COMO: a pipeline for multi-omics data integration in metabolic modeling and drug discovery.

Identifying potential drug targets using metabolic modeling requires integrating multiple modeling methods and heterogeneous biological datasets, which can be challenging without efficient tools. We developed Constraint-based Optimization of Metabolic Objectives (COMO), a user-friendly pipeline that integrates multi-omics data processing, context-specific metabolic model development, simulations, drug databases and disease data to aid drug discovery. COMO can be installed as a Docker Image or with Conda and includes intuitive instructions within a Jupyter Lab environment. It provides a comprehensive solution for the integration of bulk and single-cell RNA-seq, microarrays and proteomics outputs to develop context-specific metabolic models. Using public databases, open-source solutions for model construction and a streamlined approach for predicting repurposable drugs, COMO enables researchers to investigate low-cost alternatives and novel disease treatments. As a case study, we used the pipeline to construct metabolic models of B cells, which simulate and analyze them to predict metabolic drug targets for rheumatoid arthritis and systemic lupus erythematosus, respectively. COMO can be used to construct models for any cell or tissue type and identify drugs for any human disease where metabolic inhibition is relevant. The pipeline has the potential to improve the health of the global community cost-effectively by providing high-confidence targets to pursue in preclinical and clinical studies. The source code of the COMO pipeline is available at https://github.com/HelikarLab/COMO. The Docker image can be pulled at https://github.com/HelikarLab/COMO/pkgs/container/como.

Engineering van der Waals Contacts by Interlayer Dipoles.

Tuning the interfacial Schottky barrier with van der Waals (vdW) contacts is an important solution for two-dimensional (2D) electronics. Here we report that the interlayer dipoles of 2D vdW superlattices (vdWSLs) can be used to engineer vdW contacts to 2D semiconductors. A bipolar WSe2 with Ba6Ta11S28 (BTS) vdW contact was employed to exhibit this strategy. Strong interlayer dipoles can be formed due to charge transfer between the Ba3TaS5 and TaS2 layers. Mechanical exfoliation breaks the superlattice and produces two distinguished surfaces with TaS2 and Ba3TaS5 terminations. The surfaces thus have opposite surface dipoles and consequently different work functions. Therefore, all the devices fall into two categories in accordance with the rectifying direction, which were verified by electrical measurements and scanning photocurrent microscopy. The growing vdWSL family along with the addition surface dipoles enables prospective vdW contact designs and have practical application in nanoelectronics and nano optoelectronics.

Fully Integrated Line Array Angular Displacement Sensing Chip.

The angular displacement sensor is a digital angular displacement measurement device that integrates optics, mechanics, and electronics. It has important applications in communication, servo control, aerospace, and other fields. Although conventional angular displacement sensors can achieve extremely high measurement accuracy and resolution, they cannot be integrated because complex signal processing circuitry is required at the photoelectric receiver, which limits their suitability for robotics and automotive applications. The design of a fully integrated line array angular displacement-sensing chip is presented for the first time using a combination of pseudo-random and incremental code channel designs. Based on the charge redistribution principle, a fully differential 12-bit, 1 MSPS sampling rate successive approximation analog-to-digital converter (SAR ADC) is designed for quantization and subdivision of the incremental code channel output signal. The design is verified with a 0.35 µm CMOS process and the area of the overall system is 3.5 × 1.8 mm2. The fully integrated design of the detector array and readout circuit is realized for the angular displacement sensing.

Melatonin ameliorates osteoarthritis rat cartilage injury by inhibiting matrix metalloproteinases and JAK2/STAT3 signaling pathway.

