Direct determination of vibrational density of states change on ligand binding to a protein

The change in the vibrational density of states of a protein (dihydrofolate reductase) on binding a ligand (methotrexate) is determined using inelastic neutron scattering. The vibrations of the complex soften significantly relative to the unbound protein. The resulting free-energy change, which is directly determined by the density of states change, is found to contribute significantly to the binding equilibrium

Extracorporeal liver assist device to exchange albumin and remove endotoxin in acute liver failure: Results of a pivotal pre-clinical study

Background & AimsIn acute liver failure, severity of liver injury and clinical progression of disease are in part consequent upon activation of the innate immune system. Endotoxaemia contributes to innate immune system activation and the detoxifying function of albumin, critical to recovery from liver injury, is irreversibly destroyed in acute liver failure. University College London-Liver Dialysis Device is a novel artificial extracorporeal liver assist device, which is used with albumin infusion, to achieve removal and replacement of dysfunctional albumin and reduction in endotoxaemia. We aimed to test the effect of this device on survival in a pig model of acetaminophen-induced acute liver failure.MethodsPigs were randomised to three groups: Acetaminophen plus University College London-Liver Dialysis Device (n=9); Acetaminophen plus Control Device (n=7); and Control plus Control Device (n=4). Device treatment was initiated two h after onset of irreversible acute liver failure.ResultsThe Liver Dialysis Device resulted in 67% reduced risk of death in acetaminophen-induced acute liver failure compared to Control Device (hazard ratio=0.33, p=0.0439). This was associated with 27% decrease in circulating irreversibly oxidised human non-mercaptalbumin-2 throughout treatment (p=0.046); 54% reduction in overall severity of endotoxaemia (p=0.024); delay in development of vasoplegia and acute lung injury; and delay in systemic activation of the TLR4 signalling pathway. Liver Dialysis Device-associated adverse clinical effects were not seen.ConclusionsThe survival benefit and lack of adverse effects would support clinical trials of University College London-Liver Dialysis Device in acute liver failure patients

Randomized-controlled trial of the DIALIVE liver dialysis device vs. standard of care in patients with acute-on-chronic liver failure

BACKGROUND AND AIMS: Acute on chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange d ysfunctional albumin and remove damage- and pathogen-associated molecular patterns. This first-in-man randomized, controlled clinical trial was performed with the primary aim of assessing its safety in ACLF patients with secondary aims to evaluate its clinical effects, device performance and effect on pathophysiologically-relevant biomarkers. METHODS: 32 alcoholic cirrhosis patients with ACLF were included. Patients were treated with DIALIVE for up to 5-days and end points were assessed at Day-10. Safety was assessed in all patients (n=32). The secondary aims were assessed in a pre-specified subgroup that had at least 3-treatment sessions with DIALIVE (n=30). RESULTS: There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p=0.018) and CLIF-C ACLF scores (p=0.042) at Day-10. Time to resolution of ACLF was significantly faster in DIALIVE group (p=0.036). Biomarkers of systemic inflammation such as IL-8 (p=0.006), cell death [cytokeratin-18: M30 (p=0.005) and M65 (p=0.029)], endothelial function [asymmetric dimethylarginine (p=0.002)] and, ligands for toll-like receptor 4 (p=0.030) and inflammasome (p=0.002) improved significantly in DIALIVE group. CONCLUSIONS: These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy. LAY SUMMARY: This is the first-in-man clinical trial which tested DIALIVE, a novel liver dialysis device for the treatment of liver cirrhosis and acute on chronic liver failure, a condition associated with severe inflammation, organ failures and a high risk of death. The study met the primary end point confirming DIALIVE system to be safe. Additionally, it reduced inflammation with improved clinical parameters. It did not, however, reduce mortality in this small study and requires further larger clinical trials to re-confirm its safety and evaluate efficacy. CLINICAL TRIAL NUMBER: NCT03065699

The impact of firms’ social media initiatives on operational efficiency and innovativeness

Social media have been increasingly adopted for organizational purposes but their operational implications are not well understood. Firms’ social media initiatives might facilitate information flow and knowledge sharing within and across organizations, strengthening firm‐customer interaction, and improving internal and external collaboration. In this research we empirically examine the impact of social media initiatives on firms’ operational efficiency and innovativeness. Taking the resource‐based view of firms’ information capability, we consider firms’ social media initiatives as strategic resources for operational improvement. We posit that firms’ social media initiatives enhance dynamic knowledge‐sharing routines through an information‐rich social network, leading to both operational efficiency and innovativeness. Collecting secondary data in a longitudinal setting from multiple sources, we construct dynamic panel data (DPD) models. Based on system generalized method of moments (GMM) estimation, we show that firms’ social media initiatives improve operational efficiency and innovativeness. We identify the importance of an information‐rich social network to the creation of knowledge‐based advantage through firms’ social media initiatives, and discuss the theoretical and managerial implications from the perspective of operations management

Randomized, controlled clinical trial of the DIALIVE liver dialysis device versus standard of care in patients with acute-on- chronic liver failure

