Miracle-dz/UniFAR-FTUs huggingface dataset:
Fuzzy Comprehensive Evaluation Assistant 3D-QSAR of Environmentally Friendly FQs to Reduce ADRs

Most studies on adverse drug reactions (ADRs) of fluoroquinolones (FQs) have focused on the mechanisms of single ADRs, and no quantitative structure–activity relationship (QSAR) method studies have been carried out that combine several ADRs of FQs. In this study, an improved three-dimensional (3D) QSAR method was established using fuzzy comprehensive evaluation. This method could simultaneously consider three common ADRs of FQs using molecular parameters. The improved method could comprehensively predict three ADRs of FQs and provide direction for the development of new drugs with lower ADRs than the originals. According to the improved method, 48 derivatives with lower ADRs (decreased by 4.86% to 50.92%) were designed from pazufloxacin. Three derivatives with a higher genotoxicity, higher photodegradation, and lower bioconcentration than pazufloxacin were selected using the constructed QSAR methods of the FQs. Finally, three traditional 3D-QSAR methods of single ADR were constructed to validate the improved method. The improved method was reasonable, with a relative error range of 0.96% to 4.30%. This study provides valuable reference data and will be useful for the development of strategies to produce new drugs with few ADRs. In the absence of complementary biological studies of these adverse drug reactions, the results reported here may be quite divergent from those found in humans or experimental animals in vivo. One major reason for this is that many adverse drug reactions are dependent upon enzyme-catalyzed metabolic activation (toxication) or on non-enzymatic conversion to toxic products and are not due to the parent drug moiety.
Evolution of ICS Attacks and the Prospects for Future Disruptive Events

Headlines are full of proclamations covering the latest in industrial control system (ICS) attacks and threats to critical infrastructure. But behind each prominent event lies a trendline from the 2015 Ukraine power outage through the 2017 attack on safety systems at an oil and gas facility in Saudi Arabia. When moving beyond media reporting, two clear patterns emerge in how ICS attacks have evolved: first, initial attack vectors increasingly avoid using malware and techniques that are tell-tale signs of advanced adversary activity; second, only at the final, ICS-disruptive stages of intrusions is complex malware introduced to codify ICS-specific knowledge to enable nearly any computer network operations operator to execute complex commands. Exploration and examination of these trends reveals a definite direction in how future attacks will occur within the ICS space, as adversaries seek to satisfy the seemingly mutually-exclusive goals of evading detection while deploying increasingly advanced capabilities. By adopting and understanding a “complete kill-chain” approach to ICS attack methods, defenders – from ICS asset owners and operators to national governments to intergovernmental organizations – can begin formulating defensive plans to detect and mitigate future attacks. To describe and defend this thesis, ICS disruptive events from the past four years will be analysed in detail to identify how these threats have evolved over time, and what complementary measures are necessary to defeat these attacks. A thorough understanding of the risk posed by ICS attacks will allow stakeholders from ICS operators to policymakers to begin identifying and implementing appropriate controls and security measures to safeguard critical infrastructure and prevent future, potentially catastrophic attacks.
Words matter: age-related positivity in episodic memory for abstract but not concrete words

ABSTRACT Research continues to assess potential boundary conditions for the age-related positivity effect in emotional information processing. Beyond the valence and arousal characteristics of a stimulus, other features may play a role in the manifestation of positivity effects. Differences between abstract and concrete words (i.e., the level of imageability, presence of affective content) may lead to differences in downstream processing outcomes. The present study examined whether additional features of word stimuli, beyond valence and arousal, could influence the emergence of age-related positivity in episodic memory. Fifty-two younger adults and 51 older adults completed a categorization task where they separated a series of positive, negative, and neutral words into “abstract” or “concrete” categories. A surprise recognition task followed after a short delay. Results revealed a three-way Age × Valence × Word Type interaction. No age differences in overall recognition was observed for concrete words, regardless of emotion; however, for abstract words, an Age × Valence interaction emerged whereby older adults recognized more positive than negative words, while valence differences were less pronounced among younger adults. Concrete words were remembered better than abstract words by both age groups, regardless of valence. Conversely, preferential processing appeared to occur for positive abstract words, especially for older adults. We contend that these results provide further evidence of the top-down and controlled nature of age-related positivity effects in episodic memory.
Simultaneous Photodiagnosis and Photodynamic Treatment of Metastatic Melanoma

