CNTN4 modulates neural elongation through interplay with APP.

The neuronal cell adhesion molecule contactin-4 (CNTN4) is genetically associated with autism spectrum disorder (ASD) and other psychiatric disorders. Cntn4-deficient mouse models have previously shown that CNTN4 plays important roles in axon guidance and synaptic plasticity in the hippocampus. However, the pathogenesis and functional role of CNTN4 in the cortex has not yet been investigated. Our study found a reduction in cortical thickness in the motor cortex of Cntn4 -/- mice, but cortical cell migration and differentiation were unaffected. Significant morphological changes were observed in neurons in the M1 region of the motor cortex, indicating that CNTN4 is also involved in the morphology and spine density of neurons in the motor cortex. Furthermore, mass spectrometry analysis identified an interaction partner for CNTN4, confirming an interaction between CNTN4 and amyloid-precursor protein (APP). Knockout human cells for CNTN4 and/or APP revealed a relationship between CNTN4 and APP. This study demonstrates that CNTN4 contributes to cortical development and that binding and interplay with APP controls neural elongation. This is an important finding for understanding the physiological function of APP, a key protein for Alzheimer's disease. The binding between CNTN4 and APP, which is involved in neurodevelopment, is essential for healthy nerve outgrowth.

Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein.

Pathologic α-synuclein (α-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid ß precursor-like protein 1 (Aplp1) interacts with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic α-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by α-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of α-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by α-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for α-syn PFF induced pathology deepens our insight about molecular mechanisms of cell-to-cell transmission of pathologic α-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson's disease and related α-synucleinopathies.

Consequences of Amyloid-ß Deficiency for the Liver.

The hepatic content of amyloid beta (Aß) decreases drastically in human and rodent cirrhosis highlighting the importance of understanding the consequences of Aß deficiency in the liver. This is especially relevant in view of recent advances in anti-Aß therapies for Alzheimer's disease (AD). Here, it is shown that partial hepatic loss of Aß in transgenic AD mice immunized with Aß antibody 3D6 and its absence in amyloid precursor protein (APP) knockout mice (APP-KO), as well as in human liver spheroids with APP knockdown upregulates classical hallmarks of fibrosis, smooth muscle alpha-actin, and collagen type I. Aß absence in APP-KO and deficiency in immunized mice lead to strong activation of transforming growth factor-ß (TGFß), alpha secretases, NOTCH pathway, inflammation, decreased permeability of liver sinusoids, and epithelial-mesenchymal transition. Inversely, increased systemic and intrahepatic levels of Aß42 in transgenic AD mice and neprilysin inhibitor LBQ657-treated wild-type mice protect the liver against carbon tetrachloride (CCl4)-induced injury. Transcriptomic analysis of CCl4-treated transgenic AD mouse livers uncovers the regulatory effects of Aß42 on mitochondrial function, lipid metabolism, and its onco-suppressive effects accompanied by reduced synthesis of extracellular matrix proteins. Combined, these data reveal Aß as an indispensable regulator of cell-cell interactions in healthy liver and a powerful protector against liver fibrosis.

APP family member dimeric complexes are formed predominantly in synaptic compartments.

BACKGROUND: The amyloid precursor protein (APP), a key player in Alzheimer's disease (AD), is part of a larger gene family, including the APP like proteins APLP1 and APLP2. They share similar structures, form homo- and heterotypic dimers and exhibit overlapping functions. RESULTS: We investigated complex formation of the APP family members via two inducible dimerization systems, the FKBP-rapamycin based dimerization as well as cysteine induced dimerization, combined with co-immunoprecipitations and Blue Native (BN) gel analyses. Within the APP family, APLP1 shows the highest degree of dimerization and high molecular weight (HMW) complex formation. Interestingly, only about 20% of APP is dimerized in cultured cells whereas up to 50% of APP is dimerized in mouse brains, independent of age and splice forms. Furthermore, we could show that dimerized APP originates mostly from neurons and is enriched in synaptosomes. Finally, BN gel analysis of human cortex samples shows a significant decrease of APP dimers in AD patients compared to controls. CONCLUSIONS: Together, we suggest that loss of full-length APP dimers might correlate with loss of synapses in the process of AD.

Axonal transport of Frizzled5 by Alcadein α-containing vesicles is associated with kinesin-1.

