Miracle-dz/UniFAR-FTUs huggingface dataset:
Pushing the boundaries of molecular representation for drug discovery with graph attention mechanism.

Hunting for chemicals with favourable pharmacological, toxicological and pharmacokinetic properties remains a formidable challenge for drug discovery. Deep learning provides us with powerful tools to build predictive models that are appropriate for the rising amounts of data, but the gap between what these neural networks learn and what human beings can comprehend is growing. Moreover, this gap may induce distrust and restrict deep learning applications in practice. Here, we introduce a new graph neural network architecture called Attentive FP for molecular representation that uses a graph attention mechanism to learn from relevant drug discovery datasets. We demonstrate that Attentive FP achieves state-of-the-art predictive performances on a variety of datasets and that what it learns is interpretable. The feature visualization for Attentive FP suggests that it automatically learns non-local intramolecular interactions from specified tasks, which can help us gain chemical insights directly from data beyond human perception.
Activation of Trace Amine-Associated Receptor 1 Stimulates an Antiapoptotic Signal Cascade via Extracellular Signal-Regulated Kinase 1/2

Methamphetamine (MA) is highly addictive and neurotoxic, causing cell death in humans and in rodent models. MA, along with many of its analogs, is an agonist at the G protein–coupled trace amine-associated receptor 1 (TAAR1). TAAR1 activation protects against MA-induced degeneration of dopaminergic neurons, suggesting that TAAR1 plays a role in regulating MA-induced neurotoxicity. However, the mechanisms involved in TAAR1’s role in neurotoxicity and cell death have not been described in detail. In this study, we investigated the apoptosis pathway in Taar1 wild-type (WT) and knockout (KO) mice and in cells expressing the recombinant receptor. Bcl-2, an antiapoptotic protein, was upregulated ∼3-fold in the midbrain area (substantial nigra and ventral tegmental area) in Taar1 KO compared with WT mice, and MA significantly increased Bcl-2 expression in WT mice but decreased Bcl-2 expression in KO mice. The proapoptotic protein Bax did not differ across genotype or in response to MA. Bcl-2 expression was significantly upregulated by the TAAR1 agonist RO5166017 ((S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine) in cells expressing the recombinant mouse TAAR1. Additionally, activation of TAAR1 by RO5166017 increased phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, and protein kinase B (AKT), but only inhibition of ERK1/2 phosphorylation prevented TAAR1-induced increases in Bcl-2 levels, indicating that TAAR1 activation increases Bcl-2 through an ERK1/2-dependent pathway. All changes to ERK1/2 pathway intermediates were blocked by the TAAR1 antagonist, N-(3-ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl) benzamide. These findings suggest that TAAR1 activation protects against MA-induced cell apoptosis and TAAR1 may play a role in cell death in neurodegenerative diseases. SIGNIFICANCE STATEMENT Methamphetamine stimulates TAAR1, a G protein–coupled receptor. The role and mechanisms for TAAR1 in methamphetamine-induced neurotoxicity are not known. Here, we report that, in genetic mouse models and cells expressing the recombinant receptor, TAAR1 activates the ERK1/2 pathway but not the AKT pathway to upregulate the antiapoptotic protein Bcl-2, which protects cells from drug-induced toxicity.
Structural and Electrical Studies for Birnessite-Type Materials Synthesized by Solid-State Reactions