Metastatic melanoma (MM) has a poor prognosis and is attributed to late diagnoses only when metastases has already occurred. Thus, early diagnosis is crucial to improve its overall treatment efficacy. The standard diagnostic tools for MM are incisional biopsies and/or fine needle aspiration biopsies, while standard treatments involve surgery, chemotherapy, or irradiation therapy. The combination of photodynamic diagnosis (PDD) and therapy (PDT) utilizes a photosensitizer (PS) that, when excited by light of a low wavelength, can be used for fluorescent non-destructive diagnosis. However, when the same PS is activated at a higher wavelength of light, it can be cytotoxic and induce tumor destruction. This paper focuses on PS drugs that have been used for PDD as well as PDT treatment of MM. Furthermore, it emphasizes the need for continued investigation into enhanced PS delivery via active biomarkers and passive nanoparticle systems. This should improve PS drug absorption in MM cells and increase effectiveness of combinative photodynamic methods for the enhanced diagnosis and treatment of MM can become a reality.
Combination of Modified NS1 and NS3 as a Novel Vaccine Strategy against Dengue Virus Infection

Key Points Active immunization with DJ NS1 plus NS3 induces a strong Ab response. Active immunization with DJ NS1 plus NS3 induces specific T cell responses. Combined DJ NS1 plus NS3 provides enhanced protection against DENV infection. Dengue virus (DENV) causes a range of illness, including dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. DENV nonstructural protein (NS) 1 has been considered to be a desirable vaccine candidate for its ability to induce Ab and complement-dependent cytolysis of DENV-infected cells as well as to block the pathogenic effects of NS1. However a potential drawback of NS1 as a vaccine is that anti-DENV NS1 Abs can lead to endothelial cell damage and platelet dysfunction by antigenic cross-reactivity. Therefore, we modified the DENV NS1 by replacing the C-terminal cross-reactive epitopes with the corresponding region of Japanese encephalitis virus NS1 to generate a chimeric DJ NS1 protein. Active immunization with DJ NS1 induced a strong Ab response. To enhance cellular immunity, we further combined DJ NS1 with DENV NS3 to immunize mice and showed activation of Ag-specific CD4+ and CD8+ T cells in addition to Ab responses. We further detected NS3-specific CTL activities as well as CD107a expression of effector cells. Importantly, the protective effects attributed by DJ NS1 and NS3 immunization were demonstrated in a DENV-infected mouse model by reduced viral titers, soluble NS1 levels, mouse tail bleeding time, and vascular leakage at skin injection sites. Collectively, the results from this study reveal the humoral and cellular immune responses and the protective effects conferred by DJ NS1 and NS3 immunization in the mouse model of DENV infection and provide a potential strategy for dengue vaccine design.
The Diffusion of Balanced Scorecard from the Perspective of Adopters : Evidence from Australia

The purpose of this paper is to explore the shortcomings of the Balanced Scorecard (BSC) as a performance measurement tool, and to examine the extent of association between its diffusion and the characteristics of its adopters in practice. This study uses a survey approach and targets registered members of Chartered Institute of Management Accountants (CIMA) in Australia. The results show that ignoring the risks, environmental and sustainability factors as well as neglecting the concerns/rights of relevant stakeholders are the key shortcomings of the BSC in practice. The findings further confirm that it is vital to distinguish between the diffusion of the BSC as a practice (one single tool) and as a process (a chain of different activities). Because some attributes of adopters are only associated with the initial decisions to adopt (or not) the BSC (as a practice) but not with the sequential implementation stages of its adoption (as a process) and vice versa.
Building Extraction from High–Resolution Remote Sensing Images by Adaptive Morphological Attribute Profile under Object Boundary Constraint

