Miracle-dz/UniFAR-FTUs huggingface dataset:
A New Inhibitor of Tubulin Polymerization Kills Multiple Cancer Cell Types and Reveals p21-Mediated Mechanism Determining Cell Death after Mitotic Catastrophe

Induction of mitotic catastrophe through the disruption of microtubules is an established target in cancer therapy. However, the molecular mechanisms determining the mitotic catastrophe and the following apoptotic or non-apoptotic cell death remain poorly understood. Moreover, many existing drugs targeting tubulin, such as vincristine, have reduced efficacy, resulting from poor solubility in physiological conditions. Here, we introduce a novel small molecule 2-aminoimidazoline derivative—OAT-449, a synthetic water-soluble tubulin inhibitor. OAT-449 in a concentration range from 6 to 30 nM causes cell death of eight different cancer cell lines in vitro, and significantly inhibits tumor development in such xenograft models as HT-29 (colorectal adenocarcinoma) and SK-N-MC (neuroepithelioma) in vivo. Mechanistic studies showed that OAT-449, like vincristine, inhibited tubulin polymerization and induced profound multi-nucleation and mitotic catastrophe in cancer cells. HeLa and HT-29 cells within 24 h of treatment arrested in G2/M cell cycle phase, presenting mitotic catastrophe features, and 24 h later died by non-apoptotic cell death. In HT-29 cells, both agents altered phosphorylation status of Cdk1 and of spindle assembly checkpoint proteins NuMa and Aurora B, while G2/M arrest and apoptosis blocking was consistent with p53-independent accumulation in the nucleus and largely in the cytoplasm of p21/waf1/cip1, a key determinant of cell fate programs. This is the first common mechanism for the two microtubule-dissociating agents, vincristine and OAT-449, determining the cell death pathway following mitotic catastrophe demonstrated in HT-29 cells.
Hypoglycemia induces mitochondrial reactive oxygen species production through increased fatty acid oxidation and promotes retinal vascular permeability in diabetic mice.

AIMS Hypoglycemia is associated with increased reactive oxygen species (ROS) production and vascular events. We have previously reported that low glucose conditions (LG) induce mitochondrial ROS (mtROS) production in aortic endothelial cells (ECs). However, the mechanism by which hypoglycemia promotes diabetic retinopathy (DR) is unclear. Blood-retinal barrier (BRB) disruption occurs in the early stages of DR. We hypothesized that the mechanisms underlying hypoglycemia-induced DR are associated with BRB breakdown due to mtROS generation during hypoglycemia. Here, we aimed to determine whether hypoglycemia exacerbated mtROS production and induced BRB disruption. RESULTS We observed that hypoglycemia induced mtROS production by increasing fatty acid oxidation (FAO), which was suppressed by overexpression of mitochondrial-specific manganese superoxide dismutase (MnSOD) in retinal ECs. Furthermore, FAO blockade decreased the hypoglycemia-induced mtROS production. Recurrent hypoglycemia increased albumin leak in diabetic mice retina, which was suppressed in diabetic vascular endothelial cell-specific MnSOD transgenic (eMnSOD-Tg) mice. Pharmacological FAO blockade also reduced mtROS production, reduced vascular endothelial growth factor (VEGF) production during hypoglycemia, and prevented retinal vascular permeability in diabetic mice. MnSOD overexpression or carnitine palmitoyltransferase I (CPT1) blockade suppressed vascular endothelial-cadherin phosphorylation under LG in retinal ECs. Innovation and Conclusion: Reduction of mtROS and VEGF production via pharmacological FAO and/or CPT1 blockade may prevent hypoglycemia-induced worsening of DR.
Conserved sequence motifs in the abiotic stress response protein late embryogenesis abundant 3

