The Correlation between Diabetes Mellitus and Neurodegenerative Diseases. / Zusammenhang von Diabetes mellitus und neurodegenerativen Erkrankungen.

Today there is no longer any doubt that diabetes mellitus is associated with cognitive impairment and neurodegenerative diseases. The two most common forms of diabetes mellitus are type 1 and type 2. Type 1 diabetes mellitus is characterized by an absolute insulin deficiency that is associated with a large number of metabolic changes. This type of diabetes requires insulin therapy. Without insulin, this disease is fatal. The far more common form of diabetes mellitus nowadays is type 2 diabetes mellitus. It is characterized by insulin resistance. For a number of years drugs have been available that can be used to treat this form of diabetes in a multimodal manner. These therapy options can not only improve metabolic control, but also prevent cardiovascular events. Different cognitive alterations associated with diabetes mellitus can be distinguished. On the one hand, the change in glucose homeostasis itself leads to cognitive alterations, i.e. blood sugar levels that are too high or acutely too low are regularly associated with significant impairments in mental performance, including loss of consciousness. But not only the momentary blood sugar levels, but also long-term changes in glucose metabolism might lead to neurodegeneration and even dementia in a way that has not yet been fully understood. Insulin or insulin-like molecules have important effects in the central nervous system. In the last decades, it has been shown that insulin receptors themselves are expressed in many regions of the brain and e.g. regulate food intake and memory formation in humans and in animal models. In the animal model, disturbances in insulin signal transduction influence the development of pathologies typical of Alzheimer's disease (AD). In humans, central insulin resistance is at least part of the formal pathogenesis of AD. Vascular changes (macroangiopathy) in patients with diabetes mellitus often lead to cerebral insults, microangiopathies and vascular dementia.

Fourier spotting: a novel setup for single-color reflectometry.

Single-color reflectrometry is a sensitive and robust detection method in optical biosensor applications, for example for bioanalysis. It is based on the interference of reflected monochromatic radiation and is label free. We present a novel setup for single-color reflectometry based on the patented technology of Berner et al. from 2016. Tilting areas of micro-mirrors allow us to encode the optical reflection signal of an analyte and reference channel into a particular carrier frequency with the amplitude being proportional to the local reflection. Therefore, a single photodiode is sufficient to collect the signals from both channels simultaneously. A 180∘ phase shift in the tilt frequency of two calibrated micro-mirror areas leads to a superposition of the analyte and reference signal which enables an efficient reduction of the baseline offset and potential baseline offset drift. A performance test reveals that we are able to detect changes of the refractive index n down to Δn < 0.01 of saline solutions as regents. A further test validates the detection of heterogeneous binding interaction. This test compromises immobilized testosterone-bovine serum albumin on a three-dimensional layer of biopolymer as ligand and monoclonal anti-testosterone antibodies as analyte. Antibody/antigen binding induces a local growth of the biolayer and change in the refractive index, which is measured via the local change of the reflection. Reproducible measurements enable for the analysis of the binding kinetics by determining the affinity constant KA = 1.59 × 10- 7 M- 1. In summary, this work shows that the concept of differential Fourier spotting as novel setup for single-color reflectometry is suitable for reliable bioanalysis. Graphical Abstract.

An integrated device for fast and sensitive immunosuppressant detection.

The present paper describes a compact point of care (POC) optical device for therapeutic drug monitoring (TDM). The core of the device is a disposable plastic chip where an immunoassay for the determination of immunosuppressants takes place. The chip is designed in order to have ten parallel microchannels allowing the simultaneous detection of more than one analyte with replicate measurements. The device is equipped with a microfluidic system, which provides sample mixing with the necessary chemicals and pumping samples, reagents and buffers into the measurement chip, and with integrated thin film amorphous silicon photodiodes for the fluorescence detection. Submicrometric fluorescent magnetic particles are used as support in the immunoassay in order to improve the efficiency of the assay. In particular, the magnetic feature is used to concentrate the antibody onto the sensing layer leading to a much faster implementation of the assay, while the fluorescent feature is used to increase the optical signal leading to a larger optical dynamic change and consequently a better sensitivity and a lower limit of detection. The design and development of the whole integrated optical device are here illustrated. In addition, detection of mycophenolic acid and cyclosporine A in spiked solutions and in microdialysate samples from patient blood with the implemented device are reported.

Photoluminescence from GeSn nano-heterostructures.

We investigate the distribution of Sn in GeSn nano-heteroepitaxial clusters deposited at temperatures well exceeding the eutectic temperature of the GeSn system. The 600 °C molecular beam epitaxy on Si-patterned substrates results in the selective growth of GeSn nano-clusters having a 1.4 ± 0.5 at% Sn content. These nano-clusters feature Sn droplets on their faceted surfaces. The subsequent deposition of a thin Ge cap layer induced the incorporation of the Sn atoms segregated on the surface in a thin layer wetting the nano-dots surface with 8 ± 0.5 at% Sn. The presence of this wetting layer is associated with a relatively strong photoluminescence emission that we attribute to the direct recombination occurring in the GeSn nano-dots outer region.

