Miracle-dz/UniFAR-FTUs huggingface dataset:
Scutellarin Inhibits the Uninduced and Metal-Induced Aggregation of ɑ-Synuclein and Disaggregates Preformed Fibrils: Implications for Parkinson's disease.

The aggregation of the protein alpha synuclein (α-Syn), a known contributor in Parkinson's disease (PD) pathogenesis is triggered by transition metal ions through occupational exposure and disrupted metal ion homeostasis. Naturally occurring small molecules such as polyphenols have emerged as promising inhibitors of α-Syn fibrillation and toxicity and could be potential therapeutic agents against PD. Here, using an array of biophysical tools combined with cellular assays we demonstrate that the novel polyphenolic compound scutellarin efficiently inhibits the uninduced and metal-induced fibrillation of α-Syn by acting at the nucleation stage and stabilizes a partially-folded intermediate of α-Syn to form SDS-resistant, higher-order oligomers (~680 kDa) and also disaggregates preformed fibrils of α-Syn into similar type of higher-order oligomers. ANS binding assay, fluorescence lifetime measurements and cell-toxicity experiments reveal scutellarin-generated oligomers as compact, low hydrophobicity structures with modulated surface properties and significantly reduced cytotoxicity than the fibrillation intermediates of ɑ-Syn control. Fluorescence spectroscopy and isothermal titration calorimetry establish the binding between scutellarin and ɑ-Syn to be non-covalent in nature and of moderate affinity (Ka ~ 105 M-1). Molecular docking approaches suggest binding of scutellarin to the residues present in the NAC region and C-terminus of monomeric α-Syn and the C-terminal residues of fibrillar α-Syn, demonstrating inhibition of fibrillation upon binding to these residues and possible stabilization of the autoinhibitory conformation of α-Syn. These findings reveal interesting insights into the mechanism of scutellarin action and establish it as an efficient modulator of uninduced as well as metal-induced α-Syn fibrillation and toxicity.
Error metrics determination in functionally approximated circuits using SAT solvers

Approximate computing is an emerging design paradigm that offers trade-offs between output accuracy and computation efforts by exploiting some applications’ intrinsic error resiliency. Computation of error metrics is of paramount importance in approximate circuits to measure the degree of approximation. Most of the existing techniques for evaluating error metrics apply simulations which may not be effective for evaluation of large complex designs because of an immense increase in simulation runtime and a decrease in accuracy. To address these deficiencies, we present a novel methodology that employs SAT (Boolean satisfiability) solvers for fast and accurate determination of error metrics specifically for the calculation of an average-case error and the maximum error rate in functionally approximated circuits. The proposed approach identifies the set of all errors producing assignments to gauge the quality of approximate circuits for real-life applications. Additionally, the proposed approach provides a test generation method to facilitate design choices, and acts as an important guide to debug the approximate circuits to discover and locate the errors. The effectiveness of the approach is demonstrated by evaluating the error metrics of several benchmark-approximated adders of different sizes. Experimental results on benchmark circuits show that the proposed SAT-based methodology accurately determines the maximum error rate and an average-case error within acceptable CPU execution time in one go, and further provides a log of error-generating input assignments.
A Review of FoxO1-Regulated Metabolic Diseases and Related Drug Discoveries

FoxO1 is a conserved transcription factor involved in energy metabolism. It is tightly regulated by modifications on its mRNA and protein and responds to environmental nutrient signals. FoxO1 controls the transcription of downstream genes mediating metabolic regulation. Dysfunction of FoxO1 pathways results in several metabolic diseases, including diabetes, obesity, non-alcoholic fatty liver disease, and atherosclerosis. Here, we summarize the mechanism of FoxO1 regulation behind these diseases and FoxO1-related drug discoveries.
New Insights into the Structure-Function Relationship of the Endosomal-Type Na+, K+/H+ Antiporter NHX6 from Mulberry (Morus notabilis)

