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Type 2 diabetes (T2D) is characterized by insulin resistance in skeletal muscle. GWAS studies have shown a link between T2D and Wnt signalling, and there is evidence that mutations in LRP5, a co-receptor in the canonical Wnt signaling pathway, may alter insulin sensitivity. Here, we investigated whether a gain-of-function (GoF) LRP5 mutation causing high bone mass is accompanied by changes in insulin sensitivity and abnormalities in the insulin signalling pathway in skeletal muscle. Skeletal muscle biopsies were obtained before and after a euglycemic-hyperinsulinemic clamp (3-h, 40 mU/min/m2) from 13 patients with GoF LRP5 mutation (T253I) and 14 age, and weight-matched controls. Protein abundance/phosphorylation of key mediators of insulin signalling to glucose transport and glycogen synthesis, such as Akt, TBC1D4, glycogen synthase kinase 3 (GSK3α and ß) and Erk1/2 were investigated. Insulin sensitivity measured as insulin-stimulated glucose disposal (Rd) was reduced (25%) in GoF LRP5 mutation carriers (p<0.05). However, the insulin-stimulated phosphorylation of Akt at Ser473 and Thr308, TBC1D4 at Thr642 and Erk1/2 was fully intact in skeletal muscle of GoF LRP5 mutation carriers. Moreover, both the basal and the insulin-mediated inhibitory phosphorylation of GSK3 (α and ß) were unaltered in muscle of LRP5 mutation carriers compared with controls. To further investigate the molecular consequences of this GoF LRP5 mutation, we are currently investigating key regulators of Wnt signalling (activity of ß-catenin and CaMKII) and performing RNA-sequencing in muscle. In conclusion, our data demonstrate that reduced insulin sensitivity in GoF LRP5 mutation carriers is not explained by abnormalities in the classical components of the insulin signalling cascade in skeletal muscle. This suggests that the GOF LRP5 mutation negatively affects insulin sensitivity by other mechanisms possible involving over-activation in Wnt signalling. Disclosure: R. Sabaratnam: None. J. Lauterlein: None. M.F. Nielsen: None. K. Hojlund: None. [ABSTRACT FROM AUTHOR]

The existence of a human primary vestibular cortex is still debated. Current knowledge mainly derives from functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) acquisitions during artificial vestibular stimulation. This may be problematic as artificial vestibular stimulation entails coactivation of other sensory receptors. The use of fMRI is challenging as the strong magnetic field and loud noise during MRI may both stimulate the vestibular organ. This study aimed to characterize the cortical activity during natural stimulation of the human vestibular organ. Two fluorodeoxyglucose (FDG)‐PET scans were obtained after natural vestibular stimulation in a self‐propelled chair. Two types of stimuli were applied: (a) rotation (horizontal semicircular canal) and (b) linear sideways movement (utriculus). A comparable baseline FDG‐PET scan was obtained after sitting motion‐less in the chair. In both stimulation paradigms, significantly increased FDG uptake was measured bilaterally in the medial part of Heschl's gyrus, with some overlap into the posterior insula. This is the first neuroimaging study to visualize cortical processing of natural vestibular stimuli. FDG uptake was demonstrated in the medial‐most part of Heschl's gyrus, normally associated with the primary auditory cortex. This anatomical localization seems plausible, considering that the labyrinth contains both the vestibular organ and the cochlea. [ABSTRACT FROM AUTHOR]

As a method to experimentally study aerodynamic drag the terminal settling velocities of aerosolized silica and glass microspheres (with sizes of 1–44 μm) have been measured at various gas pressures in the range 0.6–10 mbar and using various gas compositions including He, Ar, Xe, Air, CO 2 , and water vapour. Within the molecular scattering regime, i.e. where the Knudsen number Kn > 10 and up to 500, reasonable agreement has been found with the model of Epstein (1924). Values of the scattering parameter δ were observed to be within the expected range of 1–1.44 for respectively specular/evaporative - diffuse molecular scattering processes. However, δ was seen to depend upon gas composition, specifically for H 2 O; δ = 0.96 ± 0.07, CO 2 ; δ = 1.16 ± 0.07, noble gasses; δ = 1.25–1.44 and in the case of Air δ = 1.18 ± 0.07 which is not in agreement with that conventionally used of around 1.3–1.4. These observations imply disagreement with the concept of a general or universal model of drag for all particle surfaces and atmospheres. Similarly, for Kn < 10 these results were not well described by conventional models such as the semi-empirical expression of Knudsen-Weber (1911) or the general law of fall proposed by Millikan (1923b). Image 1 • Laser Doppler technique to measure microsphere settling velocities. • Agreement with Epstein's model within molecular drag regime. • Gas dependence of molecular scattering parameter. • Poor agreement with Millikan's law of fall. [ABSTRACT FROM AUTHOR]

