Miracle-dz/UniFAR-FTUs huggingface dataset:
The anomalous pharmacology of fentanyl

Fentanyl is a key therapeutic, used in anaesthesia and pain management. It is also increasingly used illicitly and is responsible for a large and growing number of opioid overdose deaths, especially in North America. A number of factors have been suggested to contribute to fentanyl's lethality, including rapid onset of action, in vivo potency, ligand bias, induction of muscle rigidity and reduced sensitivity to reversal by naloxone. Some of these factors can be considered to represent ‘anomalous’ pharmacological properties of fentanyl when compared with prototypical opioid agonists such as morphine. In this review, we examine the nature of fentanyl's ‘anomalous’ properties, to determine whether there is really a pharmacological basis to support the existence of such properties, and also discuss whether such properties are likely to contribute to overdose deaths involving fentanyls.
Evaluation of aromatase inhibitor on radiation induced pulmonary fibrosis via TGF- β/Smad 3 and TGF- β/PDGF pathways in rats

Abstract Radiation-induced pulmonary fibrosis (RIPF) is a known complication in cancer patients after getting thoracic radiotherapy. Aromatase inhibitors (AIs) as anastrozole have been used instead of tamoxifen for adjuvant endocrine treatment of postmenopausal women with hormone sensitive breast cancer. This study is to evaluate the concurrent treatment of anastrozole and RIPF in rats. Twenty four female Wistar rats were distributed into 4 groups: Control (C), Radiation group (R) (total dose 30 Gy in 10 fractions, 5 fractions/week), anastrozole group (A) (0.003 mg/200 g body weight) orally for 14 consecutive days, and Radiation + anastrozole group (R + A). Radiation exposure resulted in a significant increase (p < 0.05) in pulmonary Transforming growth factor-beta 1 (TGF-β), SMAD family member 3 (Smad3), Platelet-derived growth factor (PDGF), malondialdehyde (MDA), Total nitrate/nitrite (NO), interleukin 1β (IL-1β) and interleukin 6 (IL-6) compared to the control group. While, significant decreases (p < 0.05) in superoxide dismutase (SOD) activity, reduced glutathione (GSH) and connective tissue growth factor (CTGF) were observed in lung tissue. These alterations were minimized by anastrozole intervention. Also, anastrozole markedly hindered the lung histopathological changes observed after radiation. Concomitant use of anastrozole with radiation seems to attenuate radiation-induced pulmonary toxicity via TGF-β/Smad 3 and TGF-β/PDGF pathways in rats.
Oral Ferric Maltol for the Treatment of Iron-Deficiency Anemia in Patients With CKD: A Randomized Trial and Open-Label Extension.

RATIONALE & OBJECTIVE Iron-deficiency anemia is common in patients with chronic kidney disease (CKD) not requiring maintenance dialysis. We evaluated effects of oral iron replacement therapy with ferric maltol in these patients. STUDY DESIGN Phase 3, double-blind, randomized, placebo-controlled trial (AEGIS-CKD) and open-label extension. SETTING & PARTICIPANTS Adults with stage 3/4 CKD and iron-deficiency anemia at 30 US centers. INTERVENTION Oral ferric maltol 30 mg or placebo twice daily for 16 weeks (2:1 randomization) followed by ferric maltol 30 mg twice daily for up to 36 weeks (all patients). OUTCOMES Change from baseline in hemoglobin (primary endpoint at week 16), ferritin, transferrin saturation, and serum iron; safety. RESULTS 167 patients were randomized (ferric maltol n = 111, placebo n = 56). At week 16, hemoglobin had increased significantly with ferric maltol versus placebo (least-squares mean [standard error] difference: 0.5 [0.2] g/dL; 95% confidence interval 0.1-0.9; P=0.01). Ferritin, transferrin saturation, and serum iron increased with ferric maltol but declined with placebo (all P<0.05). Hemoglobin levels were sustained up to week 52 in patients continuing ferric maltol and increased in patients switching from placebo to ferric maltol. The most frequent adverse events were gastrointestinal (randomized phase: ferric maltol 41%, placebo 30%; open-label phase: 56% vs 46%, respectively). Adverse events led to treatment withdrawal in 7 patients (6%) receiving ferric maltol and 5 patients (9%) receiving placebo during double-blind treatment, and 11 patients (9%) during the open-label extension. LIMITATIONS Heterogeneity in baseline ferritin levels; high proportion of female participants; single-arm open-label extension. CONCLUSIONS Ferric maltol was associated with statistically significant (week 16) and sustained (up to week 52) increases in hemoglobin and iron indices in patients with CKD and iron deficiency, and was well tolerated during treatment for up to 52 weeks.
Genetic and in silico analysis show a role of SMAD3 on recurrent pregnancy loss

