Miracle-dz/UniFAR-FTUs huggingface dataset:
Optimised methods for the production and bioconjugation of site-specific, alkyne-modified glucagon-like peptide-1 (GLP-1) analogs to azide-modified delivery platforms using copper-catalysed alkyne-azide cycloaddition.

This study aimed to develop and optimize chemistries to produce alkyne-modified glucagon-like peptide-1(7-36)-amide (GLP-1(7-36)-NH2) libraries, which could be rapidly and efficiently conjugated to other components, and screened to identify compounds with the best drug delivery properties, as potential treatments for type 2 diabetes or obesity. For this purpose, the Lys26 (K26) side-chain, and the amino (N)- and carboxy (C)-termini of a dipeptidyl peptidase 4 (DPPIV)-resistant GLP-1 sequence (GLP-1(7-36;A8G)-NH2), were modified with an alkyne (4-pentynoic acid or propiolic acid). These analogs were characterized with respect to human GLP-1 receptor (hGLP-1R) agonist activity, effects on cell viability and human serum stability, revealing that these modifications: maintained low (N-terminal; EC50 1.5 × 10-9 M) to sub-nanomolar (C-terminal and K26; ~4 × 10-10 M) agonist activity towards hGLP-1; had no effect on cell viability; and for the N-terminal and K26 modifications, increased human serum proteolytic stability (t1/2 > 24 h). Copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction conditions were investigated using the C-terminal modified GLP-1 analog and an azide-modified model lipid peptide, with respect to the effects of altering the azide:alkyne ratio, co-solvents, temperature, reducing agents, Cu(I)-stabilizing ligand, copper source, and the concentrations of reagents/reactants, in order to identify general conditions that provide fast reactions and high yields. A 1:2 azide-alkyne (lipid:GLP-1 peptide) and 4:1 sodium ascorbate/copper sulfate molar ratio in 65% v/v DMSO-water at room temperature, in the absence of Cu(I)-stabilizing ligands (THPTA or L-histidine) and buffers (phosphate, pH 7), provided the best yields. This work reports a library of characterized GLP-1 analogs, and chemistries for their attachment to other species, providing useful tools to improve GLP-1 delivery and pharmacology (e.g. through conjugation to other species that lower blood glucose, increase the duration of action, or enable delivery via a non-parenteral route).
The Rate of Compliance of Prehypertension Individuals from Dietary Approaches to Stop Hypertension (DASH): An Application of the Theory of Planned Behavior

Background: Prehypertension is a commonly occurring disease around the world as a predictor of high blood pressure. High blood pressure can be delayed by following the prehypertensive diet. This study was conducted to determine the compliance of the DASH program among pre-hypertension individuals by using the Theory of Planned Behavior. Methods: This cross-sectional study was performed on 165 prehypertension individuals in Ferdows City. A researcher-made questionnaire was used to examine the scores of the theory of protection motivation structures. The diet was measured by using a threeday dietary questionnaire. Validity and reliability of the instrument were confirmed. The data were analyzed by means of correlation coefficient, chi-square, and linear regression. Results: The average Dash diet compliance was 25.24 ± 4.7. Demographic variables did not have a meaningful relationship with the Dash diet. The positive and direct correlation was observed between all the structures. The structures of Theory of Planned Behavior predicted 72% of variance in behavioral intention. The role of the attitude construct was more than other constructs in predict of intention (β=0.392). Conclusion: Considering the medium rate of compliance of the diet plan and TPB function in predicting behavior, it is suggested to use predictive constructs in designing educational interventions in order to increase the compliance rate of the food program.
Persistent Innate Immune Stimulation Results in IRF3-Mediated but Caspase-Independent Cytostasis

