Miracle-dz/UniFAR-FTUs huggingface dataset:
Cyclization of Single-Chain Fv Antibodies Markedly Suppressed Their Characteristic Aggregation Mediated by Inter-Chain VH-VL Interactions

Single-chain Fv (scFv) antibodies are recombinant proteins in which the variable regions of the heavy chain (VH) and light chain (VL) are connected by a short flexible polypeptide linker. ScFvs have the advantages of easy genetic manipulation and low-cost production using Escherichia coli compared with monoclonal antibodies, and are thus expected to be utilized as next-generation medical antibodies. However, the practical use of scFvs has been limited due to low homogeneity caused by their aggregation propensity mediated by inter-chain VH-VL interactions. Because the interactions between the VH and VL domains of antibodies are generally weak, individual scFvs are assumed to be in equilibrium between a closed state and an open state, in which the VH and VL domains are assembled and disassembled, respectively. This dynamic feature of scFvs triggers the formation of dimer, trimer, and larger aggregates caused by the inter-chain VH-VL interactions. To overcome this problem, the N-terminus and C-terminus were herein connected by sortase A-mediated ligation to produce a cyclic scFv. Open-closed dynamics and aggregation were markedly suppressed in the cyclic scFv, as judged from dynamic light scattering and high-speed atomic force microscopy analyses. Surface plasmon resonance and differential scanning fluorometry analysis revealed that neither the affinity for antigen nor the thermal stability was disrupted by the scFv cyclization. Generality was confirmed by applying the present method to several scFv proteins. Based on these results, cyclic scFvs are expected to be widely utilized in industrial and therapeutic applications.
Lignin-Based Polyurethanes: Opportunities for Bio-Based Foams, Elastomers, Coatings and Adhesives

Polyurethane chemistry can yield diverse sets of polymeric materials exhibiting a wide range of properties for various applications and market segments. Utilizing lignin as a polyol presents an opportunity to incorporate a currently underutilized renewable aromatic polymer into these products. In this work, we will review the current state of technology for utilizing lignin as a polyol replacement in different polyurethane products. This will include a discussion of lignin structure, diversity, and modification during chemical pulping and cellulosic biofuels processes, approaches for lignin extraction, recovery, fractionation, and modification/functionalization. We will discuss the potential of incorporation of lignins into polyurethane products that include rigid and flexible foams, adhesives, coatings, and elastomers. Finally, we will discuss challenges in incorporating lignin in polyurethane formulations, potential solutions and approaches that have been taken to resolve those issues.
Circulating endothelial and progenitor cells in age-related macular degeneration

Purpose: To evaluate circulating endothelial and circulating progenitor cells as biomarkers in age-related macular degeneration patients (both exudative and atrophic forms) in order to establish the possible clinical implication of their assessment. Methods: We have enrolled 44 age-related macular degeneration patients: 22 patients with a recently diagnosed exudative (neovascular) form (Group A) and 22 patients with an atrophic (dry) form (Group B). The control group consisted of 22 age and sex-matched healthy subjects (Group C). The number of circulating endothelial progenitor cells (CD34+/KDR+, CD133+/KDR+, and CD34+/KDR+/CD133+), circulating progenitor cells (CD34+, CD133+, and CD34+/CD133+), and circulating endothelial cells were determined in the peripheral venous blood samples by flow cytometry. Neovascular age-related macular degeneration patients were evaluated at baseline and 4 weeks after a loading phase of three consequent intravitreal injections of ranibizumab. Results: Comparing age-related macular degeneration patients with the control group, endothelial progenitor cell and circulating progenitor cell levels were not significantly different, while age-related macular degeneration patients showed significantly higher levels of circulating endothelial cells (p = 0.001). Anti–vascular endothelial growth factor treatment with intravitreal ranibizumab was associated with a significant reduction of endothelial progenitor cell levels, with no significant influence on circulating progenitor cells and circulating endothelial cells. Conclusion: We reported higher levels of circulating endothelial cells in age-related macular degeneration patients in comparison with the control group, thereby supporting the hypothesis of an involvement of endothelial dysregulation in the age-related macular degeneration and a reduction of the endothelial progenitor cell level in neovascular age-related macular degeneration patients after three intravitreal injections of ranibizumab.
Storage procedures and time influence the detectability of Clostridium difficile toxin A but not toxin B in porcine fecal specimens

