Miracle-dz/UniFAR-FTUs huggingface dataset:
Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors

The delta opioid receptor is a Gi-protein-coupled receptor (GPCR) with a broad expression pattern both in the central nervous system and the body. The receptor has been investigated as a potential target for a multitude of significant diseases including migraine, alcohol use disorder, ischemia, and neurodegenerative diseases. Despite multiple attempts, delta opioid receptor-selective molecules have not been translated into the clinic. Yet, the therapeutic promise of the delta opioid receptor remains and thus there is a need to identify novel delta opioid receptor ligands to be optimized and selected for clinical trials. Here, we highlight recent developments involving the delta opioid receptor, the closely related mu and kappa opioid receptors, and in the broader area of the GPCR drug discovery research. We focus on the validity and utility of the available delta opioid receptor structures. We also discuss the increased ability to perform ultra-large-scale docking studies on GPCRs, the rise in high-resolution cryo-EM structures, and the increased prevalence of machine learning and artificial intelligence in drug discovery. Overall, we pose that there are multiple opportunities to enable in silico drug discovery at the delta opioid receptor to identify novel delta opioid modulators potentially with unique pharmacological properties, such as biased signaling.
Prevalence and Genotype Distribution of Human Papillomavirus Infection Among 40,613 Women: An Outpatient-Based Population Study in Kunming, Yunnan

Human Papillomavirus (HPV) infection is one of the most common sexually transmitted infections worldwide. The current study aimed to investigate the prevalence and genotype distribution of HPV infection among outpatient-based populations. A total of 40,613 women were recruited from the First People's Hospital of the Yunnan Province. Our study retrospectively analyzed the results of cervical HPV screening among 40,613 women. The results of study showed the prevalence and genotype distribution of HPV infection was different among various outpatient-based populations, and the prevalence of HPV infection was the highest in the gynecological outpatients (26.59%), followed by reproductive gynecological outpatients (18.51%), and the prevalence of physically examined population was the lowest (8.15%). The outpatient-based population was facing a huge threat of HPV infection, especially women from the gynecology clinic. The three most common HPV genotypes were HPV-52 (4.79%), 16 (2.95%) and 58 (2.83%). However, the distribution of HPV genotype varied by populations, especially in physically examined population, the infection rate of HPV-81 ranked third among all infections with various genotypes. Two peaks of prevalence of HPV infection were observed among women under 25 years (31.93%) and over 55 years (28.55%), while the prevalence in women aged 46–55 years (20.18%) was the lowest. Our study on the prevalence and genotype distribution of HPV infection among various outpatient-based populations will provide scientific evidence for vaccination strategies of HPV and prevention and control plans of cervical cancer in Kunming area.
Mitochondrial Respiration in Peripheral Blood Mononuclear Cells Negatively Correlates with Disease Severity in Pulmonary Arterial Hypertension

Mitochondrial and immune cell dysfunction contributes to the development of pulmonary arterial hypertension (PAH). We thus aimed to investigate mitochondrial respiration and mitochondrial gene expression patterns in the peripheral blood mononuclear cells (PBMC) of patients with idiopathic and hereditary PAH and their correlation to disease parameters. Mitochondrial respiration determined using high-resolution respirometry was not significantly different in PBMC when comparing an outpatient cohort of PAH patients with healthy controls. However, when directly comparing mitochondrial respiration to the hemodynamic parameters of an inpatient PAH cohort, mitochondrial respiration negatively correlated with pulmonary vascular resistance (PVR) and positively correlated with the cardiac index (CI). Furthermore, microarray analysis shows upregulation of mitochondrial erythroid-specific 5-aminolevulinate synthase 2 (ALAS2), as well as the regulation of genes involved in iron and heme metabolism, in the PBMC of patients with PAH, with ALAS2 upregulation in PAH patients being confirmed on the protein level. Multiple regression analysis with age and gender as confounders showed that both PVR and hemoglobin content negatively correlated with maximal respiration. Therefore, we conclude that mitochondrial function in the PBMC of PAH patients is affected by disease severity. However, further studies to investigate cell-type-specific alterations and functional consequences are necessary.
Antibiotic Exposure during the Preceding Six Months Is Related to Intestinal ESBL-Producing Enterobacteriaceae Carriage in the Elderly