Alcadein α (Alcα) and amyloid-ß protein precursor (APP) are cargo receptors that associate vesicles with kinesin-1. These vesicles, which contain either Alcα or APP, transport various proteins/cargo molecules into axon nerve terminals. Here, we analyzed immune-isolated Alcα- and APP-containing vesicles of adult mouse brains with LC-MS/MS and identified proteins present in vesicles that contained either Alcα or APP. Among these proteins, Frizzled-5 (Fzd5), a Wnt receptor, was detected mainly in Alcα vesicles. Although colocalization ratios of Fzd5 with Alcα are low in the neurites of differentiating neurons by a low expression of Fzd5 in embryonic brains, the suppression of Alcα expression decreased the localization of Fzd5 in neurites of primary cultured neurons. Furthermore, Fzd5-EGFP expressed in primary cultured neurons was preferentially transported in axons with the transport velocities of Alcα vesicles. In synaptosomal fractions of adult-mice brains that express higher levels of Fzd5, the amount of Fzd5 and the phosphorylation level of calcium/calmodulin-dependent protein kinase-II were reduced in the Alcα-deficient mice. These results suggest that reduced transport of Fzd5 by Alcα-containing vesicles associated with kinesin-1 in axon terminals may impair the response to Wnt ligands in the noncanonical Ca2+-dependent signal transduction pathway at nerve terminals of mature neurons.

Cost of Transport of Undulating Fin Propulsion.

Autonomous robots are used to inspect, repair and maintain underwater assets. These tasks require energy-efficient robots, including efficient movement to extend available operational time. To examine the suitability of a propulsion system based on undulating fins, we built two robots with one and two fins, respectively, and conducted a parametric study for combinations of frequency, amplitude, wavenumber and fin shapes in free-swimming experiments, measuring steady-state swimming speed, power consumption and cost of transport. The following trends emerged for both robots. Swimming speed was more strongly affected by frequency than amplitude across the examined wavenumbers and fin heights. Power consumption was sensitive to frequency at low wavenumbers, and increasingly sensitive to amplitude at high wavenumbers. This increasing sensitivity of amplitude was more pronounced in tall rather than short fins. Cost of transport showed a complex relation with fin size and kinematics and changed drastically across the mapped parameter space. At equal fin kinematics as the single-finned robot, the double-finned robot swam slightly faster (>10%) with slightly lower power consumption (<20%) and cost of transport (<40%). Overall, the robots perform similarly to finned biological swimmers and other bio-inspired robots, but do not outperform robots with conventional propulsion systems.

The Amyloid Precursor Protein Regulates Synaptic Transmission at Medial Perforant Path Synapses.

The perforant path provides the primary cortical excitatory input to the hippocampus. Because of its important role in information processing and coding, entorhinal projections to the dentate gyrus have been studied in considerable detail. Nevertheless, synaptic transmission between individual connected pairs of entorhinal stellate cells and dentate granule cells remains to be characterized. Here, we have used mouse organotypic entorhino-hippocampal tissue cultures of either sex, in which the entorhinal cortex (EC) to dentate granule cell (GC; EC-GC) projection is present, and EC-GC pairs can be studied using whole-cell patch-clamp recordings. By using cultures of wild-type mice, the properties of EC-GC synapses formed by afferents from the lateral and medial entorhinal cortex were compared, and differences in short-term plasticity were identified. As the perforant path is severely affected in Alzheimer's disease, we used tissue cultures of amyloid precursor protein (APP)-deficient mice to examine the role of APP at this synapse. APP deficiency altered excitatory neurotransmission at medial perforant path synapses, which was accompanied by transcriptomic and ultrastructural changes. Moreover, presynaptic but not postsynaptic APP deletion through the local injection of Cre-expressing adeno-associated viruses in conditional APPflox/flox tissue cultures increased the neurotransmission efficacy at perforant path synapses. In summary, these data suggest a physiological role for presynaptic APP at medial perforant path synapses that may be adversely affected under altered APP processing conditions.SIGNIFICANCE STATEMENT The hippocampus receives input from the entorhinal cortex via the perforant path. These projections to hippocampal dentate granule cells are of utmost importance for learning and memory formation. Although there is detailed knowledge about perforant path projections, the functional synaptic properties at the level of individual connected pairs of neurons are not well understood. In this study, we investigated the role of APP in mediating functional properties and transmission rules in individually connected neurons using paired whole-cell patch-clamp recordings and genetic tools in organotypic tissue cultures. Our results show that presynaptic APP expression limits excitatory neurotransmission via the perforant path, which could be compromised in pathologic conditions such as Alzheimer's disease.