LEA3 proteins, a family of abiotic stress proteins, are defined by the presence of a tryptophan-containing motif, which we name the W-motif. We use Pfam LEA3 sequences to search the Phytozome database to create a W-motif definition and a LEA3 sequence dataset. A comprehensive analysis of these sequences revealed four N-terminal motifs, as well as two previously undiscovered C-terminal motifs that contain conserved acidic and hydrophobic residues. The general architecture of the LEA3 sequences consisted of an N-terminal motif with a potential mitochondrial transport signal and the twin-arginine motif cut-site, followed by a W-motif and often a C-terminal motif. Analysis of species distribution of the motifs showed that one architecture was found exclusively in Commelinids, while two were distributed fairly evenly over all species. The physiochemical properties of the different architectures showed clustering in a relatively narrow range compared to the previously studied dehydrins. The evolutionary analysis revealed that the different sequences grouped into clades based on architecture, and that there appear to be at least two distinct groups of LEA3 proteins based on their architectures and physiochemical properties. The presence of LEA3 proteins in non-vascular plants but their absence in algae suggests that LEA3 may have arisen in the evolution of land plants.
Advances with RNAi-Based Therapy for Hepatitis B Virus Infection

Infection with hepatitis B virus (HBV) remains a global health challenge. Approximately 292 million people worldwide are chronically infected with HBV and the annual mortality from the infection is approaching 900,000. Despite the availability of an effective prophylactic vaccine, millions of individuals are at risk of potentially fatal complicating cirrhosis and hepatocellular carcinoma. Current drug treatments can suppress viral replication, slow the progression of liver fibrosis, and reduce infectivity, but can rarely clear the viral covalently closed circular DNA (cccDNA) that is responsible for HBV persistence. Alternative therapeutic strategies, including those based on viral gene silencing by harnessing the RNA interference (RNAi) pathway, effectively suppress HBV replication and thus hold promise. RNAi-based silencing of certain viral genes may even lead to disabling of cccDNA during chronic infection. This review summarizes different RNAi activators that have been tested against HBV, the advances with vectors used to deliver artificial potentially therapeutic RNAi sequences to the liver, and the current status of preclinical and clinical investigation.
Impact of diet and the bacterial microbiome on the mucous barrier and immune disorders

The prevalence of chronic immune and metabolic disorders is increasing rapidly. In particular, inflammatory bowel diseases, obesity, diabetes, asthma and chronic obstructive pulmonary disease have become major healthcare and economic burdens worldwide. Recent advances in microbiome research have led to significant discoveries of associative links between alterations in the microbiome and health, as well as these chronic supposedly noncommunicable, immune/metabolic disorders. Importantly, the interplay between diet, microbiome and the mucous barrier in these diseases has gained significant attention. Diet modulates the mucous barrier via alterations in gut microbiota, resulting in either disease onset/exacerbation due to a “poor” diet or protection against disease with a “healthy” diet. In addition, many mucosa‐associated disorders possess a specific gut microbiome fingerprint associated with the composition of the mucous barrier, which is further influenced by host‐microbiome and inter‐microbial interactions, dietary choices, microbe immigration and antimicrobials. Our review focuses on the interactions of diet (macronutrients and micronutrients), gut microbiota and mucous barriers (gastrointestinal and respiratory tract) and their importance in the onset and/or progression of major immune/metabolic disorders. We also highlight the key mechanisms that could be targeted therapeutically to prevent and/or treat these disorders.
Evaluating surrogates of genetic diversity for conservation planning

Protected‐area systems should conserve intraspecific genetic diversity. Because genetic data require resources to obtain, several approaches have been proposed for generating plans for protected‐area systems (prioritizations) when genetic data are not available. Yet such surrogate‐based approaches remain poorly tested. We evaluated the effectiveness of potential surrogate‐based approaches based on microsatellite genetic data collected across the Iberian Peninsula for 7 amphibian and 3 reptilian species. Long‐term environmental suitability did not effectively represent sites containing high genetic diversity (allelic richness). Prioritizations based on long‐term environmental suitability had similar performance to random prioritizations. Geographic distances and resistance distances based on contemporary environmental suitability were not always effective surrogates for identification of combinations of sites that contain individuals with different genetic compositions. Our results demonstrate that population genetic data based on commonly used neutral markers can inform prioritizations, and we could not find an adequate substitute. Conservation planners need to weigh the potential benefits of genetic data against their acquisition costs.
Effectiveness of Oat-Hull-Based Ingredient as Fat Replacer to Produce Low Fat Burger with High Beta-Glucans Content