Intestinal carriage of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE carriage) poses a health risk to the elderly. It was aimed to study the prevalence and the risk factors of intestinal ESBL-PE carriage in the elderly. An observational study of a 921-elderly cohort was examined at health checkup for intestinal ESBL-PE carriage at a tertiary medical center in Shanghai. The prevalence and risk factors of intestinal ESBL-PE carriage, especially antimicrobial use in the preceding 9 months, were studied. The prevalence of intestinal ESBL-PE carriage was 53.3% (491/921) in community-dwelling elderly people. A total of 542 ESBL-producing isolates, including E. coli (n = 484) and K. pneumoniae (n = 58), were obtained. On genotyping, the CTX-M-9 ESBL was the most prevalent for 66.0% (358/542) of all isolates. Multivariate analysis showed that antibiotic exposure, age (61–70 years), and nursing home residence were independent risk factors of the ESBL-PE carriage. The analysis on the monthly use of antimicrobials showed that antibiotic exposure during the 6 months prior to sample collection contributed to the high prevalence of ESBL-PE carriage. A single exposure to an antimicrobial increased the risk of the carriage significantly, and the risk increased with the frequency of antimicrobial exposure (RR, 1.825 to 5.255). Prior use of second or third generation cephalosporins, fluoroquinolones, and macrolides increased the risk of the carriage. The results of this study indicate the importance of using antimicrobials judiciously in clinical settings to reduce antimicrobial resistance. Further studies with multiple center surveillance and with comparison of ESBL-PE carriage in the elderly and in the general population simultaneously are needed.
Last-Mile Strategies for Urban Freight Delivery: A Systematic Review

Trends in retail and e-commerce have led to greater demand for urban freight and last-mile deliveries. This is a concern for urban planners, parcel carriers, and citizens as they struggle to cope with the demands that increased freight flows create in an urban context. This topic has also seen a corresponding expansion in the academic literature as researchers propose solutions to the problem of last-mile delivery. We conduct a systematic review of the literature to identify innovative last-mile delivery strategies as well as ways that those strategies are evaluated by researchers. This study will help academics as they consider directing future research as well as practitioners as they assess how delivery patterns may shift. We identify 22 last-mile delivery strategies and group them into four categories: innovative vehicles, urban goods consolidation, technological and routing advances in city logistics, and emerging planning tools and policies. We find that urban consolidation centers, freight bicycles, and collaborative logistics are the strategies that have received the most attention to date. Analyses of these options has focused on operational, environmental, social, and economic impacts with operational efficiency, emissions, and congestion being the three evaluation criteria discussed most in the literature. We propose that safety has not been adequately considered as a means for evaluating last-mile delivery strategies and should be a higher-priority focus for urban freight research going forward.
Shape Transformations and Self-Assembly of Hairy Particles under Confinement

Molecular dynamics simulations are used to investigate the behavior of polymer-tethered nanoparticles between two inert or attractive walls. The confinement in pores creates new possibilities for controlling the shape transformation of individual hairy particles and their self-organization. We introduce a minimalistic model of the system; only chain-wall interactions are assumed to be attractive, while the others are softly repulsive. We show how the shape of isolated particles can be controlled by changing the wall separation and the strength of the interaction with the surfaces. For attractive walls, we found two types of structures, “bridges” and “mounds”. The first structures are similar to flanged spools in which the chains are connected with both walls and form bridges between them. We observed various bridges, symmetrical and asymmetrical spools, hourglasses, and pillars. The bridge-like structures can be “nano-oscillators” in which the cores jump from one wall to the other. We also study the self-assembly of a dense fluid of hairy particles in slit-like pores and analyze how the system morphology depends on interactions with the surfaces and the wall separation. The hairy particles form layers parallel to the walls. Different ordered structures, resembling two-dimensional crystalline lattices, are reported. We demonstrate that hairy particles are a versatile soft component forming a variety of structures in the slits.
Glycyrrhizic Acid Attenuates Pulmonary Fibrosis of Silicosis by Inhibiting the Interaction between HMGB1 and BRG1 through PI3K/Akt/mTOR Pathway

