Hit and run versus long-term activation of PARP-1 by its different domains fine-tunes nuclear processes.

Poly(ADP-ribose) polymerase 1 (PARP-1) is a multidomain multifunctional nuclear enzyme involved in the regulation of the chromatin structure and transcription. PARP-1 consists of three functional domains: the N-terminal DNA-binding domain (DBD) containing three zinc fingers, the automodification domain (A), and the C-terminal domain, which includes the protein interacting WGR domain (W) and the catalytic (Cat) subdomain responsible for the poly(ADP ribosyl)ating reaction. The mechanisms coordinating the functions of these domains and determining the positioning of PARP-1 in chromatin remain unknown. Using multiple deletional isoforms of PARP-1, lacking one or another of its three domains, as well as consisting of only one of those domains, we demonstrate that different functions of PARP-1 are coordinated by interactions among these domains and their targets. Interaction between the DBD and damaged DNA leads to a short-term binding and activation of PARP-1. This hit and run activation of PARP-1 initiates the DNA repair pathway at a specific point. The long-term chromatin loosening required to sustain transcription takes place when the C-terminal domain of PARP-1 binds to chromatin by interacting with histone H4 in the nucleosome. This long-term activation of PARP-1 results in a continuous accumulation of pADPr, which maintains chromatin in the loosened state around a certain locus so that the transcription machinery has continuous access to DNA. Cooperation between the DBD and C-terminal domain occurs in response to heat shock (HS), allowing PARP-1 to scan chromatin for specific binding sites

Mechanical properties of femoral trabecular bone in dogs

BACKGROUND: Studying mechanical properties of canine trabecular bone is important for a better understanding of fracture mechanics or bone disorders and is also needed for numerical simulation of canine femora. No detailed data about elastic moduli and degrees of anisotropy of canine femoral trabecular bone has been published so far, hence the purpose of this study was to measure the elastic modulus of trabecular bone in canine femoral heads by ultrasound testing and to assess whether assuming isotropy of the cancellous bone in femoral heads in dogs is a valid simplification. METHODS: From 8 euthanized dogs, both femora were obtained and cubic specimens were cut from the centre of the femoral head which were oriented along the main pressure and tension trajectories. The specimens were tested using a 100 MHz ultrasound transducer in all three orthogonal directions. The directional elastic moduli of trabecular bone tissue and degrees of anisotropy were calculated. RESULTS: The elastic modulus along principal bone trajectories was found to be 11.2 GPa ± 0.4, 10.5 ± 2.1 GPa and 10.5 ± 1.8 GPa, respectively. The mean density of the specimens was 1.40 ± 0.09 g/cm(3). The degrees of anisotropy revealed a significant inverse relationship with specimen densities. No significant differences were found between the elastic moduli in x, y and z directions, suggesting an effective isotropy of trabecular bone tissue in canine femoral heads. DISCUSSION: This study presents detailed data about elastic moduli of trabecular bone tissue obtained from canine femoral heads. Limitations of the study are the relatively small number of animals investigated and the measurement of whole specimen densities instead of trabecular bone densities which might lead to an underestimation of Young's moduli. Publications on elastic moduli of trabecular bone tissue present results that are similar to our data. CONCLUSION: This study provides data about directional elastic moduli and degrees of anisotropy of canine femoral head trabecular bone and might be useful for biomechanical modeling of proximal canine femora

Laceration of the Sciatic Nerve After Closed Reduction of a Dislocated Total Hip Arthroplasty

Sciatic nerve injury after closed reduction of a dislocated total hip arthroplasty (THA) is an exceedingly rare but tremendously devastating complication. Closed reduction is the standard of care and is typically associated with a low complication rate. There have only been seven sciatic nerve injuries after closed reduction of a dislocated THA reported in the literature, and none were secondary to nerve laceration. We report a case of sciatic nerve laceration after attempted closed reduction of a dislocated THA. This resulted in complete loss of sensory and motor sciatic nerve function. This case highlights the importance of a detailed neurologic examination before and after closed reduction of a dislocated total hip, the importance of using careful reduction maneuvers, and transitioning to open reduction when necessary

