial in a 1 : 1 : 1 : 1 : 1 : 1 : 1 : 1 : 1 ratio to control arm (with no PrEP) or one of eight arms receiving emtricitabine–tenofovir disoproxil fumarate (F/TDF) or emtricitabine–tenofovir alafenamide (F/TAF) at one of two different doses, 5 or 21 h before undergoing voluntary medical male circumcision (VMMC). Methods: After dorsal-slit circumcision, foreskin tissue sections were embedded into Optimal Cutting Temperature media and analysed, blinded to trial allocation, to determine numbers of CD4+CCR5+, CD1a+ cells and claudin-1 expression. Cell densities were correlated with tissue-bound drug metabolites and p24 production after ex-vivo foreskin challenge with HIV-1bal. Results: There was no significant difference in CD4+CCR5+ or CD1a+ cell numbers in foreskins between treatment arms compared with the control arm. Claudin-1 expression was 34% higher (P = 0.003) in foreskin tissue from participants receiving PrEP relative to controls, but was no longer statistically significant after controlling for multiple comparisons. There was neither correlation of CD4+CCR5+, CD1a+ cell numbers, or claudin-1 expression with tissue-bound drug metabolites, nor with p24 production after ex-vivo viral challenge. Conclusion: Oral doses and timing of on-demand PrEP and in-situ drug metabolite levels in tissue have no effect on numbers or anatomical location of lymphoid or myeloid HIV target cells in foreskin tissue.
Curcumin Enhances the Anticancer Effects of Binimetinib on Melanoma Cells by Inducing Mitochondrial Dysfunction and Cell Apoptosis with Necroptosis

Background Recent studies suggest that MEK1/2 inhibitors, including binimetinib, significantly improve malignant melanoma (MM) patient survival. Growing evidence suggests that phytochemicals, especially curcumin, can overcome drug resistance in cancer cells through a variety of mechanisms. Objective This study aims to examine curcumin’s efficacy in vitro combined with binimetinib in human MM cells. Methods We used 2D monolayer and 3D spheroid human epidermal melanocyte culture models, HEMn-MP (human epidermal melanocytes, neonatal, moderately pigmented), and two human MM cell lines, G361 and SK-MEL-2, to evaluate cell viability, proliferation, migration, death, and reactive oxygen species (ROS) production following single therapy treatment, with either curcumin or binimetinib, or a combination of both. Results Compared to MM cells treated with single therapy, those with combination therapy showed significantly decreased cell viability and increased ROS production. We observed apoptosis following both single and combination therapies. However only those who had had combination therapy had necroptosis. Conclusion Collectively, our data demonstrates that curcumin exerts significant synergistic anticancer effects on MM cells by inducing ROS and necroptosis when combined with binimetinib. Therefore, a strategy of adding curcumin to conventional anticancer agents holds promise for treating MM.