Publications by authors named "Jesper Hansen"

80 Publications

A new group housing approach for non-human primate metabolism studies.

J Pharmacol Toxicol Methods 2021 Jan-Feb;107:106947. Epub 2021 Jan 9.

Novo Nordisk A/S, Novo Nordisk Park, Denmark. Electronic address:

Understanding the absorption, distribution, metabolism and excretion (ADME) of candidate drugs in preclinical species is an integral part of the safety and efficacy evaluation in drug development. For this purpose, the housing of single animals in metabolism cages has historically been common practice for ADME studies. Whilst mini-pigs and dogs are selected wherever possible, non-human primates (NHPs) are used where there is no suitable scientific alternative. Having undergone only minimal revisions over the past 30 years, the traditional single-housing metabolism cage design for NHPs significantly limits normal vertical movement and social behaviours in primates. Minimising animal suffering and improving welfare is an important aspect of working with animals in research and Novo Nordisk A/S, together with collaborators, has focused on this area for many years. A novel metabolism cage for group housing of NHPs has been designed in a joint collaboration between Novo Nordisk A/S and Covance Inc. The advantages of this novel cage are extensive, including a significantly increased cage volume and ability for socialisation, as well as improvements to alleviate stress and boredom. The excretion balance data from six male NHPs housed in single or group metabolism cages were compared using the radiolabelled test compound [C]-quetiapine. Welfare, in terms of stress and behaviour, when animals were single or group housed was also assessed. Mean recoveries of radioactivity were shown to be comparable irrespective of housing design (83.2% for group-housed animals vs. 87.1% for single-housed animals), supporting the potential suitability of NHP group housing for future metabolism ADME studies.
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http://dx.doi.org/10.1016/j.vascn.2020.106947DOI Listing
January 2021

Low incidence of HCC in chronic hepatitis C patients with pretreatment liver stiffness measurements below 17.5 kilopascal who achieve SVR following DAAs.

PLoS One 2020 10;15(12):e0243725. Epub 2020 Dec 10.

Department of Infectious Diseases, Odense University Hospital, Odense, Denmark.

Background And Aims: To evaluate the ability of pretreatment liver stiffness measurements (pLSM) to predict hepatocellular carcinoma (HCC), incident decompensation and all-cause mortality in chronic hepatitis C (CHC) patients who achieved sustained virological response (SVR) after treatment with direct-acting antivirals (DAAs).

Methods: 773 CHC patients with SVR after DAA treatment and no prior liver complications were identified retrospectively. Optimized cut-off of 17.5 kPa for incident HCC was selected by maximum Youden's index. Patients were grouped by pLSM: <10 kPa [reference], 10-17.4 kPa and ≥17.5 kPa. Primary outcomes were incident hepatocellular carcinoma and secondary outcomes were incident decompensated cirrhosis and all-cause mortality, analyzed using cox-regression.

Results: Median follow-up was 36 months and 43.5% (336) had cirrhosis (LSM>12.5 kPa). The median pLSM was 11.6 kPa (IQR 6.7-17.8, range 2.5-75) and pLSM of <10 kPa, 10-17.4 kPa and 17.5-75 kPa was seen in 41.5%, 32.2% and 26.3%. During a median follow-up time of 36 months, 11 (1.4%) developed HCC, 14 (1.5%) developed decompensated cirrhosis, and 38 (4.9%) patients died. A pLSM of 17.5 kPa identified patients with a high risk of HCC with a negative predictive value of 98.9% and incidence rate of HCC in the 17.5-75 kPa group of 1.40/100 person years compared to 0.14/100 person years and 0.12/100 person years in the 10-17.4 kPa and <10 kPa groups, p<0.001.

Conclusion: Pretreatment LSM predicts risk of HCC, decompensation and all-cause mortality in patients with SVR after DAA treatment. Patients with a pLSM <17.5 kPa and no other risk factors for chronic liver disease appear not to benefit from HCC surveillance for the first 3 years after treatment. Longer follow-up is needed to clarify if they can be safely excluded from post treatment HCC screening hereafter.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243725PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728240PMC
January 2021

Slow lactate gluconate exchange in calcium complexes during precipitation from supersaturated aqueous solutions.

Food Res Int 2020 11 15;137:109539. Epub 2020 Jul 15.

