Miracle-dz/UniFAR-FTUs huggingface dataset:
Biochemical and Computational Studies of the Interaction between a Glucosamine Derivative, NAPA, and the IKKα Kinase

The glucosamine derivative 2-(N-Acetyl)-L-phenylalanylamido-2-deoxy-β-D-glucose (NAPA), was shown to inhibit the kinase activity of IKKα, one of the two catalytic subunits of IKK complex, decreasing the inflammatory status in osteoarthritis chondrocytes. In the present work we have investigated the inhibition mechanism of IKKα by NAPA by combining computational simulations, in vitro assays and Mass Spectrometry (MS) technique. The kinase in vitro assay was conducted using a recombinant IKKα and IKKtide, a 20 amino acid peptide substrate derived from IkBα kinase protein and containing the serine residues Ser32 and Ser36. Phosphorylated peptide production was measured by Ultra Performance Liquid Chromatography coupled with Mass Spectrometry (UPLC-MS), and the atomic interaction between IKKα and NAPA has been studied by molecular docking and Molecular Dynamics (MD) approaches. Here we report that NAPA was able to inhibit the IKKα kinase activity with an IC50 of 0.5 mM, to decrease the Km value from 0.337 mM to 0.402 mM and the Vmax from 0.0257 mM·min−1 to 0.0076 mM·min−1. The computational analyses indicate the region between the KD, ULD and SDD domains of IKKα as the optimal binding site explored by NAPA. Biochemical data indicate that there is a non-significant difference between Km and Ki whereas there is a statistically significant difference between the two Vmax values. This evidence, combined with computational results, consistently indicates that the inhibition is non-competitive, and that the NAPA binding site is different than that of ATP or IKKtide.
Saudi Arabia Guidelines for diabetic macular edema

ABSTRACT Diabetes mellitus (DM) and its complications are major public health burdens in Saudi Arabia. The prevalence of diabetic retinopathy (DR) is 19.7% and the prevalence of diabetic macular edema (DME) is 5.7% in Saudi Arabia. Diabetic macular edema is a vision-threatening complication of DR and a major cause of vision loss worldwide. Ocular treatments include retinal laser photocoagulation, anti-vascular endothelial growth factor (anti-VEGF) agents, intravitreal corticosteroids, and vitreoretinal surgery when necessary. The present consensus was developed as a part of the Saudi Retina Group’s efforts to generate Saudi guidelines and consensus for the management of DME, including recommendations for its diagnosis, treatment, and best practice. The experts’ panel stipulates that the treatment algorithm should be categorized according to the presence of central macula involvement. In patients with no central macular involvement, laser photocoagulation is recommended as the first-line option. Patients with central macular involvement and no recent history of cardiovascular (CVS) or cerebrovascular disorders can be offered anti-VEGF agents as the first-line option. In the case of non-responders (defined as an improvement of <20% in optical coherence tomography or a gain of fewer than 5 letters in vision), switching to another anti-VEGF agent or steroids should be considered after 3 injections. Within the class of steroids, dexamethasone implants are recommended as the first choice. In patients with a recent history of CVS events, the use of anti-VEGF agents is not recommended, regardless of their lens status. The experts’ panel recommends that a future study be conducted to provide a cut-off point for early switching to steroid implants in pseudo-phakic eyes.
Studies on the Occurrence of Viruses in Planting Material of Grapevines in Southwestern Germany

Viral diseases in viticulture lead to annual losses in the quantity and quality of grape production. Since no direct control measures are available in practice, preventive measures are taken to keep the vines healthy. These include, for example, the testing of propagation material for viruses such as Arabis mosaic virus (ArMV), Grapevine fanleaf virus (GFLV) or Grapevine leafroll-associated virus 1 (GLRaV-1) and 3 (GLRaV-3). As long-term investigations have shown, GLRaV-1 (2.1%) occurs most frequently in southwestern German wine-growing regions, whereas GLRaV-3 (<0.1%) is almost never found. However, tests conducted over 12 years indicate that there is no general decline in virus-infected planting material. Thus, it can be assumed that a spread of the viruses via corresponding vectors still takes place unhindered. Beyond the examinations regulated within the German Wine Growing Ordinance, one-time tests were carried out on Grapevine Pinot gris virus (GPGV). This analysis showed that GPGV was found in 17.2% of the samples.
Can We Predict Individual Concentrations of Tacrolimus After Liver Transplantation? Application and Tweaking of a Published Population Pharmacokinetic Model in Clinical Practice

