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RNA helicases are molecular motors that are involved in virtually all aspects of RNA metabolism. Eukaryotic initiation factor (eIF) 4A is the prototypical member of the DEAD-box family of RNA helicases. It is thought to use energy from ATP hydrolysis to unwind mRNA structure and, in conjunction with other translation factors, it prepares mRNA templates for ribosome recruitment during translation initiation. In screening marine extracts for new eukaryotic translation initiation inhibitors, we identified the natural product hippuristanol. We show here that this compound is a selective and potent inhibitor of eIF4A RNA-binding activity that can be used to distinguish between eIF4A-dependent and -independent modes of translation initiation in vitro and in vivo . We also show that poliovirus replication is delayed when infected cells are exposed to hippuristanol. Our study demonstrates the feasibility of selectively targeting members of the DEAD-box helicase family with small-molecule inhibitors.

Background This randomized, double-blind, multi-center, non-inferiority trial was conducted to assess the efficacy and safety of a cross-linked hyaluronate (XLHA, single injection form) compared with a linear high molecular hyaluronate (HMWHA, thrice injection form) in patients with symptomatic knee osteoarthritis. Methods Two hundred eighty seven patients with osteoarthritis (Kellgren-Lawrence grade I to III) were randomized to each group. Three weekly injections were given in both groups but two times of saline injections preceded XLHA injection to maintain double-blindness. Primary endpoint was the change of weight-bearing pain (WBP) at 12 weeks after the last injection. Secondary endpoints included Western Ontario and McMaster Universities Osteoarthritis index; patient’s and investigator’s global assessment; pain at rest, at night, or in motion; OMERACT-OARSI responder rate; proportion of patients achieving at least 20 mm or 40% decrease in WBP; and rate of rescue medicine use and its total consumption. Results Mean changes of WBP at 12 weeks after the last injection were −33.3 mm with XLHA and −29.2 mm with HMWHA, proving non-inferiority of XLHA to HMWHA as the lower bound of 95% CI (−1.9 mm, 10.1 mm) was well above the predefined margin (−10 mm). There were no significant between-group differences in all secondary endpoints. Injection site pain was the most common adverse event and no remarkable safety issue was identified. Conclusions This study demonstrated that a single injection of XLHA was non-inferior to three weekly injections of HMWHA in terms of WBP reduction, and supports XLHA as an effective and safe treatment for knee osteoarthritis. Trial registration ClinicalTrials.gov ( NCT01510535 ). This trial was registered on January 6, 2012.

The achievement of a strong and stable bond between composite resin and dentin remains a challenge in restorative dentistry. Over the past two decades, dental materials have been substantially improved, with better handling and bonding characteristics. However, little attention has been paid to the contribution of collagen structure/stability to bond strength. We hypothesized that the induction of cross-linking in dentin collagen improves dentin collagen stability and bond strength. This study investigated the effects of glutaraldehyde-and grape seed extract-induced cross-linking on the dentin bond strengths of sound and caries-affected dentin, and on the stability of dentin collagen. Our results demonstrated that the application of chemical cross-linking agents to etched dentin prior to bonding procedures significantly enhanced the dentin bond strengths of caries-affected and sound dentin. Glutaraldehyde and grape seed extract significantly increased dentin collagen stability in sound and caries-affected dentin, likely via distinct mechanisms.