Storage procedures are known to affect the detectability of Clostridium difficile toxins in equine and human feces. We assessed the impact of different storage conditions on the detectability of C. difficile toxins in swine feces. Specimens were inoculated with toxins, 112 ng/g of toxin A (TcdA) and 16 ng/g of toxin B (TcdB) and subjected to the following 3 storage treatments: 4°C, −30°C, repetitive freezing at −30°C and thawing. Toxin determination was assessed at 1, 2, 7, 14, and 21 d with ELISA. A decrease in concentrations of TcdA with time was observed for samples stored at 4°C and repetitive freezing–thawing (p ≤0.05). On day 14, storage at 4°C resulted in decreased TcdA concentration as opposed to storage at −30°C and repetitive freezing–thawing (p ≤0.05). On day 21, storage at 4°C resulted in decreased TcdA detectability compared with storage at −30°C (p ≤0.05). The TcdB concentration was unaffected. These results on toxin detectability in swine feces should be carefully considered in in vitro studies on toxigenic C. difficile. Our results also offer valuable information for microbiologists and veterinarians monitoring the presence of virulent C. difficile in pigs.
The Effects of Fluvastatin on Indian Hedgehog Pathway in Endochondral Ossification

Statins have demonstrated to be effective for treating chondrodysplasia and its effects were believed to be associated with the fibroblast growth factor receptor 3 (FGFR3). Statins promoted the degradation of FGFR3 in studies using disease-specific induced pluripotent stem cells and model mice, however, recent studies using normal chondrocytes reported that statins did not degrade FGFR3. In order to further investigate the effects of statins in endochondral ossification, this study examined the influence of statins on Indian hedgehog (Ihh), another important component of endochondral ossification, and its related pathways. The chondrocyte cell line ATDC5 was used to investigate changes in cell proliferation, mRNA, and protein expression levels. In addition, an organ culture of a mouse metatarsal bone was performed followed by hematoxylin-eosin staining and fluorescent immunostaining. Results indicated that expression level of Ihh increased with the addition of statins, which activated the Ihh pathway and altered the localization of Ihh. Changes in cholesterol modification may have affected Ihh diffusibility; however, further experiments are necessary. A reactive increase in parathyroid hormone–related protein (PTHrP) was observed in addition to changes in the Wnt pathway through secreted-related protein 2/3 and low-density lipoprotein 5/6. This led to the promotion of cell proliferation, increase of the hypertrophic chondrocyte layer, inhibition of apoptosis, and decrease in mineralization. This study demonstrated that statins had an influence on Ihh, and that the hyperfunction of Ihh may prevent premature cell death caused by FGFR3-related chondrodysplasia through an indirect increase in the expression of PTHrP.
IPv6-based Interaction System with Intrusion Detection and Firewall

The interaction of intrusion detection and firewall is hot in the research of network security. Almost all of the realized system limit to IPv4 networks. This paper presents an IPv6-based distributed network security prevention system which is combined with firewall and intrusion detection system. By implementing intrusion detection agent and concentrated control server,system obtains the intrusion message and analyses it,and adjusts the rules and policies of firewall initiatively. It realizes the interaction of intrusion detection and firewall based on IPv6/IPv4. The test results show that the system is effective and dependable.
Hepatocellular Toxicity of Paris Saponins I, II, VI and VII on Two Kinds of Hepatocytes-HL-7702 and HepaRG Cells, and the Underlying Mechanisms