A novel adaptive morphological attribute profile under object boundary constraint (AMAP–OBC) method is proposed in this study for automatic building extraction from high-resolution remote sensing (HRRS) images. By investigating the associated attributes in morphological attribute profiles (MAPs), the proposed method establishes corresponding relationships between AMAP–OBC and building characteristics in HRRS images. In the preprocessing step, the candidate object set is extracted by a group of rules for screening of non-building objects. Second, based on the proposed adaptive scale parameter extraction and object boundary constraint strategies, AMAP–OBC is conducted to obtain the initial building set. Finally, a further identification strategy with adaptive threshold combination is proposed to obtain the final building extraction results. Through experiments of multiple groups of HRRS images from different sensors, the proposed method shows outstanding performance in terms of automatic building extraction from diverse geographic objects in urban scenes.
Exploring Spatiotemporal Pattern of Grassland Cover in Western China from 1661 to 1996

Historical grassland cover change is vital for global and regional environmental change modeling; however, in China, estimates of this are rare, and therefore, we propose a method to reconstruct grassland cover over the past 300 years. By synthesizing remote sensing-derived Chinese land use and land cover change (LULCC) data (1980–2015) and potential natural vegetation data simulated by the relationship between vegetation and environment, we first determined the potential extent of natural grassland vegetation (PENG) in the absence of human activities. Then we reconstructed grassland cover across western China between 1661 and 1996 at 10 km resolution by overlaying the Chinese historical cropland dataset (CHCD) over the PENG. As this land cover type has been significantly influenced by anthropogenic factors, the data show that the proportion of grassland in western China continuously decreased from 304.84 × 106 ha in 1661 to 277.69 × 106 ha in 1996. This reduction can be divided into four phases, comprising a rapid decrease between 1661 and 1724, a slow decrease between 1724 and 1873, a sharp decrease between 1873 and 1980, and a gradual increase since 1980. These reductions correspond to annual loss rates of 7.32 × 104 ha, 2.90 × 104 ha, 17.04 × 104 ha, and −2.37 × 104 ha, respectively. The data reconstructed here show that the decrease in grassland area between 1661 and 1724 was mainly limited to the Gan-Ning region (Gansu and Ningxia) and was driven by the early agricultural development policies of the Qing Dynasty. Grassland was extensively cultivated in northeastern China (Heilongjiang, Jilin, and Liaoning) and in the Xinjiang region between 1724 and 1980, a process which resulted from an exponential increase in immigrants to these provinces. The reconstruction results enable provide crucial data that can be used for modeling long-term climate change and carbon emissions.
Dietary 25-Hydroxyvitamin D3 Supplementation Alleviates Porcine Epidemic Diarrhea Virus Infection by Improving Intestinal Structure and Immune Response in Weaned Pigs

Simple Summary Porcine epidemic diarrhea is one of the major problems in current swine husbandry worldwide, and effective measures for prevention and treatment are scarce. We found that high dose 25-hydroxyvitamin D3 supplementation could ease intestinal injury and inhibit intestinal immune response induced by porcine epidemic diarrhea virus (PEDV), suggesting that feeding a high dose of 25-hydroxyvitamin D3 could be used as an approach against PEDV infection. Abstract We conducted this experiment to determine if feeding 25-hydroxyvitamin D3 (25(OH)D3) to weaned pigs would alleviate porcine epidemic diarrhea virus (PEDV) infection and immune response. Forty-two weaned pigs were allotted to 1 of 6 dietary 25(OH)D3 treatments (5.5, 5.5, 43.0, 80.5, 118.0, 155.5 μg 25(OH)D3/kg diet) for 26 days. On day 22 of the trial, all the treatments were orally administrated with PEDV except for one of the 5.5 μg 25(OH)D3/kg treatments, which was challenged with the same volume of sterile saline and served as control. Another 5.5 μg 25(OH)D3/kg group for PEDV challenge was named CON-PEDV. Average daily gain (p < 0.05) was reduced by PEDV infection. PEDV administration also induced severe diarrhea (p < 0.05), reduction of villous height and the ratio of villous height to crypt depth, and increase of crypt depth and serum diamine oxidase activity (p < 0.05). Serum IgM and complement component 4 levels were increased by PEDV challenge. However, 155.5 μg 25(OH)D3/kg supplementation alleviated intestinal damage (p < 0.05) compared with CON-PEDV. Furthermore, 155.5 μg 25(OH)D3/kg supplementation downregulated the mRNA abundance of inflammatory cytokines and interferon signal pathway-related genes (p < 0.05) compared with CON-PEDV. These results suggested that dietary supplementation of 155.5 μg 25(OH)D3/kg could alleviate intestinal damage and protect against PEDV-induced inflammatory status.
The GABA receptor GABRR1 is expressed on and functional in hematopoietic stem cells and megakaryocyte progenitors

