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Over two decades, epidemiological studies have revealed that interactions between human polymorphic apolipoprotein 4 (ApoE, isoform 4) and herpes simplex virus type 1 (HSV1) associate with higher risk of Alzheimer’s disease, a serious and increasing issue among elder populations worldwide. Nevertheless, little is known about the mechanisms behind ApoE-HSV1 interactions at molecular levels. Here, we investigate the effects of ApoE on the HSV1 infectious life cycle in in vitro cell experiments. Analysis of HSV1 growth curves shows that HSV1 production is promoted in presence of any of the three ApoE isoforms, with ApoE 3or 4 demonstrating more efficient pro-viral effects than ApoE 2. When added prior to infection, ApoE inhibits viral attachment but does not affect viral entry. qPCR-based quantification reveals that harbouring ApoE 2, 3, or 4 leads to an increase of HSV1 extracellular release but unchanged levels of viral genome copies within cells or on the cell surface, indicating that virus replication, assembly, or transport to cell membrane are not affected. Further test of virus release directly demonstrates that HSV1 detachment from the cell surface is promoted by ApoE. Subsequent results reveal that ApoE is not only present in purified HSV1 particles produced in ApoE-expressing cells after ultra-centrifugation but also able to incorporate into HSV1 particles after purification, suggesting that harbouring ApoE may promote HSV1 detachment. With the help of total internal reflection microscopy (TIRFM), this hypothesis was tested by quantifying interaction kinetics and apparent affinity between of HSV1 and native supported lipid bilayer. HSV1 particle decorated with ApoE demonstrates higher dissociation rate constants (koff) and less irreversible binding to the membrane, which is in line with the promoted virus release. Similar interaction kinetics have also been tested between non-decorated HSV1 particles and membranes harbouring ApoE but revealed no difference in the kinetics of virus particles on membranes with ApoE present or absent. Overall, our results provide new insights into the roles of ApoE during HSV1 infections, which is worth to be considered when studying their involvement during AD development.

Reaction of thiazoline fused 2-pyridones with alkyl halides in the presence of cesium carbonate opens the thiazoline ring via S-alkylation and generates N-alkenyl functionalized 2-pyridones. In the reaction with propargyl bromide, the thiazoline ring opens and subsequently closes via a [2 + 2] cycloaddition between an in situ generated allene and the α,β-unsaturated methyl ester. This method enabled the synthesis of a variety of cyclobutane fused thiazolino-2-pyridones, of which a few analogues inhibit amyloid β1–40 fibril formation. Furthermore, other analogues were able to bind mature α-synuclein and amyloid β1−40 fibrils. Several thiazoline fused 2-pyridones with biological activity tolerate this transformation, which in addition provides an exocyclic alkene as a potential handle for tuning bioactivity.

The aim of the thesis is to cast light on the earliest settlement of northern Sweden. The starting point is lithic artifacts, which have been studied from a technological as well as a more conventional typological perspective (Papers I, II, and IV). Paper III deals primarily with geological and palaeoecological methods and my contribution is mainly confined to the lithic artifacts. The main research objectives are concerned with early postglacial colonization and cultural affiliation mirrored through technological traditions. Another “main thread” is a source-critical discussion regarding dating problems, and the chronological integrity of find contexts. The chronological position of artifact types in the North Swedish Mesolithic is another related problem being discussed.The geographical area under investigation comprises northern Sweden sensu largo: Norrland plus the provinces of Varmland and Dalarna. The time period studied is the Mesolithic, with an emphasis on the earliest part, ca. 8500–7500 BP.Paper I discusses the Mesolithic in the province of Varmland. There are traits indicating both an affiliation with the Lihult/Nostvet sphere (for example, Lihult axes and saws/knives of sandstone) as well as other features more common in an eastern/northern context (quartz use, bipolar reduction, and, at least for the final Mesolithic and Neolithic, slate artifacts).Paper II aims at elucidating microblade technology in northern Sweden as regards chronological position and cultural context. It was found that microblade production from handle cores (also called wedge-shaped cores) was introduced at about the same time in northern Sweden as in other areas of Scandinavia where these artifacts occur, ca. 8000–7500 BP. The handle core tradition continued until ca. 5500/5000 BP.Paper III deals with lake-tilting caused by non-uniform glacio-isostatic uplift. This phenomenon has been used to identify potential areas of Mesolithic occupation in the Arjeplog area, Lapland. Surveys and excavations within the research project "Man, Fire, and Landscape", have significantly increased the number of Mesolithic sites in the area. The investigations have resulted in the discovery of the oldest firmly dated archaeological site in northern Sweden, Dumpokjauratj, in Arjeplog parish, Lapland, with a maximum date of 8630 ± 85 BP.Paper IV discusses the pioneering phase of occupation in northern Sweden, in the light of the above-mentioned site of Dumpokjauratj and a site at Garaselet in northern Vasterbotten. These are further compared with contemporary sites in surrounding areas of Fennoscandia. The majority of the assemblages are dominated by platform reduction, even if bipolar reduction also occurs at the earliest sites. Slate artifacts found at Dumpokjauratj suggest connections with the Finnish Mesolithic, which is the only cultural context in our region with documented slate use at this early point in time. But there are also traits that do not specifically point towards Finland, e.g. frequent use of fine-grained flint-like materials and porphyry, and (at Dumpokjauratj) a lanceolate microlith made of a microblade of this fine-grained igneous rock. The latter suggests associations with the Scandinavian Mesolithic in general.In any event, the early dates from Dumpokjauratj show that interior Lapland was occupied soon after deglaciation, probably within a few hundred years.