Evaluation of multidimensional pediatric-psychosomatic inpatient therapy: a pilot study comparing two treatment modalities.

Introduction: Multidimensional pediatric-psychosomatic inpatient treatment should be considered a highly relevant concept in the German healthcare system. This treatment concept has been successfully integrated to support youth with mental disorders and patients with chronic somatic conditions. Studies on treatment impact and empirical evidence of pediatric-psychosomatic inpatient therapies are rare, despite their clinical significance. Therefore, the study aims to provide initial indications of what constitutes to enhanced treatment effectiveness by comparing two different pediatric-psychosomatic inpatient treatment concepts. The clinics are comparable regarding the treated disorders, which include: dissociative, mood, and somatoform disorders, and psychological factors associated with chronic somatic conditions. Multidimensional treatment in both clinics include components of individual and family therapy, along with group-, art-, music-, creative-, and physio-therapy. Both clinics differed regarding their treatment philosophy in which; Clinic A practiced psychodynamic behavioral elements more strongly, while Clinic B rooted itself more strongly with psychoanalysis and family-dynamic practices. Method: Each clinic recruited 25 patients for the study. They completed two questionnaires both at admission and discharge, which measured general behavioral and emotional problems (YSR); and, respectively, difficulties in emotion perception and processing (TAS-26). The effectiveness of the treatment was examined by conducting one-sample t-test and effect sizes for each clinic. To obtain information on differentiating treatment effects, mixed ANOVAs were calculated. For estimating its influence, the treatment duration was taken into account as a covariate calculating an ANCOVA. Results: In both settings, treatment effects can be observed regarding internalizing problems. For alexithymia, no effects were seen in Clinic B, while in Clinic A, there was a significant reduction. When comparing both clinics, the ANOVAs showed significant interaction effects displaying advantages for Clinic A in the reduction of internalizing, total behavioral problems and alexithymia. Taking into account the treatment duration as a covariate, those effects level out. Significant differences between the clinics were no longer statistically detectable. Discussion: The present study provides substantial preliminary indications on the effectiveness of multidimensional pediatric-psychosomatic inpatient therapy, which seems suitable for alleviating the general symptom burden and problems by identifying and processing emotions. Furthermore, the results indicate that an extended treatment duration may contribute to more pronounced effects.

APPsα rescues CDK5 and GSK3ß dysregulation and restores normal spine density in Tau transgenic mice.

The Tau protein can be phosphorylated by numerous kinases. In Alzheimer's disease (AD) hyperphosphorylated Tau species accumulate as neurofibrillary tangles that constitute a major hallmark of AD. AD is further characterized by extracellular Aß plaques, derived from the ß-amyloid precursor protein APP. Whereas Aß is produced by amyloidogenic APP processing, APP processing along the competing non-amyloidogenic pathway results in the secretion of neurotrophic and synaptotrophic APPsα. Recently, we demonstrated that APPsα has therapeutic effects in transgenic AD model mice and rescues Aß-dependent impairments. Here, we examined the potential of APPsα to regulate two major Tau kinases, GSK3ß and CDK5 in THY-Tau22 mice, a widely used mouse model of tauopathy. Immunohistochemistry revealed a dramatic increase in pathologically phosphorylated (AT8 and AT180) or misfolded Tau species (MC1) in the hippocampus of THY-Tau22 mice between 3 and 12 months of age. Using a highly sensitive radioactive kinase assay with recombinant human Tau as a substrate and immunoblotting, we demonstrate an increase in GSK3ß and CDK5 activity in the hippocampus of THY-Tau22 mice. Interestingly, AAV-mediated intracranial expression of APPsα in THY-Tau22 mice efficiently restored normal GSK3ß and CDK5 activity. Western blot analysis revealed upregulation of the CDK5 regulatory proteins p35 and p25, indicating CDK5 hyperactivation in THY-Tau22 mice. Strikingly, AAV-APPsα rescued p25 upregulation to wild-type levels even at stages of advanced Tau pathology. Sarkosyl fractionation used to study the abundance of soluble and insoluble phospho-Tau species revealed increased soluble AT8-Tau and decreased insoluble AT100-Tau species upon AAV-APPsα injection. Moreover, AAV-APPsα reduced misfolded (MC1) Tau species, particularly in somatodendritic compartments of CA1 pyramidal neurons. Finally, we show that AAV-APPsα upregulated PSD95 expression and rescued deficits in spine density of THY-Tau22 mice. Together our findings suggest that APPsα holds therapeutic potential to mitigate Tau-induced pathology.