Significance GABA not only plays critical roles in the central nervous system but also is involved in various peripheral tissues, such as intestine, stomach, etc. Here, we tried to identity the function of GABA signaling in hematopoietic progenitors. We found GABRR1 is the only GABA receptor expressed in subsets of both human and mouse hematopoietic stem cells and megakaryocyte progenitors. Further studies showed inhibition of GABRR1 with a knockout mouse model, CRISPR-mediated deletion, or GABA antagonist treatment inhibited megakaryocyte and platelet differentiation, while activation of GABRR1 through lentivirus-mediated overexpression or GABA agonist treatment promoted platelet generation. Thus, our work identifies a link between this neural receptor and the hematopoietic system and potentially uncovers a strategy to efficiently generate megakaryocytes and platelets. GABRR1 is a rho subunit receptor of GABA, the major inhibitory neurotransmitter in the mammalian brain. While most investigations of its function focused on the nervous system, its regulatory role in hematopoiesis has not been reported. In this study, we found GABRR1 is mainly expressed on subsets of human and mouse hematopoietic stem cells (HSCs) and megakaryocyte progenitors (MkPs). GABRR1-negative (GR−) HSCs led to higher donor-derived hematopoietic chimerism than GABRR1-positive (GR+) HSCs. GR+ but not GR− HSCs and MkPs respond to GABA in patch clamp studies. Inhibition of GABRR1 via genetic knockout or antagonists inhibited MkP differentiation and reduced platelet numbers in blood. Overexpression of GABRR1 or treatment with agonists significantly promoted MkP generation and megakaryocyte colonies. Thus, this study identifies a link between the neural and hematopoietic systems and opens up the possibility of manipulating GABA signaling for platelet-required clinical applications.
Comparative Transcriptome Analysis of Gene Expression Patterns in Tomato Under Dynamic Light Conditions

Plants grown under highly variable natural light regimes differ strongly from plants grown under constant light (CL) regimes. Plant phenotype and adaptation responses are important for plant biomass and fitness. However, the underlying regulatory mechanisms are still poorly understood, particularly from a transcriptional perspective. To investigate the influence of different light regimes on tomato plants, three dynamic light (DL) regimes were designed, using a CL regime as control. Morphological, photosynthetic, and transcriptional differences after five weeks of treatment were compared. Leaf area, plant height, shoot /root weight, total chlorophyll content, photosynthetic rate, and stomatal conductance all significantly decreased in response to DL regimes. The biggest expression difference was found between the treatment with the highest light intensity at the middle of the day with a total of 1080 significantly up-/down-regulated genes. A total of 177 common differentially expressed genes were identified between DL and CL conditions. Finally, significant differences were observed in the levels of gene expression between DL and CL treatments in multiple pathways, predominantly of plant–pathogen interactions, plant hormone signal transductions, metabolites, and photosynthesis. These results expand the understanding of plant development and photosynthetic regulations under DL conditions by multiple pathways.
The PI3K/AKT/mTOR and CDK4/6 Pathways in Endocrine Resistant HR+/HER2− Metastatic Breast Cancer: Biological Mechanisms and New Treatments