OBJECTIVE: To observe the effect of melatonin intervention on rat knee osteoarthritis (KOA) model and explore its mechanism. METHODS: A total of 81 Sprague-Dawley (SD) rats were employed. Haematoxylin and eosin (H&E) staining and safranin o-solid green staining were used to observe the changes of pathology in KOA, and inflammation factors in serum were detected by enzyme-linked immunosorbent assay (ELISA), type II collagen (Col-II) was detected by immunohistochemistry, chondrocyte apoptosis was detected by TdT-mediated dUTP nick-end labeling (TUNEL). The expression of matrix metalloproteinases (MMPs) and JAK2/STAT3 signaling were detected by western blot. RESULTS: Melatonin treatment ameliorated the histomorphology of knee joint in rats compared to the model group. The contents of TNF-α, IL-6, and IL-1ß in serum were decreased after melatonin treatment. In addition, compared to the model group, the positive expression of Col-II increased, the chondrocyte apoptosis decreased after melatonin treatment. Interestingly, the expression levels of MMP3, MMP9, MMP13, p-JAK2 and p-STAT3 decreased (p < 0.05). Importantly, melatonin combined with AG490 is significantly ameliorates histomorphology of knee joint, reduced cartilage loss compared with melatonin treatment alone. CONCLUSIONS: Melatonin treatment can effectively diminish the cartilage injury. Its mechanism may be related to protect the articular cartilage by reducing the release of inflammatory factors, inhibit the expression of MMPs and JAK2/STAT3 signaling.

The Strengthened Photocatalytic NOx Removal of Composites Bi4O5Br2/BiPO4: The Efficient Regulation of Interface Carriers by Integrating a Wide-Bandgap Ornament.

A series of binary composites Bi4O5Br2/BiPO4 (PBX) was fabricated through a simple mechanical ball milling protocol. Relevant microstructural, morphological, and optical properties were thoroughly analyzed via various techniques. The integration of both components was confirmed to produce heterojunction domains at the phase boundaries. Upon exposure to visible light irradiation, the as-achieved PBX series possessed the reinforced photocatalytic NOx removal efficiencies and the weakened generation of toxic intermediate NO2 in comparison to both bare components, chiefly attributed to the efficient transport and separation of carriers and boosted production of superoxide radicals (·O2-) through the combination of a wide-bandgap ornament BiPO4 as an electron acceptor. In particular, the composite PB5 with the optimal phase composition exhibited the highest NOx removal of 40% with the lowest NO2 formation of 40 ppb among all tested candidates. According to the band structures' estimation and reactive species' detection, a reasonable mechanism was ultimately proposed to describe the migration of charge carriers and the enhancement of photocatalytic performance.

Isoorientin ameliorates osteoporosis and oxidative stress in postmenopausal rats.

CONTEXT: Isoorientin has many biological activities, including antioxidant, anti-inflammatory, antitumor. However, the effect of isoorientin on postmenopausal osteoporosis remains unclear. OBJECTIVE: To evaluate the effect of isoorientin on postmenopausal osteoporosis. MATERIALS AND METHODS: Sprague-Dawley rats were divided into five groups (n = 5): sham, model, 17-ß-oestradiol (E2, 10 µg/kg/day), low-dose isoorientin (L-Iso, 50 mg/kg), and high-dose isoorientin (H-Iso, 100 mg/kg). The rats were ovariectomized, treated by gavage daily for 12 weeks, and serum and femur samples were collected. Bone mineral density, bone metabolism, and oxidative stress were assessed. H&E staining, immunohistochemistry, and western blotting were employed. RESULTS: Isoorientin improved the bone mineral density of the lumbar vertebrae (2.01 ± 0.05 g/cm3 in H-Iso group vs. 1.74 ± 0.07 g/cm3 in model group) and femur (1.46 ± 0.06 g/cm3 vs. 1.19 ± 0.03 g/cm3), increased the trabecular bone number (1.97 ± 0.03 vs. 1.18 ± 0.13) and thickness (0.27 ± 0.02 vs. 0.16 ± 0.03 mm). Isoorientin decreased the separation degree of trabecular bone, ameliorated bone histomorphology changes, and significantly improved the mechanical properties. Isoorientin diminished MDA (by 60%) and increased SOD (by 49.2%), and GSH-Px (by 159%) activity. Furthermore, osteoprotegerin (OPG), nuclear factor erythroid 2-like 2 (Nrf2), haem oxygenase (HO-1), NAD(P)H quinone dehydrogenase 1(NQO1), and oestrogen receptor 1(ESR1) protein expression increased, while receptor activator of nuclear factor-κB ligand (RANKL) protein expression decreased after treatment. CONCLUSIONS: Isoorientin ameliorates osteoporosis via upregulating OPG and Nrf2/ARE signalling, suggesting isoorientin maybe a potential therapeutic drug for PMOP.