A BF3×OEt2 catalyzed intramolecular Povarov reaction was used to synthesize a library of 15 chromenopyridine fused thiazolino-2-pyridone peptidomimetics. The reaction works with a range of O-alkylated salicylaldehydes and amino functionalized thiazolino-2-pyridones, to generate polyheterocycles with diverse substitution. The synthesized compounds were screened for their ability to bind α-synuclein and amyloid β fibrils in vitro. Analogs substituted with a nitro group bind to mature amyloid fibrils, and the activity moreover depends on the positioning of this functional group. Previously included in thesis in manuscript form.

Amyloid formation is a pathological process associated with a wide range of degenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and diabetes mellitus type 2. During disease progression, abnormal accumulation and deposition of proteinaceous material are accompanied by tissue degradation, inflammation, and dysfunction. Agents that can interfere with the process of amyloid formation or target already formed amyloid assemblies are consequently of therapeutic interest. In this context, a few endogenous proteins have been associated with an anti-amyloidogenic activity. Here, we review the properties of transthyretin, apolipoprotein E, clusterin, and BRICHOS protein domain which all effectively interfere with amyloid in vitro, as well as displaying a clinical impact in humans or animal models. Their involvement in the amyloid formation process is discussed, which may aid and inspire new strategies for therapeutic interventions.

We herein present the synthesis of diversely functionalized pyrimidine fused thiazolino-2-pyridones

European Union policies emphasise the importance of entrepreneurship and self-employment to maintain economic growth, a solution influenced by the USA and research from schools of business. There are expectations of higher education graduates that they are innovative, will start businesses and will employ others. However, transferring a solution from one country to another may not be as simple as that. This study questions the recommendations made in EU policies which mainly focus on how to support individuals to become self-employed. Extensive data from the Swedish population registry of approximately 90,000 tertiary-educated people, all born in the mid-1970s, is used to analyse the extent to which this group became self-employed. Results show that societal and cultural differences need to be considered when creating such policies.

We study membership in Lipschitz classes Λβ(D) for a class of α-harmonic functions in the open unit disc D in the complex plane. From earlier work by Olofsson and Wittsten we know that such an α-ha...

We here describe the use of three-component reactions to synthesize tricyclic pyridine ring-fused 2-pyridones. The developed protocols have a wide substrate scope and allow for the installation of ...

We consider a class of generalized harmonic functions in the open unit disc in the complex plane. Our main results concern a canonical series expansion for such functions. Of particular interest is a certain individual generalized harmonic function which suitably normalized plays the role of an associated Poisson kernel.

Amyloid-formation by the islet amyloid polypeptide (IAPP), produced by the β-cells in the human pancreas, has been associated with the development of type II diabetes mellitus (T2DM). The human plasma-protein transthyretin (TTR), a well-known amyloid-inhibiting protein, is interestingly also expressed within the IAPP producing β-cells. In the present study, we have characterized the ability of TTR to interfere with IAPP amyloid-formation, both in terms of its intrinsic stability as well as with regard to the effect of TTR-stabilizing drugs. The results show that TTR can prolong the lag-phase as well as impair elongation in the course of IAPP-amyloid formation. We also show that the interfering ability correlates inversely with the thermodynamic stability of TTR, while no such correlation was observed as a function of kinetic stability. Furthermore, we demonstrate that the ability of TTR to interfere is maintained also at the low pH environment within the IAPP-containing granules of the pancreatic β-cells. However, at both neutral and low pH, the addition of TTR-stabilizing drugs partly impaired its efficacy. Taken together, these results expose mechanisms of TTR-mediated inhibition of IAPP amyloid-formation and highlights a potential therapeutic target to prevent the onset of T2DM.