Abstract Recurrent pregnancy loss (RPL) is one of the most common reproductive failures affecting 1–5% of couples. Smad3 is an effector of signalling of the Transforming Growth Factors-β superfamily (TGF-β), regulating the transcription of several target genes of these cytokines. The objective of this study was to evaluate the influence of a variant on SMAD3 (rs17293443) in RPL. A case-control study was carried out with 149 women who experienced RPL and 159 controls, as well as bioinformatics tools to determine the role of this variant in this condition. Our study showed an allelic (p = 0.023) and genotypic (p < 0.01) association of this variant with the RPL. Our functional in silico predictions suggest that this variant causes a change in SMAD3 expression levels. Alterations in the expression of this gene can directly compromise the Smad3-dependent signalling pathway that is fundamental for key processes for gestation such as steroid hormone regulation and implantation, as demonstrated by ontologies analyses performed and the literature. Our findings regarding the involvement of Smad3 on RPL are a novelty in this field, and they seem to be promising to the clinical management of this condition.
Phonological vs. natural gender cues in the acquisition of German by simultaneous and sequential bilinguals (German–Russian)

Abstract We investigate German–Russian bilingual children's sensitivity to formal and semantic cues when assigning gender to nouns in German. Across languages, young children have been shown to primarily rely on phonological cues, whereas sensitivity to semantic and syntactic cues increases with age. With its semi-transparent gender assignment system, where both formal and semantic cues are psycho linguistically relevant, German has weak phonological cues compared to other languages, and children have been argued to acquire semantic and phonological rules in tandem. German–Russian bilingual children face the challenge of acquiring two different gender assignment systems simultaneously. We tested 45 bilingual children (ages 4–10 years) and monolingual controls. Results show that the children are clearly sensitive to phonological cues, while semantic cues play a minor role. However, monolingual and bilingual children have different defaulting strategies, with monolinguals defaulting to neuter and bilinguals to feminine gender.
New horizons in the treatment of neurological disorders with tailorable gold nanoparticles.

Neurological disorders, such as epilepsy, dementia, Parkinson's disease, and Alzheimer's disease, occur due to disorganization of the neurons in the nervous system. Disturbances in the nervous system cause problems with memory, senses and moods. In order to treat such disorders, scientists have been working extensively by using different approaches. Nanoneurotechnology has emerged as a promising tool to manage these complicated disorders, where nanoparticles with their tunable properties such as size, shape, increased solubility, biodegradability, surface area and sharp penetration through the biological barriers target the central nervous system. This technology targets damaged neurons without affecting healthy neurons and Blood-Brain Barrier (BBB). In this review, we discuss neurological disorders and challenges in the diagnosis and treatment of neurological disorders by emphasizing the role of tailorable gold nanoparticles for therapeutic drug approaches.
Convergent validity, academic correlates and age- and SES-based normative data for the d2 Test of attention in children

Abstract The d2, test of attention is one of the most used neuropsychological tests to measure attention in clinical and research settings. To date, no studies have examined neither its convergent and divergent validity in children nor its relationship with academic skills at school age. The aims of the present study were: (1) to examine the convergent and divergent validity of the d2 Test in a non-clinical pediatric population, (2) to explore the relationship between d2 task performance and academic skills (i.e., math, reading and writing abilities) and (3) to develop normative data for Spanish-speaking children (n = 360 8- to 12-year-old children) stratified by age and socioeconomic status (SES). Pearson's correlation and Structural Equation Models (SEM) were used to analyze the d2 Test validity and its relationship with academic skills. A between-subjects factorial MANOVA was used to examine differences among SES (Middle, Low), age (8–10, 11–12), and sex (male, female). Findings revealed a significant relationship between d2 task performance and all attention and executive functions (EF) measures under analysis providing evidence of good convergent validity. Furthermore, SEM results showed that attention has direct effects on math and reading and writing skills. Finally, our study confirms the influence of age and SES on d2 task performance and provides normative data for middle- and low-SES children. These results have important implications for the assessment of attention functions in clinical and research settings in children with typical and atypical development.
Synthesis of flavour‐related linalool is regulated by PpbHLH1 and associated with changes in DNA methylation during peach fruit ripening