Rhizoma paridis is a popularly-used Chinese medicine in clinics, based on the pharmacodynamic properties of its saponin components. The four main saponins in Rhizoma paridis are designated saponins I, II, VI, and VII. At present, much attention is focused on the anticancer effect of Rhizoma paridis which is manifested in its cytotoxicity to various cancer cells. The purpose of this study was to investigate the hepatocellular toxicities of the four saponins in Rhizoma paridis and the relative intensities of their cytotoxic effects. It was found that the four saponins were cytotoxic to two types of hepatocytes-HL-7702 and HepaRG cells. The cytotoxicities of the four saponins to the two cell models were compared. One of the most cytotoxic saponins was Rhizoma paridis saponin I (PSI). This was used to determine the mechanism of hepatocellular toxicity. Results from MTT assays demonstrated that the four saponins induced apoptosis of the two hepatocyte models in a dose-dependent and time-dependent manner. In addition, fluorescent 4′,6-diamidino-2-phenylindole (DAPI) staining was used to observe the morphological changes of HepaRG cells after saponin administration. Further, as the concentration increased, PSI-induced lactate dehydrogenase (LDH) release from HepaRG cells increased gradually. In addition, PSI enhanced the levels of reactive oxygen species (ROS) and blocked the S and G2 phases of the cell cycle in HepaRG cells. A western blot indicated that PSI upregulated the protein expression levels of p53, p21, and Fas. Furthermore, the PSI-induced changes in the p53 protein increased the Bax/bcl-2 ratio, resulting in enhancement of the release of mitochondrial cytochrome c, activation of caspases-3, -8, and -9, poly-ADP ribose polymerase (PARP), and ultimately apoptosis. Increased Fas protein activated caspase-8, which led to the activation of caspase-3 and its downstream PARP protein, resulting in cell apoptosis. These results indicate that PSI induced apoptosis in HepaRG cells through activation of ROS and death receptor pathways. The results obtained in this study suggest that the hepatocellular toxicity of saponins in Rhizoma paridis should be considered during the clinical application of this drug. In addition, they provide a reference for future anti-cancer studies on Rhizoma paridis.
Socioeconomic inequalities in healthcare utilisation in Indonesia: a comprehensive survey-based overview

Objective Monitoring inequality in healthcare utilisation is essential to reduce persistent inequalities in health in lower-middle income countries. This study aimed to assess socioeconomic inequalities in the utilisation of primary care, secondary care and preventive care in Indonesia. Methods A cross-sectional study was conducted using data from the 2014 Indonesia Family Life Survey with a total of 42 083 adult participants. Socioeconomic status (SES) was measured by educational level and income. Healthcare utilisation was measured in: (1) primary care, (2) outpatient in secondary care, (3) inpatient care and (4) cardiovascular-related preventive care. The magnitude of inequalities was measured using the relative index of inequality (RII). Results Small educational inequalities were found for primary care utilisation (RII 1.13, 95% CI 1.01 to 1.26). Larger educational inequalities were found for outpatient secondary care (RII 10.35, 95% CI 8.11 to 13.22) and inpatient care (RII 2.78, 95% CI 2.32 to 3.32). The largest educational inequalities were found for preventive care, particularly regarding blood glucose tests (RII 30.31, 95% CI 26.13 to 35.15) and electrocardiography tests (RII 30.90, 95% CI 24.97 to 38.23). Compared with educational inequalities, income inequalities were larger for primary care (RII 1.68, 95% CI 1.52 to 1.85) and inpatient care (RII 3.11, 95% CI 2.63 to 3.66), but not for outpatient secondary care and preventive care. Conclusions Socioeconomic inequalities in healthcare utilisation in Indonesia are particularly large in secondary and preventive care. Therefore, it is recommended to prioritise policies focused on improving timely, geographical and financial access to secondary and preventive care for lower SES groups.
In vitro metabolism and in vivo pharmacokinetics of bentysrepinine (Y101), an investigational new drug for anti-HBV-infected hepatitis: focus on interspecies comparison