We herein present the synthesis of diversely functionalized pyrimidine fused thiazolino-2-pyridones via K2S2O8-mediated oxidative coupling of 6-amino-7-(aminomethyl)-thiazolino-2-pyridones with aldehydes. The developed protocol is mild, has wide substrate scope, and does not require transition metal catalyst or base. Some of the synthesized compounds have an ability to inhibit the formation of Amyloid-β fibrils associated with Alzheimer's disease, while others bind to mature amyloid-β and α-synuclein fibrils.

A glimpse of a Nordic model? Policy and practice in the digitalisation of the K-12 school and teacher education in Denmark, Finland, Norway and Sweden: Editorial introduction

Let $w\colon \mathbb{D}\to(0,\infty)$ be a radial continuous weight function. We consider the weighted biharmonic equation \Delta w^{-1}\Delta u=0\quad\text{in } \mathbb{D} with Dirichlet boundary conditions $u = f_0$ and $\partial_n u = f_1$ on $\mathbb{T} = \partial\mathbb{D}$. Under some extra conditions on the weight function $w$, we establish existence and uniqueness of a distributional solution $u$ of this biharmonic Dirichlet problem. Furthermore, we give a representation formula for the solution $u$. The key to our analysis is a series representation of Almansi type.

The pathological Aβ aggregates associated with Alzheimer's disease follow a nucleation-dependent path of formation. A nucleus represents an oligomeric assembly of Aβ peptides that acts as a template for subsequent incorporation of monomers to form a fibrillar structure. Nuclei can form de novo or via surface-catalyzed secondary nucleation, and the combined rates of elongation and nucleation control the overall rate of fibril formation. Transthyretin (TTR) obstructs Aβ fibril formation in favor of alternative non-fibrillar assemblies, but the mechanism behind this activity is not fully understood. This study shows that TTR does not significantly disturb fibril elongation; rather, it effectively interferes with the formation of oligomeric nuclei. We demonstrate that this interference can be modulated by altering the relative contribution of elongation and nucleation, and we show how TTR's effects can range from being essentially ineffective to almost complete inhibition of fibril formation without changing the concentration of TTR or monomeric Aβ.

The hardening distortions with respect to base body, clutch teeth and helical gears are investigated for a serial-produced main shaft gear of a 20NiCrMoS6-4 steel. The influences of casting geometr ...

The hardening distortions of serial produced crown wheels are studied with respect to gear runout, inner diameter and back-face tilt. The data analysed originates from a production data base from o ...

Low pH has a strong stabilising effect on the fibrillar assembly of amyloid β, which is associated with Alzheimer's disease. The stabilising effect is already pronounced at pH 6.0, suggesting that protonation of histidines might mediate this effect. Through the systematic substitution of the three native histidines in Aβ for alanines, we have evaluated their role in fibril stability. Using surface plasmon resonance, we show that at neutral pH the fibrillar forms of all His-Ala variants are destabilised by a factor of 4-12 compared to wild-type Aβ. However, none of the His-Ala Aβ variants impair the stabilising effect of the fibril at low pH. Alternative title: The role of histidines in amyloid beta fibril assembly

Apolipoprotein E (ApoE) has become a primary focus of research after the discovery of its strong linkage to Alzheimer&rsquo, s disease (AD), where the ApoE4 variant is the highest genetic risk factor for this disease. ApoE is commonly found in amyloid deposits of different origins, and its interaction with amyloid-&beta, peptide (A&beta, ), the hallmark of AD, is well known. However, studies on the interaction of ApoEs with other amyloid-forming proteins are limited. Islet amyloid polypeptide (IAPP) is an amyloid-forming peptide linked to the development of type-2 diabetes and has also been shown to be involved in AD pathology and vascular dementia. Here we studied the impact of ApoE on IAPP aggregation and IAPP-induced toxicity on blood vessel pericytes. Using both in vitro and cell-based assays, we show that ApoE efficiently inhibits the amyloid formation of IAPP at highly substoichiometric ratios and that it interferes with both nucleation and elongation. We also show that ApoE protects the pericytes against IAPP-induced toxicity, however, the ApoE4 variant displays the weakest protective potential. Taken together, our results suggest that ApoE has a generic amyloid-interfering property and can be protective against amyloid-induced cytotoxicity, but there is a loss of function for the ApoE4 variant.

