Codiscovering graphical structure and functional relationships within data: A Gaussian Process framework for connecting the dots.

Most problems within and beyond the scientific domain can be framed into one of the following three levels of complexity of function approximation. Type 1: Approximate an unknown function given input/output data. Type 2: Consider a collection of variables and functions, some of which are unknown, indexed by the nodes and hyperedges of a hypergraph (a generalized graph where edges can connect more than two vertices). Given partial observations of the variables of the hypergraph (satisfying the functional dependencies imposed by its structure), approximate all the unobserved variables and unknown functions. Type 3: Expanding on Type 2, if the hypergraph structure itself is unknown, use partial observations of the variables of the hypergraph to discover its structure and approximate its unknown functions. These hypergraphs offer a natural platform for organizing, communicating, and processing computational knowledge. While most scientific problems can be framed as the data-driven discovery of unknown functions in a computational hypergraph whose structure is known (Type 2), many require the data-driven discovery of the structure (connectivity) of the hypergraph itself (Type 3). We introduce an interpretable Gaussian Process (GP) framework for such (Type 3) problems that does not require randomization of the data, access to or control over its sampling, or sparsity of the unknown functions in a known or learned basis. Its polynomial complexity, which contrasts sharply with the super-exponential complexity of causal inference methods, is enabled by the nonlinear ANOVA capabilities of GPs used as a sensing mechanism.

A novel antibiotic: the antimicrobial effects of CFBSA and its application on electronspun wound dressing.

N-chloro-N-fluorobenzenesulfonylamide (CFBSA), was a novel chlorinating reagent, which exhibits potential antibacterial activities. In this study, CFBSA was confirmed as a wide-broad antimicrobial and bactericidal drug against different gram-negative bacteria, gram-positive bacteria and fungi, while it was found to have low cytotoxicity for eukaryotic cells. In addition, microorganism morphology assay and oxidative stress test was used to determine the antimicrobial mechanisms of CFBSA. According to the results, CFBSA probably had a target on cell membrane and killed microorganism by disrupting its cell membrane. Then, CFBSA was first combined with poly(L-lactide-co-caprolactone) (PLCL)/SF via electrospinning and applied in wound dressings. The characterization of different PLCL/SF of CFBSA-loaded nanofibrous mats was investigated by SEM, water contact angle, Fourier transform infrared spectroscopy, cell compatibility and antimicrobial test. CFBSA-loaded PLCL/SF nanofibrous mats showed excellent antimicrobial activities. In order to balance of the biocompatibility and antibacterial efficiency, SP-2.5 was selected as the ideal loading concentration for further application of CFBSA-loaded PLCL/SF. In conclusion, the electrospun CFBSA-loaded PLCL/SF nanofibrous mat with its broad-spectrum antimicrobial and bactericidal activity and good biocompatibility showed enormous potential for wound dressing.

Transcription Factor E2F7 Activates PKMYT1 to Partially Suppress Adriamycin Sensitivity in Gastric Cancer Through the MAPK Signaling Pathway

ABSTRACT Background: Adriamycin (ADM) resistance remains an obstacle to gastric cancer chemotherapy treatment. Objective: The objective of this study was to study the role and mechanism of transcription factor E2F7 in sensitivity to ADM chemotherapeutic agents in gastric cancer. Methods: Cell viability and cell sensitivity were assessed by CCK-8 and IC50 values of ADM were calculated. The impact of ADM on cellular proliferative capacity was assessed through colony formation assay. The binding relationship between E2F7 and PKMYT1 was then verified by dual luciferase assay and chromatin immunoprecipitation assay. ERK1/ERK2 and p-ERK1/p-ERK2 protein expression levels were detected by western blot. Results: In both gastric cancer tissue and ADM-resistant cells, a conspicuous upregulation of E2F7 and PKMYT1 was observed. Upregulated PKMYT1 was notably enriched in the MAPK signaling pathway. Enhanced levels of E2F7 were shown to not only drive gastric cancer cell proliferation but also engender a reduction in the sensitivity of these cells to ADM. Furthermore, PKMYT1 emerged as a downstream target of E2F7. Activation of E2F7 culminated in the transcriptional upregulation of PKMYT1, and silencing E2F7 reversed the inhibitory impact of PKMYT1 overexpression on ADM sensitivity in gastric cancer cells. Conclusion: E2F7/PKMYT1 axis might promote the proliferation and partially inhibit ADM sensitivity of gastric cancer cells by activating the MAPK pathway.

