Acid-sensing ion channel 1a regulates the specificity of reconsolidation of conditioned threat responses.

Recent research on altering threat memory has focused on a reconsolidation window. During reconsolidation, threat memories are retrieved and become labile. Reconsolidation of distinct threat memories is synapse dependent, whereas the underlying regulatory mechanism of the specificity of reconsolidation is poorly understood. We designed a unique behavioral paradigm in which a distinct threat memory can be retrieved through the associated conditioned stimulus. In addition, we proposed a regulatory mechanism by which the activation of acid-sensing ion channels (ASICs) strengthens the distinct memory trace associated with the memory reconsolidation to determine its specificity. The activation of ASICs by CO2 inhalation, when paired with memory retrieval, triggers the reactivation of the distinct memory trace, resulting in greater memory lability. ASICs potentiate the memory trace by altering the amygdala-dependent synaptic transmission and plasticity at selectively targeted synapses. Our results suggest that inhaling CO2 during the retrieval event increases the lability of a threat memory through a synapse-specific reconsolidation process.

Ultraviolet Light-Activated Charge Modulation Heterojunction for Versatile Organic Thin Film Transistors.

Organic thin film transistors (OTFTs) are a promising technology for the application of photosensors in smart wearable devices. Light-induced electrical behavior of OTFTs is explored to achieve diverse functional requirements. In most studies, OTFTs show an increased drain current (ID) under light irradiation. Here, we use an ultraviolet (UV) light absorption top layer, tris(8-hydroxyquinoline) aluminum (Alq3), to improve the UV light response of poly(3-hexylthiophene-2,5-diyl) (P3HT)-based OTFTs. Unexpectedly, the Alq3-covered device operated at the accumulation mode demonstrates a decreased ID during the UV light irradiation. N,N'-Ditridecyl-3,4,9,10-perylene tetracarboxylic diimide (PTCDI, electron acceptor), pentacene (electron donor), and lithium fluoride (LiF, insulator) as an interlayer were inserted between the P3HT and the Alq3 layers. The PTCDI/Alq3-covered device also shows an unusual decrease in ID under the UV light but an increase in ID under the green light. The pentacene/Alq3-covered device shows an increased ID during the UV light irradiation and, unexpectedly, a memory effect in ID after removing the UV light. The LiF/Alq3-covered device exhibits an electrical behavior similar to the bare P3HT-based device under the UV light. Results of spectroscopic analyses and theoretical calculations have shown that the occurrence of charge transfer at heterojunctions during the UV light irradiation causes charge modulation in the multilayered P3HT-based OTFTs and then results in an unusual decrease or memory effect in ID. In addition, the unexpected ID reduction can be observed in the Alq3-covered poly[2,5-bis(3-tetradecylthiophen-2-yl)thieno[3,2-b]thiophene]-based OTFTs under UV light. The features, including opposite electrical responses to different wavelengths of light and optical memory effect, provide the multilayered P3HT-based OTFTs with potential for various optical applications, such as image recognition devices, optical logic gates, light dosimeters, and optical synapses.

Activation of acid-sensing ion channels by carbon dioxide regulates amygdala synaptic protein degradation in memory reconsolidation.

Reconsolidation has been considered a process in which a consolidated memory is turned into a labile stage. Within the reconsolidation window, the labile memory can be either erased or strengthened. Manipulating acid-sensing ion channels (ASICs) in the amygdala via carbon dioxide (CO2) inhalation enhances memory retrieval and its lability within the reconsolidation window. Moreover, pairing CO2 inhalation with retrieval bears the reactivation of the memory trace and enhances the synaptic exchange of the calcium-impermeable AMPA receptors to calcium-permeable AMPA receptors. Our patch-clamp data suggest that the exchange of the AMPA receptors depends on the ubiquitin-proteasome system (UPS), via protein degradation. Ziram (50 µM), a ubiquitination inhibitor, reduces the turnover of the AMPA receptors. CO2 inhalation with retrieval boosts the ubiquitination without altering the proteasome activity. Several calcium-dependent kinases potentially involved in the CO2-inhalation regulated memory liability were identified using the Kinome assay. These results suggest that the UPS plays a key role in regulating the turnover of AMPA receptors during CO2 inhalation.