Department of Food Science, University of Copenhagen, Rolighedsvej 30, DK-1958 Frederiksberg C, Denmark. Electronic address:

Saturated solutions of calcium l-lactate in water or in deuterium oxide continuously dissolve calcium l-lactate by addition of solid sodium d-gluconate and become strongly supersaturated in calcium d-gluconate due to no or slow precipitation. The quantification of total dissolved calcium allied with the calcium complexes equilibrium constants allowed an ion speciation, which shows an initial non-thermal and spontaneous supersaturation of more than a factor of 50 at 25 °C only slowly decreasing after initiation of precipitation of calcium d-gluconate after a lag phase of several hours. A mathematical model is proposed, based on numerical solution of coupled differential equations of dynamics of l-lactate and d-gluconate exchange during the lag phase for precipitation and during precipitation. A slow exchange of l-lactate coordinated to calcium with d-gluconate is indicated with a time constant of 0.20 h in water and of 0.15 h in deuterium oxide and a kinetic deuterium/hydrogen isotope effect of 1.25. Such spontaneous non-thermal supersaturation and slow ligand exchange with a pseudo first order equilibration process with a half-life of 3.5 h in water for calcium hydroxycarboxylates can help to understand the higher calcium bioavailability from calcium hydroxycarboxylates compared to simple salts.
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http://dx.doi.org/10.1016/j.foodres.2020.109539DOI Listing
November 2020

Peptide-Oleate Complexes Create Novel Membrane-Bound Compartments.

Mol Biol Evol 2020 11;37(11):3083-3093

Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, Lund, Sweden.

A challenging question in evolutionary theory is the origin of cell division and plausible molecular mechanisms involved. Here, we made the surprising observation that complexes formed by short alpha-helical peptides and oleic acid can create multiple membrane-enclosed spaces from a single lipid vesicle. The findings suggest that such complexes may contain the molecular information necessary to initiate and sustain this process. Based on these observations, we propose a new molecular model to understand protocell division.
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http://dx.doi.org/10.1093/molbev/msaa138DOI Listing
November 2020

The RESOLUTE consortium: unlocking SLC transporters for drug discovery.

Authors:
Giulio Superti-Furga Daniel Lackner Tabea Wiedmer Alvaro Ingles-Prieto Barbara Barbosa Enrico Girardi Ulrich Goldmann Bettina Gürtl Kristaps Klavins Christoph Klimek Sabrina Lindinger Eva Liñeiro-Retes André C Müller Svenja Onstein Gregor Redinger Daniela Reil Vitaly Sedlyarov Gernot Wolf Matthew Crawford Robert Everley David Hepworth Shenping Liu Stephen Noell Mary Piotrowski Robert Stanton Hui Zhang Salvatore Corallino Andrea Faedo Maria Insidioso Giovanna Maresca Loredana Redaelli Francesca Sassone Lia Scarabottolo Michela Stucchi Paola Tarroni Sara Tremolada Helena Batoulis Andreas Becker Eckhard Bender Yung-Ning Chang Alexander Ehrmann Anke Müller-Fahrnow Vera Pütter Diana Zindel Bradford Hamilton Martin Lenter Diana Santacruz Coralie Viollet Charles Whitehurst Kai Johnsson Philipp Leippe Birgit Baumgarten Lena Chang Yvonne Ibig Martin Pfeifer Jürgen Reinhardt Julian Schönbett Paul Selzer Klaus Seuwen Charles Bettembourg Bruno Biton Jörg Czech Hélène de Foucauld Michel Didier Thomas Licher Vincent Mikol Antje Pommereau Frédéric Puech Veeranagouda Yaligara Aled Edwards Brandon J Bongers Laura H Heitman Ad P IJzerman Huub J Sijben Gerard J P van Westen Justine Grixti Douglas B Kell Farah Mughal Neil Swainston Marina Wright-Muelas Tina Bohstedt Nicola Burgess-Brown Liz Carpenter Katharina Dürr Jesper Hansen Andreea Scacioc Giulia Banci Claire Colas Daniela Digles Gerhard Ecker Barbara Füzi Viktoria Gamsjäger Melanie Grandits Riccardo Martini Florentina Troger Patrick Altermatt Cédric Doucerain Franz Dürrenberger Vania Manolova Anna-Lena Steck Hanna Sundström Maria Wilhelm Claire M Steppan

Nat Rev Drug Discov 2020 07;19(7):429-430

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http://dx.doi.org/10.1038/d41573-020-00056-6DOI Listing
July 2020

Marine Tardigrada from the Mexican Caribbean with the description of Styraconyx robertoi sp. nov. (Arthrotardigrada: Styraconyxidae).

Zootaxa 2020 Feb 10;4731(4):zootaxa.4731.4.3. Epub 2020 Feb 10.

El Colegio de la Frontera Sur-Unidad Chetumal. Departamento de Ecología y Sistemática. Av. Centenario km 5.5, Chetumal Quintana Roo, México.

Marine tardigrades were sampled at three sites on Mexico's Caribbean coast. Eleven taxa were collected, one of which is described as a new species. Styraconyx robertoi sp. nov. is characterized by: asymmetric primary clavae; dorsal cuticle with a grid-like sculpture; claws with reduced accessory hooks; females with peduncles on only two digits (the external) of legs I-IV; males with peduncles only on the external digits of legs I-III and peduncles on all four digits of leg IV. Styraconyx robertoi sp. nov. is most similar to S. craticuliformis Chang Rho, 1998 and S. kristenseni Renaud-Mornant, 1981 by having asymmetric primary clavae but differs from S. craticuliformis mainly by the number of peduncles and from S. kristenseni mainly by the presence of a grid-like dorsal sculpture. Additionally, a comparison of material collected from the same region, but reported previously only as genus level records, was carried out in order to produce a refined list of the known Mexican marine tardigrade species.
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http://dx.doi.org/10.11646/zootaxa.4731.4.3DOI Listing
February 2020

[Elimination of hepatitis C virus in Denmark].

