Improved catalytic activity of a novel aspartate kinase by site-directed saturation mutagenesis.

This study aimed to improve the catalytic activity of aspartate kinase (AK), the first key rate-limiting enzyme in the aspartic acid metabolism pathway, by site-directed saturation mutagenesis, and to weaken the synergistic feedback inhibition of metabolites and analyze its mechanism using molecular dynamics simulation (MD). The key residual sites around the inhibitor lysine (Lys) were selected to construct the mutant strains. The mutant A380M with significantly increased enzyme activity was obtained through enzyme activity screening. Kinetic analysis showed that the Vmax value increased to 15.73 U/mg, which was 4.8 times higher than that of wild-type AK (WT AK) (3.28 U/mg). The Kn value decreased to 0.61 mM, which was significantly lower than that of the wild type (4.77 mM), indicating that the substrate affinity increased. The enzyme properties analysis showed that the optimum temperature of the mutant A380M increased from 26 °C to 35 °C, the optimum pH remained unchanged. The stability was determined at optimum temperature (35 °C) and optimum pH 8.0, and it decreased from 4.8 h to 2.7 h. The feedback inhibition was weakened, showing a significant activation with the highest relative enzyme activity of 123.29% (Water was used instead of inhibitor as blank control group, and the highest enzyme activity was defined as 100%). Molecular dynamics simulations showed that the distance between ATP and Asp was shortened after mutation. The binding force and interaction between AK and ATP and substrate Asp were enhanced. The distance between catalytic residues D193 and S192 and substrate Asp was shortened.

Molecular dynamics investigation on the interaction of human angiotensin-converting enzyme with tetrapeptide inhibitors.

Angiotensin-converting enzyme (ACE) is a well-known zinc metalloenzyme whose physiological functions are vital to blood pressure regulation and management of hypertension. The development of more efficient peptide inhibitors is of great significance for the prevention and treatment of hypertension. In this research, molecular dynamics (MD) simulations were implemented to study the specific binding mechanism and interaction between human ACE (hACE) and tetrapeptides, YIHP, YKHP, YLVR, and YRHP. The calculation of relative binding free energy on the one hand verified that YLVR, an experimentally identified inhibitor, has a stronger inhibitory effect and, on the other hand, indicated that YRHP is the "best" inhibitor with the strongest binding affinity. Inspection of atomic interactions discriminated the specific binding mode of each tetrapeptide inhibitor with hACE and explained the difference of their affinity. Moreover, in-depth analysis of the MD production trajectories, including clustering, principal component analysis, and dynamic network analysis, determined the dynamic correlation between tetrapeptides and hACE and obtained the communities' distribution of a protein-ligand complex. The present study provides essential insights into the binding mode and interaction mechanism of the hACE-peptide complex, which paves a path for designing effective anti-hypertensive peptides.

Risk factors for distal radius fracture in postmenopausal women.

PURPOSE: The aim of this work was to explore the risk factors for distal radius fracture in postmenopausal women. PATIENTS AND METHODS: A total of 611 postmenopausal women with distal radius fractures were included. In all, 173 patients with unstable distal radius fractures were included (unstable fracture group), while there were 438 patients with stable distal radius fractures (stable fracture group). The control group comprised 800 postmenopausal women with no fracture. A questionnaire survey was conducted. RESULTS: Compared with the control group, the 611 postmenopausal women with distal radius fractures had a higher body mass index (BMI). Advanced age and higher BMI were more common in the unstable fracture group than in the stable fracture group (P <0.05). A higher proportion of the 611 postmenopausal women with a distal radius fracture had fallen in the last 12 months than in the control group. Comorbidities and the frequency of falls in the last 12 months were higher in the unstable fracture group than in the stable fracture group (P < 0.05). A higher proportion of the control group was taking calcium supplements, while the proportion taking calcium supplementation in the unstable fracture group was lower than that in the stable fracture group (P < 0.05). Osteoporosis in the two fracture groups (P < 0.05) was significantly higher than in the control group and was the highest in the unstable fracture group (P < 0.05). CONCLUSIONS: In postmenopausal women, obesity, falls, unknown osteoporosis status, and osteoporosis are associated with high risk of distal radius fracture. If comorbidities and advanced age are also present, this group of persons may be at higher risk for unstable distal radius fractures.