Enhanced Functionality of Dual-Gate Organic Transistors Based on Semiconducting/Insulating Polyblend-Induced Asymmetric Charge Modulation Layers.

Dual-gate organic thin-film transistors (DG-OTFTs) with enhanced functionality, including large current enhancement behavior, highly efficient threshold voltage controllability, and self-contained dual-mode logic gate features, are reported. These DG-OTFTs are based on a semiconducting/insulating polyblend-based active layer with asymmetric top and bottom charge modulation layers (atb-CMLs). The atb-CMLs are automatically generated through the preparation of multilayer stacks of phase-separated semiconducting poly(3-hexylthiophene) (P3HT):insulating poly(methylmethacrylate) (PMMA) polyblend layer, poly(vinylidene fluoride) (PVDF) layer, and cross-linked-poly(4-vinylphenol) (cPVP) layer. They consist of a thin PMMA bottom layer and an uneven-shaped PMMA:PVDF miscible mixture-based top layer. The presence of the polarizable insulating PMMA, PVDF, and PMMA:PVDF mixture regions causes the bottom and top CMLs to experience electrical polarization, which induces the dipole field to achieve efficient charge modulation functions in DG-OTFTs. Owing to the presence of atb-CMLs, the DG-OTFTs exhibit unprecedented electrical characteristics, such as the easy depletion of the bottom channel by the top gate potential. However, the top channel can work properly only when given a bottom gate potential (either positive or negative). Given these unusual electrical features, the design of the fundamental dual-mode logic gates (e.g., AND and OR gates) can be achieved with just one DG transistor. This finding opens an interesting direction for the preparation of DG-OTFTs with diverse operating modes and increasing functionality, thereby widening the application potential of such transistors.

Updates on Evidence-Based Practices to Reduce Preoperative and Intraoperative Contamination of Implants in Spine Surgery: A Narrative Review.

The current communication seeks to provide an updated narrative review on latest methods of reducing implant contaminations used during spine surgery. Recent literature review has shown that both preoperative reprocessing and intraoperative handling of implants seem to contaminate implants. In brief, during preoperative phase, the implants undergo repeated bulk cleaning with dirty instruments from the OR, leading to residue buildup at the interfaces and possibly on the surfaces too. This, due to its concealed nature, remains unnoticed by the SPD (sterile processing department) or other hospital staff. Nevertheless, these can be avoided by using individually prepackaged presterilized implants. In the intraoperative phase, the implants (in the sterile field) are directly touched by the scrub tech with soiled (assisting the surgeon dispose the tissues from the instruments in use) gloves for loading onto an insertion device. It is then kept exposed on the working table (either separately or next to the used instruments as the pedicles hole are being prepared). Latest investigation has shown that by the time it is implanted in the patient, it can harbor up to 10e7 bacterial colony-forming units. The same implants were devoid of such colony-forming units, when sheathed by an impermeable sterile sheath around the sterile implant.