Ugeskr Laeger 2020 Feb;182(9)

In Denmark, about 50% of patients with chronic hepatitis C virus (HCV) infection are undiagnosed. Since 2014, therapy containing direct-acting antivirals (DAA) has proven efficient and is available to all patients, who have a chronic HCV infection and a Danish personal identification number. The World Health Organization has a goal of elimination of viral hepatitis in 2030. Elimination of HCV in Denmark should focus on reducing HCV transmission, incidence and prevalence, combined with treatment with DAA of all infected patients. Micro-elimination strategies may play a major role, but a national strategy is lacking.
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February 2020

A novel welfare and scientific approach to conducting dog metabolism studies allowing dogs to be pair housed.

Lab Anim 2020 Dec 16;54(6):588-598. Epub 2020 Feb 16.

Novo Nordisk A/S, Måløv, Denmark.

Metabolism cages are designed to conduct absorption, distribution, metabolism and excretion (ADME) studies, enabling an 'excretion balance' scientific objective to be met. Historically, the design of dog metabolism cages has involved single housing. This type of housing has limitations for normal social behaviours and has been largely unchanged for 25-30 years. Improving animal welfare is a focus area for the authorities as well as the industry throughout the European Union. A collaboration was developed between Novo Nordisk and Covance to enhance the design of metabolism cages, allowing dogs to be pair housed. The purpose of the study was to compare excretion balance data from pair-housed and singly housed dogs in order to demonstrate that conducting excretion balance studies with a pair-housing design improves animal welfare without compromising the scientific integrity of the study. A radiolabelled test compound, [C]-Quetiapine, was selected for this investigation based on its excretion profile. The assessment of the dogs' stress levels was investigated by measuring the levels of serum cortisol as an indicative biomarker. Results were inconclusive due to large variations in cortisol levels. However, dogs appeared calmer in the pair-housing setting. The overall mean recovery (±standard deviation) for pair-housed animals (94.0 ± 0.66% of the dose) was equivalent to that from singly housed dogs (93.0 ± 2.29%). Based on these data, we conclude that pair housing of dogs for future metabolism ADME studies does not compromise the scientific integrity, and therefore is a major progression in the design of these studies, enhancing welfare.
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http://dx.doi.org/10.1177/0023677220905330DOI Listing
December 2020

Prevalence, type distribution and risk factors for oral HPV in Danish renal transplant recipients.

Oral Dis 2020 Mar 12;26(2):484-488. Epub 2019 Dec 12.

Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.

Objective: To assess the prevalence and type distribution of oral human papillomavirus (HPV) among renal transplant recipients (RTRs) and healthy controls and to examine risk factors for oral HPV among RTRs.

Materials And Methods: During 2016-2017 we recruited 250 RTRs and 250 controls. Oral samples were tested for HPV DNA with INNO-LiPA HPV Genotyping Extra II. All participants answered a questionnaire on lifestyle and sexual behaviour, and characteristics of RTRs were obtained from medical files. We assessed prevalence and type distribution of oral HPV. Using logistic regression, the risk of oral HPV and risk factors for oral HPV among RTRs were estimated as odds ratios (OR) with 95% confidence intervals (CI).

Results: Overall, 30 RTRs (12.1%) and 26 controls (10.4%) were oral HPV positive (OR = 1.14; 95% CI: 0.64-2.05). Female RTRs tended to have a higher oral HPV prevalence than controls (OR = 1.73; 95% CI: 0.63-4.77), while no difference was observed among men. HPV51 was the commonest genotype. Sexual behaviour tended to be associated with oral HPV among RTRs.

Conclusions: There was no overall difference in oral HPV prevalence between RTRs and controls, but female RTRs tended to have a higher prevalence of oral HPV than controls.
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http://dx.doi.org/10.1111/odi.13240DOI Listing
March 2020

Effect of Hydrogen Bonds on the Dielectric Properties of Interfacial Water.

Langmuir 2019 Jun 4;35(24):8159-8166. Epub 2019 Jun 4.

Department of Applied Mechanics , Indian Institute of Technology Madras , Chennai 600036 , India.