Persistent virus infection continuously produces non-self nucleic acids that activate cell-intrinsic immune responses. However, the antiviral defense evolved as a transient, acute phase response and the effects of persistently ongoing stimulation onto cellular homeostasis are not well understood. To study the consequences of long-term innate immune activation, we expressed the NS5B polymerase of Hepatitis C virus (HCV), which in absence of viral genomes continuously produces immune-stimulatory RNAs. Surprisingly, within 3 weeks, NS5B expression declined and the innate immune response ceased. Proteomics and functional analyses indicated a reduced proliferation of those cells most strongly stimulated, which was independent of interferon signaling but required mitochondrial antiviral signaling protein (MAVS) and interferon regulatory factor 3 (IRF3). Depletion of MAVS or IRF3, or overexpression of the MAVS-inactivating HCV NS3/4A protease not only blocked interferon responses but also restored cell growth in NS5B expressing cells. However, pan-caspase inhibition could not rescue the NS5B-induced cytostasis. Our results underline an active counter selection of cells with prolonged innate immune activation, which likely constitutes a cellular strategy to prevent persistent virus infections.
Molecular Investigation of Mechanical Properties and Fracture Behavior of Graphene Aerogel.

An unusual combination of ultralight-weight and outstanding mechanical properties of graphene aerogel made it popular for a wide range of applications in the fields of material science, energy and technology. In the present work, the mechanical properties and fracture behavior of graphene aerogels, which are highly brittle in nature, are investigated using molecular dynamics (MD) simulations. In tensile tests, elastic modulus and tensile strength exhibit a power-law dependence on the density with their exponents predicted to be 2.95±0.05 and 1.61±0.04, respectively, which are in an excellent agreement with the reported works in the literature. In the compression simulations, Lennard-Jones contribution in the AIREBO potential is vital to predicting early densification. Moreover, in the compression loading-unloading simulations, as the density decreases, the dissipation energy increases. At the onset of the crack propagation, as the crack length to height ratio increases, the fracture strength decreased. However, for a considered range of the ratios, the fracture toughness values were nearly constant for all densities. Furthermore, the fracture toughness shows a power-law dependence on the density, with the exponent estimated to be 1.41±0.04. The outcome of this work is a vital step in the in-depth understanding of nanomechanics while designing advanced, highly porous materials.
Effect of Different Combinations of Phosphorus and Nitrogen Fertilization on Arbuscular Mycorrhizal Fungi and Aphids in Wheat

While chemical fertilizers can be used to increase crop yield, the abuse of fertilizers aggravates environmental pollution and soil degradation. Understanding the effects of chemical fertilizers on the interaction between arbuscular mycorrhizal fungi (AMF) and pest insects is of great benefit to crop and environmental protection, because AMF can enhance the nutrition absorption and insect resistance of crops. This study tested the effect of different levels of phosphorus, nitrogen, and their interactions on AMF, secondary metabolites, Sitobion avenae in garden, as well as the wheat traits in field. The results showed that AMF colonization on roots in the P0N1 treatment (0 g P/pot, 1.3083 g N/pot in the garden, and 0 g P/plot, 299.84 g N/plot) was the highest in both the garden and the field. The abundance of aphid was reduced in the P0N1 treatment, and there were negative relationships between aphids and AMF and phenolics, but a positive relationship between AMF and phenolics. Our results indicated that a change in the ratio of phosphorus to nitrogen affects the relationship among AMF, aphid abundance, and metabolites. The results also suggested an approach to save chemical fertilizers that could improve crop health and protect the agroecosystem against pollution at the same time.
Constitutive modelling approach for evaluating the triggering of flow slides

The paper presents a methodology to evaluate flow slide susceptibility in potentially liquefiable sandy slopes. The proposed approach accounts for both contractive and dilative volumetric behaviour during shearing using the MIT-S1 constitutive model. As a result, it is possible to distinguish among different types of undrained response induced by a rapid shear perturbation. The first part of the paper describes the general methodology for infinite slopes, providing an index of stability for incipient static liquefaction in shallow deposits. The methodology accounts for the anisotropy due to the initial stress state and uses simple shear simulations to assess instability conditions as a function of slope angle, stress state, and density of the soil. The resulting stability charts define the margin of safety against static liquefaction and the depths likely to be affected by the propagation of an instability. The second part of the paper applies the methodology to the well-known series of flow failures in a.
TPC2-mediated Ca2+ signaling is required for axon extension in caudal primary motor neurons in zebrafish embryos