Transcription factor E2F7 activates PKMYT1 to partially suppress adriamycin sensitivity in gastric cancer through the MAPK signaling pathway.

Background: Adriamycin resistance remains an obstacle to gastric cancer chemotherapy treatment. Objective: The objective of this study was to study the role and mechanism of transcription factor E2F7 in sensitivity to ADM chemotherapeutic agents in gastric cancer. Methods: Cell viability and cell sensitivity were assessed by CCK-8 and IC50 values of ADM were calculated. The impact of ADM on cellular proliferative capacity was assessed through colony formation assay. The binding relationship between E2F7 and PKMYT1 was then verified by dual luciferase assay and chromatin immunoprecipitation assay. ERK1/ERK2 and p-ERK1/p-ERK2 protein expression levels were detected by western blot. Results: In both gastric cancer tissue and ADM-resistant cells, a conspicuous upregulation of E2F7 and PKMYT1 was observed. Upregulated PKMYT1 was notably enriched in the MAPK signaling pathway. Enhanced levels of E2F7 were shown to not only drive gastric cancer cell proliferation but also engender a reduction in the sensitivity of these cells to ADM. Furthermore, PKMYT1 emerged as a downstream target of E2F7. Activation of E2F7 culminated in the transcriptional upregulation of PKMYT1, and silencing E2F7 reversed the inhibitory impact of PKMYT1 overexpression on ADM sensitivity in gastric cancer cells. Conclusion: E2F7/PKMYT1 axis might promote the proliferation and partially inhibit ADM sensitivity of gastric cancer cells by activating the MAPK pathway.

Correction: Construction of perfluorohexane/IR780@liposome coating on Ti for rapid bacteria killing under permeable near infrared light.

Correction for 'Construction of perfluorohexane/IR780@liposome coating on Ti for rapid bacteria killing under permeable near infrared light' by Xiuhua Wang et al., Biomater. Sci., 2018, 6, 2460-2471, https://doi.org/10.1039/C8BM00602D.

ZC3HAV1 promotes the proliferation and metastasis via regulating KRAS in pancreatic cancer.

Proliferation and metastasis are important malignant features of pancreatic cancer (PC), but the underlying molecular mechanism is unclear. ZC3HAV1, a PARP family member of proteins-enzymes, has been considered to play a significant part in a variety of biological processes. Nonetheless, the functions of ZC3HAV1 in developing PC are still unknown. This research aims to explore the biological function and the expression of ZC3HAV1 shown in PC. In our study, PCR analysis suggested that ZC3HAV1 was expressed at a high level in PC tissues and cell lines, and high ZC3HAV1 expression was remarkably related to poor prognosis. The functional assays indicated that upregulated ZC3HAV1 accelerated PC cell proliferation along with colony formation capacities in vitro. Subsequently, ZC3HAV1 could upregulate cyclin D1 and CDK2 and also promote G1/S transition in cells of PC. What's more, we also discovered that ZC3HAV1 promotes the migration and the invasion of PC cells. It upregulates the expression of EMT (epithelial-mesenchymal transition) relevant markers. Conversely, the functional assays showed that ZC3HAV1 knockdown significantly reduced tumorigenesis. Using bioinformatics analysis and immunoprecipitation assays we found that ZC3HAV1 could directly bind to KRAS and positively regulate its expression. Furthermore, ZC3HAV1 overexpression activated MAPK signaling by increasing p-ERK levels. Conversely, knockdown of KRAS attenuated ZC3HAV1-mediated promotion of proliferation and invasion in cells of PC. The result indicated that ZC3HAV1 was in relation to poor prognosis and accelerated the proliferation and metastasis of PC cells by regulation of KRAS. Our research may offer brand-new evidence to diagnose and treat PC in clinic.

Nano-needle strontium-substituted apatite coating enhances osteoporotic osseointegration through promoting osteogenesis and inhibiting osteoclastogenesis.