Summary Linalool is one of the common flavour‐related volatiles across the plant kingdom and plays an essential role in determining consumer liking of plant foods. Although great process has been made in identifying terpene synthase (TPS) genes associated with linalool synthesis, much less is known about regulation of this pathway. We initiated study by identifying PpTPS3 encoding protein catalysing enantiomer (S)‐(+)‐linalool synthesis, which is a major linalool component (˜70%) observed in ripe peach fruit. Overexpression of PpTPS3 led to linalool accumulation, while virus‐induced gene silencing of PpTPS3 led to a 66.5% reduction in linalool content in peach fruit. We next identified transcription factor (TF) PpbHLH1 directly binds to E‐box (CACATG) in the PpTPS3 promoter and activates its expression based on yeast one‐hybrid assay and EMSA analysis. Significantly positive correlation was also observed between PpbHLH1 expression and linalool production across peach cultivars. Peach fruit accumulated more linalool after overexpressing PpbHLH1 in peach fruit and reduced approximately 54.4% linalool production after silencing this TF. DNA methylation analysis showed increased PpTPS3 expression was associated with decreased 5 mC level in its promoter during peach fruit ripening, but no reverse pattern was observed for PpbHLH1. Arabidopsis and tomato fruits transgenic for peach PpbHLH1 synthesize and accumulate higher levels of linalool compared with wild‐type controls. Taken together, these results would greatly facilitate efforts to enhance linalool production and thus improve flavour of fruits.
Platelet reticulated forms, size indexes and functional activity. Interactions in healthy volunteers.

Abstract Reticulated platelets (RP) are young, functionally active platelet forms which are detected by RNA staining. Their content in the circulation reflects the intensity of bone marrow thrombocytopoesis. The aim of this study was to assess in healthy volunteers the relationship between RP percentage and platelet size and activity. RP were quantitated by thiazole orange staining using flow cytometry. Platelet size indexes included mean platelet volume (MPV), platelet large cell ratio (P-LCR) measured in a Coulter type hematological analyzer and forward scattering (FSC) measured in a flow cytometer. Platelet functional activity was evaluated by expression of activated glycoprotein (GP) IIb-IIIa (PAC-1 antibody binding) and P-selectin with the use of flow cytometry. Platelets were activated by thrombin receptor activating peptide (TRAP) (10 and 1 µM) and ADP (20 and 2.5 µM). The percentage of RP in healthy volunteers varied from 2.9% to 23.8% (mean ± SD ‒ 11.7 ± 4.7%, n = 99) and correlated with all platelet size indexes: MPV, P-LCR and FCS (r from 0.452 to 0.529, p < .001, n = 87–99). On average, RP were distributed at a ratio of 9:1 between 50% subpopulations of large and small platelets according to their FSC index. Expression of GP IIb-IIIa activated form correlated with RP percentage and platelet size indexes when platelets were activated by TRAP and ADP at both applied concentrations (r from 0.309 to 0.560, p from 0.014 to < 0.001, n = 50–62). P-selectin expression correlated with RP percentage and platelet size indexes when platelets were activated by 10 µM TRAP inducing maximum expression of this activation marker (r from 0.332 to 0.556, p from 0.008 to < 0.001, n = 65), but not by weaker agonists: 1 µM TRAP, 20 and 2.5 µM ADP (r < 0.3, n = 54–66). Thus, high RP content in healthy volunteers is associated with increased platelet size and activity in the whole platelet population.
Altered cerebellar-cortical resting-state functional connectivity in cannabis users