Background Osteolysis resulting from wear debris production from the bearing surfaces is a major factor limiting long-term survival of hip implants. Oxidized zirconium head on crosslinked polyethylene (XLPE) is a modern bearing coupling. However, midterm in vivo wear data of this coupling are not known. Questions/purposes The purpose of this study was to investigate in vivo whether the combination of an oxidized zirconium femoral head on XLPE produces less wear than a ceramic head on XLPE or a ceramic head on conventional polyethylene (CPE) couplings and whether any of these bearing combinations results in higher hip scores. Methods Between 2003 and 2007, we performed 356 total hip arthroplasties in 288 patients; of those, 199 (69.1%) patients (199 hips) were enrolled in what began as a randomized trial. Unfortunately, after the 57 th patient, the randomization process was halted because of patients’ preference for the oxidized zirconium bearing instead of the ceramic after (as they were informed by the consent form), and after that, alternate allocation to the study groups was performed. Hips were allocated into four groups: in Group A, a 28-mm ceramic head on CPE was used; in Group B, a 28-mm ceramic head on XLPE; in Group C, a 28-mm Oxinium head on XLPE; and in Group D, a 32-mm Oxinium head on XLPE. The authors prospectively collected in vivo wear data (linear wear, linear wear rate, volumetric wear, and volumetric wear rate) using PolyWare software. Preoperative and postoperative clinical data, including Harris and Oxford hip scores, were also collected at regular intervals. Of those patients enrolled, 188 (95%) were available for final followup at a minimum of 7 years (mean, 9 years; range, 7–12 years). Results All bearing surfaces showed a varying high bedding-in effect (plastic deformation of the liner) up to the second postoperative year. At 5 years both oxidized zirconium on XLPE groups showed lower (p < 0.01) volumetric wear (mean ± SD mm 3 ) and volumetric wear rates (mean ± SD mm 3 /year) (Group C: 310 ± 55–206 ± 55 mm 3 /year, Group D: 320 ± 58–205 ± 61 mm 3 /year) when compared with ceramic on CPE (Group A: 791 ± 124–306 ± 85 mm 3 /year) and ceramic on XLPE (Group B: 1420 ± 223–366 ± 88 mm 3 /year) groups. For those patients who had completed 10 years of followup (20 patients [44.5%] of Group A, 21 [45.7%] of Group B, 23 [47.9%] of Group C, and 22 [44.9%] of Group D), at 10 years, both oxidized zirconium on XLPE groups also showed lower (p < 0.01) volumetric wear (mean ± SD mm 3 ) and volumetric wear rates (mean ± SD mm 3 /year) (Group C: 356 ± 64 to 215 ± 54 mm 3 /year, Group D: 354 ± 50 to 210 ± 64 mm 3 /year) when compared with ceramic on CPE (Group A: 895 ± 131 to 380 ± 80 mm 3 /year) and ceramic on XLPE (Group B: 1625 ± 253 to 480 ± 101 mm 3 /year) groups. When wear rates of both oxidized zirconium groups were compared, no differences were found at any time interval with the numbers available. Two hips (one from Group A and one from Group B) are scheduled for revision as a result of wear and osteolysis. There were no differences in hip scores among the groups with the numbers available. Conclusions In this study, in vivo wear parameters were lower when the combination of an oxidized zirconium head on XLPE liner was used at an average of 9 years (range, 7–12 years) followup. Further larger-scale clinical studies should confirm these findings and evaluate osteolysis and revision rates in association with the use of this bearing coupling. Level of Evidence Level II, therapeutic study.