Polyphyllin I attenuates cognitive impairments and reduces AD-like pathology through CIP2A-PP2A signaling pathway in 3XTg-AD mice.

Polyphyllin I (PPI) is a natural phytochemical drug isolated from plants which can inhibit the proliferation of cancer cells. One of the PPI tumor-inhibitory effects is through downregulating the expression of Cancerous Inhibitor of PP2A (CIP2A), the latter, is found upregulated in Alzheimer's disease (AD) brains and participates in the development of AD. In this study, we explored the application of PPI in experimental AD treatment in CIP2A-overexpressed cells and 3XTg-AD mice. In CIP2A-overexpressed HEK293 cells or primary neurons, PPI effectively reduced CIP2A level, activated PP2A, and decreased the phosphorylation of tau/APP and the level of Aß. Furthermore, synaptic protein levels were restored by PPI in primary neurons overexpressing CIP2A. Animal experiments in 3XTg-AD mice revealed that PPI treatment resulted in decreased CIP2A expression and PP2A re-activation. With the modification of CIP2A-PP2A signaling, the hyperphosphorylation of tau/APP and Aß overproduction were prevented, and the cognitive impairments of 3XTg-AD mice were rescued. In summary, PPI ameliorated AD-like pathology and cognitive impairment through modulating CIP2A-PP2A signaling pathway. It may be a potential drug candidate for the treatment of AD.

LncRNA LOC730101 promotes osteosarcoma cell survival under energy stress.

Long non-coding RNAs have been proved in tumorigenesis of various cancers, including osteosarcoma. However, the role of LOC730101 in cancer is rare to be reported, not mention to osteosarcoma. In current study, quantitative real-time PCR, was applied to evaluate the expression of LOC730101 under energy stress. The roles of LOC730101 in cell viability, apoptosis and tumor development under energy stress were analyzed by cell biological assays in vitro and in vivo. AMPK CA (continuously active) and Compound C (AMPK inhibitor) were employed to investigate the mechanism. And we further confirmed that compared with adjacent tissues, LOC730101 is remarkably increased in osteosarcoma in our fresh tissues. In addition, cellular function assays demonstrated that LOC730101 promotes cell viability, tumor development, and deficiency of LOC730101 promotes cell apoptosis under energy stress. Furthermore, we validated that up-regulated LOC730101 enhances cell viability through AMPK under energy stress. Taken together, our findings enlarged the knowledge about the roles of LOC730101 in osteosarcoma progression.

A Two-Stage Protocol With Vacuum Sealing Drainage for the Treatment of Type C Pilon Fractures.

Management of type C pilon fractures remains controversial and challenging. The aim of the present study was to provide a 2-stage protocol with vacuum sealing drainage for the treatment of type C pilon fractures. From March 2009 to March 2012, 16 patients (mean age 42.3 years) were admitted to our department with type C pilon fractures and treated with single-stage external fixation and second-stage internal fixation (anteromedial incision) combined with vacuum sealing drainage. The American Orthopaedic Foot and Ankle Society scale score averaged 86.5 for this group of patients. The range of motion was 30° ± 8.9°. An excellent or good American Orthopaedic Foot and Ankle Society scale score was obtained for all patients. None of the 16 patients developed skin necrosis, nonunion, or fixation failure during the follow-up period. Moreover, the visual analog scale pain scores were 0.7 ± 0.8, 0.9 ± 0.7, and 1.4 ± 1.0 during rest, active movement, and weightbearing, respectively. The postoperative radiographs showed excellent treatment effects. A 2-stage protocol, combined with vacuum sealing drainage, for the treatment of type C pilon fractures can eliminate deep infection and complex surgery and is a simple and effective treatment method. In addition, full exposure of the anteromedial incision, the avoidance of the anterior tibial muscle tendon sheath, and the avoidance of soft tissue injuries are generally recommended in this operation.

[Mathematical analysis of the influences of femoral and tibial bone cuts on the dynamic alignment in total knee arthroplasty].