The focus of this paper is centered on the thermal reduction of KMnO4 at controlled temperatures of 400 and 800 °C. The materials under study were characterized by atomic absorption spectroscopy, thermogravimetric analysis, average oxidation state of manganese, nitrogen adsorption–desorption, and impedance spectroscopy. The structural formulas, found as a result of these analyses, were K0.29+(Mn0.844+Mn0.163+)O2.07·0.61H2O and K0.48+(Mn0.644+Mn0.363+)O2.06·0.50H2O. The N2 adsorption–desorption isotherms show the microporous and mesoporous nature of the structure. Structural analysis showed that synthesis temperature affects the crystal size and symmetry, varying their electrical properties. Impedance spectroscopy (IS) was used to measure the electrical properties of these materials. The measurements attained, as a result of IS, show that these materials have both electronic and ionic conductivity. The conductivity values obtained at 10 Hz were 4.1250 × 10−6 and 1.6870 × 10−4 Ω−1cm−1 for Mn4 at 298 and 423 K respectively. For Mn8, the conductivity values at this frequency were 3.7074 × 10−7 (298) and 3.9866 × 10−5 Ω−1cm−1 (423 K). The electrical behavior was associated with electron hopping at high frequencies, and protonic conduction and ionic movement of the K+ species, in the interlayer region at low frequencies.
Risk of Thyroid Disorders in Patients with Gout and Hyperuricemia

Abstract The risk of thyroid autoimmunity and thyroid dysfunction among patients with gout and hyperuricemia has not been well defined. This study was undertaken to examine the impact of gout and hyperuricemia on risk of thyroid disorders including thyroid autoimmunity and thyroid dysfunction. A population-based cross-sectional study was conducted to assess the risk of thyroid autoimmunity and thyroid dysfunction related to gout and hyperuricemia, which included 115 gout patients, 439 hyperuricemic patients, and 2 254 individuals without gout and hyperuricemia. A systematic review and meta-analysis of 14 observational studies was also done to systematically evaluate the risk of thyroid dysfunction among patients with gout and hyperuricemia. Findings from the cross-sectional study suggested a significantly increased risk of hypothyroidism among female gout patients (OR=2.44, 95% CI 1.15–5.17, p=0.02). Besides, gout could also substantially increase risk of Hashimoto’s thyroiditis in women (OR=3.15, 95% CI 1.53–6.49, p=0.002). The meta-analysis proved a considerably increased risk of hypothyroidism among both gout patients (OR=1.51, 95% CI 1.23–1.85, p<0.001) and hyperuricemic patients (OR=1.34, 95% CI 1.11–1.61, p=0.002). Moreover, this meta-analysis also suggested that gout could also significantly increase the risk of hyperthyroidism (OR=1.25, 95% CI 1.06–1.48, p=0.01). The findings from the study suggest increasing risk of hypothyroidism and Hashimoto’s thyroiditis among gout patients. Moreover, gout but not hyperuricemia is linked to increased risk of hyperthyroidism. More studies are warranted to elucidate the influence of gout and hyperuricemia on thyroid disorders.
Enhanced adaptive immune responses in lung adenocarcinoma through natural killer cell stimulation

Significance T cell-targeted therapies are effective against lung cancer only in a fraction of patients, highlighting a need for complimentary approaches. In genetically engineered lung cancer in mice, stimulation of natural killer cells in established disease led to enhanced adaptive immune responses, presenting a strategy for improving the efficacy of cancer immunotherapy. Natural killer (NK) cells inhibit tumor development in mouse models and their presence in tumors correlates with patient survival. However, tumor-associated NK cells become dysfunctional; thus, stimulation of NK cells in cancer is emerging as an attractive immunotherapeutic strategy. In a mouse model of lung adenocarcinoma, NK cells localized to tumor stroma with immature phenotypes and low functional capacity. To test their responsiveness within established disease, we engineered a system for inducible expression of activating ligands in tumors. After stimulation, NK cells localized inside tumors, with increased cytokine production capacity. Strikingly, T cells were also recruited to tumors in an NK cell-dependent manner, and exhibited higher functionality. In neoantigen-expressing tumors, NK cell stimulation enhanced the number and function of tumor-specific T cells and, in long-term settings, reduced tumor growth. Thus, even in established disease NK cells can be activated to contribute to antitumor immunity, supporting their potential as an important target in cancer immunotherapy.
Impact of Astrocyte Depletion upon Inflammation and Demyelination in a Murine Animal Model of Multiple Sclerosis