The contact electrification of aerosolized micron-scale oxide particles has been investigated experimentally and the size and composition dependence determined. The net charge acquired by particles contacting the aerosolizer was seen to increase linearly with their surface area. A physically meaningful model based upon electron transfer has been applied leading to a predictive expression for the total particle surface charge concentration generated (σ) dependent on the absolute generalized relative electronegativity ( χ AGR ); σ  =  aχ AGR   −  b , where a  = 4.7 e/μm 2 /V, b  = −27 e/μm 2 and χ AGR is obtained by knowing the composition of the two contacting surfaces. The influence of relative humidity and particle cohesion on the contact electrification process was investigated. A maximum surface charge concentration of around 100 e/μm 2 was found, in agreement with previous work. [ABSTRACT FROM AUTHOR]

The contact electrification of aerosolized micro particles has been studied using a novel technique involving laser velocimetry. This has allowed the simultaneous determination of size and electrical charge of individual silica microspheres (in the range 1 – 8 µm). Interestingly the particles interacting with the injector tube have been seen to become electrified with a relatively narrow range of surface charge concentration of around Q/4πr 2 ~ −100 e - /µm 2 (~ −0.02 mC/m 2 ) for all particle sizes. Several combinations of aerosol particle and injector tube composition were also investigated, some of which led to positive particle electrification and all of which resulted in similar values of measured surface charge concentration. The electrification was not seen to be strongly affected by gas composition and is in reasonable agreement with the expected maximum surface charge observed in previous experiments (<0.1 mC/m 2 ). Possible explanations for this effect are discussed, including the possibility of field emission at the contact site. In the future this technique is intended also to be applied to particle-particle induced contact electrification and its material dependence. [ABSTRACT FROM AUTHOR]

ABSTRACT Pathogenic variants in the Wnt‐pathway co‐receptor low‐density lipoprotein (LDL) receptor‐related protein 5 (LRP5) cause high bone mass (LRP5‐HBM) due to insensitivity to the endogenous antagonist of Wnt‐signaling. Although indicating incessant progression of BMD and biomarkers reflecting bone formation, this has not been confirmed in individuals with LRP5‐HBM. We investigated how the LRP5‐HBM bone phenotype changes with age in adults and is associated with quantitative changes of bone turnover markers and bone‐related microRNAs (miRNAs) in the circulation. Whole body, lumbar spine, total hip, and femoral neck areal BMD (aBMD) and radial and tibial bone microarchitecture and geometry were assessed using DXA and HR‐pQCT scans of 15 individuals with LRP5‐HBMT253I (11 women; median age 51 years; range, 19 to 85 years) with a time interval between scans of 5.8 years (range, 4.9 to 7.6 years). Fasting P1NP and CTX were measured in 14 LRP5‐HBMT253I individuals and age‐, sex‐, and body mass index (BMI)‐matched controls, and 187 preselected miRNAs were quantified using qPCR in 12 individuals and age‐, sex‐, and BMI‐matched controls. DXA and HR‐pQCT scans were assessed in subjects who had reached peak bone mass (aged >25 years, n = 12). Femoral neck aBMD decreased by 0.8%/year (p = 0.01) and total hip by 0.3%/year, and radial volumetric BMD (vBMD) increased 0.3%/year (p = 0.03). Differences in bone turnover markers at follow‐up were not observed. Compared to controls, 11 of the 178 detectable miRNAs were downregulated and none upregulated in LRP5‐HBM individuals, and five of the downregulated miRNAs are reported to be involved in Wnt‐signaling. Bone loss at the hip in LRP5‐HBM individuals demonstrates that the bone phenotype does not uniformly progress with age. Differentially expressed miRNAs may reflect changes in the regulation of bone turnover and balance in LRP5‐HBM individuals. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Background: Ménière's disease (MD) is a chronic peripheral vestibular disorder with recurrent episodes of vertigo accompanied by fluctuating hearing loss, tinnitus and aural fullness in the affected ear. There are several unanswered fundamental questions regarding MD, one of these being cortical activity during a MD attack. However, it is not possible to plan an investigation in an episodic disease as MD.Objective: To visualize cortical activity during an attack of MD.Method:18F-FDG PET scans were used to visualize cortical activity in a 62 years old male suffering from definite MD. Two 18F-FDG PET scans were performed. One to show activity during the attack and one to show normal baseline brain activity 7 days after the attack.Results: A number of low-magnitude fluctuations in the 18F-FDG FDG uptake were found in 18F-FDG PET examination following the MD attack compared to the patient's own baseline 18F-FDG FDG scan. Across both hemispheres no significant changes were seen. However, reduced activity was observed in most of the orbitofrontal, frontal cortices as well as Heschl's gyrus and insula.Conclusion: This is the first neuroimaging showing alteration of brain activity during an attack in a patient with MD. No strong focal alterations was seen. It is noteworthy that the decreased activity observed was in the insula and Heschl's gyrus that seems to be core areas for processing information from the labyrinth. It is also of interest that decreased activity rather than hyperactivity was observed.