OBJECTIVE: To investigate the influences of the distal femoral cut, the anterior and posterior femoral cuts, the proximal tibial cut on the dynamic alignment of the lower extremity in total knee arthroplasty. METHODS: Based on the three-dimensional geometric model, imitating the flexion movement of the knee without axial rotation after total knee arthroplasty, the influence of each of the three bone cuts on the dynamic alignment was analyzed with the assumption of standard bone cuts of the other two and equality of the medial and lateral soft tissue balancing. The dynamic alignment was defined as the angle between the mechanical axis of the tibia and the sagittal plane of the body when the knee was in any angle of flexion. With two of the three major bone cuts standard, the track of the tibial movement was established when the other one bone cut deviated from the ideal section of angle A. Based on the principle of geometry, the mathematical formula were established to present the influences of three bone cuts on the dynamic alignment of the lower extremity. RESULTS: All of the three kinds of bone cuts in total knee arthroplasty influenced the dynamic alignment of the lower extremity not just in one static position, but during the whole range of motion. At the θ angle of knee flexion, the alignment of the lower extremity was arcsin(cosθsinA) when the varus/valgus femoral component alignment was A; the alignment of the lower extremity was arcsin(sinθsinA) when the rotational femoral component alignment was A; the alignment of the lower extremity was A when the varus/valgus tibial component alignment was A. CONCLUSION: The influences of the distal femoral cut, the anterior and posterior femoral cuts, the proximal tibial cut on the dynamic alignment of the lower extremity in total knee arthroplasty are dynamically changed during the flexion movement of the knee.

Femoral rotation influences dynamic alignment of the lower extremity in total knee arthroplasty.

PURPOSE: Besides the long-leg standing X-ray film focusing on static standing mechanical alignment of the lower extremity, dynamic alignment from full extension to 90° flexion after total knee arthroplasty (TKA) is rarely mentioned. Computer-assisted surgical technology enables surgeons to measure and assess knee behaviour during surgery. This study was designed to analyse the influences of femoral rotation on dynamic alignment of the lower extremity in TKA. METHODS: Seventy-six consecutive patients with end-stage knee osteoarthritis were enrolled. External rotation osteotomy of the distal femur during TKA was completed according to the pre-operative external rotation angle (ERA), intra-operative transepicondylar axis (TEA) and anteroposterior (AP) line. Passive dynamic alignment of the lower extremity during knee flexion was recorded. The variation trend of hip-knee-ankle (HKA) alignment and the influences of femoral external rotation osteotomy were analysed. RESULTS: Postoperative deviation of HKA alignment from 0° to 90° flexion was associated with the rotational alignment of the femoral component (r = -0.769, p < 0.001). Variation trend of HKA alignment during knee flexion tended to be varus, valgus and neutral according to the selected angle of external rotation osteotomy of the distal femur. CONCLUSION: External rotation osteotomy of the distal femur played a crucial role in determining dynamic HKA alignment in TKA.

Diabetes mellitus increases the incidence of deep vein thrombosis after total knee arthroplasty.

INTRODUCTION: Many patients undergoing total knee arthroplasty (TKA) have diabetes mellitus, which may increase the risk of deep vein thrombosis (DVT) after TKA. We therefore assessed whether diabetes mellitus increased the incidence of DVT within 14 days after TKA. MATERIALS AND METHODS: The incidence of DVT within 14 days of surgery was compared in diabetic and non-diabetic patients undergoing TKA in our hospital between June 2011 and February 2013. The relationships between diabetes mellitus and DVT were analyzed. RESULTS: Of the 358 enrolled patients, 70 (19.6%) had diabetes and 288 (80.4%) did not. DVT occurred within 14 days in 198 patients, 52 of 70 (74.3%) in the diabetes group and 146 of 288 (50.7%) in the non-diabetes group (p = 0.012). DVT of the contralateral leg was observed in 16 and 50 patients, respectively (p = 0.452). Logistic regression analysis showed that the risk of DVT was 2.71-fold higher in patients with than without diabetes mellitus (95% CI 1.183-6.212, p = 0.018). There were no significant differences in age, gender, hypertension, BMI, duration of surgery, intra-operative blood loss, and duration of tourniquet between the two groups. CONCLUSIONS: The incidence of DVT 14 days after TKA was significantly higher in patients with than without diabetes.