Implant loosening remains a major clinical challenge for osteoporotic patients. This is because osteoclastic bone resorption rate is higher than osteoblastic bone formation rate in the case of osteoporosis, which results in poor bone repair. Strontium (Sr) has been widely accepted as an anti-osteoporosis element. In this study, we fabricated a series of apatite and Sr-substituted apatite coatings via electrochemical deposition under different acidic conditions. The results showed that Ca and Sr exhibited different mineralization behaviors. The main mineralization products for Ca were CaHPO4·2H2O and Ca3(PO4)2 with the structure changed from porous to spherical as the pH values increased. The main mineralization products for Sr were SrHPO4 and Sr5(PO4)3OH with the structure changed from flake to needle as the pH values increased. The in vitro experiment demonstrated that coatings fabricated at high pH condition with the presence of Sr were favorable to MSCs adhesion, spreading, proliferation, and osteogenic differentiation. In addition, Sr-substituted apatite coatings could evidently inhibit osteoclast differentiation and fusion. Moreover, the in vivo study indicated that nano-needle like Sr-substituted apatite coating could suppress osteoclastic activity, improve new bone formation, and enhance bone-implant integration. This study provided a new theoretical guidance for implant coating design and the fabricated Sr-substituted coating might have potential applications for osteoporotic patients.

Novel Bionic Topography with MiR-21 Coating for Improving Bone-Implant Integration through Regulating Cell Adhesion and Angiogenesis.

Implant loosening is still the major form of the failure of artificial joints. Herein, inspired by the operculum of the river snail, we prepared a novel bionic micro/nanoscale topography on a titanium surface. This bionic topography promoted early cell adhesion through up-regulating the expression of ITG α5ß1 and thus accelerated the following cell spreading, proliferation, and differentiation. Moreover, a miR-21 coating, which promoted the angiogenic differentiation of MSCs, was fabricated on the bionic topography. Benefiting from both bionic micro/nanoscale topography and miR-21, blood vessel growth and bone formation and mineralization around the implant, as well as bone-implant bonding strength, were significantly improved. Collectively, the present study highlights the combination of the bionic micro/nanoscale topography and miR-21 on promoting cell adhesion and angiogenic differentiation and improving in vivo angiogenesis and bone-implant osseointegration. This work provides a new train of thought propelling the development of implants for potential application in the orthopedics field.

Overcoming Multidrug-Resistant MRSA Using Conventional Aminoglycoside Antibiotics.

Global multidrug-resistant (MDR) bacteria are spreading rapidly and causing a great threat to human health due to the abuse of antibiotics. Determining how to resensitize MDR bacteria to conventional inefficient antibiotics is of extreme urgency. Here, a low-temperature photothermal treatment (PTT, 45 °C) is utilized with red phosphorus nanoparticles to resensitize methicillin-resistant Staphylococcus aureus (MRSA) to conventional aminoglycoside antibiotics. The antibacterial mechanism is studied by the proteomic technique and molecular dynamics (MD) simulation, which proves that the aminoglycoside antibiotics against MRSA can be selectively potentiated by low-temperature PTT. The catalytic activity of 2-aminoglycoside phosphotransferase (APH (2″))-a modifying enzyme-is demonstrated to be obviously inhibited via detecting the consumption of adenosine triphosphate (ATP) in the catalytic reaction. It is also found that the active site of aspartic acid (ASP) residues in APH (2″) is thermally unstable from the results of molecular dynamics simulation. Its catalytic ability is inhibited by preventing the deprotonating procedure for the target -OH of gentamycin. The combined therapy also exhibits great biocompatibility and successfully treats MRSA infections in vivo. This low-temperature PTT strategy has the potential to be an exogenous-modifying enzyme inhibitor for the treatment of MDR bacterial infection.

miR-21 promotes osseointegration and mineralization through enhancing both osteogenic and osteoclastic expression.