Low-fat beef burgers with high beta-glucan content was obtained using a gel made from an oat-hull-based ingredient as fat replacer. Two levels of fat substitution were considered: 50% (T1) and 100% (T2). The nutritional composition, cooking yield, textural properties, color characteristics and consumer preference were evaluated, in comparison with a burger without fat replacer (CTRL). After cooking, T2 burger showed a significant increase in the cooking yield and a very low lipid content (3.48 g 100 g−1) as well as a level of beta-glucans per single portion (2.96 g 100 g−1) near the recommended daily intake. In T1 burger, the decrease of lipid content was mitigated during the cooking process, because the beta-glucans added had a fat-retaining effect. Compared to CTRL, replacing fat led to a softer texture of cooked burgers evaluated by Texture Profile Analysis. The differences in color, significant in raw burgers, were smoothed with cooking. The consumer evaluation, carried out according to the duo-trio test, highlighted significant differences between CTRL and T2 burgers in terms of odor, taste, color and texture. The consumers expressed a higher preference for the T2 burger, probably due to its softer texture and greater juiciness.
Ultra‐processed foods and the nutrition transition: Global, regional and national trends, food systems transformations and political economy drivers

Understanding the drivers and dynamics of global ultra‐processed food (UPF) consumption is essential, given the evidence linking these foods with adverse health outcomes. In this synthesis review, we take two steps. First, we quantify per capita volumes and trends in UPF sales, and ingredients (sweeteners, fats, sodium and cosmetic additives) supplied by these foods, in countries classified by income and region. Second, we review the literature on food systems and political economy factors that likely explain the observed changes. We find evidence for a substantial expansion in the types and quantities of UPFs sold worldwide, representing a transition towards a more processed global diet but with wide variations between regions and countries. As countries grow richer, higher volumes and a wider variety of UPFs are sold. Sales are highest in Australasia, North America, Europe and Latin America but growing rapidly in Asia, the Middle East and Africa. These developments are closely linked with the industrialization of food systems, technological change and globalization, including growth in the market and political activities of transnational food corporations and inadequate policies to protect nutrition in these new contexts. The scale of dietary change underway, especially in highly populated middle‐income countries, raises serious concern for global health.
Healthcare-Seeking Behavior for Respiratory Illness Among Flu Near You Participants in the United States During the 2015–2016 Through 2018–2019 Influenza Seasons

Abstract Background Flu Near You (FNY) is an online participatory syndromic surveillance system that collects health-related information. In this article, we summarized the healthcare-seeking behavior of FNY participants who reported influenza-like illness (ILI) symptoms. Methods We applied inverse probability weighting to calculate age-adjusted estimates of the percentage of FNY participants in the United States who sought health care for ILI symptoms during the 2015–2016 through 2018–2019 influenza season and compared seasonal trends across different demographic and regional subgroups, including age group, sex, census region, and place of care using adjusted χ 2 tests. Results The overall age-adjusted percentage of FNY participants who sought healthcare for ILI symptoms varied by season and ranged from 22.8% to 35.6%. Across all seasons, healthcare seeking was highest for the <18 and 65+ years age groups, women had a greater percentage compared with men, and the South census region had the largest percentage while the West census region had the smallest percentage. Conclusions The percentage of FNY participants who sought healthcare for ILI symptoms varied by season, geographical region, age group, and sex. FNY compliments existing surveillance systems and informs estimates of influenza-associated illness by adding important real-time insights into healthcare-seeking behavior.
Dermal and inhalable cobalt exposure—Uptake of cobalt for workers at Swedish hard metal plants