Targeting macrophages by an aza-anthrapyrazole to ameliorate experimental autoimmune encephalomyelitis.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease in the central nerve system, in which both innate and adaptive immune cells are involved. BBR3378, an aza-anthrapyrazole prevents experimental autoimmune encephalomyelitis (EAE), an inflammatory condition similar to MS, by antagonizing T cell autoimmune responses. Here, we report BBR3378's regulatory effect on macrophages. METHODS: EAE was induced in ten-week-old female C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein peptides followed by BBR3378 or sham treatment administered intraperitoneally, and clinical signs were assessed using a 0-5 scoring system. These mice were subjected to serum ELISA for cytokine IFNγ and TNFα levels, RT qPCR analysis of macrophage markers in isolated monocytes, and flow cytometry analysis for macrophage infiltration in the brain. Macrophages derived from primary monocytes and macrophage cell line RAW 264.7 were used to investigate BBR3378's effect on LPS-stimulated pro-inflammatory cytokine induction. RAW 264.7 cells expressing NF-κB-driven luciferase reporter were treated with LPS with or without BBR3378, and luciferase assays performed to assess the inhibition on NF-κB activation. LPS-induced activation of mitogen-activated protein kinases (MAPKs) with or without the presence of BBR3378 was also investigated by Western blot analysis. RESULTS: BBR3378 down-regulated cytokine-induced macrophage differentiation and activation in EAE mice, contributing to protection against macrophage infiltration in the brain and clinical symptoms from EAE. Treating macrophages with BBR3378 counteracted LPS-induced cytokine production via blocking activation of key signal molecules mediating inflammatory responses, such as NF-κB and MAPKs. CONCLUSIONS: These data suggest that in addition to T cells, BBR3378 can also target macrophages to attenuate the inflammation associated with EAE.

A Multicenter Trial Demonstrating Presence or Absence of Bacterial Contamination at the Screw-Bone Interface Owing to Absence or Presence of Pedicle Screw Guard, Respectively, During Spinal Fusion.

STUDY DESIGN: A prospective multicenter study. OBJECTIVE: The objective of this study was to assess bacterial contamination in current practices of pedicle screw handling and comparing it to a novel method of using an intraoperative, sterile implant guard for screws. SUMMARY OF BACKGROUND DATA: Postoperative infections occur at the higher end of 2%-13%, as cited in the literature, and are underestimated due to various reasons in such publications. Despite concerns associated with vancomycin application immediately before closure, it is theoretically impossible to irrigate the screw-bone interface postimplantation. Consequently, any contamination of pedicle screw before implantation is permanent, and has the potential to cause deep-bone infection, or hardware loosening due to encapsulation of biofilm between the bone and the screw. Therefore, continued vigilance and effective preventive measures should be undertaken if available. MATERIALS AND METHODS: Two groups of presterile individually-packaged pedicle screws, one incased in a sterile, protective guard (group 1: G) and the other without such a guard (group 2: NG), 31 samples in each group were distributed over 28 spinal fusion surgeries at 5 independent hospitals groups. Each were loaded onto the insertion device by the scrub tech and left on the sterile table. Twenty minutes later, the lead surgeon who had just finished preparing the surgical site, handles the pedicle screw, to check the fit with the insertion device. Then, instead of implantation, it was transferred to a sterile container using fresh sterile gloves for bacterial analysis. RESULTS: The standard unguarded pedicle screws presented bioburden in the range of 10 to 10 colonies forming units per screw, whereas the guarded pedicle screws showed no bioburden. CONCLUSION: Standard, current, handling of pedicle screws leads to bacterial contamination, which can be avoided if the screws are sterilely prepackaged with an intraoperative guard (preinstalled).

Biochemical and microbiological evaluation of N-aryl urea derivatives against mycobacteria and mycobacterial hydrolases.

A focused library of 24 N-aryl urea derivatives was prepared and evaluated against serine esterases of Mycobacterium tuberculosis (Mtb) Rv3802c and Mtb Ag85C. The members of the library were evaluated for both selectivity and mode of inhibition. Furan-based urea derivative 6c was found to be the most potent non-covalent inhibitor of Rv3802c with a K i value of 5.2 ± 0.7 µM. On the other hand, triazole-based ureas 10a and 10b selectively inhibited Ag85C irreversibly with a k inact/K i value of 2.3 ± 0.3 and 5.5 ± 0.4 × 10-3 µM-1 min-1, respectively. The library was also evaluated for minimum inhibitory concentration (MIC) against two strains of Mtb, Mycobacterium smegmatis, and Mycobacterium abscessus. Compounds 4a and 4c were active against Mtb H37Rv mc26206 with MIC values of 3.12 and 1.5 µM, respectively. Closely related 4e showed similar activity against Mtb H37Rv mc26206 but also possessed activity against Mtb H37Ra, Mycobacterium smegmatis and Mycobacterium abscessus. Compounds 4a, 4c, and 4e all contained a common 1-(cyclohexylmethyl)-3-phenylurea motif. In summary, we identified a selective non-covalent inhibitor of Rv3802c and covalently irreversible inhibitors of Ag85C as well as the 1-(cyclohexylmethyl)-3-phenylurea motif which showed activity against a variety of mycobacteria.