Purpose: High mobility group protein 1 (HMGB1) is a highly conserved DNA-binding nuclear protein that participates in the occurrence and development of silicosis. HMGB1 binds to its specific receptor and activates phosphatidylinositol 3-kinase (PI3K)/protein kinase B, (PKB; Akt)/mammalian target of rapamycin (mTOR) pathway. Brahma-related genes 1 (BRG1; SMARCA4) is the core subunit of SWI/SNF. HMGB1 activates the Akt pathway through BRG1 to promote the proliferation of prostate cancer. Glycyrrhizic acid is a new pharmacological inhibitor of HMGB1, which may inhibit the occurrence and development of silicosis. We speculate that glycyrrhizic acid inhibits the interaction between HMGB1 and BRG1 through the PI3K/Akt/mTOR pathway to affect the progression of silicosis. Methods: We carried out an in vitro study and stimulated A549 with TGF-β1 to establish an epithelial–mesenchymal transition (EMT) model, knocked down the HMGB1 and BRG1 genes in cells, observed the expression of EMT markers, and detected the interaction between HMGB1 and BRG1 by co-immunoprecipitation. In vivo, we injected glycyrrhizic acid into the mouse silicosis model to inhibit the expression of HMGB1. Results: Both HMGB1 and BRG1 were highly expressed in the process of EMT. After knocking down HMGB1 and BRG1, the process of EMT was inhibited through the PI3K/Akt/mTOR pathway, and their expressions were influenced by each other. HMGB1 and BRG1 interact with each other in A549 cells. HMGB1 and BRG1 are also highly expressed in the mouse silicosis model, and glycyrrhizic acid can inhibit the expression of HMGB1/BRG1 through the PI3K/Akt/mTOR pathway. Conclusion: Glycyrrhizic acid can inhibit the interaction between HMGB1 and BRG1 through the PI3K/Akt/mTOR pathway to affect the progression of silicosis.
Can government investment expansion benefit everyone: a study with state-owned enterprises in the Chinese context

ABSTRACT The main difference between China and other major economies is the presence of a large number of state-owned enterprises. Focusing on the Chinese context, we divide firms into state-owned and private enterprises, and households into working and capitalist class; thereafter, we simulate the effects of government investment expansion on income distribution under different financing instruments. We found that when financed by corporate income tax or value-added tax, government investment expansion makes the working class in both types of enterprises better off, but the capitalist class worse off; however, when financed by labour income tax, government investment expansion yields the opposite result. When the expansion is financed by government debt, the real wealth of the working class in state-owned enterprises and the capitalist class increases, but that of the working class in private enterprises decreases. The difference in income distribution outcomes between the working class and capitalist class is due to the differing composition of their wealth, and the difference in income distribution outcomes among working class is because the enterprises for which they work perform differently in undertaking government investment projects and obtaining loans from the financial market.
ARETE: Accurate Error Assessment via Machine Learning-Guided Dynamic-Timing Analysis

Nanometer circuits are increasingly prone to timing errors, escalating the need for fault injection frameworks to accurately evaluate their impact on applications. In this paper, we propose ARETE, a novel cross-layer, fault-injection framework that combines dynamic-binary instrumentation with machine learning-guided dynamic-timing analysis. ARETE enables accurate fault-injection into any application by estimating the location of the injecting errors via dynamic-timing analysis. To accelerate fault-injection, we develop a novel, data-aware, machine learning-based mechanism that dynamically pre-selects the error-prone instructions and limits the application of the costly dynamic-timing analysis only to them. To evaluate ARETE's accuracy, our fully automated toolflow is configured to support fault-injection based on detailed post-layout gate-level simulations as well as via existing workload-agnostic error models. Our results for various workloads, including an autonomous-driving library, show that the location and time of injected errors performed by ARETE, is 89.9% consistent with fault-injection based on full gate-level simulation. On average, ARETE executes 84.6× faster than gate-level simulation and at a cost of 3.4% loss in the program output quality estimation. When compared to the existing statistical fault-injection tools that are based on workload-agnostic error models, ARETE improves the accuracy of fault-injection rate and output quality estimation by 143.9% and 40.4% on average, respectively.
Parenting Styles of Adolescents’ Parents in Kandy District, Sri Lanka: An Exploratory Analysis