The endosomal-type Na+, K+/H+ antiporters (NHXs) play important roles in K+, vesicle pH homeostasis, and protein trafficking in plant. However, the structure governing ion transport mechanism and the key residues related to the structure–function of the endosomal-type NHXs remain unclear. Here, the structure-function relationship of the only endosomal-type NHX from mulberry, MnNHX6, was investigated by homology modeling, mutagenesis, and localization analyses in yeast. The ectopic expression of MnNHX6 in arabidopsis and Nhx1 mutant yeast can enhance their salt tolerance. MnNHX6’s three-dimensional structure, established by homology modeling, was supported by empirical, phylogenetic, and experimental data. Structure analysis showed that MnNHX6 contains unusual 13 transmembrane helices, but the structural core formed by TM5-TM12 assembly is conserved. Localization analysis showed that MnNHX6 has the same endosomal localization as yeast Nhx1/VPS44, and Arg402 is important for protein stability of MnNHX6. Mutagenesis analysis demonstrated MnNHX6 contains a conserved cation binding mechanism and a similar charge-compensated pattern as NHE1, but shares a different role in ion selectivity than the vacuolar-type NHXs. These results improve our understanding of the role played by the structure–function related key residues of the plant endosomal-type NHXs, and provide a basis for the ion transport mechanism study of endosomal-type NHXs.
Adaptation and Evaluation of Myfood24-Germany: A Web-Based Self-Administered 24-h Dietary Recall for the German Adult Population

Our aim was to develop and evaluate a German adaptation of myfood24, a fully automated, web-based 24-h dietary recall (24HDR). To complete a self-administered 24HDR with myfood24, users have to search and enter consumed foods within the underlying database by a free text search. The adaptation process thus mainly consisted of the development of an appropriate food database. myfood24-Germany was evaluated in 92 adults aged 17–78 years (study 1). Participants completed four non-consecutive 24HDRs and answered an evaluation questionnaire after the final recall. The System Usability Scale Score (SUS Score, 0–100) was calculated. Users’ search behavior was examined with screen recordings in 15 adults aged 20–60 years (study 2). Participants had to enter three sample meals presented as food packaging or pictures. The final database included 11,501 food items (7203 generic and 4298 branded items) with up to 131 nutrients. In study 1, the median completion time for a 24HDR was 15 min. The median SUS score of 78 indicated good usability. The majority of participants considered the overall user-friendliness as good (46%) or very good (21%), and 75% were willing to use myfood24-Germany regularly. Both studies showed that finding and choosing an appropriate item within the database was a major challenge. A German version of myfood24 was successfully developed. The user evaluation indicated a short completion time, good usability and acceptability of the tool, and confirmed its feasibility for repeated short-term application.
Tracking activity patterns of a multispecies community of gymnotiform weakly electric fish in their neotropical habitat without tagging

ABSTRACT Field studies on freely behaving animals commonly require tagging and often are focused on single species. Weakly electric fish generate a species- and individual-specific electric organ discharge (EOD) and therefore provide a unique opportunity for individual tracking without tagging. Here, we present and test tracking algorithms based on recordings with submerged electrode arrays. Harmonic structures extracted from power spectra provide fish identity. Localization of fish based on weighted averages of their EOD amplitudes is found to be more robust than fitting a dipole model. We apply these techniques to monitor a community of three species, Apteronotus rostratus, Eigenmannia humboldtii and Sternopygus dariensis, in their natural habitat in Darién, Panama. We found consistent upstream movements after sunset followed by downstream movements in the second half of the night. Extrapolations of these movements and estimates of fish density obtained from additional transect data suggest that some fish cover at least several hundreds of meters of the stream per night. Most fish, including E. humboldtii, were traversing the electrode array solitarily. From in situ measurements of the decay of the EOD amplitude with distance of individual animals, we estimated that fish can detect conspecifics at distances of up to 2 m. Our recordings also emphasize the complexity of natural electrosensory scenes resulting from the interactions of the EODs of different species. Electrode arrays thus provide an unprecedented window into the so-far hidden nocturnal activities of multispecies communities of weakly electric fish at an unmatched level of detail. Highlighted Article: Detailed movement patterns and complex electrosensory scenes of three species of weakly electric fish were tracked without tagging using a submerged electrode array in a small neotropical stream.
Influence of a Field Hamstring Eccentric Training on Muscle Strength and Flexibility