Background & Aims Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange dysfunctional albumin and remove damage- and pathogen-associated molecular patterns. This first-in-man randomized-controlled trial was performed with the primary aim of assessing the safety of DIALIVE in patients with ACLF, with secondary aims of evaluating its clinical effects, device performance and effect on pathophysiologically relevant biomarkers. Methods Thirty-two patients with alcohol-related ACLF were included. Patients were treated with DIALIVE for up to 5 days and end points were assessed at Day 10. Safety was assessed in all patients (n = 32). The secondary aims were assessed in a pre-specified subgroup that had at least three treatment sessions with DIALIVE (n = 30). Results There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in the DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p = 0.018) and CLIF-C ACLF scores (p = 0.042) at Day 10. Time to resolution of ACLF was significantly faster in DIALIVE group (p = 0.036). Biomarkers of systemic inflammation such as IL-8 (p = 0.006), cell death [cytokeratin-18: M30 (p = 0.005) and M65 (p = 0.029)], endothelial function [asymmetric dimethylarginine (p = 0.002)] and, ligands for Toll-like receptor 4 (p = 0.030) and inflammasome (p = 0.002) improved significantly in the DIALIVE group. Conclusions These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy. Impact and implications This is the first-in-man clinical trial which tested DIALIVE, a novel liver dialysis device for the treatment of cirrhosis and acute-on-chronic liver failure, a condition associated with severe inflammation, organ failures and a high risk of death. The study met the primary endpoint, confirming the safety of the DIALIVE system. Additionally, DIALIVE reduced inflammation and improved clinical parameters. However, it did not reduce mortality in this small study and further larger clinical trials are required to re-confirm its safety and to evaluate efficacy. Clinical trial number NCT03065699

Comparative characterization of bovine testicular hyaluronidase and a hyaluronate lyase from Streptococcus agalactiae in pharmaceutical preparations

Although bovine testicular hyaluronidase (BTH) has been used in several medical fields for many years, these drugs are poorly characterized. We compared pharmaceutical BTH preparations (Neopermease®, Hylase® “Dessau”) and a hyaluronate lyase from Streptococcus agalactiae. The BTH preparations were complex mixtures of proteins (SDS–PAGE, gel filtration) with enzymatic activity in different fractions. In the case of Neopermease® the highest specific activity was found in the 58 kDa fraction (optimum at pH 3.6), whereas the 77 and 33 kDa fractions showed markedly lower specific activities at an optimal pH of 6.2. Maximum specific activity of the bacterial enzyme (approx. 1000 μmol min−1 mg−1) was found at pH 5.0, being 410- and 5100-times higher compared to Neopermease® and Hylase® “Dessau”, respectively. The hyaluronate lyase preparation was separated into two main proteins [100 kDa (pI=8.9) and 85 kDa (pI=9.2)] which were enzymatically active in SDS substrate–PAGE. Zymography after limited proteolysis of the bacterial enzyme with trypsin revealed active fragments (75–50 kDa). Our results suggest that hyaluronate lyase is an alternative for BTH, of which there has been a shortage, since companies have stopped the production of BTH preparations due to the risk of BSE

Isoenzyme-specific differences in the degradation of hyaluronic acid by mammalian-type hyaluronidases.

Bovine testicular hyaluronidase (BTH) has been used as a spreading factor for many years and was primarily characterized by its enzymatic activity. As recombinant human hyaluronidases are now available the bovine preparations can be replaced by the human enzymes. However, data on the pH-dependent activity of hyaluronidases reported in literature are inconsistent in part or even contradictory. Detection of the pH-dependent activity of PH-20 type hyaluronidases, i.e. recombinant human PH-20 (rhPH-20) and BTH, showed a shift of the pH optimum from acidic pH values in a colorimetric activity assay to higher pH values in a turbidimetric activity assay. Contrarily, recombinant human Hyal-1 (rhHyal-1) and bee venom hyaluronidase (BVH) exhibited nearly identical pH profiles in both commonly used types of activity assays. Analysis of the hyaluronic acid (HA) degradation products by capillary zone electrophoresis showed that hyaluronan was catabolized by rhHyal-1 continuously into HA oligosaccharides. BTH and, to a less extent, rhPH-20 exhibited a different mode of action: at acidic pH (pH 4.5) HA was degraded as described for rhHyal-1, while at elevated pH (pH 5.5) small oligosaccharides were produced in addition to HA fragments of medium molecular weight, thus explaining the pH-dependent discrepancies in the activity assays. Our results suggest a sub-classification of mammalian-type hyaluronidases into a PH-20/BTH and a Hyal-1/BVH subtype. As the biological effects of HA fragments are reported to depend on the size of the molecules it can be speculated that different pH values at the site of hyaluronan degradation may result in different biological responses

Fully Coherent UAV-based Near-Field Measurement and Transformation of the S67-15 m Ground Station Antenna at the German Space Operations Center in Weilheim

Abstract—Fully coherent unmanned aerial vehicle (UAV)-based near-field measurements of the S67 parabolic ground station antenna in Weilheim, Germany at 2.063 92 GHz are presented. The utilized measurement setup involves a vector network analyzer (VNA), radio frequency optical fiber connections, a laser tracking device (LT), and a specially designed light-weight dual-polarized Vivaldi antenna. The measurement data has been collected on a quasi-planar measurement surface in front of the reflector and the far-field patterns are obtained by field transformation from the irregular near-field data. Despite the complexity of this outdoor measurement setup with full exposure to varying weather conditions and the influence of the UAV on the near-field probe antenna, the far-field results show remarkable agreement with satellite based far-field measurement data

Device for continuous extracorporeal blood purification using target-specific metal nanomagnets

Magnetic separation can be successfully implemented into an extracorporeal blood purification device. Simultaneous and specific filtering of high-molecular compounds may offer promising new therapeutic tools for the future treatment of complex diseases, such as sepsis and autoimmune disorders