Abstract The objective of this study was to clarify the species differences of pharmacokinetics of Y101 (N-[N-benzoyl-O-(2-dimethylaminoethyl)-l-tyrosyl]-l-phenylalaninol hydrochloride), a derivative of herbal ingredient with anti-HBV hepatitis activity, in rats, dogs, monkeys and humans. The metabolic stability and metabolite identification studies using liver microsomes in vitro, plasma protein binding using a rapid equilibrium dialysis in vitro, pharmacokinetic studies in vivo were carried out to evaluate the interspecies differences. The toxicokinetic study in monkeys was also investigated. The metabolic profiles were similar in monkeys and humans, which were significant different from rats and dogs in vitro. In vitro plasma protein binding showed no major differences between species with medium to high protein binding rates. After single oral dose to rats, dogs, and monkeys, the absolute oral bioavailability of Y101 was 44.9%, 43.1%, and 19.2%, respectively. There was no accumulation for Y101 toxicokinetics in monkeys after oral administration for 90 d. The metabolic profiles indicated monkey was the very animal model for preclinical safety evaluation of Y101. Our results have demonstrated the favorable pharmacokinetics profile of Y101, which supports the clinical trials in humans.
Making Decision under Real-Time, Unpredicted Environments:a Multi-Layer Model

This paper describes our work in developing an agent architecture based on a multi-layer model which will help to solve the problem of real time decision-making in dynamic, unpredicted environments. The high levels of this architecture use BDI model to support long-term planning and reasoning while use reactive model in the lower level which ensures the system to react timely in real-time environments. Experiments show that such a multi-layer archi- tecture is effective in some complicated real-time domains.
Selection and assembly of indigenous bacteria and methanogens from spent metalworking fluids and their potential as a starting culture in a fluidized bed reactor

Waste metalworking fluids (MWFs) are highly biocidal resulting in real difficulties in the, otherwise favoured, bioremediation of these high chemical oxygen deman (COD) wastes anaerobically in bioreactors. We have shown, as a proof of concept, that it is possible to establish an anaerobic starter culture using strains isolated from spent MWFs which are capable of reducing COD or, most significantly, methanogenesis in this biocidal waste stream. Bacterial strains (n = 99) and archaeal methanogens (n = 28) were isolated from spent MWFs. The most common bacterial strains were Clostridium species (n = 45). All methanogens were identified as Methanosarcina mazei. Using a random partitions design (RPD) mesocosm experiment, we found that bacterial diversity and species–species interactions had significant effects on COD reduction but that bacterial composition did not. The RPD study showed similar effects on methanogenesis, except that composition was also significant. We identified bacterial species with positive and negative effects on methane production. A consortium of 16 bacterial species and three methanogens was used to initiate a fluidized bed bioreactor (FBR), in batch mode. COD reduction and methane production were variable, and the reactor was oscillated between continuous and batch feeds. In both microcosm and FBR experiments, periodic inconsistencies in bacterial reduction in fermentative products to formic and acetic acids were identified as a key issue.
A Multilayer-Learning Current-Mode Neuromorphic System With Analog-Error Compensation

Internet-of-things applications that use machine-learning algorithms have increased the demand for application-specific energy-efficient hardware that can perform both learning and inference tasks to adapt to endpoint users or environmental changes. This paper presents a multilayer-learning neuromorphic system with analog-based multiplier-accumulator (MAC), which can learn training data by stochastic gradient descent algorithm. As a component of the proposed system, a current-mode MAC processor, fabricated in 28-nm CMOS technology, performs both forward and backward processing in a crossbar structure of 500 × 500 6-b transposable SRAM arrays. The proposed system is verified in a two-layer neural network by using two prototype chips and an FPGA. Without any calibration circuit for the analog-based MAC, the proposed system compensates for non-idealities from analog operations by learning training data with the analog-based MAC. With 1-b (+1, 0, –1) batch update of 6-b synaptic weights, the proposed system achieves a recognition rate of 96.6% with a peak energy efficiency of 2.99 TOPS/W (1 OP = one unsigned 8-b × signed 6-b MAC operation) in the classification of the MNIST dataset.
Similar Safety Profile of the Enantiomeric N-Aminoalkyl Derivatives of Trans-2-Aminocyclohexan-1-ol Demonstrating Anticonvulsant Activity