Supplemental Digital Content is Available in the Text. Background: Various population pharmacokinetic models have been developed to describe the pharmacokinetics of tacrolimus in adult liver transplantation. However, their extrapolated predictive performance remains unclear in clinical practice. The purpose of this study was to predict concentrations using a selected literature model and to improve these predictions by tweaking the model with a subset of the target population. Methods: A literature review was conducted to select an adequate population pharmacokinetic model (L). Pharmacokinetic data from therapeutic drug monitoring of tacrolimus in liver-transplanted adults were retrospectively collected. A subset of these data (70%) was exploited to tweak the L-model using the $PRIOR subroutine of the NONMEM software, with 2 strategies to weight the prior information: full informative (F) and optimized (O). An external evaluation was performed on the remaining data; bias and imprecision were evaluated for predictions a priori and Bayesian forecasting. Results: Seventy-nine patients (851 concentrations) were enrolled in the study. The predictive performance of L-model was insufficient for a priori predictions, whereas it was acceptable with Bayesian forecasting, from the third prediction (ie, with ≥2 previously observed concentrations), corresponding to 1 week after transplantation. Overall, the tweaked models showed a better predictive ability than the L-model. The bias of a priori predictions was −41% with the literature model versus −28.5% and −8.73% with tweaked F and O models, respectively. The imprecision was 45.4% with the literature model versus 38.0% and 39.2% with tweaked F and O models, respectively. For Bayesian predictions, whatever the forecasting state, the tweaked models tend to obtain better results. Conclusions: A pharmacokinetic model can be used, and to improve the predictive performance, tweaking the literature model with the $PRIOR approach allows to obtain better predictions.
WWII trauma impacts physical and mental health in the oldest old: results from a German population-based study

Abstract Introduction Epidemiological studies in different traumatised samples indicate an increased risk for numerous physical and mental diseases. It is suspected that this is due to chronic changes in fundamental processes in the immune, nervous, and endocrine systems, which take years to manifest pathologically. Previous studies have considered intervals of a few decades. However, little is known about whether a link between trauma and physical and mental health can be established over very long periods of time and in the oldest old population. Materials and methods A total of 1,299 German citizens aged 80 and above were interviewed about on-going suffering from the effects of traumatic World War II (WWII) events as well as about physical and mental health. Multiple linear and logistic regression models were used to assess the impact of suffering from the effects of traumatic events on general health, several medical conditions, multimorbidity, pain, and depression. Results 43.94% of the oldest old were still suffering from the effects of traumatic events in connection with WWII. Participants who were still suffering from the effects of traumatic events were more likely to be treated for heart failure, blood diseases, bladder problems, back pain, respiratory or lung diseases, and sleep disorders. They also had poorer general health, higher multimorbidity, more pain, and higher depression scores. Discussion Findings suggest that chronic psychological suffering from the effects of traumatic events in early life is associated with impaired physical and mental health even seven decades after the events.
Perceptions of Signs of Addiction Among Opioid Naive Patients Prescribed Opioids in the Emergency Department

Objectives: Patient knowledge deficits related to opioid risks, including lack of knowledge regarding addiction, are well documented. Our objective was to characterize patients’ perceptions of signs of addiction. Methods: This study utilized data obtained as part of a larger interventional trial. Consecutively discharged English-speaking patients, age >17 years, at an urban academic emergency department, with a new opioid prescription were enrolled from July 2015 to August 2017. During a follow-up phone interview 7 to 14 days after discharge, participants were asked a single question, “What are the signs of addiction to pain medicine? ” Verbatim transcribed answers were analyzed using a directed content analysis approach and double coding. These codes were then grouped into themes. Results: There were 325 respondents, 57% female, mean age 43.8 years, 70.1% privately insured. Ten de novo codes were added to the 11 DSM-V criteria codes. Six themes were identified: (1) effort spent acquiring opioids, (2) emotional and physical changes related to opioid use, (3) opioid use that is “not needed, (4) increasing opioid use, (5) an emotional relationship with opioids, and (6) the inability to stop opioid use. Conclusions: Signs of addiction identified by opioid naive patients were similar to concepts identified in medical definitions. However, participants’ understanding also included misconceptions, omissions, and conflated misuse behaviors with signs of addiction. Identifying these differences will help inform patient-provider risk communication, providing an opportunity for counseling and prevention.
An Atherogenic Diet Disturbs Aquaporin 5 Expression in Liver and Adipocyte Tissues of Apolipoprotein E-Deficient Mice: New Insights into an Old Model of Experimental Atherosclerosis