Distributed dynamic event-triggered algorithm for optimization problem with time delay.

This paper focuses on studying the optimization problem of multi-agent systems (MAS) under undirected graph. To reduce the communication frequency among agents, a zero-gradient-sum (ZGS) algorithm based on dynamic event-triggered (DET) mechanism is investigated. The event-triggered condition of each agent only uses its own state information and the neighbor's state information at the previous triggering instants, without requiring continuous state information from the neighbor. In addition, the designed algorithm allows for the sampling period to be arbitrarily large. The Lyapunov method is utilized to derive the sufficient conditions that incorporate time delay and parameters. As the event is only checked at the periodic moment, zeno behavior can be directly excluded. Finally, numerical simulations demonstrate the effectiveness of the theoretical results.

Zeroth-order gradient tracking for decentralized learning with privacy guarantees.

This paper proposes a differential privacy decentralized zeroth-order gradient tracking optimization (DP-DZOGT) algorithm for solving optimization problems of decentralized systems, where the gradient information of the function is unknown. To address the challenge of unknown gradient information, a one-point zeroth-order gradient estimator (OPZOGE) is constructed, which can estimate the gradient based on the function value and guide the update of decision variables. Additionally, to prevent privacy leakage of agents, random noise is introduced into both the state and the gradient of the agents, which effectively enhances the level of privacy protection. The linear convergence of the proposed DP-DZOGT under a fixed step size can be guaranteed. Moreover, it has been applied to the fields of smart grid (SG) and decentralized federated learning (DFL). Finally, the effectiveness of the algorithm is validated through three numerical simulations.

A preliminary attempt at capacitive deionization with PVA/PSS gel coating as an alternative to ion exchange membrane.

PVA/PSS composite gel membrane electrode for membrane capacitive deionization (MCDI) was fabricated and characterised in the present study. The composite electrode with ion exchange surface is prepared by coating glutaraldehyde cross-linked polyvinyl alcohol (PVA) composite hydrogel, with Poly (Sodium 4-Styrenesulfonate) (PSS) added into the network, on the surface of activated carbon (AC) electrode. The feasibility of the gel membrane is analyzed by rheological, swelling rates and ion exchange capacity tests. Then electrochemical test and desalination test are used to study the performance of the MCDI electrode. The results show that coating of composite hydrogel layer improved the hydrophilicity, specific capacitance and lower interfacial electron transfer resistance of the electrode. Finally, we assemble the asymmetrical CDI cell with PVA/PSS composite gel electrode and AC electrode. Compared with the AC electrode, the salt adsorption capacity of PVA6-PSS15 can reach 18.9 mg g-1 and stable charge efficiency at 73.0% at operating voltage of 1.2 V. The decrease in specific capacitance of PVA6-PSS15 after 50 cycles is 1.33%, indicating that the electrode has a good cycling life. The gel membrane coated electrode prepared by PSS provides a new idea for the development of MCDI.

Knockdown of DAPK1 inhibits IL-1ß-induced inflammation and cartilage degradation in human chondrocytes by modulating the PEDF-mediated NF-κB and NLRP3 inflammasome pathway.

Osteoarthritis (OA) is a common joint disease that is characterized by inflammation and cartilage degradation. Death-associated protein kinase 1 (DAPK1) is a multi-domain serine/threonine kinase and has been reported to be involved in the progression of OA. However, its role and mechanism in OA remain unclear. Here, we found the expression of DAPK1 in OA cartilage tissues was higher than that in normal cartilage tissues. The expression of DAPK1 in chondrocytes was up-regulated by IL-1ß. Knockdown of DAPK1 promoted cell viability and anti-apoptotic protein expression, while it inhibited the apoptosis rate and pro-apoptotic protein expressions in IL-1ß-induced chondrocytes. In addition, DAPK1 inhibition reduced the levels of inflammatory cytokines and expressions of matrix metalloproteinases (MMPs), and increased the expressions of collagen II and aggrecan. The data of mechanistic investigation indicated that the expression of pigment epithelium-derived factor (PEDF) was positively regulated by DAPK1. Overexpression of PEDF attenuated the effects of DAPK1 knockdown on IL-1ß-induced cell viability, apoptosis, inflammation, and cartilage degradation. Furthermore, PEDF overexpression restored the activity of the NF-κB pathway and NLRP3 inflammasome after DAPK1 knockdown. Collectively, down-regulation of DAPK1 inhibited IL-1ß-induced inflammation and cartilage degradation via the PEDF-mediated NF-κB and NLRP3 inflammasome pathways.