Abstract Muscle strength imbalances and poor flexibility are frequently described as risk factors for hamstring injury. Preventive strategies include eccentric exercises, but the influence of field eccentric exercises on these risk factors remains unclear. We investigated the influence of a field hamstring eccentric program on hamstring strength and flexibility. Twenty-seven amateur athletes were randomly assigned to an intervention (n=13) or control group (n=14). In the intervention group, participants were involved in 15 sessions of four eccentric exercises. Peak torque, hamstring-to-quadriceps ratios, passive and active flexibility were analyzed. No significant modifications of strength, passive or active flexibility were observed in the control group (p>0.05). Hamstring eccentric peak torque (+7.1%) and functional hamstring-to-quadriceps ratios (9.3%) were significantly increased (p<0.05) in the intervention group, but not concentric strength (p<0.05). Passive straight leg raise was significantly increased by 11.4° (+12.7%, p<0.001), but not active flexibility (+3.1%, p>0.05). In conclusion, a 6-week eccentric program, including four field exercises for hamstring muscles, is an effective method of improving eccentric strength, functional ratios and, especially, passive flexibility. As this program may be easily implemented in a real-world context, this association of multiple eccentric exercises might be useful in an injury prevention strategy.
Elucidation of Molecular Mechanism of a Selective PPARα Modulator, Pemafibrate, through Combinational Approaches of X-ray Crystallography, Thermodynamic Analysis, and First-Principle Calculations

The selective PPARα modulator (SPPARMα) is expected to medicate dyslipidemia with minimizing adverse effects. Recently, pemafibrate was screened from the ligand library as an SPPARMα bearing strong potency. Several clinical pieces of evidence have proved the usefulness of pemafibrate as a medication; however, how pemafibrate works as a SPPARMα at the molecular level is not fully known. In this study, we investigate the molecular mechanism behind its novel SPPARMα character through a combination of approaches of X-ray crystallography, isothermal titration calorimetry (ITC), and fragment molecular orbital (FMO) analysis. ITC measurements have indicated that pemafibrate binds more strongly to PPARα than to PPARγ. The crystal structure of PPARα-ligand binding domain (LBD)/pemafibrate/steroid receptor coactivator-1 peptide (SRC1) determined at 3.2 Å resolution indicates that pemafibrate binds to the ligand binding pocket (LBP) of PPARα in a Y-shaped form. The structure also reveals that the conformation of the phenoxyalkyl group in pemafibrate is flexible in the absence of SRC1 coactivator peptide bound to PPARα; this gives a freedom for the phenoxyalkyl group to adopt structural changes induced by the binding of coactivators. FMO calculations have indicated that the accumulation of hydrophobic interactions provided by the residues at the LBP improve the interaction between pemafibrate and PPARα compared with the interaction between fenofibrate and PPARα.
Fabrication and Plasma Modification of Nanofibrous Tissue Engineering Scaffolds

This paper provides a comprehensive overview of nanofibrous structures for tissue engineering purposes and the role of non-thermal plasma technology (NTP) within this field. Special attention is first given to nanofiber fabrication strategies, including thermally-induced phase separation, molecular self-assembly, and electrospinning, highlighting their strengths, weaknesses, and potentials. The review then continues to discuss the biodegradable polyesters typically employed for nanofiber fabrication, while the primary focus lies on their applicability and limitations. From thereon, the reader is introduced to the concept of NTP and its application in plasma-assisted surface modification of nanofibrous scaffolds. The final part of the review discusses the available literature on NTP-modified nanofibers looking at the impact of plasma activation and polymerization treatments on nanofiber wettability, surface chemistry, cell adhesion/proliferation and protein grafting. As such, this review provides a complete introduction into NTP-modified nanofibers, while aiming to address the current unexplored potentials left within the field.
The MicroRNA-23b/27b/24 Cluster Facilitates Colon Cancer Cell Migration by Targeting FOXP2