Background: Cannabis use has been associated with abnormalities in cerebellar mediated motor and non-motor (i.e. cognition and personality) phenomena. Since the cerebellum is a region with high cannabinoid type 1 receptor density, these impairments may reflect alterations of signaling between the cerebellum and other brain regions. Aims: We hypothesized that cerebellar-cortical resting-state functional connectivity (rsFC) would be altered in cannabis users, relative to their non-using peers. It was also hypothesized that differences in rsFC would be associated with cannabis use features, such as age of initiation and lifetime use. Methods: Cerebellar-cortical and subcortical rsFCs were computed between 28 cerebellar lobules, defined by a spatially unbiased atlas template of the cerebellum, and individual voxels in the cerebral regions, in 41 regular cannabis users (20 female) and healthy non-using peers (N = 31; 18 female). We also investigated associations between rsFC and cannabis use features (e.g. lifetime cannabis use and age of initiation). Results: Cannabis users demonstrated hyperconnectivity between the anterior cerebellar regions (i.e. lobule I-IV) with the posterior cingulate cortex, and hypoconnectivity between the rest of the cerebellum (i.e. Crus I and II, lobule VIIb, VIIIa, VIIIb, IX, and X) and the cortex. No associations were observed between features of cannabis use and rsFC. Conclusions: Cannabis use was associated with altered patterns of rsFC from the cerebellum to the cerebral cortex which may have a downstream impact on behavior and cognition.
Methylammonium Lead Bromide Perovskite-Based Solar Cells by Vapor-Assisted Deposition

The past two years have seen the uniquely rapid emergence of a new class of solar cell based on organic–inorganic halide perovskite. Although less explored than its tri-iodide counterparts, CH3NH3PbBr3 has a larger bandgap of 2.3 eV with a higher voltage potential that is suitable for tandem solar cell applications. In this paper, we report a vapor-assisted method for depositing and fully crystallizing CH3NH3PbBr3 film on mesoporous TiO2 with good coverage. CH3NH3PbBr3 fabricated using this method has demonstrated long carrier diffusion length (>1 μm) as estimated by transient photoluminescence-quenching measurements. We demonstrate solar cells fabricated using such films and spiro-OMeTAD as the hole transport layer with an averaged (from forward and reverse scans) conversion efficiency of 8.7%, Voc of 1.45 V, Jsc of 9.75 mA/cm2, and fill factor of 61.5%.
Comparing the Impacts of Sediment‐Spiked Cadmium on Chironomidae Larvae in Laboratory Bioassays and Field Microcosms and the Implications for Field Validation of Site‐Specific Threshold Concentrations

Information on the effects of pollutants in sediments at an ecosystem level to validate current and proposed risk‐assessment procedures is scarce. The most frequent criticism of these procedures is that responses of surrogate species in the laboratory are not representative of responses of natural populations. A tiered approach using both laboratory and microcosm exposures (96‐h and 21‐d laboratory bioassays and a 3‐mo field microcosm) was conducted to compare the impacts of sediment‐spiked cadmium on the mortality, development, and abundance of Chironomidae larvae. The 96‐h and 21‐d lethal concentrations of sediment‐spiked Cd to 50% of the species Chironomus riparius were estimated to be 201.07 and 172.66 mg/kg, respectively. In the 21‐d laboratory bioassay, the endpoints, including the development rate and emergence ratio, were compared, and the lowest‐observed‐effect concentration (LOEC) values were 325.8 and 10.7 mg/kg, respectively. The abundance, richness, and biomass of field‐collected larvae were compared among the different treatments in the field microcosm, and it was found that the order of sensitivities using different endpoints was biomass (2.6/5.2 mg/kg of no‐observed‐effect concentration/LOEC) > diversity (10.7/21.2 mg/kg) > abundance (41.2/82.7 mg/kg). The toxicity values based on lethal/sublethal changes in the laboratory bioassays might not fully protect field organisms against damage from chemicals, such as Cd, unless an assessment factor of 5 is used. These findings highlight the need to conduct field validation of criteria/guidelines before they are introduced to protect organisms/ecosystems in the field and provide a preliminary template for future field validation of criteria elsewhere. Environ Toxicol Chem 2021;40:2450–2462. © 2021 SETAC
Implant- and anesthesia-related factors affecting cardiopulmonary threshold intensities for vagus nerve stimulation