Purpose Cobalt exposure is known to cause adverse effects on health. A major use of cobalt is in the manufacture of hard metal. Exposure can lead to asthma, hard metal lung disease, contact allergy and increased risk of cancer. Cobalt is mainly absorbed from the pulmonary tract, however penetration through skin may occur. The relationships between exposure to inhalable cobalt in air and on skin and the uptake in blood and urine will be investigated, as well as the association between dermal symptoms and dermal exposure. Methods Cobalt exposure in 71 workers in hard metal production facilities was measured as inhalable cobalt in the breathing zone and cobalt found on skin with acid wash. Uptake of cobalt was determined with concentrations in blood and urine. Correlations between exposure and uptake were analysed. Results Inhalable cobalt in air and cobalt in blood and urine showed rank correlations with coefficients 0.40 and 0.25. Cobalt on skin and uptake in blood and urine presented correlation coefficients of 0.36 and 0.17. Multiple linear regression of cobalt in air and on skin with cobalt in blood showed regression coefficients with cobalt in blood (β = 203 p < 0.0010, and β = 0.010, p = 0.0040) and with cobalt in urine (β = 5779, p = 0.0010, and β = 0.10, p = 0.60). Conclusions Our data presents statistically significant correlations between exposure to cobalt in air with uptake of cobalt in blood and urine. Cobalt on skin was statistically significant with cobalt in blood but not with urine.
Straightforward Stepwise Excited State Dual Proton Transfer Mechanism for 9-10-HBQ System

A new molecule 9,10-dihydroxybenzo[h] quinoline (i.e. 9-10-HBQ) is focused in the present work about its excited state proton transfer (ESPT) mechanism. Though comparing potential energy barriers, it is found that the ultrafast ESPT process could occur in the S1 state without potential energy barrier along with hydrogen bond O3-H4···N5 forming 9-10-HBQ-PT1 structure, subsequently, the second proton transfers via another intramolecular hydrogen bonded wire O1-H2···N3 with a low potential energy barrier (about 7.69 kcal/mol) in the S1 state forming 9-10-HBQ-PT2 configuration. After completing excited state dynamical process, the S1-state could turn back to S0 state with occurring reversed ground state proton transfer forming initial 9-10-HBQ structure. AMS subject classifications: 65D18, 78M50, 74E40
Conceptualizing Pathways of Sustainable Development in the Union for the Mediterranean Countries with an Empirical Intersection of Energy Consumption and Economic Growth

The availability of sufficient and trustworthy energy services at the reasonable cost in a securely and environmentally friendly manner, and conventionality with economic and social development requirements, is an important factor of sustainable development (SD). Energy plays a significant role in eliminating poverty and increasing living standards. However, most of the present energy forms of energy supply and consumption are unsustainable. This paper analyzes the association between economic growth (EG), energy consumption (EC), and sustainable development (SD) among other economic factors. The sample of 14 developed and developing member states of the Union for the Mediterranean (UFM) was selected. To deal with the endogeneity issue, the system- generalized method of moment (GMM) model was employed. Moreover, panel co-integration, Granger causality tests, and robustness tests were employed to examine the long-run and short-run causality among variables of interest. The results confirmed the short-run dynamic association from sustainable development (SD) to energy consumption (EC), and economic growth (EG) to sustainable development (SD). Moreover, the results validated the presence of long-run equilibrium association in the equations of EC and sustainable development (SD). The findings of this study will be supportive for the policymakers to formulate sustainable energy policies to stimulate the economic growth (EG) in the way of sustainable development (SD) in the UFM countries.
Designing and Identifying the Variables of the Pricing Model for the Company’s Brand Value in Merger and Acquisition Strategies

Strong brands bring numerous benefits for both the companies and their customers such as decreasing purchasing risk and searching cost and increasing the likelihood of repurchasing. It is not presented an applied model for determining the price of this asset in Iran, especially in terms of merger and acquisition. The purpose of this study is to develop a model for pricing brand value in Iran’s capital supply companies in terms of marketing strategies of merger and acquisition. The current study is qualitative research which is done by conducting grounded theory in MAXQDA software. Needed data were gathered from interviews and panel sessions with all the 21 pricing experts in capital supply companies during the year 2018, and were analyzed to extract the variables of the model of brand pricing to Rial. After that, open codes were categorized into 5 main categories and 2 sub-categories titled as: communication and performance environmental factors, marketing, brand, performance (financial and non-financial), and corporate audit reports. Research findings; in addition, has developed an operational brand pricing model for Iran’s semi-public economy that is unprecedented in other studies.
Accuracy of a novel urine test, Fujifilm SILVAMP TB LAM, for the diagnosis of pulmonary tuberculosis in children.