ABSTRACT The role of two-pore channel type 2 (TPC2, encoded by tcpn2)-mediated Ca2+ release was recently characterized in zebrafish during establishment of the early spinal circuitry, one of the key events in the coordination of neuromuscular activity. Here, we extend our study to investigate the in vivo role of TPC2 in the regulation of caudal primary motor neuron (CaP) axon extension. We used a combination of TPC2 knockdown with a translation-blocking morpholino antisense oligonucleotide (MO), TPC2 knockout via the generation of a tpcn2dhkz1a mutant line of zebrafish using CRISPR/Cas9 gene-editing and pharmacological inhibition of TPC2 via incubation with bafilomycin A1 (an H+-ATPase inhibitor) or trans-ned-19 (an NAADP receptor antagonist), and showed that these treatments attenuated CaP Ca2+ signaling and inhibited axon extension. We also characterized the expression of an arc1-like transcript in CaPs grown in primary culture. MO-mediated knockdown of ARC1-like in vivo led to attenuation of the Ca2+ transients in the CaP growth cones and an inhibition of axon extension. Together, our new data suggest a link between ARC1-like, TPC2 and Ca2+ signaling during axon extension in zebrafish. Summary: Characterization of two-pore channel type 2 (TPC2)-mediated Ca2+ release and ADP-ribosyl cyclase 1-like (ARC1-like) activity during axon extension of caudal primary motor neurons (CaPs) in zebrafish embryos.
Mental Health of Spanish Immigrants in Germany and the UK in Comparison to Non-Immigrants and Migration Protective Factors

The global economic crisis of the previous decade has accelerated internal mobility in the European Union. The main objective was to analyse perceived stress and mental health among Spanish immigrants and non-immigrants, as well as gender differences, and to examine the mediation role of perceived stress in the relationship between migration protective factors and mental health. A convenience sample (N = 941) was obtained by snowball sampling, contacting with social networks during 2014 and 2015. Spanish immigrants (n = 719) living in Germany or United Kingdom and non-immigrants (n = 222) living in Spain answered an online survey with a questionnaire about socio-demographic and migration variables (immigrants) as well as PSS-14 and GQH-28. The low level of perceived stress and mental health symptoms found were similar in Spanish immigrants and non-immigrants. Women immigrants presented slightly higher rates of prevalence of somatisation and anxiety/insomnia and higher perceived stress. A parsimonious structural equation model with two protective migration factors was obtained (R2 = .58), which had direct and indirect effects on mental health through perceived stress. The migration process was not related to poorer mental health in the European context, and gender differences were small. These findings could be explained by the privileged migration conditions of Spanish immigrants.
Voltage-Dependent Anion Channels Influence Cytotoxicity of ME-344, a Therapeutic Isoflavone

ME-344 is a second-generation cytotoxic isoflavone with anticancer activity promulgated through interference with mitochondrial functions. Using a click chemistry version of the drug together with affinity-enriched mass spectrometry, voltage-dependent anion channels (VDACs) 1 and 2 were identified as drug targets. To determine the importance of VDAC1 or 2 to cytotoxicity, we used lung cancer cells that were either sensitive (H460) or intrinsically resistant (H596) to the drug. In H460 cells, depletion of VDAC1 and VDAC2 by small interfering RNA impacted ME-344 effects by diminishing generation of reactive oxygen species (ROS), preventing mitochondrial membrane potential dissipation, and moderating ME-344–induced cytotoxicity and mitochondrial-mediated apoptosis. Mechanistically, VDAC1 and VDAC2 knockdown prevented ME-344–induced apoptosis by inhibiting Bax mitochondrial translocation and cytochrome c release as well as apoptosis in these H460 cells. We conclude that VDAC1 and 2, as mediators of the response to oxidative stress, have roles in modulating ROS generation, Bax translocation, and cytochrome c release during mitochondrial-mediated apoptosis caused by ME-344. SIGNIFICANCE STATEMENT Dissecting preclinical drug mechanisms are of significance in development of a drug toward eventual Food and Drug Administration approval.
Comparison of Metabolome and Transcriptome of Flavonoid Biosynthesis Pathway in a Purple-Leaf Tea Germplasm Jinmingzao and a Green-Leaf Tea Germplasm Huangdan reveals Their Relationship with Genetic Mechanisms of Color Formation