The demand for orthopedic implants continues to increase with the aging population. As the most widely used orthopedic materials, titanium and its alloys have achieved high success rates. However, the lack of bone tissue integration remains a barrier to successful operations. In this study, the titanium surface was acid-treated and functionalized with miR-21 nanocapsules via an in situ polymerization method. This coating showed a uniform miR-21 distribution and sustainable miR-21 release. The in vitro studies indicated that miR-21 could not only promote angiogenic and osteogenic differentiation of MSCs but also enhance osteoclastic activity. Additionally, in vivo evaluations, including X-ray, micro-CT, histology, immunohistochemistry, biomechanical testing, Raman and SEM-EDS, demonstrated that the micro-rough surface could increase the bone-implant contact and, thus, improved osseointegration during the early stages. More importantly, the miR-21 nanocapsule coating accelerated vascularization (high expression of CD31), bone remodeling (high expression of both osteogenesis- and osteoclast-related proteins) and bone maturation (high proportion of apatite), resulting in a significantly improved bone-implant contact and enhanced bone-implant bonding strength (twice the Ti at 1 month). These results indicated that a Ti-based micro-rough surface functionalized with miR-21 nanocapsules had potential applications in the orthopedic field.

5,6-Fused bicyclic tetrazolo-pyridazine energetic materials.

This study presents the synthesis of 5,6-fused bicyclic conjugated energetic compounds through a combined strategy of anchoring the catenated nitrogen-atom chain and introducing vicinal C-amino and C-nitro groups into a tetrazolo-pyridazine ring. Their crystal structures were confirmed by single crystal X-ray diffraction. Both compounds display good thermal stability, high energetic properties and low sensitivities as energetic materials.

"Imitative" click chemistry to form a sticking xerogel for the portable therapy of bacteria-infected wounds.

Xerogels usually possess a stable structure and have a low swelling rate due to their inferior dynamics. Herein, a xerogel was synthesized by "imitative" click chemistry based on lipoic acid for picking up bacteria from wound sites, and thus accelerating tissue repair. The cross-linking structure of disulfide and thioether inside the xerogel not only exhibited good ductility and intrinsic self-healing performance, but also showed superior biocompatibility. The xerogel captured more than 60% of the bacteria Staphylococcus aureus via strong electrostatic adsorption in the colonies with a bacteria count of 106. In addition, this xerogel can stick to the skin in the form of patches in the wounds during therapy for wound healing and can be easily stripped from the skin after treatment, which makes it appropriate for the portable therapy of bacteria-infected wounds in emergency circumstances.

Zinc-doped Prussian blue enhances photothermal clearance of Staphylococcus aureus and promotes tissue repair in infected wounds.

The application of photothermal therapy to treat bacterial infections remains a challenge, as the high temperatures required for bacterial elimination can damage healthy tissues. Here, we develop an exogenous antibacterial agent consisting of zinc-doped Prussian blue (ZnPB) that kills methicillin-resistant Staphylococcus aureus in vitro and in a rat model of cutaneous wound infection. Local heat triggered by the photothermal effect accelerates the release and penetration of ions into the bacteria, resulting in alteration of intracellular metabolic pathways and bacterial killing without systemic toxicity. ZnPB treatment leads to the upregulation of genes involved in tissue remodeling, promotes collagen deposition and enhances wound repair. The efficient photothermal conversion of ZnPB allows the use of relatively few doses and low laser flux, making the platform a potential alternative to current antibiotic therapies against bacterial wound infections.

Dual Metal-Organic Framework Heterointerface.

Herein, a core-shell dual metal-organic framework (MOF) heterointerface is synthesized. The Prussian blue (PB) MOF acts as a core for the growth of a porphyrin-doped MOF which is named PB@MOF. Porphyrins can significantly enhance the transfer of photoinspired electrons from PB and suppress the recombination of electrons and holes, thus enhancing the photocatalytic properties and consequently promoting the yields of singlet oxygen rapidly under 660 nm illumination. PB@MOF can exhibit a better photothermal conversion efficiency up to 29.9% under 808 nm near-infrared irradiation (NIR). The PB@MOF heterointerface can possess excellent antibacterial efficacies of 99.31% and 98.68% opposed to Staphylococcus aureus and Escherichia coli, separately, under the dual light illumination of 808 nm NIR and 660 nm red light for 10 min. Furthermore, the trace amount of Fe and Zr ions can trigger the immune system to favor wound healing, promising that PB@MOF achieves the rapid therapy of bacterial infected wounds and environmental disinfection.

Highly Effective and Noninvasive Near-Infrared Eradication of a Staphylococcus aureus Biofilm on Implants by a Photoresponsive Coating within 20 Min.