The dielectric constant for water is reduced under confinement. Although this phenomenon is well known, the underlying physical mechanism for the reduction is still in debate. In this work, we investigate the effect of the orientation of hydrogen bonds on the dielectric properties of confined water using molecular dynamics simulations. We find a reduced rotational diffusion coefficient for water molecules close to the solid surface. The reduced rotational diffusion arises due to the hindered rotation away from the plane parallel to the channel walls. The suppressed rotation in turn affects the orientational polarization of water, leading to a low value for the dielectric constant at the interface. We attribute the constrained out-of-plane rotation to originate from a higher density of planar hydrogen bonds formed by the interfacial water molecules.
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http://dx.doi.org/10.1021/acs.langmuir.9b00543DOI Listing
June 2019

Is early measles vaccination associated with stronger survival benefits than later measles vaccination?

BMC Public Health 2018 08 7;18(1):984. Epub 2018 Aug 7.

Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark.

Background: Measles vaccine (MV) may protect against non-measles mortality. We tested whether survival depended on age of measles vaccination.

Methods: Bandim Health Project follows children under 5 years of age through a Health and Demographic Surveillance System in rural Guinea-Bissau. Children aged 6-36 months with a vaccination card inspected were followed to the next visit or for a maximum of 6 months. In Cox proportional-hazards models adjusted for age and village cluster, we compared the survival of children vaccinated with MV early (< 9 months), as recommended (9-11 months) or late (> 12+ months) with the survival of measles-unvaccinated children. Among measles-vaccinated children, we modelled the effect of age at measles vaccination linearly to assess mortality changes per month increase in vaccination age.

Results: From 1999 to 2006, 14,813 children (31,725 observations) were included. Children vaccinated with MV had a Hazard Ratio (HR) of 0.76 (95% CI: 0.63-0.91) compared with measles-unvaccinated children; censoring measles deaths did not change the results (HR = 0.79 (0.65-0.95)). For early MV the HR was 0.68 (0.53-0.87), for MV as recommended the HR was 0.77 (0.62-0.96) and for late MV the HR was 0.86 (0.67-1.11). Limiting the analysis to measles-vaccinated children, age at measles vaccination was associated with a 2.6% (0.4-5.1%) increase in mortality per month increase in vaccination age.

Conclusion: Early MV was associated with a large survival advantage. The current policy to increase vaccination age, when measles control improves, may not optimize the impact of MV on child survival.
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http://dx.doi.org/10.1186/s12889-018-5866-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081866PMC
August 2018

Mannose-binding lectin genotypes and outcome in end-stage renal disease: a prospective cohort study.

Nephrol Dial Transplant 2018 11;33(11):1991-1997

Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: Patients with end-stage renal disease (ESRD) have high morbidity and mortality rates, with cardiovascular diseases and infections being the major causes of death. Mannose-binding lectin (MBL) has been suggested to play a protective role in this regard. The aim of this study was to investigate a possible clinical association of MBL genotypes (MBL2) with outcome among patients on dialysis or with a functioning graft.

Methods: A total of 98 patients with ESRD accepted for living-donor renal transplantation or on the waiting list for transplantation were included and prospectively followed for an average of 9 years (range 7.5-9.9). Medical records were evaluated regarding transplantation status, diabetes mellitus, vascular parameters and infections for all the patients. Cox regression models and logistic regression analysis were used for statistical analyses. The cohort was divided into two groups according to the MBL2 genotype (normal A/A versus variant A/O or O/O).

Results: We found no evidence for an association between the MBL2 genotype and all-cause mortality, cardiovascular events or bacterial infections (pneumonia, urinary tract infection, fistula infection or other infections).

Conclusion: In this cohort, the MBL2 genotype did not seem to be associated with any long-term clinical effects in ESRD patients on dialysis or with a functioning graft.
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http://dx.doi.org/10.1093/ndt/gfy034DOI Listing
November 2018

Reply to: Correspondence regarding the impact of kidney transplantation on insulin sensitivity.

Transpl Int 2018 04;31(4):458-459

Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

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http://dx.doi.org/10.1111/tri.13134DOI Listing
April 2018

Glucose Transport Activity Measured in Giant Vesicles.

Methods Mol Biol 2018 ;1713:77-91

Department of Experimental Medical Science, Lund University, BMC C13, 221 84, Lund, Sweden.

Incorporation of membrane proteins and internal reporter systems directly into giant vesicles, during their formation from a hydrogel surface, has emerged as a promising new concept in membrane protein characterization. Here, we provide the detailed protocol for a glucose transporter activity assay based on giant vesicles containing a fluorescent enzyme-linked reporter system internally. This assay is applicable for the functional analysis of a variety of hexose-transporting proteins. We furthermore believe that it can aid in the development of drugs targeting hexose transporters.
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http://dx.doi.org/10.1007/978-1-4939-7507-5_7DOI Listing
July 2018

Visualization of lipid directed dynamics of perilipin 1 in human primary adipocytes.

Sci Rep 2017 11 8;7(1):15011. Epub 2017 Nov 8.

Department of Experimental Medical Science, Lund University, BMC, 221 84, Lund, Sweden.