We here describe the use of three-component reactions to synthesize tricyclic pyridine ring-fused 2-pyridones. The developed protocols have a wide substrate scope and allow for the installation of diverse chemical functionalities on the tricyclic central fragment. Several of these pyridine-fused rigid polyheterocycles are shown to bind to Aβ and α-synuclein fibrils, which are associated with neurodegenerative diseases.

The back-face tilt of press-hardened crown wheels is investigated for continuous and ingot cast material. Two different geometries are studied, one with a flat back-face and one with a step. For two ingots, the original material position is tracked and coupled to back-face tilt, cross section hardness and chemical segregation. The chemical gradients are shifted from top to bottom of the ingot and are strongly coupled to the back-face tilt.

We continue our study of weighted harmonic functions. The emphasis is put on properties of conformal invariance and associated Green functions. A classical result of Littlewood about pointwise limits almost everywhere of Green potentials of measures in the disc is, as far as the unit disc is concerned, generalized to the full scale of Green potentials considered.

Thyroid-disrupting chemicals (TDCs) are xenobiotics that can interfere with the endocrine system and cause adverse effects in organisms and their offspring. TDCs affect both the thyroid gland and regulatory enzymes associated with thyroid hormone homeostasis. Transthyretin (TTR) is found in the serum and cerebrospinal fluid of vertebrates, where it transports thyroid hormones. Here, we explored the interspecies variation in TDC binding to human and fish TTR (exemplified by Gilthead seabream ( Sparus aurata)). The in vitro binding experiments showed that TDCs bind with equal or weaker affinity to seabream TTR than to the human TTR, in particular, the polar TDCs (500-fold lower affinity). Crystal structures of the seabream TTR-TDC complexes revealed that all TDCs bound at the thyroid binding sites. However, amino acid substitution of Ser117 in human TTR to Thr117 in seabream prevented polar TDCs from binding deep in the hormone binding cavity, which explains their low affinity to seabream TTR. Molecular dynamics and in silico alanine scanning simulation also suggested that the protein backbone of seabream TTR is more rigid than the human one and that Thr117 provides fewer electrostatic contributions than Ser117 to ligand binding. This provides an explanation for the weaker affinities of the ligands that rely on electrostatic interactions with Thr117. The lower affinities of TDCs to fish TTR, in particular the polar ones, could potentially lead to milder thyroid-related effects in fish.

In Sweden, the digitalization of K-12 schools has been ongoing for more than 30 years. Several larger governmental initiatives targeting issues such as the one-to-one classroom and teachers’ develo ...

This paper is concerned with teacher education students’ views on 21st century skills. Today, western societies are becoming more and more reliant on digital technologies as digital technology is p ...

We demonstrate the use of Scanning Electron microscopy (SEM) in combination with Surface Plasmon Resonance (SPR) to probe and verify the formation of amyloid and its morphology on an SPR chip. SPR is a technique that measures changes in the immobilized weight on the chip surface and is frequently used to probe the formation and biophysical properties of amyloid structures. In this context it is of interest to also monitor the morphology of the formed structures. The SPR chip surface is made of a layer of gold, which represent a suitable material for direct analysis of the surface using SEM. The standard SPR chip used here (CM5-chip, GE Healthcare, Uppsala, Sweden) can easily be disassembled and directly analyzed by SEM. In order to verify the formation of amyloid fibrils in our experimental conditions we analyzed also in-solution produced structures by using Transmission Electron Microscopy (TEM). For further details and experimental findings, please refer to the article published in Journal of Molecular Biology, (Brännström K. et al., 2018) [1]. Refers to: Kristoffer Brännström, Tohidul Islam, Anna L. Gharibyan, Irina Iakovleva, Lina Nilsson, Cheng Choo Lee, Linda Sandblad, Annelie Pamrén, Anders Olofsson. The Properties of Amyloid-β Fibrils Are Determined by their Path of Formation. Journal of Molecular Biology, Volume 430, Issue 13, 22 June 2018, Pages 1940-1949