Astrocytes play a key role in demyelinating diseases, like multiple sclerosis (MS), although many of their functions remain unknown. The aim of this study was to investigate the impact of astrocyte depletion upon de- and remyelination, inflammation, axonal damage, and virus distribution in Theiler’s murine encephalomyelitis (TME). Groups of two to six glial fibrillary acidic protein (GFAP)-thymidine-kinase transgenic SJL mice and SJL wildtype mice were infected with TME virus (TMEV) or mock (vehicle only). Astrocyte depletion was induced by the intraperitoneal administration of ganciclovir during the early and late phase of TME. The animals were clinically investigated while using a scoring system and a rotarod performance test. Necropsies were performed at 46 and 77 days post infection. Cervical and thoracic spinal cord segments were investigated using hematoxylin and eosin (H&E), luxol fast blue-cresyl violet (LFB), immunohistochemistry targeting Amigo2, aquaporin 4, CD3, CD34, GFAP, ionized calcium-binding adapter molecule 1 (Iba1), myelin basic protein (MBP), non-phosphorylated neurofilaments (np-NF), periaxin, S100A10, TMEV, and immunoelectron microscopy. The astrocyte depleted mice showed a deterioration of clinical signs, a downregulation and disorganization of aquaporin 4 in perivascular astrocytes accompanied by vascular leakage. Furthermore, astrocyte depleted mice showed reduced inflammation and lower numbers of TMEV positive cells in the spinal cord. The present study indicates that astrocyte depletion in virus triggered CNS diseases contributes to a deterioration of clinical signs that are mediated by a dysfunction of perivascular astrocytes.
Midwives' use of best available evidence in practice: An integrative review

Abstract Aims and objectives To synthesise international research that relates to midwives' use of best available evidence in practice settings and identify key issues relating to the translation of latest evidence into everyday maternity care. Background Midwifery is a research‐informed profession. However, a gap persists in the translation of best available evidence into practice settings, compromising gold standard maternity care and delaying the translation of new knowledge into everyday practice. Design A five‐step integrative review approach, based on a series of articles published by the Joanna Briggs Institute (JBI) for conducting systematic reviews, was used to facilitate development of a search strategy, selection criteria and quality appraisal process, and the extraction and synthesis of data to inform an integrative review. Methods The databases CINAHL, MEDLINE, Web of Science, Implementation Science Journal and Scopus were searched for relevant articles. The screening and quality appraisal process complied with the PRISMA 2009 checklist. Narrative analysis was used to develop sub‐categories and dimensions from the data, which were then synthesised to form two major categories that together answer the review question. Results The six articles reviewed report on midwives' use of best available evidence in Australia, the UK and Asia. Two major categories emerged that confirm that although midwifery values evidence‐based practice (EBP), evidence‐informed maternity care is not always employed in clinical settings. Additionally, closure of the evidence‐to‐practice gap in maternity care requires a multidimensional approach. Conclusion Collaborative partnerships between midwives and researchers are necessary to initiate strategies that support midwives' efforts to facilitate the timely movement of best available evidence into practice. Relevance to clinical practice Understanding midwives' use of best available evidence in practice will direct future efforts towards the development of mechanisms that facilitate the timely uptake of latest evidence by all maternity care providers working in clinical settings.
Talking about Decisions: The Facilitating Effect of a Celebrity Health Announcement on the Communication of Online Personal Experiences around Decision-making

ABSTRACT This study examines how posters on an online forum discussed their own current and past decision-making in response to a celebrity health announcement. We examined messages in response to a celebrity narrative, and extracted those explicitly related to decision-making around genetic testing and preventative surgery. Using deductive coding we identified different types of decision-making narratives, and with inductive coding we examined how users discussed decision-making activities. Guided by the literature on narrative content types in decision-making, and on celebrity health narratives, we found that the celebrity decision announcement facilitated social sharing in relation to two key decision-making activities. First, identifying with the celebrity allowed people to reflect and compare their own personal health circumstances. This empowered readers to appraise and select options about their current decision-making regarding preventative surgery. Second, the announcement allowed an extension of the discussion beyond the celebrity, and acted as a catalyst encouraging other people to share their own previous decision-making experiences. These experiences contained a mix of narratives content types, and provided an opportunity for posters to evaluate their decisions, and to contribute to a repository of decision-making examples for others. Health narratives act as communication devices in decision-making, and we discuss the findings in relation to the extension of the educational and persuasive function of celebrity health narratives.
An evaluation of the use and handling errors of currently available recombinant human follicle-stimulating hormone pen injectors by women with infertility and fertility nurses