BACKGROUND An accurate point-of-care test for tuberculosis in children remains an elusive goal. Recent evaluation of a novel point-of-care urinary lipoarabinomannan test, Fujifilm SILVAMP TB LAM (FujiLAM) in HIV-infected adults showed significantly superior sensitivity than the current Alere Determine TB LAM test (AlereLAM). We therefore compared the accuracy of FujiLAM and AlereLAM in children with suspected tuberculosis. METHODS Children hospitalized with suspected tuberculosis in Cape Town, South Africa were enrolled (consecutive admissions plus enrichment for a group of HIV-infected children with tuberculosis), urine collected and biobanked, and sputum tested with mycobacterial culture and Xpert MTB/RIF or Xpert MTB/RIF Ultra. Biobanked urine was subsequently batch tested with FujiLAM and AlereLAM. Children were categorised as having microbiologically-confirmed TB, unconfirmed TB (clinically diagnosed) or unlikely TB. RESULTS A total of 204 children were enrolled and had valid results from both index tests as well as sputum microbiological testing. Compared to a microbiological reference standard, the sensitivity of FujiLAM and AlereLAM was similar (42% and 50% respectively), but lower than Xpert MTB/RIF of sputum (74%). Sensitivity of FujiLAM was higher in HIV-infected children (60%) and malnourished children (62%). Specificity of FujiLAM was substantially higher than AlereLAM (92% vs. 66%). Specificity of both tests was higher in children two years or older (FujiLAM 96% and AlereLAM 72%). CONCLUSION The high specificity of FujiLAM suggests utility as a 'rule-in' test for children with a high pretest probability of tuberculosis, including hospitalized children with HIV-infection or malnutrition.
Sigma 1 receptor as a therapeutic target for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is an adult disease causing a progressive loss of upper and lower motoneurons, muscle paralysis and early death. ALS has a poor prognosis of 3–5 years after diagnosis with no effective cure. The aetiopathogenic mechanisms involved include glutamate excitotoxicity, oxidative stress, protein misfolding, mitochondrial alterations, disrupted axonal transport and inflammation. Sigma non‐opioid intracellular receptor 1 (sigma 1 receptor) is a protein expressed in motoneurons, mainly found in the endoplasmic reticulum (ER) on the mitochondria‐associated ER membrane (MAM) or in close contact with cholinergic postsynaptic sites. MAMs are sites that allow the assembly of several complexes implicated in essential survival cell functions. The sigma 1 receptor modulates essential mechanisms for motoneuron survival including excitotoxicity, calcium homeostasis, ER stress and mitochondrial dysfunction. This review updates sigma 1 receptor mechanisms and its alterations in ALS, focusing on MAM modulation, which may constitute a novel target for therapeutic strategies.
Ultrasound imaging and guidance in the management of post-injection sciatic neuropathy: Love, loss and space.

‘For love, you never look where you lost it’ and post-injection sciatic neuropathy is simply not love. As such, we, first and foremost, disagree with the authors in their look concerning the diagnostic algorithm. Herein, although we disagree with them, they might actually agree with us in the sense that imaging should have initially been done for the sciatic nerve and the nearby soft tissues. Yet, they have already/supportingly observed thickening of the nerve in one of their patients. So, why not putting an ultrasound (US) probe on the sciatic nerve and scan it throughout? This patient and physician-friendly technique with an appropriate/prompt use would have definitely changed the overall scenario: i.e., not only for the clinical decision making, but also for better interventional targeting (Figure 1). [2] Needless to say, there is simply no better imaging method for these patients, if sono-palpation or sono-Tinel yields consistent findings during dynamic and interactive imaging. To this end, US scanning is already referred as an examination method, not imaging anymore. [3,4] Ultrasound imaging and guidance in the management of post-injection sciatic neuropathy: Love, loss and space