Post-stroke neuronal circuits and mental illnesses.

Stroke is one of the leading causes of death in the United States. It is also associated with severe mental illnesses, such as depression and anxiety, that hinder the rehabilitation of surviving patients. Thus, a better understanding of how stroke causes mental illnesses is crucial, but little is known about the neurological mechanisms involved. In this review, we summarized the most common mental illnesses developed after stroke, as well as the underlying mechanisms at the neuronal circuit level.

Efficacy of Intraoperative Implant Prophylaxis in Reducing Intraoperative Microbial Contamination.

STUDY DESIGN: A prospective single-center study. OBJECTIVES: Assess to what degree contamination of pedicle screws occur in standard intraoperative practice and if use of an impermeable guard could mitigate or reduce such an occurrence. METHODS: Two groups of sterile prepackaged pedicle screws, one with an intraoperative guard (group 1) and the other without such a guard (group 2), each consisting of 5 samples distributed over 3 time points, were loaded onto the insertion device by the scrub tech and left on the sterile table. Approximately 20 minutes later, the lead surgeon who had just finished preparing the surgical site touches the pedicle screw. Then instead of implantation it was transferred to a sterile container using fresh clean gloves for bacterial and gene analysis. Guarded screw implies that even after unwrapping from the package, the screw carries an impermeable barrier along its entire length, which is only removed seconds prior to implantation. RESULTS: The standard unguarded pedicle screws presented bioburden in the range of 105 to 107 (colony forming units/implant) with bacterial genus mostly consisting of Staphylococcus and Micrococcus, the 2 most common genera found in surgical site infection reports. The common species among them were Staphylococcus epidermis, Staphylococcus aureus, Micrococcus luteus, and Staphylococcus pettenkoferi, whereas the guarded pedicle screws showed no bioburden. CONCLUSIONS: Shielding the pedicle screws intraoperatively using a guard provides a superior level of asepsis than currently practiced. All unshielded pedicles screws were carrying bioburden of virulent bacterial species, which provides an opportunity for the development of postoperative infections.

Understanding the impact of water distribution system conditions on the biodegradation of haloacetic acids and expression of bacterial dehalogenase genes.

The objective of this study is to evaluate the influence of water distribution system conditions (pH, total organic carbon, residual chlorine, and phosphate) on haloacetic acids (HAAs) biodegradation. A series of batch microcosm tests were conducted to determine biodegradation kinetics and collected biomass was used for real time quantitative reverse transcription polymerase chain reaction analyses to monitor how these drinking water distribution system conditions affect the relative expression of bacterial dehalogenase genes. It was observed that tested water distribution system conditions affected HAA biodegradation with different removal efficiencies (0-100%). HAA biodegradation was improved in tested samples with TOC (3 mg/L) and pH 8.5 compared to those of TOC (0 mg/L) and pH 7, respectively. However, slight improvement was observed with the increased PO4 concentration (3.5 mg/L), and the presence of residual chlorine even at low concentration prohibited biodegradation of HAAs. The observed trend in the relative expression of dehII genes was compatible with the HAA biodegradation trend. Overall relative expression ratio of dehII genes was lower at pH 7, phosphate (0.5 mg/L), and TOC (0 mg/L) in comparison with pH 8.5, phosphate (3.5 mg/L), and TOC (3 mg/L) in the same experimental conditions.