Purple-leaf tea is a phenotype with unique color because of its high anthocyanin content. The special flavor of purple-leaf tea is highly different from that of green-leaf tea, and its main ingredient is also of economic value. To probe the genetic mechanism of the phenotypic characteristics of tea leaf color, we conducted widely targeted metabolic and transcriptomic profiling. The metabolites in the flavonoid biosynthetic pathway of purple- and green-leaf tea were compared, and results showed that phenolic compounds, including phenolic acids, flavonoids, and tannins, accumulated in purple-leaf tea. The high expression of genes related to flavonoid biosynthesis (e.g., PAL and LAR) exhibits the specific expression of biosynthesis and the accumulation of these metabolites. Our result also shows that two CsUFGTs were positively related to the accumulation of anthocyanin. Moreover, genes encoding transcription factors that regulate flavonoids were identified by coexpression analysis. These results may help to identify the metabolic factors that influence leaf color differentiation and provide reference for future research on leaf color biology and the genetic improvement of tea.
Windborne debris risk analysis - Part II. Application to structural vulnerability modeling

The `chain reaction` effect of the interaction between wind pressure and windborne debris is likely to be a major cause of damage to residential buildings during severe wind events. The current paper (Part II) concerns the quantification of such pressure-debris interaction in an advanced vulnerability model that integrates the debris risk model developed in Part I and a component-based wind-pressure damage model. This vulnerability model may be applied to predict the cumulative wind damage during the passage of particular hurricanes, to estimate annual hurricane losses, or to conduct system reliability analysis for residential developments, with the effect of windborne debris fully considered.
Predictors of rate of cognitive decline in patients with amnestic mild cognitive impairment

Abstract Objective Amnestic mild cognitive impairment (MCI) is a known risk factor for conversion to Alzheimer’s disease (AD). Although substantial research has been conducted on the general profile of amnestic MCI subjects and predictors of conversion to AD, research on predictors of rate of decline has been considerably less extensive. The present study sought to more systematically and comprehensively examine predictors of rate of cognitive decline in a longitudinal sample of individuals with MCI, including age, genetic vulnerability, baseline cognitive performance, and baseline neuropsychiatric severity. Method Participants with single or multi-domain amnestic MCI (N = 151) were assessed at baseline and for a mean of 1.32 follow-up visits (mean interval from baseline to last follow-up = 1.61 years). Results Results showed that carriers of the ApoE ε4 allele declined more quickly on all three dementia severity measures compared to non-carriers. Older individuals did not decline more rapidly in dementia severity. Participants with lower executive functions composite scores and greater memory impairment severity at baseline predicted faster decline on dementia severity measures. Contrary to hypotheses, those with lower levels of depression at baseline declined more rapidly on dementia severity measures compared to those with higher levels of depression. Conclusion Identifying potential predictors of rate of decline from amnestic MCI to AD could be clinically meaningful for prognostic purposes, understanding risk and protective factors, as well as guiding future treatments and clinical trials that could aim to target and delay progression among those patients who are vulnerable to more quickly convert to AD.
Prevalence and Epitope Recognition of Anti-Trypanosoma cruzi Antibodies in Two Procyonid Species: Implications for Host Resistance

More than 180 mammalian species have been found naturally infected with Trypanosoma cruzi. Many of them play an important role in the maintenance of this parasite. In particular, new studies have appeared which indicate that some species of Procyonidae family may play a role as T. cruzi hosts, however, more data are needed to evaluate their long-term physiological response to parasite infection, especially for specific antibodies. In this study, antibodies to T. cruzi were detected and prevalence and epitope recognition were assessed by ELISA (using discrete typing unit (DTU) I as antigen) and WB (using DTU I and DTU II as antigens) and sera from two procyonid species obtained through five-year follow-up of two semicaptive populations living in the same habitat. Marked heterogeneity in antigens recognition between species and differences in seroprevalence (p = 0.0002) between white-nosed coatis (Nasua narica), 51.8% (115/222), and common raccoons (Procyon lotor), 28.3% (23/81), were found. Antigens with high molecular weight when DTU-I was used were the most recognized, while a greater antigen diversity recognition was observed with DTU-II; for white-nosed coatis, low-molecular-weight antigens were mainly recognized, while for common raccoons proteins with molecular weights greater than 80 kDa were recognized most. These divergent humoral immune responses could be related to an alleged pattern of recognition receptors and major histocompatibility complex molecules difference in the procyonids species.
The Advertising Policies of Major Social Media Platforms Overlook the Imperative to Restrict the Exposure of Children and Adolescents to the Promotion of Unhealthy Foods and Beverages