The dysfunction of vascular endothelial cells is profoundly implicated in the pathogenesis of atherosclerosis and cardiovascular disease, the global leading cause of death. Aquaporins (AQPs) are membrane channels that facilitate water and glycerol transport across cellular membranes recently implicated in the homeostasis of the cardiovascular system. Apolipoprotein-E deficient (apoE−/−) mice are a common model to study the progression of atherosclerosis. Nevertheless, the pattern of expression of AQPs in this atheroprone model is poorly characterized. In this study, apoE−/− mice were fed an atherogenic high-fat (HF) or a control diet. Plasma was collected at multiple time points to assess metabolic disturbances. At the endpoint, the aortic atherosclerotic burden was quantified using high field magnetic resonance imaging. Moreover, the transcriptional levels of several AQP isoforms were evaluated in the liver, white adipocyte tissue (WAT), and brown adipocyte tissue (BAT). The results revealed that HF-fed mice, when compared to controls, presented an exacerbated systemic inflammation and atherosclerotic phenotype, with no major differences in systemic methylation status, circulating amino acids, or plasma total glutathione. Moreover, an overexpression of the isoform AQP5 was detected in all studied tissues from HF-fed mice when compared to controls. These results suggest a novel role for AQP5 on diet-induced atherosclerosis that warrants further investigation.
The FasLane to ocular pathology—metalloproteinase cleavage of membrane‐bound FasL determines FasL function

Fas ligand (FasL) is best known for its ability to induce cell death in a wide range of Fas‐expressing targets and to limit inflammation in immunoprivileged sites such as the eye. In addition, the ability of FasL to induce a much more extensive list of outcomes is being increasingly explored and accepted. These outcomes include the induction of proinflammatory cytokine production, T cell activation, and cell motility. However, the distinct and opposing functions of membrane‐associated FasL (mFasL) and the C‐terminal soluble FasL fragment (sFasL) released by metalloproteinase cleavage is less well documented and understood. Both mFasL and sFasL can form trimers that engage the trimeric Fas receptor, but only mFasL can form a multimeric complex in lipid rafts to trigger apoptosis and inflammation. By contrast, a number of reports have now documented the anti‐apoptotic and anti‐inflammatory activity of sFasL, pointing to a critical regulatory function of the soluble molecule. The immunomodulatory activity of FasL is particularly evident in ocular pathology where elimination of the metalloproteinase cleavage site and the ensuing increased expression of mFasL can severely exacerbate the extent of inflammation and cell death. By contrast, both homeostatic and increased expression of sFasL can limit inflammation and cell death. The mechanism(s) responsible for the protective activity of sFasL are discussed but remain controversial. Nevertheless, it will be important to consider therapeutic applications of sFasL for the treatment of ocular diseases such as glaucoma.
Endogenous Metabolites Released by Sanitized Sprouting Alfalfa Seed Inhibit the Growth of Salmonella enterica