Lack of APLP1 leads to subtle alterations in neuronal morphology but does not affect learning and memory.

The amyloid precursor protein APP plays a crucial role in Alzheimer pathogenesis. Its physiological functions, however, are only beginning to be unraveled. APP belongs to a small gene family, including besides APP the closely related amyloid precursor-like proteins APLP1 and APLP2, that all constitute synaptic adhesion proteins. While APP and APLP2 are ubiquitously expressed, APLP1 is specific for the nervous system. Previous genetic studies, including combined knockouts of several family members, pointed towards a unique role for APLP1, as only APP/APLP1 double knockouts were viable. We now examined brain and neuronal morphology in APLP1 single knockout (KO) animals, that have to date not been studied in detail. Here, we report that APLP1-KO mice show normal spine density in hippocampal CA1 pyramidal cells and subtle alterations in dendritic complexity. Extracellular field recordings revealed normal basal synaptic transmission and no alterations in synaptic plasticity (LTP). Further, behavioral studies revealed in APLP1-KO mice a small deficit in motor function and reduced diurnal locomotor activity, while learning and memory were not affected by the loss of APLP1. In summary, our study indicates that APP family members serve both distinct and overlapping functions that need to be considered for therapeutic treatments of Alzheimer's disease.

Dynamic in Situ Confinement Triggers Ligand-Free Neuropeptide Receptor Signaling.

Membrane receptor clustering is fundamental to cell-cell communication; however, the physiological function of receptor clustering in cell signaling remains enigmatic. Here, we developed a dynamic platform to induce cluster formation of neuropeptide Y2 hormone receptors (Y2R) in situ by a chelator nanotool. The multivalent interaction enabled a dynamic exchange of histidine-tagged Y2R within the clusters. Fast Y2R enrichment in clustered areas triggered ligand-independent signaling as determined by an increase in cytosolic calcium and cell migration. Notably, the calcium and motility response to ligand-induced activation was amplified in preclustered cells, suggesting a key role of receptor clustering in sensitizing the dose response to lower ligand concentrations. Ligand-independent versus ligand-induced signaling differed in the binding of arrestin-3 as a downstream effector, which was recruited to the clusters only in the presence of the ligand. This approach allows in situ receptor clustering, raising the possibility to explore different receptor activation modalities.

Linker Engineering of Ligand-Decorated DNA Origami Nanostructures Affects Biological Activity.

News from an old acquaintance: The streptavidin (STV)-biotin binding system is frequently used for the decoration of DNA origami nanostructures (DON) to study biological systems. Here, a surprisingly high dynamic of the STV/DON interaction is reported, which is affected by the structure of the DNA linker system. Analysis of different mono- or bi-dentate linker architectures on DON with a novel high-speed atomic force microscope (HS-AFM) enabling acquisition times as short as 50 ms per frame gave detailed insights into the dynamics of the DON/STV interaction, revealing dwell times in the sub-100 millisecond range. The linker systems are also used to present biotinylated epidermal growth factor on DON to study the activation of the epidermal growth factor receptor signaling cascade in HeLa cells. The studies confirm that cellular activation correlated with the binding properties of linker-specific STV/DON interactions observed by HS-AFM. This work sheds more light on the commonly used STV/DON system and will help to further standardize the use of DNA nanostructures for the study of biological processes.

APPsα Rescues Tau-Induced Synaptic Pathology.