Introduction: The cortical metabolic activity in patients with Menière's disease has not been investigated. The aim of this study was to investigate the 18F-FDG cerebral uptake in Menière's patients compared to healthy controls.Method: Eight patients with right-sided Menière's disease and fourteen healthy controls underwent a video head impulse test (vHIT), test of utricular function with ocular vestibular evoked myogenic potentials (oVEMP) and three 18F-FDG-based PET examinations of the brain. Participants were seated in a self-propelled chair, injected with 18F-FDG and then exposed to 35 min of chair motion stimulation, followed by a PET scan. Two types of natural vestibular stimuli were applied, predominantly toward the right horizontal semicircular canal (angular acceleration) and right utriculus (linear acceleration). For baseline scans, participants were injected with 18F-FDG while seated without movement.Results: Analyses of baseline scans revealed decreased 18F-FDG-uptake in the medial part of Heschl's gyrus in the left hemisphere in patients with Menière's disease compared to healthy controls. During angular vestibular stimulation there was also a significantly decreased 18F-FDG uptake in the intersection between the medial part of Heschl's gyrus and the parietal operculum in the left hemisphere and bilaterally in the posterior part of insula. During linear stimulation, Menière's patients showed decreased 18F-FDG uptake in the medial part of Heschl's gyrus in the right hemisphere and also bilaterally in the posterior insula. In addition, decreased 18F-FDG uptake was seen in the thalamus during vestibular stimulation.Conclusion: Heschl's gyrus, the posterior part of insula, and thalamus have previously been shown to be core areas for processing vestibular inputs. Patients with Menière's disease solely differed from the healthy controls with lower cortical activity in these areas at baseline and during natural vestibular stimulation.

Summary: Obesity is associated with increased risk for fragility fractures. However, the cellular mechanisms are unknown. Using a translational approach combining RNA sequencing and cellular analyses, we investigated bone marrow stromal stem cells (BM-MSCs) of 54 men divided into lean, overweight, and obese groups on the basis of BMI. Compared with BM-MSCs obtained from lean, obese BM-MSCs exhibited a shift of molecular phenotype toward committed adipocytic progenitors and increased expression of metabolic genes involved in glycolytic and oxidoreductase activity. Interestingly, compared with paired samples of peripheral adipose tissue-derived stromal cells (AT-MSCs), insulin signaling of obese BM-MSCs was enhanced and accompanied by increased abundance of insulin receptor positive (IR+) and leptin receptor positive (LEPR+) cells in BM-MSC cultures. Their hyper-activated metabolic state was accompanied by an accelerated senescence phenotype. Our data provide a plausible explanation for the bone fragility in obesity caused by enhanced insulin signaling leading to accelerated metabolic senescence of BM-MSCs. : Tencerova et al. show that in human obesity, BM-MSCs exhibit a hypermetabolic state defined by upregulation of insulin signaling with enhanced adipogenesis and increased intracellular reactive oxygen species (ROS), leading to a senescence bone microenvironment contributing to bone fragility. Moreover, increased abundance of IR+ and LEPR+ BM-MSCs is characteristic of this phenotype, with an activated metabolic rate in obese subjects. Keywords: obesity, skeletal fragility, bone marrow skeletal stem cells, adipose-derived stem cells, differentiation potential, adipogenesis, insulin signaling