Perilipin 1 is a lipid droplet coating protein known to regulate lipid metabolism in adipocytes by serving as a physical barrier as well as a recruitment site for lipases to the lipid droplet. Phosphorylation of perilipin 1 by protein kinase A rapidly initiates lipolysis, but the detailed mechanism on how perilipin 1 controls lipolysis is unknown. Here, we identify specific lipid binding properties of perilipin 1 that regulate the dynamics of lipolysis in human primary adipocytes. Cellular imaging combined with biochemical and biophysical analyses demonstrate that perilipin 1 specifically binds to cholesteryl esters, and that their dynamic properties direct segregation of perilipin 1 into topologically distinct micro domains on the lipid droplet. Together, our data points to a simple unifying mechanism that lipid assembly and segregation control lipolysis in human primary adipocytes.
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http://dx.doi.org/10.1038/s41598-017-15059-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678101PMC
November 2017

Tuning biomimetic membrane barrier properties by hydrocarbon, cholesterol and polymeric additives.

Bioinspir Biomim 2017 12 4;13(1):016005. Epub 2017 Dec 4.

Department of Physics, Technical University of Denmark (DTU), 2800 Kgs. Lyngby, Denmark. These authors contributed equally to this work.

The barrier properties of cellular membranes are increasingly attracting attention as a source of inspiration for designing biomimetic membranes. The broad range of potential technological applications makes the use of lipid and lately also polymeric materials a popular choice for constructing biomimetic membranes, where the barrier properties can be controlled by the composition of the membrane constituent elements. Here we investigate the membrane properties reported by the light-induced proton pumping activity of bacteriorhodopsin (bR) reconstituted in three vesicle systems of different membrane composition. Specifically we quantify how the resulting proton influx and efflux rates are influenced by the membrane composition using a variety of membrane modulators. We demonstrate that by adding hydrocarbons to vesicles with reconstituted bR formed from asolectin lipids the resulting transmembrane proton fluxes changes proportional to the carbon chain length when compared against control. We observe a similar proportionality in single-component 1,2-Dioleoyl-sn-glycero-3-phosphocholine model membranes when using cholesterol. Lastly we investigate the effects of adding the amphiphilic di-block co-polymer polybutadiene-polyethyleneoxide (PB-PEO) to phospholipid membranes formed from 1,2-Dioleoyl-sn-glycero-3-phosphocholine, 1,2-Dioleoyl-sn-glycero-3-phosphatidylethanolamine, and 1,2-Dioleoyl-sn-glycero-3-phosphatidylserine. The proton pumping activity of bR (measured as a change in extra-vesicular pH) in mixed lipid/PB-PEO lipid systems is up to six-fold higher compared to that observed for bR containing vesicles made from PB-PEO alone. Interestingly, bR inserts with apparent opposite orientation in pure PB-PEO vesicles as compared to pure lipid vesicles. Addition of equimolar amounts of lipids to PB-PEO results in bR orientation similar to that observed for pure lipids. In conclusion our results show how the barrier properties of the membranes can be controlled by the composition of the membrane. In particular the use of mixed lipid-polymer systems may pave the way for constructing biomimetic membranes tailored for optimal properties in various applications including drug delivery systems, biosensors and energy conservation technology.
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http://dx.doi.org/10.1088/1748-3190/aa92beDOI Listing
December 2017

Quantification of the Intracellular Life Time of Water Molecules to Measure Transport Rates of Human Aquaglyceroporins.

J Membr Biol 2017 Dec 15;250(6):629-639. Epub 2017 Sep 15.

Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, 405 30, Göteborg, Sweden.

Orthodox aquaporins are transmembrane channel proteins that facilitate rapid diffusion of water, while aquaglyceroporins facilitate the diffusion of small uncharged molecules such as glycerol and arsenic trioxide. Aquaglyceroporins play important roles in human physiology, in particular for glycerol metabolism and arsenic detoxification. We have developed a unique system applying the strain of the yeast Pichia pastoris, where the endogenous aquaporins/aquaglyceroporins have been removed and human aquaglyceroporins AQP3, AQP7, and AQP9 are recombinantly expressed enabling comparative permeability measurements between the expressed proteins. Using a newly established Nuclear Magnetic Resonance approach based on measurement of the intracellular life time of water, we propose that human aquaglyceroporins are poor facilitators of water and that the water transport efficiency is similar to that of passive diffusion across native cell membranes. This is distinctly different from glycerol and arsenic trioxide, where high glycerol transport efficiency was recorded.
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http://dx.doi.org/10.1007/s00232-017-9988-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696491PMC
December 2017

Grazoprevir, ruzasvir, and uprifosbuvir for hepatitis C virus after NS5A treatment failure.

Hepatology 2017 12 30;66(6):1794-1804. Epub 2017 Oct 30.

Service d'Hépatologie, Hôpital Saint-Antoine, Université Pierre & Marie Curie, Paris, France.