ABSTRACT Background: This study compared preference ratings of women with infertility and nurses before and after simulated injection, and handling errors, with the GONAL-f®, Bemfola®, Ovaleap® and Rekovelle® pen injectors. Research design and methods: Injector-naïve women and injector-experienced fertility nurses tested injectors with masked labels in a randomized testing order. Injections were made into a foam pad and injectors were rated before and after use. Handling errors were recorded during the study. Ratings and errors were compared between pen injectors using ordinal or Poisson linear mixed models adjusted for testing order. Results: 120 women and 60 nurses participated. All participants tested GONAL-f and Bemfola injectors. Because of their similarity, participants tested either Rekovelle (71 women; 30 nurses) or Ovaleap (49 women; 30 nurses) injectors. The ratings from women were higher for GONAL-f vs other injectors after simulated use (p < 0.001 for all comparisons). Fertility nurses rated GONAL-f injector higher than other injectors both before and after use (p < 0.01 for all comparisons). Adjusted rates of total handling errors were lower with the GONAL-f vs other injectors (p < 0.001 for all comparisons) for both groups. Conclusions: GONAL-f injector was rated significantly higher than other injectors, which may be related to less handling errors observed with the GONAL-f injector.
Carotid artery stenting is safe and effective for symptomatic patients with acute coronary syndrome

Patients with symptomatic carotid stenosis recently treated with percutaneous transluminal coronary angioplasty (PTCA) for acute coronary syndrome (ACS) are always classified as at high risk for surgery, given that they are required uninterrupted dual antiplatelet therapy. In this regard, carotid artery stenting (CAS) may represent a valid alternative.
Computing Relative Binding Affinity of Ligands to Receptor: An Effective Hybrid Single-Dual-Topology Free-Energy Perturbation Approach in NAMD

An effective hybrid single-dual topology protocol is designed for the calculation of relative binding affinities of small ligands to a receptor. The protocol was developed as an expansion of the NAMD molecular dynamics program, which exclusively supports a dual-topology framework for relative alchemical free-energy perturbation (FEP) calculations. In this protocol, the alchemical end states are represented as two separate molecules sharing a common substructure identified through maximum structural mapping. Within the substructure, an atom-to-atom correspondence is established, and each pair of corresponding atoms are holonomically constrained to share identical coordinates at all time throughout the simulation. The forces are projected and combined at each step for propagation. Following this formulation, a set of illustrative calculations of reliable experiment/simulation data, including relative solvation free energies of small molecules and relative binding affinities of drug compounds to proteins are presented. To enhance sampling of the dual-topology region, the FEP calculations were carried out within a replica-exchange MD scheme supported by the multiple-copy algorithm module of NAMD, with periodic attempted swapping of the thermodynamic coupling parameter λ between neighboring states. The results are consistent with experiments and benchmarks reported in the literature, lending support to the validity of the current protocol. In summary, this novel hybrid single-dual topology approach combines the conceptual simplicity of the dual topology paradigm with the advantageous sampling efficiency of the single topology approach, making it an ideal strategy for high throughput in silico drug design.
ROBOKOP: an abstraction layer and user interface for knowledge graphs to support question answering