Single‐chain variable fragments (scFv) are widely used in several fields. However, they can be challenging to purify unless using expensive Protein L‐based affinity adsorbents or affinity tags. In this work, a purification process for a scFv using mixed‐mode (MM) chromatography was developed by design of experiments (DoE) and proteomics for host cell protein (HCP) quantification. Capture of scFv from human embryonic kidney 293 (HEK293) cell feedstocks was performed by hydrophobic charge induction chromatography (MEP HyperCel™), whereafter polishing was performed by anion hydrophobic MM chromatography (Capto Adhere™). The DoE designs of the polishing step included both binding and flow‐through modes, the latter being the standard mode for HCP removal. Chromatography with Capto Adhere™ in binding‐mode with elution by linear salt gradient at pH 7.5 resulted in optimal yield, purity and HCP reduction factor of 98.9 > 98.5%, and 14, respectively. Totally, 258 different HCPs were removed, corresponding to 84% of identified HCPs. The optimized conditions enabled binding of the scFv to Capto Adhere™ below its theoretical pI, while the majority of HCPs were in the flow‐through. Surface property maps indicated the presence of hydrophobic patches in close proximity to negatively charged patches that could potentially play a role in this unique selectivity. [ABSTRACT FROM AUTHOR]

A wind tunnel test campaign has been conducted prior to the landing of the Exomars2016 EDM module on the Meridiani Planum on the 19th of October 2016. Test were performed in the Mars wind tunnel facility at Aahrus University (DK) under the 2015 Europlanet Call. The facility was available for a 5 days campaign where different environmental configurations were tested and both a full scale DREAMS (Dust Characterisation, Risk Assessment, and Environment Analyser on the Martian Surface) Metmast model and a Descent Module mockup were studied. In particular the MarsTEM (Mars TEMperature sensor), the temperature sensor of the DREAMS package onboard Exomars2016, was studied for different wind velocities and directions, effect of light sources and presence of dust. The test showed that the sensor response is dependent on wind direction but only slightly on wind velocities. It also seems that the presence of the dust in the wind and the consequent dust deposit on the Metmast and the sensor itself uniforms the response for different wind velocities and directions. Light is also affecting the measurements but it is still not so clear what will be the effect on Mars due to the particular light sources used for the test. [ABSTRACT FROM AUTHOR]

BACKGROUND: Suppression Head Impulse Paradigm (SHIMP), a novel variant of the Head Impulse Test has been introduced. At the same time, the Head Impulse Test was renamed to the Head Impulse Paradigm (HIMP). Contrary to HIMP saccades, SHIMP saccades are a sign of vestibular function. OBJECTIVE: 1) To compare SHIMP and HIMP feasibility, vestibular-ocular reflex (VOR) gain value and the saccadic pattern in healthy adolescents. 2) To compare SHIMP and HIMP feasibility in the hands of an experienced and an inexperienced HIMP examiner. METHOD: A total of 29 adolescents from Skåde Municipal School, Denmark were tested with HIMP and then with SHIMP. RESULTS: Neither covert nor overt saccades were observed in the HIMP, whereas SHIMP saccades were observed in all SHIMP reports. SHIMP gain values were statistically lower than HIMP gain values. A statistically significant difference was observed between the two examiners' right SHIMP gain values, but not for the left SHIMP gain values or the HIMP gain values. CONCLUSIONS: We found that HIMP and SHIMP tests are feasible in healthy adolescents for experienced as well as inexperienced examiners. However, one must be aware of potential pitfalls in the execution and interpretation of both tests. This is a well-known fact for the HIMP test, but additional considerations are needed to obtain reliable results from the SHIMP test. [ABSTRACT FROM AUTHOR]

Objective. The purpose of this study was to evaluate whether elderly patients with vestibular dysfunction are able to preserve physical functional level, reduction in dizziness, and the patient’s quality of life when assistive computer technology is used in comparison with printed instructions. Materials and Methods. Single-blind, randomized, controlled follow-up study. Fifty-seven elderly patients with chronic dizziness were randomly assigned to a computer-assisted home exercise program or to home exercises as described in printed instructions and followed for tree month after discharge from an outpatient clinic. Results. Both groups had maintained their high functional levels three months after finishing the outpatient rehabilitation. No statistically significant difference was found in outcome scores between the two groups. In spite of moderate compliance levels, the patients maintained their high functional level indicating that the elderly should not necessarily exercise for the first three months after termination of the training in the outpatient clinic. Conclusion. Elderly vestibular dysfunction patients exercising at home seem to maintain their functional level, level of dizziness, and quality of life three months following discharge from hospital. In this specific setup, no greater effect was found by introducing a computer-assisted training program, when compared to standard home training guided by printed instructions. This trial is registered with NCT01344408.