Development of a UHPLC-MS/MS method for the quantification of Pristinamycin â A and â ¡A in beagle dog plasma and its pharmacokinetic application.

The aim of this study was to develop and fully validate a sensitive and rapid ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for simultaneous quantification of pristinamycin ⅠA (PⅠA) and pristinamycin ⅡA (PⅡA) in plasma of beagle dogs after oral administration of pristinamycin tablets. PⅠA, PⅡA and quinupristin (internal standard, IS) were separated on an Agilent Eclipse Plus C18 column (2.1 mm × 100 mm, 3.5 µm particle size) by using gradient elution consisting of methanol and water (0.1 % formic acid) at a flow rate of 0.4 mL/min in 4.0 min. Multiple reaction monitoring (MRM) mode was performed to quantify data under monitoring precursor-product ion transitions of m/z 867.6→134.1, 548.4→287.1 and 1022.7→133.9 for PⅠA, PⅡA and IS at positive ion mode, respectively. The method was developed at linearity ranging from 1.0 to 1000 ng/mL for all analytes.The accuracy of PⅠA and PⅡA was observed to range between -10.6 % and 7.1 %, while the precision was found to be within 8.9 %. No significant matrix effect was observed. PⅠA and PⅡA demonstrated stability during sample storage, preparation and analytic procedures. Furthermore, this method was successfully applied in the investigation of the pharmacokinetic profile of PⅠA and PⅡA in beagle dogs after oral administration of pristinamycin tablets (75 mg for PⅠA and 175 mg for PⅡA). The biological half-life (t1/2) was determined to be 1.75 ± 0.07 h and 1.44 ± 0.31 h for PⅠA and PⅡA, respectively. The areas under curves (AUC0-t) of PⅠA and PⅡA were 80.7 ± 24.6 and 230 ± 94.8 µg/L·h, respectively.

Two-Dimensional Vertical Transistor with One-Dimensional van der Waals Contact.

Two-dimensional (2D) materials enable vertical field effect transistors (VFETs), which provide an alternative path for scaling down the channels of transistors. The challenge is the short channel effect when the thickness of the 2D channel decreases to ∼10 nm. Here, we show that a VFET with an ultrashort channel can be accomplished by employing a semimetal carbon nanotube (CNT) as a 1D van der Waals (vdW) contact. The CNT-VFETs with 5-10 nm MoS2 channels exhibit high on/off ratios exceeding 105, low subthreshold swing values of 160-120 mV/dec, and high current densities over 104 A/cm2. Such a switch even works with an ∼ 3.4 nm thick channel. The excellent comprehensive performance can be ascribed to the reduced short channel effect as the sub-2 nm CNT contact has weaker electrostatic screening to the gate, a reduced Fermi level pinning effect, and a highly tunable barrier. The VFETs with 1D vdW contacts hold great promise for ultrascaled transistors and are prospective in future nanoelectronics and nano-optoelectronics.

Microheater Chips with Carbon Nanotube Resistors.

The specific and excellent properties of the low-dimensional nanomaterials have made them promising building blocks to be integrated into microelectromechanical systems with high performances. Here, we present a new microheater chip for in situ TEM, in which a cross-stacked superaligned carbon nanotube (CNT) film resistor is located on a suspended SiNx membrane via van der Waals (vdW) interactions. The CNT microheater has a fast high-temperature response and low power consumption, thanks to the micro/nanostructure of the CNT materials. Moreover, the membrane bulging amplitude is significantly reduced to only ∼100 nm at 800 °C for the vdW interaction between the CNTs and the SiNx membrane. An in situ observation of the Sn melting process is successfully conducted with the assistance of a customized flexible temperature control system. The uniform wafer-scaled CNT films enable a high level of consistency and cost-effective mass production of such chips. The as-developed in situ chips, as well as the related techniques, hold great promise in nanoscience, materials science, and electrochemistry.