Purpose – The purpose of this paper is to look at how results from a large-scale study can be understood in the context of contemporary gender and entrepreneurship research. Design/methodology/approach – This study is inspired by a mixed methods methodology. To gain a qualitative understanding of the general patterns in a large-scale study, research results in articles from the International Journal of Gender and Entrepreneurship (IJGE) were used. To make such a heterogeneous research field as appears in IJGE comparable, a model was created that helped us to focus our attention when reading the articles. The core of each article was identified. Findings – The categorisation of the articles in IJGE resulted in three perspectives: liberal, functional and structural. The liberal and functional perspectives improved our understanding only partially because these perspectives usually focused on a certain aspect in the society. The structural perspective more readily lent itself for interpretation of our large-scale results. Research limitations/implications – The dissonance between our perspective and the perspective of others has been a challenge; it has been a delicate task. Originality/value – This could be a way to improve communication of research not only within a perspective, but also between perspectives. It is important that scholarly journals provide the possibility to express different perspectives on, as in this example, gender and entrepreneurship.

The population of brain pericytes, a cell type important for vessel stability and blood brain barrier function, has recently been shown altered in patients with Alzheimer's disease (AD). The underlying reason for this alteration is not fully understood, but progressive accumulation of the AD characteristic peptide amyloid-beta (Aβ) has been suggested as a potential culprit. In the current study, we show reduced number of hippocampal NG2+ pericytes and an association between NG2+ pericyte numbers and Aβ1-40 levels in AD patients. We further demonstrate, using in vitro studies, an aggregation-dependent impact of Aβ1-40 on human NG2+ pericytes. Fibril-EP Aβ1-40 exposure reduced pericyte viability and proliferation and increased caspase 3/7 activity. Monomer Aβ1-40 had quite the opposite effect: increased pericyte viability and proliferation and reduced caspase 3/7 activity. Oligomer-EP Aβ1-40 had no impact on either of the cellular events. Our findings add to the growing number of studies suggesting a significant impact on pericytes in the brains of AD patients and suggest different aggregation forms of Aβ1-40 as potential key regulators of the brain pericyte population size. Listed as co-author in the publication: The Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands

Fibril formation of the amyloid-β peptide (Aβ) follows a nucleation-dependent polymerization process and is associated with Alzheimer's disease. Several different lengths of Aβ are observed in vivo, but Aβ1-40 and Aβ1-42 are the dominant forms. The fibril architectures of Aβ1-40 and Aβ1-42 differ and Aβ1-42 assemblies are generally considered more pathogenic. We show here that monomeric Aβ1-42 can be cross-templated and incorporated into the ends of Aβ1-40 fibrils, while incorporation of Aβ1-40 monomers into Aβ1-42 fibrils is very poor. We also show that via cross-templating incorporated Aβ monomers acquire the properties of the parental fibrils. The suppressed ability of Aβ1-40 to incorporate into the ends of Aβ1-42 fibrils and the capacity of Aβ1-42 monomers to adopt the properties of Aβ1-40 fibrils may thus represent two mechanisms reducing the total load of fibrils having the intrinsic, and possibly pathogenic, features of Aβ1-42 fibrils in vivo. We also show that the transfer of fibrillar properties is restricted to fibril-end templating and does not apply to cross-nucleation via the recently described path of surface-catalyzed secondary nucleation, which instead generates similar structures to those acquired via de novo primary nucleation in the absence of catalyzing seeds. Taken together these results uncover an intrinsic barrier that prevents Aβ1-40 from adopting the fibrillar properties of Aβ1-42 and exposes that the transfer of properties between amyloid-β fibrils are determined by their path of formation.

The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen andthat bio-selection and changes in BabA bindingproperties through mutation and recombination with babA-related genes are selected by differencesamong individuals and by changes in gastric acidity over time. These processes generate diverse H.pylori subpopulations, in which BabA's adaptive evolution contributes to H.pylori persistence and overt gastric disease.