Monoclonal antibody (mAb) based affinity resins usually suffer from low binding capacity, most probably as a result of steric hindrance by the large 150 kDa size of the mAb and a random immobilisation approach. The present work investigates the influence of a variety of factors on dynamic binding capacity (DBC) such as pore/ligand size ratio, accessibility of ligand and ligand density. The effect of pore/ligand size ratio was investigated using Fab and scFv fragments on various resins with different pore sizes. The accessibility of the ligand was investigated by a site-directed immobilisation approach, where three C-terminal tags, PPKPPK, FLAG™ and Cys, were introduced into the Fab fragments for immobilisation on resins via amino-, carboxyl- and thiol-groups, respectively. The scFv fragments were tagged at the C-terminal only with FLAG™ to enable a straight forward purification procedure, and were immobilised to resins via amino- and carboxyl-groups. The target protein had a molecular weight (MW) of 50 kDa. A 3-fold higher dynamic binding capacity at 100% breakthrough (DBC 100% ) was observed for Fab wild-type (wt) on CNBr-activated Sepharose 4 FF relative to mAb on same resin at the same ligand density. However, no major difference in DBC 100% was observed between Fab wt and scFv immobilised on CNBr-activated Sepharose 4 FF at the same ligand density. Thus, further increase of pore/ligand size ratio from Fab to scFv on a resin with average pore size of 300 Å, did not seem to be beneficial. Among the tested tags, only the C-terminal Cys tag proved to site-direct the ligands during immobilisation as it allowed the DBC 100% to increase 1.6-fold as compared to Fab wt immobilised via amino-groups on CNBr-activated Sepharose 4 FF and Actigel ALD Superflow at the same ligand density. The influence of ligand density was investigated by selecting immobilised Fab Cys on Sulfhydryl-reactive resin. Increasing ligand density from 0.103 to 0.202 μmol/mL resulted in the same utilisation yield (82–85%), whereas a further increase in ligand density from 0.202 to 0.328 μmol/mL resulted in a 20%-unit decrease in utilisation yield and less steep breakthrough curve, suggesting steric hindrance in the pores of the resin. In addition, site-directed affinity ligands resulted in a more pronounced, sigmoid-shaped breakthrough curve, leading to more efficient use of capacity. The highest DBC 100% was obtained for Fab Cys on Sulfhydryl-reactive resin and scFv on Actigel ALD Superflow; 11 mg/mL and 10 mg/mL, respectively, as compared to the DBC 100% of 0.8 mg/mL for mAb on CNBr-activated Sepharose 4 FF. Pore/ligand size ratio of 3, which was achieved for Fab ligands on the studied resins, was shown to be feasible for capturing a protein in MW of 50 kDa. Totally, a 13.8-fold improvement in DBC 100% was achieved with the Fab-based affinity resin coupled via the C-terminal Cys as compared to the mAb-based affinity resin. [ABSTRACT FROM AUTHOR]

Background: The regulation of factor X (FX) is critical to maintain the balance between blood coagulation and fluidity., Objectives: To functionally characterize the role of the FX autolysis loop in the regulation of the zymogen and active form of FX., Methods: We introduced novel N-linked glycosylations on the surface-exposed loop spanning residues 143-150 (chymotrypsin numbering) of FX. The activity and inhibition of recombinant FX variants was quantified in pure component assays. The in vitro thrombin generation potential of the FX variants was evaluated in FX-depleted plasma., Results: The factor VIIa (FVIIa)-mediated activation and prothrombin activation was reduced, presumably through steric hinderance. Prothrombin activation was, however, recovered in presence of cofactor factor Va (FVa) despite a reduced prothrombinase assembly. The introduced N-glycans exhibited position-specific effects on the interaction with two FXa inhibitors: tissue factor pathway inhibitor (TFPI) and antithrombin (ATIII). K i for the inhibition by full-length TFPI of these FXa variants was increased by 7- to 1150-fold, whereas ATIII inhibition in the presence of the heparin-analog Fondaparinux was modestly increased by 2- to 15-fold compared with wild-type. When supplemented in zymogen form, the FX variants exhibited reduced thrombin generation activity relative to wild-type FX, whereas enhanced procoagulant activity was measured for activated FXa variants., Conclusion: The autolysis loop participates in all aspects of FX regulation. In plasma-based assays, a modest decrease in FX activation rate appeared to knock down the procoagulant response even when down regulation of FXa activity by inhibitors was reduced., (© 2021 International Society on Thrombosis and Haemostasis.)