Warm, humid, and nutrient-rich conditions that are used to produce sprouts encourage Salmonella enterica to proliferate. However, many disparate sanitation methods exist, and there is currently no single treatment that can guarantee pathogen-free seeds. ABSTRACT Sprouts are the leading cause of foodborne disease outbreaks globally, mainly because the specialized conditions required to germinate seed sprouts for human consumption contribute to an environment that allows pathogenic bacteria to flourish. To reduce risk of illness, current food safety guidelines in the United States and Canada recommend hypochlorite treatment for seed sanitation. However, many growers and consumers have become wary of the impact of hypochlorite on human health and the environment and are actively seeking less caustic approaches. Here, we evaluated the effects of both the traditional hypochlorite treatment and a milder alternative on nontyphoidal Salmonella enterica colonization of germinating alfalfa seed. Moreover, we explored three biological factors as potential contributors for inhibition of S. enterica growth: colonization by indigenous bacteria, seed composition changes, and seed metabolite release. In this experimental setting, we found that a combinatorial treatment of heat, peroxide, and acetic acid was as effective as hypochlorite for inhibiting S. enterica growth. Notably, we pinpointed N-acetyl-spermidine as an endogenous metabolite exuded by treated seeds that strongly inhibits S. enterica growth. In doing so, we both elucidated one of the mechanisms of chemical sanitation and highlighted a potential seed-derived mode of antimicrobial treatment that may apply to modernized food safety protocols. IMPORTANCE Warm, humid, and nutrient-rich conditions that are used to produce sprouts encourage Salmonella enterica to proliferate. However, many disparate sanitation methods exist, and there is currently no single treatment that can guarantee pathogen-free seeds. Here, we compared the ability of traditional hypochlorite treatment against a combinatorial treatment of heat, peroxide, and vinegar (HPA) commonly used in organic farming practices to inhibit S. enterica colonization and growth during alfalfa germination and found HPA to be at least as effective. Furthermore, we explored seed-based changes following sanitization treatments using metabolomics and identified polyamines as strong inhibitors of Salmonella growth on germinating alfalfa. Our findings enable a better understanding of host-pathogen interactions in sprout microbial communities and promote in-depth, evidence-based research in seed sprout safety.
Does the High Prevalence of Vitamin D Deficiency in African Americans Contribute to Health Disparities?

African Americans have higher incidence of, and mortality from, many health-related problems than European Americans. They also have a 15 to 20-fold higher prevalence of severe vitamin D deficiency. Here we summarize evidence that: (i) this health disparity is partly due to insufficient vitamin D production, caused by melanin in the skin blocking the UVB solar radiation necessary for its synthesis; (ii) the vitamin D insufficiency is exacerbated at high latitudes because of the combination of dark skin color with lower UVB radiation levels; and (iii) the health of individuals with dark skin can be markedly improved by correcting deficiency and achieving an optimal vitamin D status, as could be obtained by supplementation and/or fortification. Moderate-to-strong evidence exists that high 25-hydroxyvitamin D levels and/or vitamin D supplementation reduces risk for many adverse health outcomes including all-cause mortality rate, adverse pregnancy and birth outcomes, cancer, diabetes mellitus, Alzheimer’s disease and dementia, multiple sclerosis, acute respiratory tract infections, COVID-19, asthma exacerbations, rickets, and osteomalacia. We suggest that people with low vitamin D status, which would include most people with dark skin living at high latitudes, along with their health care provider, consider taking vitamin D3 supplements to raise serum 25-hydroxyvitamin D levels to 30 ng/mL (75 nmol/L) or possibly higher.
Multiscale Metal Oxide Particles to Enhance Photocatalytic Antimicrobial Activity against Escherichia coli and M13 Bacteriophage under Dual Ultraviolet Irradiation

Antimicrobial activity of multiscale metal oxide (MO) particles against Escherichia coli (E. coli) and M13 bacteriophage (phage) was investigated under dual ultraviolet (UV) irradiation. Zinc oxide (ZnO), magnesium oxide (MgO), cuprous oxide (Cu2O), and cupric oxide (CuO) were selected as photocatalytic antimicrobials in MO particles. Physicochemical properties including morphology, particle size/particle size distribution, atomic composition, crystallinity, and porosity were evaluated. Under UV-A and UV-C irradiation with differential UV-C intensities, the antimicrobial activity of MO particles was monitored in E. coli and phage. MO particles had nano-, micro- and nano- to microscale sizes with irregular shapes, composed of atoms as ratios of chemical formulae and presented crystallinity as pure materials. They had wide-range specific surface area levels of 0.40–46.34 m2/g. MO particles themselves showed antibacterial activity against E. coli, which was the highest among the ZnO particles. However, no viral inactivation by MO particles occurred in phage. Under dual UV irradiation, multiscale ZnO and CuO particles had superior antimicrobial activities against E. coli and phage, as mixtures of nano- and microparticles for enhanced photocatalytic antimicrobials. The results showed that the dual UV-multiscale MO particle hybrids exhibit enhanced antibiotic potentials. It can also be applied as a next-generation antibiotic tool in industrial and clinical fields.
Fecal Immunochemical Tests Detect Screening Participants with Multiple Advanced Adenomas Better than T1 Colorectal Cancers