People with hepatitis C virus (HCV) infection who have failed treatment with an all-oral regimen represent a challenging treatment population. The present studies evaluated the safety and efficacy of grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, in participants who had failed an NS5A inhibitor-containing regimen. C-SURGE (PN-3682-021) and C-CREST Part C (PN-3682-011 and -012) were open-label, multicenter studies. Participants who had previously relapsed following an NS5A inhibitor-containing all-oral regimen were retreated with grazoprevir 100 mg, ruzasvir 60 mg, and uprifosbuvir 450 mg alone for 24 weeks or with ribavirin for 16 weeks. The primary efficacy endpoint was sustained virologic response (HCV RNA below the limit of quantitation [<15 IU/mL]) 12 weeks after treatment completion (SVR12). In C-SURGE, SVR12 was achieved by 49/49 (100%) and 43/44 (98%) genotype (GT)1 participants in the 24-week no ribavirin arm and the 16-week plus ribavirin arm (lost to follow-up, n = 1), respectively. In C-CREST Part C, SVR12 was achieved by 23/24 (96%) participants treated for 16 weeks with ribavirin (GT1, 2/2 [100%]; GT2, 13/14 [93%]; GT3, 8/8 [100%]). One participant with GT2 infection discontinued study medication after a single dose of grazoprevir, ruzasvir, and uprifosbuvir plus ribavirin due to serious adverse events of vomiting and tachycardia. The presence of baseline resistance-associated substitutions had no impact on SVR12. No participant who completed treatment in either study experienced virologic failure.

Conclusion: Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, for 16 or 24 weeks was safe and highly effective in participants with HCV infection who had previously failed NS5A inhibitor-containing therapy. (Hepatology 2017;66:1794-1804).
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http://dx.doi.org/10.1002/hep.29358DOI Listing
December 2017

Thermal stability and structural changes in bacterial toxins responsible for food poisoning.

PLoS One 2017 16;12(2):e0172445. Epub 2017 Feb 16.

Department of Experimental Medical Science, Lund University, BMC, Lund, Sweden.

The staphylococcal enterotoxins (SEs) are secreted by the bacteria Staphylococcus aureus and are the most common causative agent in staphylococcal food poisoning. The staphylococcal enterotoxin A (SEA) has been associated with large staphylococcal food poisoning outbreaks, but newer identified SEs, like staphylococcal enterotoxin H (SEH) has recently been shown to be present at similar levels as SEA in food poisoning outbreaks. Thus, we set out to investigate the thermo-stability of the three-dimensional structures of SEA, SEH and staphylococcal enterotoxin E (SEE), since heat inactivation is a common method to inactivate toxins during food processing. Interestingly, the investigated toxins behaved distinctly different upon heating. SEA and SEE were more stable at slightly acidic pH values, while SEH adopted an extremely stable structure at neutral pH, with almost no effects on secondary structural elements upon heating to 95°C, and with reversible formation of tertiary structure upon subsequent cooling to room temperature. Taken together, the data suggests that the family of staphylococcal enterotoxins have different ability to withstand heat, and thus the exact profile of heat inactivation for all SEs causing food poisoning needs to be considered to improve food safety.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172445PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5313198PMC
September 2017

The impact of kidney transplantation on insulin sensitivity.

Transpl Int 2017 Mar 9;30(3):295-304. Epub 2017 Feb 9.

Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

To investigate the impact of kidney transplantation (KTx) on insulin sensitivity affecting glucose metabolism. 9 nondiabetic patients awaiting living donor KTx were examined prior to transplantation with an oral glucose tolerance test and a 3-h hyperinsulinaemic-euglycaemic clamp. The clamp was repeated 6 months after KTx. Nine age-, gender- and body mass index (BMI)-matched individuals with normal kidney function served as controls. Endogenous glucose production and glucose disappearance rate (N = 6) were measured in a subgroup of patients with corresponding controls. Results presented as mean [range]. Two patients had pretransplant prediabetes, whereas all others had normal glucose tolerance. After KTx, average glucose infusion rate to maintain euglycaemia during clamp declined significantly from 15.1 [9.1-23.7] to 9.8 [2.8-14.6] μmol/kg/min (P < 0.01) with 20.2 [9.9-33.7] μmol/kg/min in controls. Endogenous glucose production increased from 7.0 [4.8-8.5] to 9.4 [7.4-11.8] μmol/kg/min (P < 0.05) with 7.0 [-3.8 to 10.1] μmol/kg/min in controls. Glucose disappearance rate was unchanged (18.1 [12.9-24.5] vs. 17.1 [12.2-22.7] μmol/kg/min, NS) with 22.3 [14.6-34.3] in controls. In conclusion, insulin sensitivity is reduced 6 months after KTx and characterized mainly by impaired suppression of the endogenous glucose production.
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http://dx.doi.org/10.1111/tri.12907DOI Listing
March 2017

Perilipin 1 binds to aquaporin 7 in human adipocytes and controls its mobility via protein kinase A mediated phosphorylation.

Metabolism 2016 Dec 22;65(12):1731-1742. Epub 2016 Sep 22.