Pathogenic variants in the Wnt-pathway co-receptor low-density lipoprotein (LDL) receptor-related protein 5 (LRP5) cause high bone mass (LRP5-HBM) due to insensitivity to the endogenous antagonist of Wnt-signaling. Although indicating incessant progression of BMD and biomarkers reflecting bone formation, this has not been confirmed in individuals with LRP5-HBM. We investigated how the LRP5-HBM bone phenotype changes with age in adults and is associated with quantitative changes of bone turnover markers and bone-related microRNAs (miRNAs) in the circulation. Whole body, lumbar spine, total hip, and femoral neck areal BMD (aBMD) and radial and tibial bone microarchitecture and geometry were assessed using DXA and HR-pQCT scans of 15 individuals with LRP5-HBM T253I (11 women; median age 51 years; range, 19 to 85 years) with a time interval between scans of 5.8 years (range, 4.9 to 7.6 years). Fasting P1NP and CTX were measured in 14 LRP5-HBM T253I individuals and age-, sex-, and body mass index (BMI)-matched controls, and 187 preselected miRNAs were quantified using qPCR in 12 individuals and age-, sex-, and BMI-matched controls. DXA and HR-pQCT scans were assessed in subjects who had reached peak bone mass (aged >25 years, n  = 12). Femoral neck aBMD decreased by 0.8%/year ( p  = 0.01) and total hip by 0.3%/year, and radial volumetric BMD (vBMD) increased 0.3%/year ( p  = 0.03). Differences in bone turnover markers at follow-up were not observed. Compared to controls, 11 of the 178 detectable miRNAs were downregulated and none upregulated in LRP5-HBM individuals, and five of the downregulated miRNAs are reported to be involved in Wnt-signaling. Bone loss at the hip in LRP5-HBM individuals demonstrates that the bone phenotype does not uniformly progress with age. Differentially expressed miRNAs may reflect changes in the regulation of bone turnover and balance in LRP5-HBM individuals. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research., Competing Interests: MH and MW report personal fees from TAmiRNA GmbH, outside the submitted work. RE reports grants from Amgen, grants and personal fees from IDS, grants from Alexion, grants and personal fees from Roche, personal fees from GSK Nutrition, personal fees from Mereo, personal fees from Sandoz, grants and personal fees from Nittobo, personal fees from AbbVie, personal fees from Samsung, personal fees from Haoma Medica, personal fees from Elsevier, personal fees from CL Bio, personal fees from FNIH, personal fees from Viking, personal fees from UCSF, personal fees from Biocon, from Lyramid, outside the submitted work., (© 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.)

Aeolian sediment transport is observed to occur on Mars as well as other extraterrestrial environments, generating ripples and dunes as on Earth. The search for terrestrial analogs of planetary bedforms, as well as environmental simulation experiments able to reproduce their formation in planetary conditions, are powerful ways to question our understanding of geomorphological processes toward unusual environmental conditions. Here, we perform sediment transport laboratory experiments in a closed-circuit wind tunnel placed in a vacuum chamber and operated at extremely low pressures to show that Martian conditions belong to a previously unexplored saltation regime. The threshold wind speed required to initiate saltation is only quantitatively predicted by state-of-the art models up to a density ratio between grain and air of [Formula: see text] but unexpectedly falls to much lower values for higher density ratios. In contrast, impact ripples, whose emergence is continuously observed on the granular bed over the whole pressure range investigated, display a characteristic wavelength and propagation velocity essentially independent of pressure. A comparison of these findings with existing models suggests that sediment transport at low Reynolds number but high grain-to-fluid density ratio may be dominated by collective effects associated with grain inertia in the granular collisional layer., Competing Interests: The authors declare no competing interest.

Background: Early Warning Score systems are used to monitor patients at risk of deterioration. How comorbidities impact Early Warning Score's ability to predict short-term mortality in the emergency department is not fully elucidated. The aim of the study was to investigate how comorbidities impact Early Warning Score as predictor of 7-day mortality., Methods: This is an observational cohort study of adult emergency department patients attending one of the five emergency departments in Central Region Denmark from 1 March 2015 to 31 May 2015. Charlson Comorbidity Index was used as a measure of comorbidities. Logistic regression was used to calculate the odds ratio for 7-day mortality. Patients were compared in three groups: Charlson Comorbidity Index: 0, 1-2, 3+., Results: A total of 30 060 adult patients attended one of the five emergency departments. Nineteen thousand one hundred twenty-three patients were included. Charlson Comorbidity Index 3+ patients presenting with Early Warning Score 0, 1-2 or 3-4 had significantly higher odds ratio of 7-day mortality compared to Charlson Comorbidity Index 0 patients with equal Early Warning Score. For patients with Early Warning Score 5+, Charlson Comorbidity Index -status had no significant impact on 7-day mortality after adjusting for age., Conclusion: In patients presenting with lower acuity (Early Warning Score 0-4) Charlson Comorbidity Index has a significant impact on 7-day mortality regardless of Early Warning Score. Including Charlson Comorbidity Index status in Early Warning Score or adjusting for Charlson Comorbidity Index -status could increase the predictive value of Early Warning Score in predicting 7-day mortality.