Precursor recommendation for inorganic synthesis by machine learning materials similarity from scientific literature.

Synthesis prediction is a key accelerator for the rapid design of advanced materials. However, determining synthesis variables such as the choice of precursor materials is challenging for inorganic materials because the sequence of reactions during heating is not well understood. In this work, we use a knowledge base of 29,900 solid-state synthesis recipes, text-mined from the scientific literature, to automatically learn which precursors to recommend for the synthesis of a novel target material. The data-driven approach learns chemical similarity of materials and refers the synthesis of a new target to precedent synthesis procedures of similar materials, mimicking human synthesis design. When proposing five precursor sets for each of 2654 unseen test target materials, the recommendation strategy achieves a success rate of at least 82%. Our approach captures decades of heuristic synthesis data in a mathematical form, making it accessible for use in recommendation engines and autonomous laboratories.

COVIDScholar: An automated COVID-19 research aggregation and analysis platform.

The ongoing COVID-19 pandemic produced far-reaching effects throughout society, and science is no exception. The scale, speed, and breadth of the scientific community's COVID-19 response lead to the emergence of new research at the remarkable rate of more than 250 papers published per day. This posed a challenge for the scientific community as traditional methods of engagement with the literature were strained by the volume of new research being produced. Meanwhile, the urgency of response lead to an increasingly prominent role for preprint servers and a diffusion of relevant research through many channels simultaneously. These factors created a need for new tools to change the way scientific literature is organized and found by researchers. With this challenge in mind, we present an overview of COVIDScholar https://covidscholar.org, an automated knowledge portal which utilizes natural language processing (NLP) that was built to meet these urgent needs. The search interface for this corpus of more than 260,000 research articles, patents, and clinical trials served more than 33,000 users at an average of 2,000 monthly active users and a peak of more than 8,600 weekly active users in the summer of 2020. Additionally, we include an analysis of trends in COVID-19 research over the course of the pandemic with a particular focus on the first 10 months, which represents a unique period of rapid worldwide shift in scientific attention.

Efficacy and safety of an HDACi- and HMA-based protocol in adults with acute myeloid leukemia of intermediate- and adverse-risk categories: a retrospective study.

OBJECTIVE: Anthracyclines and cytarabine have comprised standard induction therapy for acute myeloid leukemia (AML) for decades. Low overall survival of AML is due to non-remission or relapse after remission. Hypomethylating agent (HMA) decitabine combined with low-dose chemotherapy or other targeted agents has shown promising effect for AML in clinical trials, especially in t(8;21) acute myeloid leukemia. We previously investigated histone deacetylase inhibitor (HDACi) chidamide could regulate Wnt/ß-catenin signaling pathway in leukemia cell lines. METHODS: Adult patients with de novo or relapsed/refractory AML who were treated with chidamide and decitabine in combination with chemotherapy (chidamide group, n = 23) or only decitabine combination with chemotherapy (decitabine group, n = 17) were analyzed. RESULTS: Chidamide group represented higher complete response rate (82.6% and 52.9%, p = 0.0430, vs. decitabine group), progression-free survival and overall survival rates (p = 0.0088 and p = 0.0139, respectively), especially for patients with de novo AML. Hematological toxicity and infections were the most common adverse events (AEs) in both groups, and they were manageable by supportive treatments. CONCLUSIONS: This HDACi- and HMA-based protocol is an effective and tolerable therapy for patients with AML. The comprehensive mechanism and effects of chidamide in combination with decitabine are worth to be further explored in AML.

Text-mined dataset of gold nanoparticle synthesis procedures, morphologies, and size entities.