Abstract Summary Knowledge graphs (KGs) are quickly becoming a common-place tool for storing relationships between entities from which higher-level reasoning can be conducted. KGs are typically stored in a graph-database format, and graph-database queries can be used to answer questions of interest that have been posed by users such as biomedical researchers. For simple queries, the inclusion of direct connections in the KG and the storage and analysis of query results are straightforward; however, for complex queries, these capabilities become exponentially more challenging with each increase in complexity of the query. For instance, one relatively complex query can yield a KG with hundreds of thousands of query results. Thus, the ability to efficiently query, store, rank and explore sub-graphs of a complex KG represents a major challenge to any effort designed to exploit the use of KGs for applications in biomedical research and other domains. We present Reasoning Over Biomedical Objects linked in Knowledge Oriented Pathways as an abstraction layer and user interface to more easily query KGs and store, rank and explore query results. Availability and implementation An instance of the ROBOKOP UI for exploration of the ROBOKOP Knowledge Graph can be found at http://robokop.renci. org. The ROBOKOP Knowledge Graph can be accessed at http://robokopkg.renci. org. Code and instructions for building and deploying ROBOKOP are available under the MIT open software license from https://github.com/NCATS-Gamma/robokop. Supplementary information Supplementary data are available at Bioinformatics online.
Satellite images and machine learning can identify remote communities to facilitate access to health services

OBJECTIVE Community health systems operating in remote areas require accurate information about where people live to efficiently provide services across large regions. We sought to determine whether a machine learning analyses of satellite imagery can be used to map remote communities to facilitate service delivery and planning. MATERIALS AND METHODS We developed a method for mapping communities using a deep learning approach that excels at detecting objects within images. We trained an algorithm to detect individual buildings, then examined building clusters to identify groupings suggestive of communities. The approach was validated in southeastern Liberia, by comparing algorithmically generated results with community location data collected manually by enumerators and community health workers. RESULTS The deep learning approach achieved 86.47% positive predictive value and 79.49% sensitivity with respect to individual building detection. The approach identified 75.67% (n = 451) of communities registered through the community enumeration process, and identified an additional 167 potential communities not previously registered. Several instances of false positives and false negatives were identified. DISCUSSION Analysis of satellite images is a promising solution for mapping remote communities rapidly, and with relatively low costs. Further research is needed to determine whether the communities identified algorithmically, but not registered in the manual enumeration process, are currently inhabited. CONCLUSIONS To our knowledge, this study represents the first effort to apply image recognition algorithms to rural healthcare delivery. Results suggest that these methods have the potential to enhance community health worker scale-up efforts in underserved remote communities.
Progenitor/Stem Cell Delivery by Suprarenal Aorta Route in Acute Kidney Injury

Progenitor/stem cell-based kidney regenerative strategies are a key step towards the development of novel therapeutic regimens for kidney disease treatment. However, the route of cell delivery, e.g., intravenous, intra-arterial, or intra-parenchymal, may affect the efficiency for kidney repair in different models of acute and chronic injury. Here, we describe a protocol of intra-aorta progenitor/stem cell injection in rats following either acute ischemia-reperfusion injury or acute proteinuria induced by puromycin aminonucleoside (PAN) – the experimental prototype of human minimal change disease and early stages of focal and segmental glomerulosclerosis. Vascular clips were applied across both renal pedicles for 35 min, or a single dose of PAN was injected via intra-peritoneal route, respectively. Subsequently, 2 x 106 stem cells [green fluorescent protein (GFP)-labeled c-Kit+ progenitor/stem cells or GFP-mesenchymal stem cells] or saline were injected into the suprarenal aorta, above the renal arteries, after application of a vascular clip to the abdominal aorta below the renal arteries. This approach contributed to engraftment rates of ∼10% at day 8 post ischemia-reperfusion injury, when c-Kit+ progenitor/stem cells were injected, which accelerated kidney recovery. Similar rates of engraftment were found after PAN-induced podocyte damage at day 21. With practice and gentle surgical technique, 100% of the rats could be injected successfully, and, in the week following injection, ∼ 85% of the injected rats will recover completely. Given the similarities in mammals, much of the data obtained from intra-arterial delivery of progenitor/stem cells in rodents can be tested in translational research and clinical trials with endovascular catheters in humans.