Fusion mass bone quality after uninstrumented spinal fusion in older patients

Older people are at increased risk of non-union after spinal fusion, but little is known about the factors determining the quality of the fusion mass in this patient group. The aim of this study was to investigate fusion mass bone quality after uninstrumented spinal fusion and to evaluate if it could be improved by additional direct current (DC) electrical stimulation. A multicenter RCT compared 40 and 100 μA DC stimulation with a control group of uninstrumented posterolateral fusion in patients older than 60 years. This report comprised 80 patients who underwent DEXA scanning at the 1 year follow-up. The study population consisted of 29 men with a mean age of 72 years (range 62–85) and 51 women with a mean age of 72 years (range 61–84). All patients underwent DEXA scanning of their fusion mass. Fusion rate was assessed at the 2 year follow-up using thin slice CT scanning. DC electrical stimulation did not improve fusion mass bone quality. Smokers had lower fusion mass BMD (0.447 g/cm2) compared to non-smokers (0.517 g/cm2) (P = 0.086). Women had lower fusion mass BMD (0.460 g/cm2) compared to men (0.552 g/cm2) (P = 0.057). Using linear regression, fusion mass bone quality, measured as BMD, was significantly influenced by gender, age of the patient, bone density of the remaining part of the lumbar spine, amount of bone graft applied and smoking. Fusion rates in this cohort was 34% in the control group and 33 and 43% in the 40 and 100 μA groups, respectively (not significant). Patients classified as fused after 2 years had significant higher fusion mass BMD at 1 year (0.592 vs. 0.466 g/cm2, P = 0.0001). Fusion mass bone quality in older patients depends on several factors. Special attention should be given to women with manifest or borderline osteoporosis. Furthermore, bone graft materials with inductive potential might be considered for this patient population

Birth of biomolecules from the warm wet sheets of clays near spreading centers

The role of clay minerals in the abiotic synthesis of organic molecules near seafloor spreading centers was simulated experimentally. Clays are common hydrothermal alteration products of volcanic glass and due to their nano-scale crystal size, provide extensive and variably charged surfaces that interact with aqueous organic species. Volcanic gases H2 and CO2 have been shown to react on magnetite surfaces to form methanol, a primary organic molecule, under hydrothermal conditions. Therefore, our experiments simulated the temperature and pressure conditions (300°C, 100 MPa) that exist beneath hydrothermal vents, in stockwork fractures through which hydrothermal fluids interact with fresh basalt. We examined the products of reactions between aqueous methanol and three common clay minerals found in those environments (montmorillonite, saponite, illite). Montmorillonite reacted to ~60% illite over 6 weeks, while saponite and illite were mineralogically stable. Organic products extracted with dichloromethane from the two expandable smectite clays (montmorillonite, saponite) contained a variety of complex organic molecules including: alkanes, alkyl-benzenes, alkyl-naphthalenes, alkyl-phenols, alkyl-naphthols, alkyl-anthrols, methoxy and alkyl-methoxy-phenols, methoxy and alkyl-methoxy-naphthols, and long-chain methyl esters. Experiments with the non-expandable illite yielded only traces of alkanes and alkyl-benzene after 6 weeks. We infer that the interlayer surfaces of smectites provide crystallographic sites involved in the organic synthesis of polycyclic aromatic hydrocarbons. The largest variety and quantity of organic products was produced from montmorilloniteas the layer charge increased during conversion to illite

Effects of a pre-workout supplement on hyperemia following leg extension resistance exercise to failure with different resistance loads

Abstract Background We sought to determine if a pre-workout supplement (PWS), containing multiple ingredients thought to enhance blood flow, increases hyperemia associated with resistance training compared to placebo (PBO). Given the potential interaction with training loads/time-under-tension, we evaluated the hyperemic response at two different loads to failure. Methods Thirty males participated in this double-blinded study. At visit 1, participants were randomly assigned to consume PWS (Reckless™) or PBO (maltodextrin and glycine) and performed four sets of leg extensions to failure at 30% or 80% of their 1-RM 45-min thereafter. 1-wk. later (visit 2), participants consumed the same supplement as before, but exercised at the alternate load. Heart rate (HR), blood pressure (BP), femoral artery blood flow, and plasma nitrate/nitrite (NOx) were assessed at baseline (BL), 45-min post-PWS/PBO consumption (PRE), and 5-min following the last set of leg extensions (POST). Vastus lateralis near infrared spectroscopy (NIRS) was employed during leg extension exercise. Repeated measures ANOVAs were performed with time, supplement, and load as independent variables and Bonferroni correction applied for multiple post-hoc comparisons. Data are reported as mean ± SD. Results With the 30% training load compared to 80%, significantly more repetitions were performed (p  0.05). NIRS derived minimum oxygenated hemoglobin (O2Hb) was lower in the 80% load condition compared to 30% for all rest intervals between sets of exercise (p < 0.0167). HR and BP did not vary as a function of supplement or load. Femoral artery blood flow at POST was higher independent of exercise load and treatment. However, a time*supplement*load interaction was observed revealing greater femoral artery blood flow with PWS compared to PBO at POST in the 80% (+56.8%; p = 0.006) but not 30% load condition (+12.7%; p = 0.476). Plasma NOx was ~3-fold higher with PWS compared to PBO at PRE and POST (p < 0.001). Conclusions Compared to PBO, the PWS consumed herein augmented hyperemia following multiple sets to failure at 80% of 1-RM, but not 30%. This specificity may be a product of interaction with local perturbations (e.g., reduced tissue oxygenation levels [minimum O2Hb] in the 80% load condition) and/or muscle fiber recruitment