Simple Summary Fecal occult blood tests (FOBTs) detect colorectal cancer (CRC) at high levels of sensitivity and specificity. However, the detection of early-stage cancers is highly important to reduce CRC mortality. We aimed to assess the sensitivity of a large number of different FOBTs according to various tumor characteristics. We observed among all FOBTs consistently lower sensitivities for UICC stage I cancers in comparison to more advanced cancer stages. An even stronger gradient was found according to T status, with substantially lower sensitivities for T1 than for T2–T4 cancers. Furthermore, sensitivities for T1 cancers were even lower than sensitivities for detection of multiple advanced adenomas. Further research should focus on improving the sensitivity of non-invasive tests for detection of UICC stage I and T1 cancers. Abstract Background: Fecal immunochemical tests (FITs) are widely used for colorectal cancer (CRC) screening. The detection of early-stage cancer and advanced adenoma (AA), the most important premalignant lesion, is highly relevant to reducing CRC-related deaths. We aimed to assess sensitivity for the detection of CRC and AA stratified by tumor stage; number; size; histology of AA; and by location, age, sex, and body mass index (BMI). Methods: Participants of screening colonoscopy (n = 2043) and newly diagnosed CRC patients (n = 184) provided a stool sample before bowel preparation or CRC surgery. Fecal hemoglobin concentration was determined in parallel by nine different quantitative FITs among 94 CRC patients, 200 AA cases, and 300 participants free of advanced neoplasm. Sensitivities were calculated at original cutoffs and at adjusted cutoffs, yielding 93% specificity among all FITs. Results: At adjusted cutoffs, UICC stage I cancers yielded consistently lower sensitivities (range: 62–68%) compared to stage II–IV cancers (range: 73–89%). An even stronger gradient was observed according to T status, with substantially lower sensitivities for T1 (range: 39–57%) than for T2–T4 cancers (range: 71–100%). Sensitivities for the detection of participants with multiple AAs ranged from 55% to 64% and were by up to 25% points higher than sensitivities for T1 cancers. Conclusions: FITs detect stage I cancers and especially T1 cancers at substantially lower sensitivities than more advanced cancer stages. Participants with multiple AAs were detected with slightly lower sensitivities than stage I cancers and with even higher sensitivities than T1 cancers. Further research should focus on improving the detection of early-stage cancers.
Who would be targeted by increasing the legal age of sale of cigarettes from 18 to 21? A cross‐sectional study exploring the number and characteristics of smokers in England

Abstract Aims To establish the number of smokers in England who would be targeted by increasing the age of sale of cigarettes from 18 to 21 years and to assess the smoking and socio‐demographic profile of those smokers. Design and setting Nationally representative cross‐sectional survey of adults in England conducted between January 2009 and July 2019. Participants A total of 219 720 adults. Measurements All participants reported their current smoking status and socio‐demographic characteristics (i.e. age, gender, home ownership, social grade and ethnicity). Smokers reported motivation to quit, urges to smoke and the Heaviness of Smoking Index (HIS). Weighted prevalence statistics were calculated. Multinomial regression and logistic regression were used to assess differences in smoking characteristics among smokers and socio‐demographic characteristics relative to non‐smokers. Findings The prevalence of smoking between January 2009 and July 2019 was highest among those aged 21–30. In 2019, 15.6% [95% confidence interval (CI) = 12.8–18.8%] of 18–20‐year‐olds reported smoking, which is estimated to represent 364 000 individuals in England. Relative to smokers aged 18–20, older smokers (aged 21+) had a higher motivation to quit smoking [odds ratios (ORs) = 1.40–1.45 range] and higher nicotine dependency as measured by urges to smoke (ORs = 1.06–1.24 range) and HSI (ORs = 1.05–2.85 range). Compared with non‐smokers aged 18–20, smokers in this age group had lower odds of being female (OR = 0.89) and higher odds of being of white ethnicity (OR = 2.78) and from social grades C1–E (lower social grades) compared with AB (higher social grades) (OR = 1.19–1.83 range). Conclusion Increasing the age of sale of cigarettes to 21 years in England would currently target approximately 364 000 lower dependent smokers from more disadvantaged backgrounds aged 18–20, who have less motivation to quit.