Gold nanoparticles are highly desired for a range of technological applications due to their tunable properties, which are dictated by the size and shape of the constituent particles. Many heuristic methods for controlling the morphological characteristics of gold nanoparticles are well known. However, the underlying mechanisms controlling their size and shape remain poorly understood, partly due to the immense range of possible combinations of synthesis parameters. Data-driven methods can offer insight to help guide understanding of these underlying mechanisms, so long as sufficient synthesis data are available. To facilitate data mining in this direction, we have constructed and made publicly available a dataset of codified gold nanoparticle synthesis protocols and outcomes extracted directly from the nanoparticle materials science literature using natural language processing and text-mining techniques. This dataset contains 5,154 data records, each representing a single gold nanoparticle synthesis article, filtered from a database of 4,973,165 publications. Each record contains codified synthesis protocols and extracted morphological information from a total of 7,608 experimental and 12,519 characterization paragraphs.

Dataset of solution-based inorganic materials synthesis procedures extracted from the scientific literature.

The development of a materials synthesis route is usually based on heuristics and experience. A possible new approach would be to apply data-driven approaches to learn the patterns of synthesis from past experience and use them to predict the syntheses of novel materials. However, this route is impeded by the lack of a large-scale database of synthesis formulations. In this work, we applied advanced machine learning and natural language processing techniques to construct a dataset of 35,675 solution-based synthesis procedures extracted from the scientific literature. Each procedure contains essential synthesis information including the precursors and target materials, their quantities, and the synthesis actions and corresponding attributes. Every procedure is also augmented with the reaction formula. Through this work, we are making freely available the first large dataset of solution-based inorganic materials synthesis procedures.

[Study of the morphology of heel spur and clinical significance: base on three-dimensional computed tomography].

OBJECTIVES: To evaluate the characteristic morphology of heel spur, and to investigate the relationship of heel spur and plantar heel pain. METHODS: From June 2005 to April 2009, 210 cases (254 feet) with heel spur (according to Denis Pain Scale) were divided into cases group 1 (P2, n = 46), 2 (P3, n = 44), 3 (P4, n = 42), 4 (P5, n = 36) and controls group (P1, n = 42). Three-dimensional reconstruction of heel spur was performed in all groups using volume rendering based on multi-slice CT data by Super Image orthopedics edition 1.0. The characteristic morphology of heel spur was observed and the data were measured and analyzed, involving the width of basilar part, the length, the angle between heel spur and planta pedis, and the angle between the longitudinal axis of calcaneus and heel spur. RESULTS: Parts of cases groups displayed coarse arcuate edge and undersurface with one or more little heel spurs adhere to heel spur, of which the numbers were greater than controls group, especially in cases group 4. No significant difference of the width of basilar part of heel spur was found among 5 groups (F = 2.32, P > 0.05). However, obvious difference was found in the length, the angle between heel spur and planta pedis, and the angle between the longitudinal axis of calcaneus and heel spur (F = 8.23, 6.82, 5.87, P < 0.05). Compared with the controls group, the angle between heel spur and planta pedis of cases groups had higher degrees, but the difference of the other data presented irregular. CONCLUSIONS: The characteristic morphology of heel spur varies in patients associated with plantar heel pain. No correlation is found between the severity and the morphological data, including the width of basilar part, the length, the angle between heel spur and planta pedis, and the angle between the longitudinal axis of calcaneus and heel spur.

Sacrificial template method for the synthesis of three-dimensional nanofibrous 58S bioglass scaffold and its in vitro bioactivity and cell responses.