There have been global calls to action to protect children (aged <18) from exposure to the marketing of unhealthy foods and beverages (‘unhealthy foods’). In this context, the rising popularity of social media, particularly amongst adolescents, represents an important focus area. This study aimed to examine the advertising policies of major global social media platforms related to the advertising of unhealthy foods, and to identify opportunities for social media platforms to take action. We conducted a desk-based review of the advertising policies of the 16 largest social media platforms globally. We examined their publicly available advertising policies related to food and obesity, as well as in relation to other areas impacting public health. The advertising policies for 12 of the selected social media platforms were located. None of these platforms adopted comprehensive restrictions on the advertising of unhealthy foods, with only two platforms having relevant (but very limited) policies in the area. In comparison, 11 of the 12 social media platforms had policies restricting the advertising of alcohol, tobacco, gambling, and/or weight loss. There is, therefore, an opportunity for major social media platforms to voluntarily restrict the exposure of children to the marketing of unhealthy foods, which can contribute to efforts to improve populations’ diets.
Separate N‐acetyl aspartyl glutamate, N‐acetyl aspartate, aspartate, and glutamate quantification after pediatric mild traumatic brain injury in the acute phase

To separately measure N‐acetyl aspartul glutamate (NAAG), N‐acetyl aspartate (NAA), aspartate (Asp), and glutamate (Glu) concentrations in white matter (WM) using J‐editing techniques in patients with mild traumatic brain injury (mTBI) in the acute phase.
Comparison between Communicated and Calculated Exposure Estimates Obtained through Three Modeling Tools

This study aims to evaluate the risk assessment approach of the REACH legislation in industrial chemical departments with a focus on the use of three models to calculate exposures, and discuss those factors that can determine a bias between the estimated exposure (and therefore the expected risk) in the extended safety data sheets (e-SDS) and the expected exposure for the actual scenario. To purse this goal, the exposure estimates and risk characterization ratios (RCRs) of registered exposure scenarios (ES; “communicated exposure” and “communicated RCR”) were compared with the exposure estimates and the corresponding RCRs calculated for the actual, observed ES, using recommended tools for the evaluation of exposure assessment and in particular the following tools: (i) the European Centre for Ecotoxicology and Toxicology of Chemicals Targeted Risk Assessment v.3. 1 (ECETOC TRA), (ii) STOFFENMANAGER® v.8. 0 and (iii) the Advanced REACH Tool (ART). We evaluated 49 scenarios in three companies handling chemicals. Risk characterization ratios (RCRs) were calculated by dividing estimated exposures by derived no-effect levels (DNELs). Although the calculated exposure and RCRs generally were lower than communicated, the correlation between communicated and calculated exposures and RCRs was generally poor, indicating that the generic registered scenarios do not reflect actual working, exposure and risk conditions. Further, some observed scenarios resulted in calculated exposure values and RCR higher than those communicated through chemicals’ e-SDSs; thus ‘false safe’ scenarios (calculated RCRs > 1) were also observed. Overall, the obtained evidences contribute to doubt about whether the risk assessment should be performed using generic (communicated by suppliers) ES with insufficient detail of the specific scenario at all companies. Contrariwise, evidences suggested that it would be safer for downstream users to perform scenario-specific evaluations, by means of proper scaling approach, to achieve more representative estimates of chemical risk.
Latency and Asset Prices

We measure message processing time or latency inside an automated trading platform. We show that latency is a random variable that has a strong predictive power over both volatility and the volatility of volatility of a highly liquid asset over and above changes in message traffic. We argue that in automated markets, processing time contains valuable nontrade information about the price formation process. We recommend that automated trading platforms improve pre-trade price transparency by reporting characteristics of latency to market participants on an ongoing basis along with order book events, transaction prices, and trading volume.