Introduction: The cortical metabolic activity in patients with Menière's disease has not been investigated. The aim of this study was to investigate the 18 F-FDG cerebral uptake in Menière's patients compared to healthy controls. Method: Eight patients with right-sided Menière's disease and fourteen healthy controls underwent a video head impulse test (vHIT), test of utricular function with ocular vestibular evoked myogenic potentials (oVEMP) and three 18 F-FDG-based PET examinations of the brain. Participants were seated in a self-propelled chair, injected with 18 F-FDG and then exposed to 35 min of chair motion stimulation, followed by a PET scan. Two types of natural vestibular stimuli were applied, predominantly toward the right horizontal semicircular canal (angular acceleration) and right utriculus (linear acceleration). For baseline scans, participants were injected with 18 F-FDG while seated without movement. Results: Analyses of baseline scans revealed decreased 18 F-FDG-uptake in the medial part of Heschl's gyrus in the left hemisphere in patients with Menière's disease compared to healthy controls. During angular vestibular stimulation there was also a significantly decreased 18 F-FDG uptake in the intersection between the medial part of Heschl's gyrus and the parietal operculum in the left hemisphere and bilaterally in the posterior part of insula. During linear stimulation, Menière's patients showed decreased 18 F-FDG uptake in the medial part of Heschl's gyrus in the right hemisphere and also bilaterally in the posterior insula. In addition, decreased 18 F-FDG uptake was seen in the thalamus during vestibular stimulation. Conclusion: Heschl's gyrus, the posterior part of insula, and thalamus have previously been shown to be core areas for processing vestibular inputs. Patients with Menière's disease solely differed from the healthy controls with lower cortical activity in these areas at baseline and during natural vestibular stimulation., (Copyright © 2020 Devantier, Hansen, Mølby-Henriksen, Christensen, Lildal, Pedersen, Magnusson, Borghammer and Ovesen.)

Aggregation can be a major challenge in the development of antibody-based pharmaceuticals as it can compromise the quality of the product during bioprocessing, formulation, and drug administration. To avoid aggregation, developability assessment is often run in parallel with functional optimization in the early screening phases to flag and deselect problematic molecules. As developability assessment can be demanding with regard to time and resources, there is a high focus on the development of molecule design strategies for engineering molecules with a high developability potential. Previously, Dudgeon et al. [(2012) Proc. Natl. Acad. Sci. U. S. A. 109, 10879-10884] demonstrated how Asp substitutions at specific positions in human variable domains and single-chain variable fragments could decrease the aggregation propensity. Here, we have investigated whether these Asp substitutions would improve the developability potential of a murine antigen binding fragment (Fab). A full combinatorial library consisting of 393 Fab variants with single, double, and triple Asp substitutions was first screened in silico with Rosetta; thereafter, 26 variants with the highest predicted thermodynamic stability were selected for production. All variants were subjected to a set of developability studies. Interestingly, most variants had thermodynamic stability on par with or improved relative to that of the wild type. Twenty-five of the variants exhibited improved nonspecificity. Half of the variants exhibited improved aggregation resistance. Strikingly, while we observed remarkable improvement in the developability potential, the Asp substitutions had no substantial effect on the antigenic binding affinity. Altogether, by combining the insertion of negative charges and the in silico screen based on computational models, we were able to improve the developability of the Fab rapidly.