This research examines parenting styles of adolescents’ parents in Kandy District, Sri Lanka to understand the various individual and cultural factors that shape parenting practices in this context. Based on surveys with 120 participants as well as in-depth interviews with 16 of the initial participants, the study highlights four main themes and subthemes that reveal how parents’ childhood experiences, cultural preferences, and role models shape their parenting practices. The results indicate that authoritative and permissive parents tend to have positive childhood experiences, positive relationships with their own parents in their childhood, and positive role models that have influenced their parenting practices. Authoritarian and uninvolved parents, on the other hand, report mostly negative childhood experiences with their own parents and fewer positive role models. Cultural preferences also vary within the four main parenting styles. For example, authoritative parents report more preference to apply what they perceive as both Eastern and Western cultural elements regarding parenting compared with other parenting styles. Authoritarian parents report using corporal punishment more than other study participants who represent the other parenting styles. The study concludes that more parenting styles-focused research regarding these factors is needed globally and in the Sri Lankan context.
If Everybody Knows, then Every Child Knows

Here’s a recipe for one kind of argument from the poverty of the stimulus. To start, present an array of linguistic facts to be explained. Begin with a basic observation about form and/or meaning in some language (or, even better, an observation that crosses linguistic borders). Then show how similar forms and/or meanings crop up in other linguistic phenomena. Next, explain how one could account for the array of facts using domain-general learning mechanisms – such as distributional learning algorithms, ‘cut and paste’ operations or analogy. Follow this by introducing other phenomena that resist explanation on a learning-theoretic account. Make it clear that domain-general learning mechanisms would leave the learner short of the target language or would cause the learner to overshoot, resulting in ‘generalizations’ that are not characteristic of the natural language(s) under consideration. The next step in the recipe is to show how the entire array of linguistic phenomena can be explained using ‘abstract’ principles of Universal Grammar. These principles are not likely to be ‘learned’ because, as just witnessed, the kinds of mechanisms that are offered by learning-theoretic approaches to language development would direct learners away from the target, rather than towards it. This raises the alternative to learning, i.e., innate specification. From that point onward, the proof is in the pudding – the argument should contain an empirical demonstration that children never form the kinds of mistaken generalizations that are anticipated by learning-theoretic accounts of language acquisition. Instead, the argument should be supported by a demonstration that children form the correct generalizations, despite the apparent complexity of the phenomena, and in the absence of supporting evidence in the input. QED. There are several side issues, such as the availability of negative evidence or some substitute for it, but let us ignore such issues, and follow the recipe from the poverty of the stimulus we just sketched. Our specific argument takes, as principles of Universal Grammar, the syntactic property of c-command and the semantic property of downward entailment. We begin with the basic observation in (1).
Customizing and Evaluating Accessible Multisensory Music Experiences with Pre-Verbal Children - A Case Study on the Perception of Musical Haptics Using Participatory Design with Proxies

Research on Accessible Digital Musical Instruments (ADMIs) has highlighted the need for participatory design methods, i.e., to actively include users as co-designers and informants in the design process. However, very little work has explored how pre-verbal children with Profound and Multiple Disabilities (PMLD) can be involved in such processes. In this paper, we apply in-depth qualitative and mixed methodologies in a case study with four students with PMLD. Using Participatory Design with Proxies (PDwP), we assess how these students can be involved in the customization and evaluation of the design of a multisensory music experience intended for a large-scale ADMI. Results from an experiment focused on communication of musical haptics highlighted the diversity in employed interaction strategies used by the children, accessibility limitations of the current multisensory experience design, and the importance of using a multifaceted variety of qualitative and quantitative methods to arrive at more informed conclusions when applying a design with proxies methodology.
Effect of the Crohn’s Disease Exclusion Diet (CDED) on the Fecal Calprotectin Level in Children with Active Crohn’s Disease