Department of Experimental Medical Science, Lund University, BMC, 221 84, Lund, Sweden. Electronic address:

Accumulating evidence suggests that dysregulated glycerol metabolism contributes to the pathophysiology of obesity and type 2 diabetes. Glycerol efflux from adipocytes is regulated by the aquaglyceroporin AQP7, which is translocated upon hormone stimulation. Here, we propose a molecular mechanism where the AQP7 mobility in adipocytes is dependent on perilipin 1 and protein kinase A. Biochemical analyses combined with ex vivo studies in human primary adipocytes, demonstrate that perilipin 1 binds to AQP7, and that catecholamine activated protein kinase A phosphorylates the N-terminus of AQP7, thereby reducing complex formation. Together, these findings are indicative of how glycerol release is controlled in adipocytes, and may pave the way for the future design of drugs against human metabolic pathologies.
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http://dx.doi.org/10.1016/j.metabol.2016.09.004DOI Listing
December 2016

Cancer risk and mortality after kidney transplantation: a population-based study on differences between Danish centres using standard immunosuppression with and without glucocorticoids.

Nephrol Dial Transplant 2016 12 1;31(12):2149-2156. Epub 2016 Sep 1.

Department of Medicine, Zealand University Hospital, Roskilde, Denmark.

Background: Kidney recipients receive immunosuppression to prevent graft rejection, and long-term outcomes such as post-transplant cancer and mortality may vary according to the different protocols of immunosuppression.

Methods: A national register-based historical cohort study was conducted to examine whether post-transplant cancer and all-cause mortality differed between Danish renal transplantation centres using standard immunosuppressive protocols including steroids (Centres 2, 3, 4) or a steroid-free protocol (Centre 1). The Danish Nephrology Registry, the Danish Civil Registration System, the Danish National Cancer Registry and the Danish National Patient Register were used. A historical cohort of 1450 kidney recipients transplanted in 1995-2005 was followed up with respect to post-transplant cancer and death until 31 December 2011.

Results: Compared with Center 1 the adjusted post-transplant cancer risk was 6-39% lower in Centre 3 [hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.67-1.32], in Centre 2 (HR 0.72, 95% CI 0.52-0.98) and in Centre 4 (HR 0.61, 95% CI 0.44-0.83). Compared with Center 1, the adjusted post-transplant mortality was 21-55% higher in Centre 4 (HR 1.21, 95% CI 0.91-1.61), in Centre 3 (HR 1.35, 95% CI 0.98-1.86) and in Centre 2 (HR 1.55, 95% CI 1.17-2.05). On average, post-transplant cancer was associated with a 4-fold increase in the risk of death (HR 4.25, 95% CI 3.36-5.38).

Conclusions: There was a tendency of a higher post-transplant cancer occurrence, but lower all-cause mortality, in the Danish transplantation centre that adhered to a standard steroid-free immunosuppressive protocol.
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http://dx.doi.org/10.1093/ndt/gfw304DOI Listing
December 2016

Identification of Structural Relaxation in the Dielectric Response of Water.

Phys Rev Lett 2016 Jun 9;116(23):237601. Epub 2016 Jun 9.

Department of Chemistry, University of Tennessee, Knoxville, Tennessee 37996, USA.

One century ago pioneering dielectric results obtained for water and n-alcohols triggered the advent of molecular rotation diffusion theory considered by Debye to describe the primary dielectric absorption in these liquids. Comparing dielectric, viscoelastic, and light scattering results, we unambiguously demonstrate that the structural relaxation appears only as a high-frequency shoulder in the dielectric spectra of water. In contrast, the main dielectric peak is related to a supramolecular structure, analogous to the Debye-like peak observed in monoalcohols.
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http://dx.doi.org/10.1103/PhysRevLett.116.237601DOI Listing
June 2016

Dynamics and Structure of Bitumen-Water Mixtures.

J Phys Chem B 2016 06 9;120(24):5470-80. Epub 2016 Jun 9.

DNRF Centre "Glass and Time", IMFUFA, Department of Sciences, Roskilde University , Universitetsvej 1, Postbox 260, DK-4000 Roskilde, Denmark.

Systems of Cooee bitumen and water up to 4% mass are studied by molecular dynamics simulations. The cohesive energy density of the system is shown to decrease with an increasing water content. This decrease is due mainly to an increase in the interaction energy which is not high enough to counterbalance the increase in volume due to the addition of water. It is not due to a decrease of interaction energy between the slightly polar asphaltene molecules. The water molecules tend to form a droplet in bitumen. The size and the distribution of sizes of the droplets are quantified, with multiple droplets being more stable at the highest temperature simulated. The droplet is mainly located close to the saturates molecules in bitumen. Finally, it is shown that the water dynamics is much slower in bitumen than in pure water because it is governed by the diffusion of the droplet and not of the single molecules.
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http://dx.doi.org/10.1021/acs.jpcb.6b01451DOI Listing
June 2016

Finite-size effects in a model for plasticity of amorphous composites.