Epilepsy is one of the most common neurological disorder in the world. Many antiepileptic drugs cause multiple adverse effects. Moreover, multidrug resistance is a serious problem in epilepsy treatment. In the present study we evaluated the safety profile of three (1–3) new chiral N-aminoalkyl derivatives of trans-2-aminocyclohexan-1-ol demonstrating anticonvulsant activity. Our aim was also to determine differences between the enantiomeric compounds with respect to their safety profile. The results of the study indicated that compounds 1–3 are non-cytotoxic for astrocytes, although they exhibit cytotoxic activity against human glioblastoma cells. Moreover, 1–3 did not affect the viability of HepG2 cells and did not produce adducts with glutathione. Compounds 1–3 demonstrated no mutagenic activity either in the Salmonella typhimurium or in Vibrio harveyi tests. Additionally, the compounds displayed a strong or moderate antimutagenic effect. Finally, the P-glycoprotein (P-gp) ATPase assay demonstrated that both enantiomers are potent P-gp inhibitors. To sum up, our results indicate that the newly synthesized derivatives may be considered promising candidates for further research on anticonvulsant drug discovery and development. Our study indicated the similar safety profile of the enantiomeric N-aminoalkyl derivatives of trans-2-aminocyclohexan-1-ol, although in the previous studies both enantiomers differ in their biotransformation pathways and pharmacological activity.
Automated Test Case Generation Based on UML Activity Diagram Model

In order to design and generate test cases of workflows, test outline model is defined. The three tier process to transform an activity diagram into its test outline model and then into its test case model,as well as the test coverage criteria, is introduced, including a set of basic rules, by which unstructured flows is eliminated to modularize test outline units, and concurrency flows can be instantiated. The principles on the instantiated input data for each input operation in the system and the creation of the test case model by assigning the instantiated set of input data to the outline model,and then methods to generate the complete set of test cases based on the model are discussed.
Modeling and Simulation of Fiber Optic Gyros Based on Allan Variance Method

In this paper,a high fidelity gyro model is described,and a method is presented for the random errors simulated according to the angular random walk(ARW)and rate random walk(RRW)coefficients of fiber optic gyros estimated by using the Allan variance method.It is shown that the power spectral densities(PSD)of the generated random errors are coincident with those of the real angular random walk and rate random walk.The effectiveness of the presented random error generation method is validated by the simulation.This method can be used to evaluate the performance of the satellite attitude determination system that consists of gyros and star sensors.
Synthesis of Graphene Oxide-Fe3O4 Based Nanocomposites Using the Mechanochemical Method and in Vitro Magnetic Hyperthermia

The study presented in this work consists of two parts: The first part is the synthesis of Graphene oxide-Fe3O4 nanocomposites by a mechanochemical method which, is a mechanical process that is likely to yield extremely heterogeneous particles. The second part includes a study on the efficacy of these Graphene oxide-Fe3O4 nanocomposites to kill cancerous cells. Iron powder, ball milled along with graphene oxide in a toluene medium, underwent a controlled oxidation process. Different phases of GO-Fe3O4 nanocomposites were obtained based on the composition used for milling. As synthesized nanocomposites were characterized by x-ray diffraction (XRD), alternating magnetic field (AFM), Raman spectroscopy, and a vibrating sample magnetometer (VSM). Additionally, the magnetic properties required to obtain high SAR values (Specific Absorption Rate-Power absorbed per unit mass of the magnetic nanocomposite in the presence of an applied magnetic field) for the composite were optimized by varying the milling time. Nanocomposites milled for different extents of time have shown differential behavior for magneto thermic heating. The magnetic composites synthesized by the ball milled method were able to retain the functional groups of graphene oxide. The efficacy of the magnetic nanocomposites for killing of cancerous cells is studied in vitro using HeLa cells in the presence of an AC (Alternating Current) magnetic field. The morphology of the HeLa cells subjected to 10 min of AC magnetic field changed considerably, indicating the death of the cells.