(1) Background: The CDED + PEN (partial enteral nutrition) is a promising method of nutritional treatment in active Crohn’s disease (CD). An increase in fecal calprotectin (FCP) level—a marker of mucosal inflammation—happens to be the first evidence of Crohn’s disease exacerbation that appears ahead of clinical symptoms and usually co-exists with them. In this study, we present our own experience with using the CDED + PEN in the treatment of children with CD and an increased FCP level. (2) Methods: In total, 48 children (male/female: 27/21) aged 4–17 years (median value = 13.43; IQR = 4.00) were treated with CDED + PEN between June 2019 and July 2021. The main inclusion criteria for the study was active CD defined as an FCP level ≥ 250.00 µg/g. Patients with severe clinical manifestation of CD (PCDAI >40.00), as well as ones who started any new concomitant CD treatment later than at least 4 weeks before the start of dietary intervention, were excluded from the analysis. The PCDAI and fecal calprotectin level were assessed at weeks 0 and 12. The primary endpoint was ITT normalization of FCP level, i.e., a result < 250.00 µg/g at week 12. The Wilcoxon Matched Pairs Test was used for statistical analysis. (3) Results: The normalization of the FCP level was obtained in 17 children (35.42%) and an FCP level decrease of at least 50% occurred in 26 patients (54.17%). The reduction in fecal calprotectin level between week 0 and week 12 was statistically significant with a median value of 1045.00 µg/g; IQR = 1188.00, and 363.00 µg/g; IQR = 665.00, respectively (p < 0.05). Among 29 patients who were not in clinical remission at baseline, 16 (55.17%) achieved clinical remission (PCDAI < 10.00) at week 12 and 20 (68.97%) obtained a clinical response defined as at least a 12.50 point drop in PCDAI or remission. In this group, the reduction in PCDAI between baseline and week 12 was statistically significant (median value = 20.00 points; IQR = 7.50 and 5.00 points; IQR = 5.00, respectively (p < 0.05)). All patients with a normal FCP level at week 12 were in clinical remission and 16 (94.13%) of them had a normal CRP (C-reactive protein) value. In 10 children (20.83%) the full course of 12 weeks with CDED + PEN was not completed or the concomitant therapy had been started before week 12 due to the lack of efficacy/intolerance of nutritional treatment. (4) Conclusions: The 12-week course of treatment with the CDED + PEN has a beneficial effect on the fecal calprotectin level in children with active CD. The dietary intervention led to a significant decrease in the FCP level in the studied group and to the normalization of this parameter in every third patient.
Quantification of Caffeine Interactions in Choline Chloride Natural Deep Eutectic Solvents: Solubility Measurements and COSMO-RS-DARE Interpretation

Solubility of active pharmaceutical ingredients is an important aspect of drug processing and formulation. Although caffeine was a subject of many studies aiming to quantify saturated solutions, many applied solvents suffer from not being environmentally friendly. This work fills this gap by presenting the results of solubility measurements in choline chloride natural deep eutectic solvents, ccNADES, comprising one of seven of the following polyalcohols: glycerol, sorbitol, xylitol, glucose, sucrose, maltose and fructose. The ratio of ccNADES components was optimized for maximizing caffeine solubility at room temperature. Additionally, temperature dependent solubility was measured for the first four systems exhibiting the highest solubility potential, both in their neat forms and in mixtures with water. Results were used for intermolecular interactions assessments using the COSMO-RS-DARE approach, which led to a perfect match between experimental and computed solubility values. An important methodological discussion was provided for an appropriate definition of the systems. Surprising linear trends were observed between the values of fitting parameters and water-ccNADES composition. In addition, comments on selection of the values of the fusion thermodynamic parameters were provided, which led to the conclusion that COSMO-RS-DARE solubility computations can effectively compensate for the inaccuracies of these important physicochemical properties.