Introduction: Recent studies implicate the presence of Fusobacterium necrophorum (FN) in recurrent tonsillitis (RT), acute tonsillitis and peritonsillar abscess. The objective of the present study was to determine whether FN plays a role in RT by comparing bacteriologic results from patients suffering from RT, tonsillar hypertrophy and halitosis or persistent sore throat syndrome (PSTS). We analyzed both tonsils to determine the degree of concordance., Material and Methods: A prospective study was conducted in 80 patients aged 8-30 years who were undergoing elective tonsillectomy. The patients were divided into four groups according to indication for surgery. Aerobic and anaerobic cultures from the tonsillar surface and core were analyzed., Results: FN was detected less frequently in the tonsillar cores of RT patients (22%) than in those of patients without RT (30%) (p=0.44). FN detection frequencies ranged between 20% and 35% across the four groups. Betahaemolytic streptococci groups A/C/G (BHS) were detected significantly (p=0.007) more often in the RT group than in the halitosis/PSTS group., Conclusion: A possible role of FN in RT was not substantiated. Our results indicate that FN is likely to be part of the normal flora. The tonsillar surface and core flora carry considerable interpersonal diversity, but is very similar bilaterally in each individual. Other factors seem to play a major role in the development of the represented tonsillar diseases., Funding: Not relevant., Trial Registration: The study was approved by The Research Ethics Committee of Aarhus County (no. 20050034).

Background and Objective: We have developed an expert computer system for the control of oral anticoagulation therapy, accessible by the patients via their own computer. To investigate if the weekly measurement and dosing of international normalized ratio (INR) at home using the online Internet-based system was superior to conventional treatment, we performed a randomized, controlled trial., Patients and Methods: All 669 patients in our anticoagulation clinic were asked to participate in the trial, providing that they had Internet access and could use the CoaguChek XS system. A total of 140 patients were included and randomized to (A) once weekly measurement and report online, (B) twice weekly measurement and report online, and (C) continued conventional treatment with INR measurement in the lab every 4 weeks and dose adjustment by letter., Results: Group A had 79.7% (95% CI 79.0-80.3) of time in therapeutic range (TTR), group B 80.2% (95% CI 79.4-80.9) of TTR, and group C 72.7% (95% CI 71.9-73.4) TTR. Groups A and B perform statistically significantly better than the conventional group C, with a difference of TTR of 7% points (p < 2.2 × 10(-16)), whereas no difference was seen between A and B., Conclusion: Home measurement of INR and the reporting and dosing of results online once a week increase TTR from 72% to 79% as compared to conventional computer-assisted monitoring in an anticoagulation clinic.

Objective: The inflammatory biomarker YKL-40 is elevated and associated with mortality in patients with stable coronary artery disease (CAD). The aim was to investigate the influence of statin treatment and lipid status on serum YKL-40 and Hs-CRP in patients with stable CAD., Design: Serum YKL-40, HsCRP, total cholesterol, HDL-c, LDL-c and triglycerides levels were measured in 404 statin treated and in 404 matched non-statin treated patients with stable CAD., Results: YKL-40 was significantly higher in non-statin treated 110 µg/l (median) compared with 65 µg/l in statin treated (p < 0.001). HsCRP was 3.3 mg/l in non-statin treated compared with 2.1 mg/l in statin treated (p < 0.001). YKL-40 was not related to cholesterol levels for either statin or non-statin treated patients in the univariate analysis. In statin treated patients, HsCRP was related to a high level of total-cholesterol (p = 0.01) and a low level of HDL-c (p < 0.001)., Conclusions: HsCRP, but not YKL-40, is associated with the cholesterol levels in statin treated patients. This indicates that YKL-40 could be a superior prognostic biomarker in patients with stable CAD, since it is independent of changes in cholesterol levels in both statin and non-statin treated patients.

Molecular chaperones assist protein folding, and variations in their encoding genes may be disease-causing in themselves or influence the phenotypic expression of disease-associated or susceptibility-conferring variations in many different genes. We have screened three candidate patient groups for variations in the HSPD1 and HSPE1 genes encoding the mitochondrial Hsp60/Hsp10 chaperone complex: two patients with multiple mitochondrial enzyme deficiency, 61 sudden infant death syndrome cases (MIM: #272120), and 60 patients presenting with ethylmalonic aciduria carrying non-synonymous susceptibility variations in the ACADS gene (MIM: *606885 and #201470). Besides previously reported variations we detected six novel variations: two in the bidirectional promoter region, and one synonymous and three non-synonymous variations in the HSPD1 coding region. One of the non-synonymous variations was polymorphic in patient and control samples, and the rare variations were each only found in single patients and absent in 100 control chromosomes. Functional investigation of the effects of the variations in the promoter region and the non-synonymous variations in the coding region indicated that none of them had a significant impact. Taken together, our data argue against the notion that the chaperonin genes play a major role in the investigated diseases. However, the described variations may represent genetic modifiers with subtle effects.