Uncertainty and the ranking of economics journals

Scientometrics - Journal rankings often show significant changes compared to previous rankings. This gives rise to the question of how well estimated the rank of a journal is. In this contribution,...     

Preclinical Evaluation of 99mTc-ZHER2:41071, a Second-Generation Affibody-Based HER2-Visualizing Imaging Probe with a Low Renal Uptake

Radionuclide imaging of HER2 expression in tumours may enable stratification of patients with breast, ovarian, and gastroesophageal cancers for HER2-targeting therapies. A first-generation HER2-binding affibody molecule [^99mTc]Tc-ZHER2:V2 demonstrated favorable imaging properties in preclinical studies. Thereafter, the affibody scaffold has been extensively modified, which increased its melting point, improved storage stability, and increased hydrophilicity of the surface. In this study, a second-generation affibody molecule (designated ZHER2:41071) with a new improved scaffold has been prepared and characterized. HER2-binding, biodistribution, and tumour-targeting properties of [^99mTc]Tc-labelled ZHER2:41071 were investigated. These properties were compared with properties of the first-generation affibody molecules, [^99mTc]Tc-ZHER2:V2 and [^99mTc]Tc-ZHER2:2395. [^99mTc]Tc-ZHER2:41071 bound specifically to HER2 expressing cells with an affinity of 58 ± 2 pM. The renal uptake for [^99mTc]Tc-ZHER2:41071 and [^99mTc]Tc-ZHER2:V2 was 25–30 fold lower when compared with [^99mTc]Tc-ZHER2:2395. The uptake in tumour and kidney for [^99mTc]Tc-ZHER2:41071 and [^99mTc]Tc-ZHER2:V2 in SKOV-3 xenografts was similar. In conclusion, an extensive re-engineering of the scaffold did not compromise imaging properties of the affibody molecule labelled with ^99mTc using a GGGC chelator. The new probe, [^99mTc]Tc-ZHER2:41071 provided the best tumour-to-blood ratio compared to HER2-imaging probes for single photon emission computed tomography (SPECT) described in the literature so far. [^99mTc]Tc-ZHER2:41071 is a promising candidate for further clinical translation studies.     

Distributed dynamic load balancing with applications in radio access networks

Managing and balancing load in distributed systems remains a challenging problem in resource management, especially in networked systems where scalability concerns favour distributed and dynamic approaches. Distributed methods can also integrate well with centralised control paradigms if they provide high‐level usage statistics and control interfaces for supporting and deploying centralised policy decisions. We present a general method to compute target values for an arbitrary metric on the local system state and show that autonomous rebalancing actions based on the target values can be used to reliably and robustly improve the balance for metrics based on probabilistic risk estimates. To balance the trade‐off between balancing efficiency and cost, we introduce 2 methods of deriving rebalancing actuations from the computed targets that depend on parameters that directly affects the trade‐off. This enables policy level control of the distributed mechanism based on collected metric statistics from network elements. Evaluation results based on cellular radio access network simulations indicate that load balancing based on probabilistic overload risk metrics provides more robust balancing solutions with fewer handovers compared to a baseline setting based on average load.     

The Critical Role of Passive Permeability in Designing Successful Drugs

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.     

Double Mutant Cycles as a Tool to Address Folding,Binding, and Allostery

Quantitative measurement of intramolecular and intermolecular interactions in protein structure is an elusive task, not easy to address experimentally. The phenomenon denoted ‘energetic coupling’ describes short- and long-range interactions between two residues in a protein system. A powerful method to identify and quantitatively characterize long-range interactions and allosteric networks in proteins or protein–ligand complexes is called double-mutant cycles analysis. In this review we describe the thermodynamic principles and basic equations that underlie the double mutant cycle methodology, its fields of application and latest employments, and caveats and pitfalls that the experimentalists must consider. In particular, we show how double mutant cycles can be a powerful tool to investigate allosteric mechanisms in protein binding reactions as well as elusive states in protein folding pathways.     

Effect of additives on the melt rheology and thermal degradation of poly[(R)‐3‐hydroxybutyric acid]

Thermal degradation of poly[(R)−3‐hydroxybutyric acid] (PHB) during melt mixing results in random chain scission that produces shorter polymer chains containing crotonic and carboxyl end groups. One way of preventing this serious reduction of molar mass is to add agents that react with at least two of the newly generated end groups. Different types of commercially available additives known to react with carboxyl group, namely bis(3,4‐epoxycyclohexylmethyl) adipate (BECMA), 2,2'‐bis(2‐oxazoline) (BOX), trimethylolpropane tris(2‐methyl‐1‐aziridinepropionate) (PETAP), triphenyl phosphate (TPP), tris(nonylphenyl) phosphate (TNPP), polycarbodiimide (PCDI), and poly(methyl metharylate‐co‐glycidyl methacrylate) (GMA.MMA) were mixed with PHB by cocasting from solution in chloroform. Dynamic rheology as well as measurements of molar masses before and after dynamic analysis was used to evaluate the effect of the additives on the melt stability of PHB. Measurements of the dynamic shear modulus and the molar mass of molten PHB with the additives PCDI and GMA.MMA showed a minor improvement on the thermal stability. Furthermore, TPP and TNPP did not affect the thermal stability of PHB, whereas the presence of BECMA, BOX, and PETAP gave a strong decrease of the dynamic modulus compared with neat PHB. © 2014 The Authors Journal of Applied Polymer Science Published by Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41836.     