Microwave assisted coating of bioactive amorphous magnesium phosphate (AMP) on polyetheretherketone (PEEK).

Polyetheretherketone (PEEK) with great thermal and chemical stability, desirable mechanical properties and promising biocompatibility is being widely used as orthopedic and dental implant materials. However, the bioinert surface of PEEK can hinder direct osseointegration between the host tissue and PEEK based implants. The important signatures of this paper are as follows. First, we report for the formation of osseointegrable amorphous magnesium phosphate (AMP) coating on PEEK surface using microwave energy. Second, coatings consist of nano-sized AMP particles with a stacked thickness of 800nm. Third, coatings enhance bioactivity in-vitro and induce significantly high amount of bone-like apatite coating, when soaked in simulated body fluid (SBF). Fourth, the as-deposited AMP coatings present no cytotoxicity effects and are beneficial for cell adhesion at early stage. Finally, the high levels of expression of osteocalcin (OCN) in cells cultured on AMP coated PEEK samples indicate that AMP coatings can promote new bone formation and hence osseointegration.

Single-Phase, Antibacterial Trimagnesium Phosphate Hydrate Coatings on Polyetheretherketone (PEEK) Implants by Rapid Microwave Irradiation Technique.

This Article reports the fabrication and evaluation of single-phase, silver-doped trimagnesium phosphate hydrate (Ag-TMPH) nanosheet coatings on polyetheretherketone (PEEK), a well-known material used to fabricate orthopedic and spinal implants. While PEEK has better biomechanical compatibility with bone compared to metallic implants, it is also quite inert. Therefore, it is a common practice to coat PEEK implants with conventional calcium phosphates (CaPs) to enhance cell attachment, proliferation and differentiation. As opposed to well-studied CaP compounds, relatively less-explored magnesium phosphates (MgPs) are also becoming interesting orthopedic biomaterials and is the prime focus in this research. The novel aspects of this paper are as follows. First, we report developing TMPH coatings within minutes with the help of microwave irradiation technology. Microwave irradiation plays an important role in the coating formation with accelerated kinetics. Scanning electron microscopy (SEM) confirmed the fabrication of approximately 650 nm thick TMPH coatings. The coatings resulted in submicron level surface roughness and in vitro cell studies confirmed enhanced MC3T3 cell adhesion within 4 h on such surfaces. The coatings also resulted in significant apatite formation after immersing in simulated body fluid for 7 days. Second, multifunctionality was achieved by doping TMPH coatings with Ag, thus rendering the coatings antibacterial. The antibacterial properties were evaluated against two most common infection-causing bacterial strains-Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus. The results indicated good bacterial resistance and bactericidal properties of the Ag-TMPH coatings. Third, in spite of Ag doping, the single-phase nature of the coatings were retained (without forming composite systems) with the help of the low-processing temperature of the microwave irradiation. The inductive coupled plasma technique confirmed that the doped single-phase TMPH coatings supported a uniform and controlled release of Ag+ ions over a period of 3 weeks. MTT assay evaluations and SEM micrographs confirmed no signs of cytotoxicity and healthy proliferation of cells in all cases. Quantitative real time PCR (qRT-PCR) indicated a significant rise in collagen (Col1) and osteocalcin (OCN) gene expression levels in the case of TMPH coated PEEK. Thus, microwave irradiation was successfully employed in forming multifunctional, that is, bioactive, cytocompatible, and antibacterial MgP coatings on PEEK.

Regulation of RANKL-induced osteoclastogenesis by RING finger protein RNF114.