Background Charnley low-friction torque total hip arthroplasty (THA) remains the gold standard in THA. The main cause for failure is wear of the socket. Highly crosslinked polyethylene (HXLPE) has been associated with reduced wear rates. Also, oxidized zirconium has shown in vitro reduced wear rates. However, to our knowledge, there are no data comparing oxidized zirconium femoral heads with metal heads against HXLPE or ultrahigh-molecular-weight polyethylene (UHMWPE) when 22.25-mm bearings were used, which was the same size that performed so well in Charnley-type THAs. Questions/purposes We hypothesized that after a minimal 4-year followup (1) use of HXLPE would result in lower radiographic wear than UHMWPE when articulating with a stainless steel head or with an oxidized zirconium head; (2) use of oxidized zirconium would result in lower radiographic wear than stainless steel when articulating with UHMWPE and HXLPE; and (3) there would be no difference in terms of Merle d’Aubigné scores between the bearing couple combinations. Methods One hundred patients were randomized to receive cemented THA with either oxidized zirconium or a stainless steel femoral head. UHMWPE was used in the first 50 patients, whereas HXLPE was used in the next 50 patients. There were 25 patients in each of the four bearing couple combinations. All other parameters were identical in both groups. Complete followup was available in 86 of these patients. Femoral head penetration was measured using a validated computer-assisted method dedicated to all-polyethylene sockets. Clinical results were compared between the groups using the Merle d’Aubigné score. Results In the UHMWPE series, the median steady-state penetration rate from 1 year onward was 0.03 mm/year (range, 0.003–0.25 mm/year) in the oxidized zirconium group versus 0.11 mm/year (range, 0.03–0.29 mm/year) in the metal group (difference of medians 0.08, p < 0.001). In the HXLPE series, the median steady-state penetration rate from 1 year onward was 0.02 mm/year (range, −0.32 to 0.07 mm/year) in the oxidized zirconium group versus 0.05 mm/year (range, −0.39 to 0.11 mm/year) in the metal group (difference of medians 0.03, p < 0.001). The Merle d’Aubigné scores were no different between the groups with a median of 18 in each of the groups (range, 16–18). Conclusions This study demonstrated femoral head penetration was reduced by oxidized zirconium when compared with metal on both UHMWPE and HXLPE. However, apart the metal-UHMWE group, all other groups had a steady-state penetration rate well below the osteolysis threshold with a low difference between groups that might not be clinically important at this point. Longer-term followup is needed to warrant whether wear reduction will generate less occurrence of osteolysis and aseptic loosening. Level of Evidence Level II, therapeutic study.

Background Concern regarding osteolysis attributable to polyethylene wear after TKA, particularly in younger patients, has prompted the introduction of highly crosslinked-remelted polyethylene (HXLPE) for TKAs. However, few in vivo comparative results of TKAs using HXLPE and less-crosslinked polyethylene inserts in the same patients are available, regarding fracture or failure of the locking mechanism of tibial polyethylene inserts or of osteolysis in patients younger than 60 years. Questions/Purposes We wanted to determine whether (1) survivorship free from aseptic loosening in knees with HXLPE inserts was different from survivorship in knees with less-crosslinked polyethylene inserts, (2) the prevalence of fracture or failure of the locking mechanism of the tibial polyethylene insert was greater in knees with HXLPE than in those with less-crosslinked polyethylene, and (3) the proportion of patients who had osteolysis develop was greater with HXLPE than with less-crosslinked polyethylene inserts. Methods One hundred seventy-one patients with a mean age of 58 ± 8 years (range, 35−59 years) received posterior cruciate-retaining prostheses with a less-crosslinked polyethylene tibial insert in one knee and a HXLPE tibial insert in the contralateral knee. From January 2007 to January 2010, we performed 366 same-day bilateral simultaneous sequential posterior cruciate-retaining TKAs in 183 patients, of whom 171 (93%) participated in this study. All patients during this study period underwent posterior cruciate-retaining TKAs regardless of deformity of the knees and we did not perform posterior-stabilized TKAs during the same period. Patients who had bilateral end-stage osteoarthritis and were younger than 60 years were selected for inclusion. Six patients (4%) were lost to followup before 5 years. Twenty-six patients were males and 145 were females. The mean duration of followup was 6 years (range, 5−8 years). At each followup, patients were assessed for loosening of the components, fracture or failure of the locking mechanism of the polyethylene inserts, or osteolysis. Results The survival rate of the knee prosthesis at a mean of 5.8 years after surgery was 100% (95% CI, 0.95–1.00) in both groups for the endpoint aseptic loosening and 99.4% (95% CI, 0.95–1.00) in both groups for the endpoint revision. No knee in either group had fracture or failure of the locking mechanism of the tibial polyethylene insert, and none had osteolysis. Conclusions With the numbers available, we found no clinically important differences between HXLPE and less-crosslinked polyethylene inserts in posterior cruciate-retaining TKAs. Given that HXLPE is newer, as-yet unproven, and more expensive than the proven technology (less-crosslinked polyethylene), we suggest not adopting HXLPE for clinical use until it shows superiority. Level of Evidence Level I, therapeutic study.