Alzheimer's disease (AD) is histopathologically characterized by Aß plaques and the accumulation of hyperphosphorylated Tau species, the latter also constituting key hallmarks of primary tauopathies. Whereas Aß is produced by amyloidogenic APP processing, APP processing along the competing nonamyloidogenic pathway results in the secretion of neurotrophic and synaptotrophic APPsα. Recently, we demonstrated that APPsα has therapeutic effects in transgenic AD model mice and rescues Aß-dependent impairments. Here, we examined the potential of APPsα to mitigate Tau-induced synaptic deficits in P301S mice (both sexes), a widely used mouse model of tauopathy. Analysis of synaptic plasticity revealed an aberrantly increased LTP in P301S mice that could be normalized by acute application of nanomolar amounts of APPsα to hippocampal slices, indicating a homeostatic function of APPsα on a rapid time scale. Further, AAV-mediated in vivo expression of APPsα restored normal spine density of CA1 neurons even at stages of advanced Tau pathology not only in P301S mice, but also in independent THY-Tau22 mice. Strikingly, when searching for the mechanism underlying aberrantly increased LTP in P301S mice, we identified an early and progressive loss of major GABAergic interneuron subtypes in the hippocampus of P301S mice, which may lead to reduced GABAergic inhibition of principal cells. Interneuron loss was paralleled by deficits in nest building, an innate behavior highly sensitive to hippocampal impairments. Together, our findings indicate that APPsα has therapeutic potential for Tau-mediated synaptic dysfunction and suggest that loss of interneurons leads to disturbed neuronal circuits that compromise synaptic plasticity as well as behavior.SIGNIFICANCE STATEMENT Our findings indicate, for the first time, that APPsα has the potential to rescue Tau-induced spine loss and abnormal synaptic plasticity. Thus, APPsα might have therapeutic potential not only because of its synaptotrophic functions, but also its homeostatic capacity for neuronal network activity. Hence, APPsα is one of the few molecules which has proven therapeutic effects in mice, both for Aß- and Tau-dependent synaptic impairments and might therefore have therapeutic potential for patients suffering from AD or primary tauopathies. Furthermore, we found in P301S mice a pronounced reduction of inhibitory interneurons as the earliest pathologic event preceding the accumulation of hyperphosphorylated Tau species. This loss of interneurons most likely disturbs neuronal circuits that are important for synaptic plasticity and behavior.

Insights into Imprinting: How Is the Phenomenon of Tribocorrosion at Head-Neck Taper Interfaces Related to Corrosion, Fretting, and Implant Design Parameters?

BACKGROUND: Wear and corrosion at modular neck tapers in THA can lead to major clinical implications such as periprosthetic osteolysis, adverse local tissue reactions, or implant failure. The material degradation processes at the taper interface are complex and involve fretting corrosion, third-body abrasion, as well as electrochemical and crevice corrosion. One phenomenon in this context is imprinting of the head taper, where the initially smooth surface develops a topography that reflects the rougher neck taper profile. The formation mechanism of this specific phenomenon, and its relation to other observed damage features, is unclear. An analysis of retrieved implants may offer some insights into this process. QUESTIONS/PURPOSES: (1) Is imprinting related to time in situ of the implants and to the taper damage modes of corrosion and fretting? (2) Are implant design parameters like neck taper profile, stem material, or head seating associated with the formation of imprinting? (3) Is imprinting created by an impression of the neck taper profile or can a different mechanistic explanation for imprinting be derived? METHODS: Thirty-one THAs with cobalt-chromium-molybdenum-alloy (CoCrMo) heads retrieved between 2013 and 2019 at revision surgery from an institutional registry were investigated. Inclusion criteria were: 12/14 tapers, a head size of 36 mm or smaller, time in situ more than 1 year, and intact nonmodular stems without sleeve adaptors. After grouping the residual THAs according to stem type, stem material, and manufacturer, all groups of three or more were included. Of the resulting subset of 31 retrievals, nine THAs exhibited a still assembled head-neck taper connection. The median (range) time in situ was 5 years (1 to 23). Two stem materials (21 titanium-alloy and 10 stainless steel), three kinds of bearing couples (11 metal-on-metal, 13 metal-on-polyethylene, and seven dual-mobility heads), and two different neck taper profiles (six wavy profile and 25 fluted profile) were present in the collection. Four THAs exhibited signs of eccentric head seating. The 31 investigated THAs represented 21% of the retrieved THAs with a CoCrMo alloy head during the specified period.At the head tapers, the damage modes of corrosion, fretting, and imprinting were semiquantitatively rated on a scale between 0 (no corrosion/fretting/imprinting) and 3 (severe corrosion/fretting/imprinting). Corrosion and fretting were assessed applying the Goldberg score, with the modification that the scale started at 0 and not at 1. Imprinting was assessed with a custom scoring system. Rating was done individually at the proximal and distal head taper half and summed to one total damage score for each retrieval and damage mode. Correlations between the damage modes and time in situ and between the damage modes among each other, were assessed using the Spearman rank order correlation coefficient (ρ). Associations between imprinting and implant design parameters were investigated by comparing the total imprinting score distributions with the Mann-Whitney U-test. Metallographically prepared cross-sections of assembled head-neck taper connections were examined by optical microscopy and disassembled head and neck taper surfaces were assessed by scanning electron microscopy (SEM). RESULTS: The imprinting damage score increased with time in-situ (ρ = 0.72; p < 0.001) and the corrosion damage score (ρ = 0.63; p < 0.001) but not with the fretting damage score (ρ = 0.35; p = 0.05). There was no difference in total imprinting score comparing neck taper profiles or stem materials, with the numbers available. Eccentric head seating had elevated total imprinting score (median 6 [interquartile range 0]) compared with centric seating (median 1 [2]; p = 0.001). Light optical investigations showed that imprinting can be present on the head taper surfaces even if the depth of abraded material exceeds the neck taper profile height. SEM investigations showed bands of pitting corrosion in the imprinted grooves. CONCLUSION: The microscopic investigations suggest that imprinting is not an independent phenomenon but a process that accompanies the continuous material degradation of the head taper surface because of circular damage on the passive layer induced by grooved neck tapers. CLINICAL RELEVANCE: Material loss from head-neck taper connections involving CoCrMo alloy heads is a source of metal ions and could potentially be reduced if hip stems with smooth neck tapers were used. Surgeons should pay attention to the exact centric seating of the femoral head onto the stem taper during joining of the parts.