Three-dimensional nanofibrous scaffolds that morphologically mimic natural extracellular matrices hold great promises in tissue engineering and regenerative medicine due to their increased cell attachment and differentiation compared with block structure. In this work, for the first time, three-dimensional porous nanofibrous 58S bioglass scaffolds have been fabricated using a sacrificial template method. During the process, a natural three-dimensional nanofibrous bacterial cellulose was used as the sacrificial template on which precursor 58S glass was deposited via a sol-gel route. SEM and TEM results verify that the as-prepared 58S scaffolds can inherit the three-dimensional nanofibrous feature of bacterial cellulose. Pore structure characterizations by nitrogen adsorption-desorption and mercury intrusion porosimetry demonstrate that the 58S scaffolds are highly porous with a porosity of 75.1% and contain both mesopores (39.4 nm) and macropores (60 µm) as well as large BET surface area (127.4 m2 g-1). In vitro cell studies suggest that the 58S scaffold is bioactive and biocompatible with primary mouse osteoblast cells, suggesting that the nanofibrous structure of 58S is able to provide an appropriate environment for cellular functioning. These results strongly suggest that the three-dimensional nanofibrous 58S scaffold has great potential for application in bone tissue engineering and regenerative medicine.

Mechanical properties and cytotoxicity of nanoplate-like hydroxyapatite/polylactide nanocomposites prepared by intercalation technique.

Hydroxyapatite (HAp) in the forms of fiber, needle, and whisker has been employed as fillers in polymer composites. Herein, nanoplate-like HAp synthesized by template-assisted self-assembly was used to reinforce polylactide (PLA) nanocomposites via the solution intercalation method. Dynamic and static mechanical properties and cytotoxicity of the as-prepared HAp/PLA nanocomposites were assessed in addition to characterizations by XRD, FTIR, and TGA. XRD analysis confirms the formation of exfoliated structure in the HAp/PLA nanocomposites. The HAp/PLA nanocomposites exhibit better static and dynamic mechanical properties than unreinforced PLA. Furthermore, the HAp/PLA nanocomposite with an optimum HAp content of 20wt% (20HAp/PLA) demonstrates not only the best mechanical performance but also the highest thermal stability among the nanocomposite samples. Cell studies using a mouse fibroblast cell line (L929) suggest that 20HAp/PLA shows excellent biocompatibility, which makes it a promising material for biomedical applications.

VEGFR, RET, and RAF/MEK/ERK pathway take part in the inhibition of osteosarcoma MG63 cells with sorafenib treatment.

Osteosarcoma (OS) is the leading primary malignant bone tumor in children and young adults. It is response for a high mortality rate. Nowadays, few researches have been performed on sorafenib against OS and no tools are available to guide the use of sorafenib in the OS treatment. In this study, we aim to investigate the effect of sorafenib on OS cell MG63 and figure the potential effective molecular pathway of its function. In the present study, we performed assays of cell proliferation, RT-PCR, and western blot to investigate the effect of sorafenib on OS MG63 cells and to elucidate the molecular actions of sorafenib against RTKs VEGFR2 and RET, as well as MEK/ERK signaling pathway. The present study confirmed that sorafenib could inhibit the proliferation of OS MG63 cells and caused a series of biomolecule effects, including the change of VEGFR2 and ERK gene expression, and the phosphorylation alteration of VEGFR2, RET, and MEK1 proteins. VEGFR2, RET, and MEK/ERK signaling pathway are involved in the pharmacological mechanism of sorafenib. They are potential candidate targets for OS treatment.

Preparation of three-dimensional braided carbon fiber-reinforced PEEK composites for potential load-bearing bone fixations. Part I. Mechanical properties and cytocompatibility.

In this study, we focused on fabrication and characterization of three-dimensional carbon fiber-reinforced polyetheretherketone (C3-D/PEEK) composites for orthopedic applications. We found that pre-heating of 3-D fabrics before hot-pressing could eliminate pores in the composites prepared by 3-D co-braiding and hot-pressing techniques. The manufacturing process and the processing variables were studied and optimum parameters were obtained. Moreover, the carbon fibers were surface treated by the anodic oxidization and its effect on mechanical properties of the composites was determined. Preliminary cell studies with mouse osteoblast cells were also performed to examine the cytocompatibility of the composites. Feasibility of the C3-D/PEEK composites as load-bearing bone fixation materials was evaluated. Results suggest that the C3-D/PEEK composites show good promising as load-bearing bone fixations.