The national guidelines for design of silage bunker silo walls are not available today. The present calculation and design is based on previously issued guidelines. These were elaborated to be used in designing silo wall heights of maximum 3 m. There are reasons to believe that these guidelines overestimate the forces and pressures, mainly from silage juice, that are occurring especially for silo walls > 3 m. This could result in over-sizing, material waste and increased investment costs. The aim of the project is to determine silage physical properties of importance for the horizontal wall pressure and evaluate maximum silage juice level of silos with a wall height of 3 m or more. The data will form a basis for new national design guidelines and a revised Swedish Standard. The ultimate goal is to lower the investment costs for silage bunker silos. A pressure profile was acquired by means of transducers mounted on a “ladder rack” placed vertically along the inside silo wall. The pressure on the transducers was recorded by a data acquisition system displaying static and total load (pressures imposed by silage matter and compacting tractor). The silage juice levels were measured by slotted 16 mm steel pipes placed vertically along the silo walls. The level inside the pipe was determined by a measuring stick. Additionally the juice level could be registered in one of the legs of the “ladder rack”. Silage juice level measurement were carried out during two seasons, all together in 24 silos, while pressure profiles were measured during 10 grass and maize harvests in one season, with approximately 400 pressure profiles at each harvest. The static loads were recorded with no tractor present and total loads as a tractor was passing in front of the transducer racks. The difference between the static and the total load was defined as the dynamic load. Preliminary results show that the silage juice level can vary considerably between harvests within the farm due to weather conditions and geographic location in Sweden. Mean of peak levels was approximately 40% of the silage height. A direct relation was found between grass silage juice level and silage total solid content. The silage juice level tends to remain stable during the storage but can be radically redistributed between layers within the silo. Tentative pressure profile results show that the dynamic pressure created by the compacting tractor is largely concentrated to the first half metre below the vehicle when driving 0.1-0.5 m from the silo wall. Pressure measurements after filling the silo show an increase in wall pressure. The pressure profile results are presently under evaluation. Key words: Silo, wall, silage, pressure, force.

Alzheimer's disease is linked to a pathological polymerization of the endogenous amyloid β-peptide (Aβ) that ultimately forms amyloid plaques within the human brain. We used surface plasmon resonance (SPR) to measure the kinetic properties of Aβ fibril formation under different conditions during the polymerization process. For all polymerization processes, a critical concentration of free monomers, as defined by the dissociation equilibrium constant (K(D)), is required for the buildup of the polymer, for example, amyloid fibrils. At concentrations below the K(D), polymerization cannot occur. However, the K(D) for Aβ has previously been shown to be several orders of magnitude higher than the concentrations found in the cerebrospinal and interstitial fluids of the human brain, and the mechanism by which Aβ amyloid forms in vivo has been a matter of debate. Using SPR, we found that the K(D) of Aβ dramatically decreases as a result of lowering the pH. Importantly, this effect enables Aβ to polymerize within a picomolar concentration range that is close to the physiological Aβ concentration within the human brain. The stabilizing effect is dynamic, fully reversible, and notably pronounced within the pH range found within the endosomal and lysosomal pathways. Through sequential truncation, we show that the N-terminal region of Aβ contributes to the enhanced fibrillar stability due to a gain of function mechanism at low pH. Our results present a possible route for amyloid formation at very low Aβ concentrations and raise the question of whether amyloid formation in vivo is restricted to a low pH environment. These results have general implications for the development of therapeutic interventions.

In this paper, we introduce a scale of differential operators which is shown to correspond canonically to a certain scale of solution kernels generalizing the classical Poisson kernel for the unit disc. The scale of kernels studied is very natural and appears in many places in mathematical analysis, such as in the theory of integral representations of biharmonic functions in the unit disc.

Pro-inflammatory S100A9 protein is increasingly recognized as an important contributor to inflammation-related neurodegeneration. Here, we provide insights into S100A9 specific mechanisms of action in Alzheimer’s disease (AD). Due to its inherent amyloidogenicity S100A9 contributes to amyloid plaque formation together with Aβ. In traumatic brain injury (TBI) S100A9 itself rapidly forms amyloid plaques, which were reactive with oligomer-specific antibodies, but not with Aβ and amyloid fibrillar antibodies. They may serve as precursor-plaques for AD, implicating TBI as an AD risk factor. S100A9 was observed in some hippocampal and cortical neurons in TBI, AD and non-demented aging. In vitro S100A9 forms neurotoxic linear and annular amyloids resembling Aβ protofilaments. S100A9 amyloid cytotoxicity and native S100A9 pro-inflammatory signaling can be mitigated by its co-aggregation with Aβ, which results in a variety of micron-scale amyloid complexes. NMR and molecular docking demonstrated transient interactions between native S100A9 and Aβ. Thus, abundantly present in AD brain pro-inflammatory S100A9, possessing also intrinsic amyloidogenic properties and ability to modulate Aβ aggregation, can serve as a link between the AD amyloid and neuroinflammatory cascades and as a prospective therapeutic target. Electronic supplementary material The online version of this article (doi:10.1007/s00401-013-1208-4) contains supplementary material, which is available to authorized users.