Normal bone remodeling is a continuous process orchestrated by bone-resorbing osteoclasts and bone-forming osteoblasts, which an imbalance in bone remodeling results in metabolic bone diseases. RANKL, a member of the TNF cytokine family, functions as a key stimulator for osteoclast differentiation and maturation. Here, we report that RNF114, previously identified as a psoriasis susceptibility gene, plays a regulatory role in the RANKL/RANK/TRAF6 signaling pathway that mediates osteoclastogenesis. Our results demonstrated that RNF114 expression was significantly down-regulated in mouse osteoclast precursor cells undergoing RANKL-induced osteoclast differentiation. RNF114 knockout did not affect development or viability of the subpopulation of bone marrow macrophages capable of differentiating into osteoclasts in culture. However, in the presence of RANKL, RNF114 knockout bone marrow macrophages exhibited enhanced cell proliferation and augmented osteoclast differentiation, as shown by an increased expression of mature osteoclast markers, increased osteoclastic TRAP activity and bone resorption. Conversely, ectopic expression of RNF114 inhibited CTSK expression, TRAP activity, and bone resorption in RANKL-treated pre-osteoclasts. RNF114 also suppressed RANKL-activated NFATc1 expression and NFAT-regulated promoter activity. RNF114 suppressed TRAF6-, but not TAK1/TAB2-mediated NF-κB activation downstream of RANKL/RANK. In particular, TRAF6 protein levels were down-regulated by RNF114, possibly via K48-mediated proteasome-dependent degradation. These data suggested that RNF114's inhibitory effect on RANKL-stimulated osteoclastogenesis was mediated by blocking RANK/TRAF6/NF-κB signal transduction. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:159-166, 2018.

Microwave-assisted magnesium phosphate coating on the AZ31 magnesium alloy.

Due to the combination of many unique properties, magnesium alloys have been widely recognized as suitable metallic materials for fabricating degradable biomedical implants. However, the extremely high degradation kinetics of magnesium alloys in the physiological environment have hindered their clinical applications. This paper reports for the first time the use of a novel microwave-assisted coating process to deposit magnesium phosphate (MgP) coatings on the Mg alloy AZ31 and improve its in vitro corrosion resistance. Newberyite and trimagnesium phosphate hydrate (TMP) layers with distinct features were fabricated at various processing times and temperatures. Subsequently, the corrosion resistance, degradation behavior, bioactivity and cytocompatibility of the MgP coated AZ31 samples were investigated. The potentiodynamic polarization tests reveal that the corrosion current density of the AZ31 magnesium alloy in simulated body fluid (SBF) is significantly suppressed by the deposited MgP coatings. Additionally, it is seen that MgP coatings remarkably reduced the mass loss of the AZ31 alloy after immersion in SBF for two weeks and promoted precipitation of apatite particles. The high viability of preosteoblast cells cultured with extracts of coated samples indicates that the MgP coatings can improve the cytocompatibility of the AZ31 alloy. These attractive results suggest that MgP coatings, serving as the protective and bioactive layer, can enhance the corrosion resistance and biological response of magnesium alloys.

Negative regulation of the RLH signaling by the E3 ubiquitin ligase RNF114.

The retinoic acid-inducible gene-I (RIG-I)-like helicases (RLH)s are cytoplasmic pattern recognition receptors expressed in both immune and non-immune cells that are essential for detection of intracellular RNA products, primarily of viral origin. Upon binding to viral RNA, RLHs interact with mitochondrial antiviral signaling protein (MAVS) to activate interferon (IFN)-mediated antiviral responses. The RLH/MAVS signaling pathway is regulated by ubiquitination/deubiquitination, in which several ubiquitin-editing proteins play critical roles. The really interesting new gene (RING) finger protein 114 (RNF114) was originally identified as a psoriasis susceptibility gene broadly expressed in human tissues. Earlier studies implicated RNF114 in regulating cellular dsRNA responses, cell cycle progression, NF-κB activity and T-cell activation. We found that RNF114 inhibited cellular dsRNA responses and RLH-mediated IFN production. RNF114 functioned as an E3 ubiquitin ligase, and MAVS was identified as a potential target for RNF114-mediated polyubiquitination and degradation. Splenocytes and blood harvested from RNF114 KO showed increased basal IFN level and sensitized responses to dsRNA. However, RNF114 knockout mice failed to exhibit enhance resistance to infection by two acute RNA viruses. These data suggested the potential physiological function of RNF114 in inflammation and host antiviral responses, but demonstrate complexity in the regulation of innate immunity by ubiquitin ligases.