Objective. Vagus nerve stimulation (VNS) is typically delivered at increasing stimulus intensity until a neurological or physiological response is observed (‘threshold’) for dose calibration, preclinically and therapeutically. Factors affecting VNS thresholds have not been studied systematically. In a rodent model of VNS we measured neural and physiological responses to increasing VNS intensity, determined neurological and physiological thresholds and examined the effect of implant- and anesthesia-related factors on thresholds. Approach. In acute and chronic vagus implants (45 and 20 rats, respectively) VNS was delivered under isoflurane, ketamine-xylazine, or awake conditions. Evoked compound action potentials (CAPs) were recorded and activation of different fiber types was extracted. Elicited physiological responses were registered, including changes in heart rate (HR), breathing rate (BR), and blood pressure (BP). CAP and physiological thresholds were determined. Main results. The threshold for evoking discernable CAPs (>10 µV) (CAP threshold) is significantly lower than what elicits 5%–10% drop in heart rate (heart rate threshold, HRT) (25 µA ± 1.8 vs. 80 µA ± 5.1, respectively; mean ± SEM). Changes in BP and small changes in BR (bradypnea) occur at lowest intensities (70 µA ± 8.3), followed by HR changes (80 µA ± 5.1) and finally significant changes in BR (apnea) (310 μA ± 32.5). HRT and electrode impedance are correlated in chronic (Pearson correlation r= 0.47; p< 0.001) but not in acute implants (r = −0.34; p NS); HRT and impedance both increase with implant age (r= 0.44; p< 0.001 and r = 0.64; p < 0.001, respectively). HRT is lowest when animals are awake (200 µA ± 35.5), followed by ketamine-xylazine (640 µA ± 151.5), and isoflurane (1000 µA ± 139.5). The sequence of physiological responses with increasing VNS intensity is the same in anesthetized and awake animals. Pulsing frequency affects physiological responses but not CAPs. Significance. Implant age, electrode impedance, and type of anesthesia affect VNS thresholds and should be accounted for when calibrating stimulation dose.
MAP4K4 expression in cardiomyocytes: multiple isoforms, multiple phosphorylations and interactions with striatins

The Ser/Thr kinase MAP4K4, like other GCKIV kinases, has N-terminal kinase and C-terminal citron homology (CNH) domains. MAP4K4 can activate c-Jun N-terminal kinases (JNKs), and studies in the heart suggest it links oxidative stress to JNKs and heart failure. In other systems, MAP4K4 is regulated in striatin-interacting phosphatase and kinase (STRIPAK) complexes, in which one of three striatins tethers PP2A adjacent to a kinase to keep it dephosphorylated and inactive. Our aim was to understand how MAP4K4 is regulated in cardiomyocytes. The rat MAP4K4 gene was not properly defined. We identified the first coding exon of the rat gene using 5′-RACE, we cloned the full-length sequence and confirmed alternative-splicing of MAP4K4 in rat cardiomyocytes. We identified an additional α-helix C-terminal to the kinase domain important for kinase activity. In further studies, FLAG-MAP4K4 was expressed in HEK293 cells or cardiomyocytes. The Ser/Thr protein phosphatase inhibitor calyculin A (CalA) induced MAP4K4 hyperphosphorylation, with phosphorylation of the activation loop and extensive phosphorylation of the linker between the kinase and CNH domains. This required kinase activity. MAP4K4 associated with myosin in untreated cardiomyocytes, and this was lost with CalA-treatment. FLAG-MAP4K4 associated with all three striatins in cardiomyocytes, indicative of regulation within STRIPAK complexes and consistent with activation by CalA. Computational analysis suggested the interaction was direct and mediated via coiled-coil domains. Surprisingly, FLAG-MAP4K4 inhibited JNK activation by H2O2 in cardiomyocytes and increased myofibrillar organisation. Our data identify MAP4K4 as a STRIPAK-regulated kinase in cardiomyocytes, and suggest it regulates the cytoskeleton rather than activates JNKs.
A Computational and Experimental Study to Compare the Effectiveness of Bipolar Mode With Phase‐Shift Angle Mode in Radiofrequency Fat Dissolution on Subcutaneous Tissue

Radiofrequency (RF) energy exposure refers to a popular non‐invasive method employed to generate heat in cutaneous and subcutaneous tissues. RF thermal stimulation of adipose tissue has been considered to cause adipocyte metabolism and enzymatic degradation of triglycerides into free fatty acids and glycerol. Bipolar mode (BM) has achieved extensive applications in clinical studies on RF fat dissolution, whereas BM has a less penetration depth than monopolar, result in a higher RF voltage that may be required to increase power to the deeper fat layer of the subcutaneous tissue, and improper power control may easily cause the skin layer to be thermally damaged. To tackle down the mentioned defect, a novel phase‐shift angle mode (PM) was proposed in this study based on double‐channel bipolar RF. By employing the finite element method (FEM) and performing the ex vivo experiment, the effectiveness of BM was compared with that of PM in RF fat dissolution on subcutaneous tissue. In addition, this study attempted to develop reasonable phase‐shift angles capable of achieving fat dissolution effects, while the RF energy of which would not cause the skin layer to be thermally damaged.