Biofilms have been related to the persistence of infections on medical implants, and these cannot be eradicated because of the resistance of biofilm structures. Therefore, a biocompatible phototherapeutic system is developed composed of MoS2, IR780 photosensitizer, and arginine-glycine-aspartic acid-cysteine (RGDC) to safely eradicate biofilms on titanium implants within 20 min. The magnetron-sputtered MoS2 film possesses excellent photothermal properties, and IR780 can produce reactive oxygen species (ROS) with the irradiation of near-infrared (NIR, λ = 700-1100 nm) light. Consequently, the combination of photothermal therapy (PTT) and photodynamic therapy (PDT), assisted by glutathione oxidation accelerated by NIR light, can provide synergistic and rapid killing of bacteria, i.e., 98.99 ± 0.42% eradication ratio against a Staphylococcus aureus biofilm in vivo within 20 min, which is much greater than that of PTT or PDT alone. With the assistance of ROS, the permeability of damaged bacterial membranes increases, and the damaged bacterial membranes become more sensitive to heat, thus accelerating the leakage of proteins from the bacteria. In addition, RGDC can provide excellent biosafety and osteoconductivity, which is confirmed by in vivo animal experiments.

Lysozyme-Assisted Photothermal Eradication of Methicillin-Resistant Staphylococcus aureus Infection and Accelerated Tissue Repair with Natural Melanosome Nanostructures.

Patients often face the challenge of antibiotic-resistant bacterial infections and lengthy tissue reconstruction after surgery. Herein, human hair-melanosome derivatives (HHMs), comprising keratins and melanins, are developed using a simple "low-temperature alkali heat" method for potentially personalized therapy. The mulberry-shaped HHMs have an average width of ∼270 nm and an average length of ∼700 nm, and the negatively charged HHMs can absorb positively charged Lysozyme (Lyso) to form the HHMs-Lyso composites through electrostatic interaction. These naturally derived biodegradable nanostructures act as exogenous killers to eliminate methicillin-resistant Staphylococcus aureus (MRSA) infection with a high antibacterial efficacy (97.19 ± 2.39%) by synergistic action of photothermy and "Lyso-assisted anti-infection" in vivo. Additionally, HHMs also serve as endogenous regulators of collagen alpha chain proteins through the "protein digestion and absorption" signaling pathway to promote tissue reconstruction, which was confirmed by quantitative proteomic analysis in vivo. Notably, the 13 upregulated collagen alpha chain proteins in the extracellular matrix (ECM) after HHMs treatment demonstrated that keratin from HHMs in collagen-dependent regulatory processes serves as a notable contributor to augmented wound closure. The current paradigm of natural material-tissue interaction regulates the cell-ECM interaction by targeting cell signaling pathways to accelerate tissue repair. This work may provide insight into the protein-level pathways and the potential mechanisms involved in tissue repair.

Rapid Biofilm Elimination on Bone Implants Using Near-Infrared-Activated Inorganic Semiconductor Heterostructures.

Bacterial infections often cause orthopedic surgery failures. It is hard for the immune system and antibiotics to clear bacteria adhered to implants after they form a mature biofilm, and a secondary surgery is required to remove the infected implants. To avoid this, a hybrid coating of Bi2 S3 @Ag3 PO4 /Ti is prepared to eliminate biofilm using near-infrared (NIR) light. Bi2 S3 nanorod (NR) arrays are prepared on titanium (Ti) implants through hydrothermal methods, and Ag3 PO4 nanoparticles (NPs) are loaded on Bi2 S3 NR arrays using a stepwise electrostatic adsorption strategy. The introduction of Ag3 PO4 NPs enhances the photocatalysis performances of Bi2 S3 , and the hybrid coating also exhibits good photothermal effects. After 808 nm light irradiation for 15 min, it shows superior bactericidal efficiency of 99.45% against Staphylococcus aureus, 99.74% against Escherichia coli in vitro, and 94.54% against S. aureus biofilm in vivo. Bi2 S3 @Ag3 PO4 /Ti also shows good cell viability compared to pure Ti. This NIR-activated-inorganic hybrid semiconductor heterojunction coating is biocompatible and could be employed to eliminate biofilm effectively, which makes it a very promising strategy for the surface modification of bone implant materials.