Influence of FeCl3 and H2O2 in corrosion testing of modular taper connections in total hip arthroplasty: An in vitro study.

Corrosion at the modular taper junctions in total hip arthroplasty is clinically relevant because wear particles and ions generated at this interface can lead to adverse local tissue reactions or even implant failure. In vitro tribo-corrosion tests are usually accomplished in saline solutions or calf serum (CS), but the addition of H2O2 and FeCl3 have been suggested to mimic inflammatory conditions in the joint. Inflammatory conditions may aggravate corrosive processes and, therefore, should lead in vitro to a more severe and realistic tribo-corrosive material attack. Corrosion testing at 12/14 tapers comprising a CoCrMo head taper and a Ti6Al4V trunnion was accomplished in five electrolytes (Ringer's solution (RS), RS with 30 mM H2O2 and/or 0.7 mM FeCl3 and CS) under dynamical loading for five million cycles. Resulting material loss was determined gravimetrically and by ion analysis. The tribo-corrosive material degradation was investigated by light and electron microscopy. FeCl3 enhanced the material loss from taper connections while H2O2 did not lead to a significant alteration of total material loss. In comparison to pure RS, corrosion testing in CS decreased material loss at the head taper while it increased material loss at the trunnion. The combination of FeCl3 and H2O2 led to an enhanced occurrence of micro cracks at the trunnion surface. Adding FeCl3 and optionally also H2O2 aggravates material loss in in vitro corrosion testing of taper junctions and leads to harsher and probably more realistic testing conditions. STATEMENT OF SIGNIFICANCE: Tribo-corrosive processes at taper connections in hip implants are complex and can lead to major clinical implications. Joint inflammation is assumed to aggravate taper corrosion in vivo, why FeCl3 and H2O2 have been proposed as additives to electrolytes to simulate inflammatory conditions in vitro. Often used fretting test setups, however, do not involve real taper geometries. Besides, testing is often accomplished in saline solutions or calf serum, which do not induce a clinically significant amount of corrosive material degradation. This study presents an approach to increase tribo-corrosive processes at realistic taper connections by adding FeCl3 and/or H2O2. Unlike H2O2, FeCl3 increased material loss from taper connections. The combination of both additives enhanced micro crack formation at the trunnion surfaces.

Effect of surface topography and residual stress on the taper connection stability in total hip arthroplasty.

In the present work, the influence of the trunnion surface topography and the near-surface residual stresses on the joining process of a taper connection is examined using a replicate of the realistic taper connection as it occurs in conventional hip joint implants. The focus of the work is on the surface of the taper trunnion made of Ti6Al4V ELI and its effect on the connection stability with a CoCrMo counterpart. In this regard, the interrelation between surface topography, residual stresses, the joining behavior and the corrosion behavior under dynamic loading have been systematically investigated. For this purpose, taper trunnions produced by means of three different machining processes were considered, i.e. fine machining, rough machining and a novel furrowing process. These mechanical surface treatments result in different surface topographies and near-surface work hardening and residual stress states. The results show that the primary taper stability is hardly altered by the different types of trunnion surfaces. For all three surface states, the joining/dismantling procedure did not change the residual stress state at the surface. After corrosion testing under dynamic loading, the fine machined taper surface exhibits the highest stability. Moreover, fine machined tapers consolidated during the dynamic corrosion experiment as the ratio between joining and dismantling force increased from 0.49 ± 0.04 to 0.83 ± 0.08. For the furrowed and rough machined taper surfaces, the connection stability showed a tendency towards increase and decrease, respectively, in the course of dynamic corrosion testing. The results indicate that for choosing an optimal taper trunnion surface, the effects of corrosion must be taken into account.