Detecting Premature Ventricular Contraction by Using Regulated Discriminant Analysis with Very Sparse Training Data

Pathological electrocardiogram is often used to diagnose abnormal cardiac disorders where accurate classification of the cardiac beat types is crucial for timely diagnosis of dangerous conditions. However, accurate, timely, and precise detection of arrhythmia-types like premature ventricular contraction is very challenging as these signals are multiform, i.e. a reliable detection of these requires expert annotations.

In this paper, a multivariate statistical classifier that is able to detect premature ventricular contraction beats is presented. This novel classifier can be trained with a very sparse amount of expert annotated data. To enable this, the dimensionality of the feature vector is kept very low, it uses strong designed features and a regularization mechanism. This approach is compared to other classifiers by using the MIT-BIH arrhythmia database. It has been found that the average accuracy, specificity, and sensitivity are above 96%, which is superior given the sparse amount of training data.     

Hydrodynamic control of nitrogen and phosphorus turnover in an eutrophicated estuary in the Baltic

The turnover of phosphorus and nitrogen have been studied in a low salinity estuary in the Bothnian Sea. The estuary, G?rdsfj?rden, has a high loading of nutrients from a pulp and paper mill which supplies the estuary with three times the annual natural input of phosphorus and nitrogen, respectively. The turnover of nutrients was to a great extent determined by hydrodynamic variations. During periods of intense resuspension there was a net export of particulate bound nutrients from the estuary to the sea but since these periods were short there was an overall net retention of particulate nutrients. The estuary was a source for dissolved phosphorus to the sea. The major source of phosphorus export was release of dissolved P from anoxic sediments. G?rdsfj?rden was a sink for dissolved nitrogen which most likely escaped the estuary by denitrification. Nitrate was supplied by degradation of particulate organic nitroge'n but the main source was import from the sea.     

Flocculation of activated sludge flocs by stimulation of the aerobic biological activity

Activated sludge flocs are known to deflocculate under short-term anaerobic conditions, but little is known about possible reflocculation under subsequent aerobic conditions. When activated sludge flocs from two wastewater treatment plants deflocculated under anaerobic conditions with well-defined shear conditions, they could be almost, but not completely, reflocculated by aeration for 1-2 h under the same shear conditions. If the biological activity was reduced by adding azide, chloramphenicol or by decreasing the temperature, no or only very little reflocculation took place. This indicated that the reflocculation was under direct or indirect microbial control. Only a small part of the reflocculation was due to improved flocculation properties obtained by oxidation of Fe(II) to Fe(III), which is a better flocculant. Fe(II) was produced under the anaerobic conditions by microbial iron reduction, and it was oxidized to Fe(III) within less than one hour after the aeration was started. However, by comparing two different sludges with different capabilities for iron reduction, iron oxidation and responses to substrate addition, it was found that the aerobic biological activity most likely was of greatest significance for the observed reflocculation and floc formation under aerobic conditions. This was further supported by adding organic substrates (glucose or ethanol) during the aerobic reflocculation phase, which promoted reflocculation. However, some substrates had the opposite effect (acetate and lactate), where a deterioration of the reflocculation was observed, probably due to different responses from different groups of microorganisms in the sludges.     

Gravity drainage of activated sludge: new experimental method and considerations of settling velocity, specific cake resistance and cake compressibility

A laboratory scale setup was used for characterization of gravitational drainage of waste activated sludge. The aim of the study was to assess how time of drainage and cake dry matter depended on volumetric load, SS content and sludge floc properties. It was demonstrated that activated sludge forms compressible cakes, even at the low pressures found in gravitational drainage. The values of specific cake resistance were two to three orders of magnitude lower than those obtained in pressure filtration. Despite the compressible nature of sludge, key macroscopic parameters such as time of drainage and cake solid content showed simple functional dependency of the volumetric load and SS of a given sludge. This suggests that the proposed method may be applied for design purposes without the use of extensive numerical modeling. The possibilities for application of this new technique are, among others, the estimation of sludge drainability prior to mechanical dewatering on a belt filter, or the application of surplus sludge on reed beds, as well as adjustments of sludge loading, concentration or sludge pre-treatment in order to optimize the drainage process.