Acquisition of cell migration capacity is an early and essential process in cancer development. The aim of this study was to identify microRNA gene expression networks that induced high migration capacity. Using colon cancer HCT116 cells subcloned by transwell-based migrated cell selection, microRNA array analysis was performed to examine the microRNA expression profile. Promoter activity and microRNA targets were assessed with luciferase reporters. Cell migration capacity was assessed by either the transwell or scratch assay. In isolated subpopulations with high migration capacity, the expression levels of the miR-23b/27b/24 cluster increased in accordance with the increased expression of the short C9orf3 transcript, a host gene of the miR-23b/27b/24 cluster. E2F1-binding sequences were involved in the basic transcription activity of the short C9orf3 expression, and E2F1-small-interfering (si)RNA treatment reduced the expression of both the C9orf3 and miR-23b/27b/24 clusters. Overexpression experiments showed that miR-23b and miR-27b promoted cell migration, but the opposite effect was observed with miR-24. Forkhead box P2 (FOXP2) mRNA and protein levels were reduced by both/either miR-23b and miR-27b. Furthermore, FOXP2 siRNA treatment significantly promoted cell migration. Our findings demonstrated a novel role of the miR-23b/27b/24 cluster in cell migration through targeting FOXP2, with potential implications for the development of microRNA-based therapy targeted at inhibiting cancer migration.
Thioredoxin-interacting protein regulates glucose metabolism and improves the intracellular redox state in bovine oocytes during in vitro maturation.

The extent of glucose metabolism during oocyte maturation is closely related to oocyte developmental potential. Thioredoxin-interacting protein (TXNIP) is an α-arrestin family protein that negatively regulates glucose uptake into cells. However, little information is available regarding the function of TXNIP in bovine oocytes. Accordingly, the present study was performed to investigate the influence of TXNIP on glucose metabolism in bovine oocytes during in vitro maturation. Pharmacological inhibition of TXNIP by azaserine enhanced glucose uptake and imparted a specific metabolic effect on glycolysis and pentose phosphate pathway (PPP). RNA interference (RNAi) was adopted to further determine the biological significance of TXNIP in regulating glucose metabolism. The maturation rate and the developmental competence of TXNIP siRNA-treated oocytes were significantly improved. Knockdown of TXNIP in bovine oocytes significantly increased glycolysis by increasing the activities of phosphofructokinase (PFK), pyruvate kinase, and lactate dehydrogenase; pyruvate and lactate production; and intracellular ATP level, as well as mitochondrial activity. Furthermore, glucose metabolism through PPP was also enhanced by TXNIP depletion, as TXNIP siRNA treatment promotes glucose-6-phosphate dehydrogenase (G6PDH) activity and NADPH content, and helped maintain a high level of glutathione and a low level of reactive oxygen species within the oocytes. Further studies revealed that inhibition of TXNIP resulted increases in GLUT1 expression, as well as PFKP and G6PDH mRNA levels. These results reveal that TXNIP depletion promotes oocyte maturation by enhancing both glycolysis and the PPP. During in vitro maturation of bovine oocytes, TXNIP serves as a key regulator of glucose uptake by controlling GLUT1 expression.
Production of antifungal saponins in an airlift bioreactor with a cell line transformed from Solanum chrysotrichum and its activity against strawberry phytopathogens

Abstract Biotechnology through plant cell cultures in bioreactors is a tool that allows increasing the production of secondary metabolites of commercial interest. The hydrodynamic characterization, in addition to the transfer (OTR) and uptake (OUR) of oxygen through the dynamic method with different aeration rate, were used to see their influence on the production of biomass and saponins. The culture poisoning technique was used to determine the antifungal activity of the SC-2 and SC-3 saponins in vitro. Likewise, the shear or hydrodynamic stress of 273.6 mN/m2 were calculated based on the Reynolds Number. The oxygen supply (OTR) was always greater than the demand (OUR) for all the aeration rate evaluated. Dry weight values of 8.6 gDW/L and a concentration of 2.7 mg/L and 187.3 mg/L of the saponins SC-2 and SC-3 respectively were obtained with an air flow of 0.1 vvm. In addition, it was possible to inhibit the growth of phytopathogenic fungi in vitro by up to 93%, while in vivo it was possible to reduce the infections of strawberry seeds inoculated with phytopathogens, obtaining up to 94% of germinated seeds. This information will facilitate the rational operation of the bioreactor culture system that produces secondary metabolites.
A Review on Optoelectrokinetics-Based Manipulation and Fabrication of Micro/Nanomaterials