Bioadhesives such as tissue adhesives, hemostatic agents, and tissue sealants have potential advantages over sutures and staples for wound closure, hemostasis, and integration of implantable devices onto wet tissues. However, existing bioadhesives display several limitations including slow adhesion formation, weak bonding, low biocompatibility, poor mechanical match with tissues, and/or lack of triggerable benign detachment. Here, we report a bioadhesive that can form instant tough adhesion on various wet dynamic tissues and can be benignly detached from the adhered tissues on demand with a biocompatible triggering solution. The adhesion of the bioadhesive relies on the removal of interfacial water from the tissue surface, followed by physical and covalent cross-linking with the tissue surface. The triggerable detachment of the bioadhesive results from the cleavage of bioadhesive’s crosslinks with the tissue surface by the triggering solution. After it is adhered to wet tissues, the bioadhesive becomes a tough hydrogel with mechanical compliance and stretchability comparable with those of soft tissues. We validate in vivo biocompatibility of the bioadhesive and the triggering solution in a rat model and demonstrate potential applications of the bioadhesive with triggerable benign detachment in ex vivo porcine models.

DNA–protein interactions regulate critical biological processes. Identifying proteins that bind to specific, functional genomic loci is essential to understand the underlying regulatory mechanisms on a molecular level. Here we describe a co-binding-mediated protein profiling (CMPP) strategy to investigate the interactome of DNA G-quadruplexes (G4s) in native chromatin. CMPP involves cell-permeable, functionalized G4-ligand probes that bind endogenous G4s and subsequently crosslink to co-binding G4-interacting proteins in situ. We first showed the robustness of CMPP by proximity labelling of a G4 binding protein in vitro. Employing this approach in live cells, we then identified hundreds of putative G4-interacting proteins from various functional classes. Next, we confirmed a high G4-binding affinity and selectivity for several newly discovered G4 interactors in vitro, and we validated direct G4 interactions for a functionally important candidate in cellular chromatin using an independent approach. Our studies provide a chemical strategy to map protein interactions of specific nucleic acid features in living cells.DNA–protein interactions are essential to genome function, but they are challenging to map in a cellular environment. Now, a chemical proteomics approach, which uses DNA G-quadruplex-specific ligands containing a photocrosslinking motif, has enabled the systematic identification of DNA G-quadruplex-binding proteins in live cells.

Defining protein–protein interactions (PPIs) in their native environment is crucial to understanding protein structure and function. Cross-linking–mass spectrometry (XL-MS) has proven effective in capturing PPIs in living cells; however, the proteome coverage remains limited. Here, we have developed a robust in vivo XL-MS platformto facilitate in-depth PPI mapping by integrating a multifunctional MS-cleavable cross-linker with sample preparation strategies and high-resolution MS. The advancement of click chemistry–based enrichment significantly enhanced the detection of cross-linked peptides for proteome-wide analyses. This platform enabled the identification of 13,904 unique lysine–lysine linkages from in vivo cross-linked HEK 293 cells, permitting construction of the largest in vivo PPI network to date, comprising 6,439 interactions among 2,484 proteins. These results allowed us to generate a highly detailed yet panoramic portrait of human interactomes associated with diverse cellular pathways. The strategy presented here signifies a technological advancement for in vivo PPI mapping at the systems level and can be generalized for charting protein interaction landscapes in any organisms.

Stimuli-responsive materials activated by biological signals play an increasingly important role in biotechnology applications. We exploit the programmability of CRISPR-associated nucleases to actuate hydrogels containing DNA as a structural element or as an anchor for pendant groups. After activation by guide RNA–defined inputs, Cas12a cleaves DNA in the gels, thereby converting biological information into changes in material properties. We report four applications: (i) branched poly(ethylene glycol) hydrogels releasing DNA-anchored compounds, (ii) degradable polyacrylamide-DNA hydrogels encapsulating nanoparticles and live cells, (iii) conductive carbon-black–DNA hydrogels acting as degradable electrical fuses, and (iv) a polyacrylamide-DNA hydrogel operating as a fluidic valve with an electrical readout for remote signaling. These materials allow for a range of in vitro applications in tissue engineering, bioelectronics, and diagnostics.