Endocrine-based treatments are the normal standard-of-care in women with hormone receptor-positive/Human Epidermal growth factor Receptor 2-negative metastatic breast cancer. Despite the well-known efficacy of these drugs as first-line therapies, about 50% of women develop endocrine resistance and disease progression. The treatment of these patients has represented one of the most important research fields in the last few years, with several multicenter phase II/III trials published or still ongoing. Novel therapies, such as cyclin-dependent kinase (CDK)4/6 and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors, have significantly changed the prognosis of patients progressing to a previous endocrine treatment, allowing a great benefit in terms of progression-free survival and, in some cases, of overall survival. However, identifying response predictors is essential for the rational use of these drugs to avoid unnecessary toxicity and costs, and to ensure the optimal therapeutic sequence is used. In this review, we analyze the PI3K/AKT/mTOR and CDK4/6 pathways and their roles in endocrine resistant metastatic breast cancer. We then focus on the new treatments developed and the roles of these drugs in overcoming endocrine resistance, describing the latest clinical trials that led to the approval of the drugs in clinical practice.
The uric acid crystal receptor Clec12A potentiates type I interferon responses

Significance Viral infections are accompanied by the release of pathogen-associated molecular patterns (PAMPs) during the virus life-cycle and damage-associated molecular patterns (DAMPs) from collateral injured cells. The sensing of viral PAMPs by pattern recognition receptors (PRRs) such as Toll-like receptors RIG-I and cGAS is essential in initiating host antiviral responses, especially the type I interferon (IFN-I) response. Here, we report that the DAMP-sensing C-type lectin receptor Clec12A positively regulates the IFN-I response induced by RIG-I, providing a mechanism of cross-talk between PAMP- and DAMP-triggered signaling pathways. Moreover, this modulatory function of Clec12A has functional consequences in both acute and chronic viral infection in mice. The detection of microbes and damaged host cells by the innate immune system is essential for host defense against infection and tissue homeostasis. However, how distinct positive and negative regulatory signals from immune receptors are integrated to tailor specific responses in complex scenarios remains largely undefined. Clec12A is a myeloid cell-expressed inhibitory C-type lectin receptor that can sense cell death under sterile conditions. Clec12A detects uric acid crystals and limits proinflammatory pathways by counteracting the cell-activating spleen tyrosine kinase (Syk). Here, we surprisingly find that Clec12A additionally amplifies type I IFN (IFN-I) responses in vivo and in vitro. Using retinoic acid-inducible gene I (RIG-I) signaling as a model, we demonstrate that monosodium urate (MSU) crystal sensing by Clec12A enhances cytosolic RNA-induced IFN-I production and the subsequent induction of IFN-I–stimulated genes. Mechanistically, Clec12A engages Src kinase to positively regulate the TBK1-IRF3 signaling module. Consistently, Clec12A-deficient mice exhibit reduced IFN-I responses upon lymphocytic choriomeningitis virus (LCMV) infection, which affects the outcomes of these animals in acute and chronic virus infection models. Thus, our results uncover a previously unrecognized connection between an MSU crystal-sensing receptor and the IFN-I response, and they illustrate how the sensing of extracellular damage-associated molecular patterns (DAMPs) can shape the immune response.
(Ab)use of Health Claims in Websites: The Case of Italian Bottled Waters

The massive use of web marketing makes the monitoring of nutrition and health claims used in advertising campaigns much more difficult. The present study aimed at reviewing the website content for bottled waters produced in Italy to assess (i) if nutrition and health claims are reported, (ii) what types of nutrition and health claims are reported most frequently, and (iii) if the nutrition and health claims could be considered appropriate according to the current regulation in the field. A review of the website content of the 253 bottled waters produced in Italy and reported in the annual report of Bevitalia 2016–2017 was conducted. For each brand, indications related to the preventive, curative or therapeutic properties of the water reported were examined. Bottled waters that included potentially misleading information apparently not consistent with the European Directive on the exploitation and marketing of natural mineral waters were identified. Forty bottled waters with uncertain website content were identified. The information reported in the websites referred most often to beneficial effects for urinary tract and cardiovascular systems. Present results highlight, using the bottled water case study, that website content sometimes happens to deliver misleading information to consumers, also thanks to uncertain regulation in this sensitive field.