Phys Rev E 2016 Feb 8;93(2):023004. Epub 2016 Feb 8.

Laboratoire PMMH, CNRS-UMR 7636/ESPCI/UPMC/Univ. Paris 7 Diderot, 10, rue Vauquelin, 75231 Paris cedex 05, France.

We discuss the plastic behavior of an amorphous matrix reinforced by hard particles. A mesoscopic depinning-like model accounting for Eshelby elastic interactions is implemented. Only the effect of a plastic disorder is considered. Numerical results show a complex size dependence of the effective flow stress of the amorphous composite. In particular, the departure from the mixing law shows opposite trends associated to the competing effects of the matrix and the reinforcing particles, respectively. The reinforcing mechanisms and their effects on localization are discussed. Plastic strain is shown to gradually concentrate on the weakest band of the system. This correlation of the plastic behavior with the material structure is used to design a simple analytical model. The latter nicely captures reinforcement size effects in (logN/N)(1/2), where N is the linear size of the system, observed numerically. Predictions of the effective flow stress accounting for further logarithmic corrections show a very good agreement with numerical results.
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http://dx.doi.org/10.1103/PhysRevE.93.023004DOI Listing
February 2016

Onset of main Phanerozoic marine radiation sparked by emerging Mid Ordovician icehouse.

Sci Rep 2016 Jan 6;6:18884. Epub 2016 Jan 6.

Palaeoecosystems Group, Department of Earth Sciences, Durham University, Durham DH1 3LE, UK.

The Great Ordovician Biodiversification Event (GOBE) was the most rapid and sustained increase in marine Phanerozoic biodiversity. What generated this biotic response across Palaeozoic seascapes is a matter of debate; several intrinsic and extrinsic drivers have been suggested. One is Ordovician climate, which in recent years has undergone a paradigm shift from a text-book example of an extended greenhouse to an interval with transient cooling intervals - at least during the Late Ordovician. Here, we show the first unambiguous evidence for a sudden Mid Ordovician icehouse, comparable in magnitude to the Quaternary glaciations. We further demonstrate the initiation of this icehouse to coincide with the onset of the GOBE. This finding is based on both abiotic and biotic proxies obtained from the most comprehensive geochemical and palaeobiological dataset yet collected through this interval. We argue that the icehouse conditions increased latitudinal and bathymetrical temperature and oxygen gradients initiating an Early Palaeozoic Great Ocean Conveyor Belt. This fuelled the GOBE, as upwelling zones created new ecospace for the primary producers. A subsequent rise in δ(13)C ratios known as the Middle Darriwilian Isotopic Carbon Excursion (MDICE) may reflect a global response to increased bioproductivity encouraged by the onset of the GOBE.
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http://dx.doi.org/10.1038/srep18884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702064PMC
January 2016

Simple Statistical Model for Branched Aggregates: Application to Cooee Bitumen.

J Phys Chem B 2015 Nov 21;119(44):14323-31. Epub 2015 Oct 21.

DNRF Centre "Glass and Time", IMFUFA, Department of Sciences, Roskilde University , Universitetsvej 1, Postbox 260, DK-4000 Roskilde, Denmark.

We propose a statistical model that can reproduce the size distribution of any branched aggregate, including amylopectin, dendrimers, molecular clusters of monoalcohols, and asphaltene nanoaggregates. It is based on the conditional probability for one molecule to form a new bond with a molecule, given that it already has bonds with others. The model is applied here to asphaltene nanoaggregates observed in molecular dynamics simulations of Cooee bitumen. The variation with temperature of the probabilities deduced from this model is discussed in terms of statistical mechanics arguments. The relevance of the statistical model in the case of asphaltene nanoaggregates is checked by comparing the predicted value of the probability for one molecule to have exactly i bonds with the same probability directly measured in the molecular dynamics simulations. The agreement is satisfactory.
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http://dx.doi.org/10.1021/acs.jpcb.5b08320DOI Listing
November 2015

Continuum Nanofluidics.

Langmuir 2015 Dec 12;31(49):13275-89. Epub 2015 Oct 12.

Department of Physics, Technical University of Denmark , DTU Physics Building 309, DK-2800 Kongens Lyngby, Denmark.

This paper introduces the fundamental continuum theory governing momentum transport in isotropic nanofluidic systems. The theory is an extension of the classical Navier-Stokes equation, and includes coupling between translational and rotational degrees of freedom as well as nonlocal response functions that incorporate spatial correlations. The continuum theory is compared with molecular dynamics simulation data for both relaxation processes and fluid flows, showing excellent agreement on the nanometer length scale. We also present practical tools to estimate when the extended theory should be used. It is shown that in the wall-fluid region the fluid molecules align with the wall, and in this region the isotropic model may fail and a full anisotropic description is necessary.
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http://dx.doi.org/10.1021/acs.langmuir.5b02237DOI Listing
December 2015