We prove an operator identity for the shift operator in the scale of standard weighted Bergman spaces in the unit disc. This operator identity is then applied in the context of functional calculus for the shift operator and a characterization of harmonic symbol Bergman space Toeplitz operators is obtained generalizing an earlier result by Louhichi and Olofsson. Duality arguments lead to operator inequalities and structure formulas for reproducing kernel functions which make contact with work of Richter, Shimorin, and others.

Enzymatic activity is ultimately defined by the structure, chemistry, and dynamics of the Michaelis complex. A large number of experimentally determined structures between enzymes and substrates, substrate analogues, or inhibitors exist. However, transient, short-lived encounter and equilibrium structures also play fundamental roles during enzymatic reaction cycles. Such structures are inherently difficult to study with conventional experimental techniques. The enzyme adenylate kinase undergoes major conformational rearrangements in response to binding of its substrates, ATP and AMP. ATP is sandwiched between two binding surfaces in the closed and active enzyme conformation. Thus, adenylate kinase harbors two spatially distant surfaces in the substrate free open conformation, of which one is responsible for the initial interaction with ATP. Here, we have performed primarily nuclear magnetic resonance experiments on Escherichia coli adenylate kinase (AK(eco)) variants that allowed identification of the site responsible for the initial ATP interaction. This allowed a characterization of the structural topology of an initial equilibrium complex between AK(eco) and ATP. On the basis of the results, we suggest that the ATP binding mechanism for AK(eco) is a mixture between "induced fit" and "conformational selection" models. It is shown that ATP is activated in the initial enzyme-bound complex because it displays an appreciable rate of nonproductive ATP hydrolysis. In summary, our results provide novel structural and functional insights into adenylate kinase catalysis.

We prove an operator inequality for the Bergman shift operator on weighted Bergman spaces of analytic functions in the unit disc with weight function controlled by a curvature parameter α assuming ...

Curli are functional amyloids produced by enteric bacteria. The major curli fiber subunit, CsgA, self-assembles into an amyloid fiber in vitro. The minor curli subunit protein, CsgB, is required for CsgA polymerization on the cell surface. Both CsgA and CsgB are composed of five predicted β-strand-loop-β-strand-loop repeating units that feature conserved glutamine and asparagine residues. Because of this structural homology, we proposed that CsgB might form an amyloid template that initiates CsgA polymerization on the cell surface. To test this model, we purified wild-type CsgB and found that it self-assembled into amyloid fibers in vitro. Preformed CsgB fibers seeded CsgA polymerization as did soluble CsgB added to the surface of cells secreting soluble CsgA. To define the molecular basis of CsgB nucleation, we generated a series of mutants that removed each of the five repeating units. Each of these CsgB deletion mutants was capable of self-assembly in vitro. In vivo, membrane-localized mutants lacking the first, second, or third repeating units were able to convert CsgA into fibers. However, mutants missing either the fourth or fifth repeating units were unable to complement a csgB mutant. These mutant proteins were not localized to the outer membrane but were instead secreted into the extracellular milieu. Synthetic CsgB peptides corresponding to repeating units 1, 2, and 4 self-assembled into ordered amyloid polymers, while peptides corresponding to repeating units 3 and 5 did not, suggesting that there are redundant amyloidogenic domains in CsgB. Our results suggest a model where the rapid conversion of CsgB from unstructured protein to a β-sheet-rich amyloid template anchored to the cell surface is mediated by the C-terminal repeating units.

SPINK9, a Kazal-type serine protease inhibitor, is almost exclusively expressed in the palmo-plantar epidermis. SPINK9 selectively inhibits kallikrein-related peptidase 5 (KLK5), no other target enzyme is known at present. In this study, we defined the reactive loop to residues 48 and 49 of SPINK9 and characterized the inhibition and binding of different SPINK9 variants towards KLK5, KLK7, KLK8 and KLK14. Substitutions of single amino acids in the reactive loop had a large impact on both inhibitory efficiency and specificity. Binding studies showed that it is mainly the dissociation rate that is affected by the amino acid substitutions. The inhibitory effect of wild-type SPINK9 was clearly pH-dependent with an improved effect at a pH similar to that of the outer layers of the skin. Modeling of the enzyme-inhibitor complexes showed that the reactive loop of SPINK9 fits very well into the deep negatively charged binding pocket of KLK5. A decrease in pH protonates His48 of the wild-type protein resulting in a positively charged residue, thereby explaining the observed decreased dissociation rate. Interestingly, substitution with a positively charged amino acid at position 48 resulted in a more efficient inhibitor at higher pH.