APP accumulates with presynaptic proteins around amyloid plaques: A role for presynaptic mechanisms in Alzheimer's disease?

In Alzheimer's disease (AD), the distribution of the amyloid precursor protein (APP) and its fragments other than amyloid beta, has not been fully characterized. Here, we investigate the distribution of APP and its fragments in human AD brain samples and in mouse models of AD in reference to its proteases, synaptic proteins, and histopathological features characteristic of the AD brain, by combining an extensive set of histological and analytical tools. We report that the prominent somatic distribution of APP observed in control patients remarkably vanishes in human AD patients to the benefit of dense accumulations of extra-somatic APP, which surround dense-core amyloid plaques enriched in APP-Nter. These features are accentuated in patients with familial forms of the disease. Importantly, APP accumulations are enriched in phosphorylated tau and presynaptic proteins whereas they are depleted of post-synaptic proteins suggesting that the extra-somatic accumulations of APP are of presynaptic origin. Ultrastructural analyses unveil that APP concentrates in autophagosomes and in multivesicular bodies together with presynaptic vesicle proteins. Altogether, alteration of APP distribution and its accumulation together with presynaptic proteins around dense-core amyloid plaques is a key histopathological feature in AD, lending support to the notion that presynaptic failure is a strong physiopathological component of AD.

Fishes regulate tail-beat kinematics to minimize speed-specific cost of transport.

Energetic expenditure is an important factor in animal locomotion. Here we test the hypothesis that fishes control tail-beat kinematics to optimize energetic expenditure during undulatory swimming. We focus on two energetic indices used in swimming hydrodynamics, cost of transport and Froude efficiency. To rule out one index in favour of another, we use computational-fluid dynamics models to compare experimentally observed fish kinematics with predicted performance landscapes and identify energy-optimized kinematics for a carangiform swimmer, an anguilliform swimmer and larval fishes. By locating the areas in the predicted performance landscapes that are occupied by actual fishes, we found that fishes use combinations of tail-beat frequency and amplitude that minimize cost of transport. This energy-optimizing strategy also explains why fishes increase frequency rather than amplitude to swim faster, and why fishes swim within a narrow range of Strouhal numbers. By quantifying how undulatory-wave kinematics affect thrust, drag, and power, we explain why amplitude and frequency are not equivalent in speed control, and why Froude efficiency is not a reliable energetic indicator. These insights may inspire future research in aquatic organisms and bioinspired robotics using undulatory propulsion.

Subcellular Dynamic Immunopatterning of Cytosolic Protein Complexes on Microstructured Polymer Substrates.

Analysis of protein-protein interactions in living cells by protein micropatterning is currently limited to the spatial arrangement of transmembrane proteins and their corresponding downstream molecules. Here, we present a robust and straightforward method for dynamic immunopatterning of cytosolic protein complexes by use of an artificial transmembrane bait construct in combination with microstructured antibody arrays on cyclic olefin polymer substrates. As a proof, the method was used to characterize Grb2-mediated signaling pathways downstream of the epidermal growth factor receptor (EGFR). Ternary protein complexes (Shc1:Grb2:SOS1 and Grb2:Gab1:PI3K) were identified, and we found that EGFR downstream signaling is based on constitutively bound (Grb2:SOS1 and Grb2:Gab1) as well as on agonist-dependent protein associations with transient interaction properties (Grb2:Shc1 and Grb2:PI3K). Spatiotemporal analysis further revealed significant differences in stability and exchange kinetics of protein interactions. Furthermore, we could show that this approach is well suited to study the efficacy and specificity of SH2 and SH3 protein domain inhibitors in a live cell context. Altogether, this method represents a significant enhancement of quantitative subcellular micropatterning approaches as an alternative to standard biochemical analyses.