Optoelectrokinetics (OEK), a fusion of optics, electrokinetics, and microfluidics, has been demonstrated to offer a series of extraordinary advantages in the manipulation and fabrication of micro/nanomaterials, such as requiring no mask, programmability, flexibility, and rapidness. In this paper, we summarize a variety of differently structured OEK chips, followed by a discussion on how they are fabricated and the ways in which they work. We also review how three differently sized polystyrene beads can be separated simultaneously, how a variety of nanoparticles can be assembled, and how micro/nanomaterials can be fabricated into functional devices. Another focus of our paper is on mask-free fabrication and assembly of hydrogel-based micro/nanostructures and its possible applications in biological fields. We provide a summary of the current challenges facing the OEK technique and its future prospects at the end of this paper.
Excess BMI Accelerates Islet Autoimmunity in Older Children and Adolescents

OBJECTIVE Sustained excess BMI increases the risk of type 1 diabetes (T1D) in autoantibody-positive relatives without diabetes of patients. We tested whether elevated BMI also accelerates the progression of islet autoimmunity before T1D diagnosis. RESEARCH DESIGN AND METHODS We studied 706 single autoantibody–positive pediatric TrialNet participants (ages 1.6–18.6 years at baseline). Cumulative excess BMI (ceBMI) was calculated for each participant based on longitudinally accumulated BMI ≥85th age- and sex-adjusted percentile. Recursive partitioning analysis and multivariable modeling defined the age cut point differentiating the risk for progression to multiple positive autoantibodies. RESULTS At baseline, 175 children (25%) had a BMI ≥85th percentile. ceBMI range was −9.2 to 15.6 kg/m2 (median −1.91), with ceBMI ≥0 kg/m2 corresponding to persistently elevated BMI ≥85th percentile. Younger age increased the progression to multiple autoantibodies, with age cutoff of 9 years defined by recursive partitioning analysis. Although ceBMI was not significantly associated with progression from single to multiple autoantibodies overall, there was an interaction with ceBMI ≥0 kg/m2, age, and HLA (P = 0.009). Among children ≥9 years old without HLA DR3-DQ2 and DR4-DQ8, ceBMI ≥0 kg/m2 increased the rate of progression from single to multiple positive autoantibodies (hazard ratio 7.32, P = 0.004) and conferred a risk similar to that in those with T1D-associated HLA haplotypes. In participants <9 years old, the effect of ceBMI on progression to multiple autoantibodies was not significant regardless of HLA type. CONCLUSIONS These data support that elevated BMI may exacerbate islet autoimmunity prior to clinical T1D, particularly in children with lower risk based on age and HLA. Interventions to maintain normal BMI may prevent or delay the progression of islet autoimmunity.
Epigallocatechin-3-Gallate Suppresses Vasculogenic Mimicry through Inhibiting the Twist/VE-Cadherin/AKT Pathway in Human Prostate Cancer PC-3 Cells

Vasculogenic mimicry (VM) is the alternative process of forming vessel-like networks by aggressive tumor cells, and it has an important role in tumor survival, growth, and metastasis. Epigallocatechin-3-gallate (EGCG) is well known to have diverse bioactivities including anti-cancer effects. However, the efficacy of EGCG on VM is elusive. In this study, we explored whether and how EGCG affects VM in human prostate cancer (PCa) PC-3 cells. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Invasive and VM formation abilities were assessed by an invasion assay and a three-dimensional (3D) culture VM tube formation assay, respectively. Western blots were carried out. An immunofluorescence assay was performed to detect nuclear twist expression. EGCG effectively inhibited the invasive ability, as well as tubular channel formation, without affecting cell viability. EGCG significantly downregulated the expression of vascular endothelial cadherin (VE-cadherin) and its transcription factor, twist, N-cadherin, vimentin, phosphor-AKT, and AKT, but not phospho-erythropoietin-producing hepatocellular receptor A2 (EphA2) and EphA2. In addition, EGCG diminished the nuclear localization of twist. Treatment with SC79, an AKT activator, effectively rescued EGCG-inhibited VM formation. These results demonstrated for the first time that EGCG causes marked suppression of VM through inhibiting the twist/VE-cadherin/AKT pathway in human PCa PC-3 cells.