Mediator is a multiprotein coregulatory complex that conveys signals from DNA-bound transcriptional regulators to the RNA polymerase II transcription machinery in eukaryotes. The molecular mechanisms for how these signals are transmitted are still elusive. By using purified transcription factor Dreb2a, mediator subunit Med25 from Arabidopsis thaliana, and a combination of biochemical and biophysical methods, we show that binding of Dreb2a to its canonical DNA sequence leads to an increase in secondary structure of the transcription factor. Similarly, interaction between the Dreb2a and Med25 in the absence of DNA results in conformational changes. However, the presence of the canonical Dreb2a DNA-binding site reduces the affinity between Dreb2a and Med25. We conclude that transcription regulation is facilitated by small but distinct changes in energetic and structural parameters of the involved proteins.

Aβ (beta-amyloid peptide) is an important contributor to Alzheimer's disease (AD). We modeled Aβ toxicity in yeast by directing the peptide to the secretory pathway. A genome-wide screen for toxicity modifiers identified the yeast homolog of phosphatidylinositol binding clathrin assembly protein (PICALM) and other endocytic factors connected to AD whose relationship to Aβ was previously unknown. The factors identified in yeast modified Aβ toxicity in glutamatergic neurons of Caenorhabditis elegans and in primary rat cortical neurons. In yeast, Aβ impaired the endocytic trafficking of a plasma membrane receptor, which was ameliorated by endocytic pathway factors identified in the yeast screen. Thus, links between Aβ, endocytosis, and human AD risk factors can be ascertained with yeast as a model system.

Archaeological flint artefacts from the late Mesolithic/early Neolithic site of Vuollerim, northern Sweden, have been geochemically investigated with ICP-SFMS and MC-ICP-MS in search for the geolog ...

An operator identity satisfied by the shift operator in a class of standard weighted Bergman spaces is studied. We show that subject to a pureness condition this operator identity characterizes the associated Bergman shift operator up to unitary equivalence allowing for a general multiplicity. The analysis of the general case makes contact with the class of n-isometries studied by Agler and Stankus.

We develop a Wold decomposition for the shift semigroup on the Hardy space H 2 of square summable Dirichlet series convergent in the half-plane 1=2. As an application we have that a shift invariant subspace of H 2 is unitarily equivalent to H 2 if and only if it has the form 'H 2 for some H 2 -inner function '.

We show that operator-valued Bergman inner functions have the so-called expansive multiplier property generalizing a well-known result of Hedenmalm in the scalar case. This analysis leads to norm bounds for input output maps for a related class of discrete time linear systems. The proof uses properties of the biharmonic Green function. (C) 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This study is a case study conducted over 6 years. In the first round of visits to schools 6 years ago, in the ISSPP context (Hoog et al. J Educ Adm 43(6): 595–606, 2005), we found two very self-confident and successful principals who had created, over the last 3–4 years, very successful schools out of schools in challenging situations. Their students had started to produce good marks over the national average.

Alzheimer's disease, a neurodegenerative disorder causing synaptic impairment and neuronal cell death, is strongly correlated with aggregation of the amyloid-beta peptide (Abeta). Divalent metal ions such as Cu(2+) and Zn(2+) are known to significantly affect the rate of aggregation and morphology of Abeta assemblies in vitro and are also found at elevated levels within cerebral plaques in vivo. The present investigation characterized the architecture of the aggregated forms of Abeta(1-40) and Abeta(1-42) in the presence or absence of either Cu(2+) or Zn(2+) using quenched hydrogen/deuterium exchange combined with solution NMR spectroscopy. The NMR analyses provide a quantitative and residue-specific structural characterization of metal-induced Abeta aggregates, showing that both the peptide sequence and the type of metal ion exert an impact on the final architecture. Common features among the metal-complexed peptide aggregates are two solvent-protected regions with an intervening minimum centered at Asn27, and a solvent-accessible N-terminal region, Asp1-Lys16. Our results suggest that Abeta in complex with either Cu(2+) or Zn(2+) can attain an aggregation-prone beta-strand-turn-beta-strand motif, similar to the motif found in fibrils, but where the metal binding to the N-terminal region guides the peptide into an assembly distinctly different from the fibril form.

Human transthyretin (hTTR) is one of several proteins known to cause amyloid disease. Conformational changes in its native structure result in aggregation of the protein, leading to insoluble amylo ...