A new method to produce macroporous Mg-phosphate bone growth substitutes.

This paper is a sequel to our previous effort in developing Mg-phosphate orthopedic cements using amorphous Mg-phosphate (AMP) as the precursor. In this paper, we report a new real-time in situ technique to create macroporous bone growth substitute (BGS). The method uses biodegradable Mg-particles as the porogen. As opposed to the conventional wisdom of providing corrosion protection layers to biodegradable Mg-alloys, the present method uses the fast corrosion kinetics of Mg to create macropores in real time during the setting of the cement. An aqueous solution of PVA was used as the setting solution. Using this technique, a macroporous cement containing up to 91% porosity is obtained, as determined by pycnometry. Due to formation of H2 gas bubbles from corrosion of Mg, the cement becomes macroporous. The pore sizes as big as 760µm were observed. The results of SBF soaking indicated change in crystallinity as confirmed via scanning electron microscopy (SEM) and X-ray diffraction (XRD). Our in vitro cytocompatibility evaluation also revealed that the macroporous bone growth substitute composed of bobierrite is cytocompatible and can improve gene expression.

X-linked inhibitor of apoptosis-associated factor 1 regulates TNF receptor 1 complex stability.

X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a cytokine-regulated, tumor necrosis factor (TNF) receptor-associated factor (TRAF) domain-containing protein that has a poorly defined cellular function. Here, we show that ectopically expressed XAF1 inhibits TNF-ɑ-induced NF-κB activation, whereas shRNA silencing of endogenous XAF1 augments it. Our data suggest that XAF1 may inhibit TNF-ɑ-induced NF-κB activation by disrupting the assembly of the TRADD/TRAF2/RIP1 complex (complex I) downstream of TNF receptor activation. XAF1 interacts with TRAF2 and inhibits TRAF2-dependent NF-κB activation, in part, by blocking TRAF2 polyubiquitination. Our findings also indicate that although XAF1 does not directly inhibit RIP1-dependent NF-κB activation, it binds RIP1 and disrupts RIP1/TRADD association. Our data suggest that XAF1 acts as a feedback regulator of the TNF receptor signaling pathway to suppress NF-κB activation.

Evaluation of amorphous magnesium phosphate (AMP) based non-exothermic orthopedic cements.

This paper reports for the first time the development of a biodegradable, non-exothermic, self-setting orthopedic cement composition based on amorphous magnesium phosphate (AMP). The occurrence of undesirable exothermic reactions was avoided through using AMP as the solid precursor. The phenomenon of self-setting with optimum rheology is achieved by incorporating a water soluble biocompatible/biodegradable polymer, polyvinyl alcohol (PVA). Additionally, PVA enables a controlled growth of the final phase via a biomimetic process. The AMP powder was synthesized using a precipitation method. The powder, when in contact with the aqueous PVA solution, forms a putty resulting in a nanocrystalline magnesium phosphate phase of cattiite. The as-prepared cement compositions were evaluated for setting times, exothermicity, compressive strength, biodegradation, and microstructural features before and after soaking in SBF, and in vitro cytocompatibility. Since cattiite is relatively unexplored in the literature, a first time evaluation reveals that it is cytocompatible, just like the other phases in the MgO-P2O5 (Mg-P) system. The cement composition prepared with 15% PVA in an aqueous medium achieved clinically relevant setting times, mechanical properties, and biodegradation. Simulated body fluid (SBF) soaking resulted in coating of bobierrite onto the cement particle surfaces.