A self-ordered, body-centered tetragonal superlattice of SiGe nanodot growth by reduced pressure CVD.

Self-ordered three-dimensional body-centered tetragonal (BCT) SiGe nanodot structures are fabricated by depositing SiGe/Si superlattice layer stacks using reduced pressure chemical vapor deposition. For high enough Ge content in the island (>30%) and deposition temperature of the Si spacer layers (T > 700 °C), we observe the formation of an ordered array with islands arranged in staggered position in adjacent layers. The in plane periodicity of the islands can be selected by a suitable choice of the annealing temperature before the Si spacer layer growth and of the SiGe dot volume, while only a weak influence of the Ge concentration is observed. Phase-field simulations are used to clarify the driving force determining the observed BCT ordering, shedding light on the competition between heteroepitaxial strain and surface-energy minimization in the presence of a non-negligible surface roughness.

Do ground reaction forces during unilateral and bilateral movements exhibit compensation strategies following ACL reconstruction?

PURPOSE: The aims of the study were (1) to evaluate the leg asymmetry assessed with ground reaction forces (GRFs) during unilateral and bilateral movements of different knee loads in anterior cruciate ligament (ACL) reconstructed patients and (2) to investigate differences in leg asymmetry depending on the International Knee Documentation Committee Subjective Form (IKDC) in order to identify potential compensation strategies. METHODS: The knee function of 50 ACL reconstructed (patella tendon) patients was examined at 31 ± 7 months after the surgery. GRFs were quantified during the sit-to-stand and stand-to-sit test, the step-up and step-down test, and the two- and one-leg vertical jump. Further, the IKDC score, the anterior-posterior knee laxity, and the concentric torque of the quadriceps and hamstring muscles were evaluated. RESULTS: Differences between the operated and non-operated leg were found in the knee laxity, the quadriceps torque, and GRFs. The patients with low IKDC scores demonstrated greater leg asymmetries in GRFs compared to the patients with high IKDC scores. CONCLUSIONS: ACL reconstructed patients showed GRF asymmetries during unilateral and bilateral movements of different knee loads. Three compensation strategies were found in patients with low subjective knee function: (1) a reduced eccentric load, (2) an inter-limb compensation during bilateral movements, and (3) the avoidance of high vertical impact forces. These compensation strategies may be indicative of a protective adaptation to avoid excessive ACL strain. GRF measurements are practicable and efficient tools to identify individual compensation strategies during early rehabilitation.

Liver adapts mitochondrial function to insulin resistant and diabetic states in mice.

BACKGROUND & AIMS: To determine if diabetic and insulin-resistant states cause mitochondrial dysfunction in liver or if there is long term adaptation of mitochondrial function to these states, mice were (i) fed with a high-fat diet to induce obesity and T2D (HFD), (ii) had a genetic defect in insulin signaling causing whole body insulin resistance, but not full blown T2D (IR/IRS-1(+/-) mice), or (iii) were analyzed after treatment with streptozocin (STZ) to induce a T1D-like state. METHODS: Hepatic lipid levels were measured by thin layer chromatography. Mitochondrial respiratory chain (RC) levels and function were determined by Western blot, spectrophotometric, oxygen consumption and proton motive force analysis. Gene expression was analyzed by real-time PCR and microarray. RESULTS: HFD caused insulin resistance and hepatic lipid accumulation, but RC was largely unchanged. Livers from insulin resistant IR/IRS-1(+/-) mice had normal lipid contents and a normal RC, but mitochondria were less well coupled. Livers from severely hyperglycemic and hypoinsulinemic STZ mice had massively depleted lipid levels, but RC abundance was unchanged. However, liver mitochondria isolated from these animals showed increased abundance and activity of the RC, which was better coupled. CONCLUSIONS: Insulin resistance, induced either by obesity or genetic manipulation and steatosis do not cause mitochondrial dysfunction in mouse liver. Also, mitochondrial dysfunction is not a prerequisite for liver steatosis. However, severe insulin deficiency and high blood glucose levels lead to an enhanced performance and better coupling of the RC. This may represent an adaptation to fuel overload and the high energy-requirement of an unsuppressed gluconeogenesis.

Dwarfism in mice lacking collagen-binding integrins α2ß1 and α11ß1 is caused by severely diminished IGF-1 levels.

Mice with a combined deficiency in the α2ß1 and α11ß1 integrins lack the major receptors for collagen I. These mutants are born with inconspicuous differences in size but develop dwarfism within the first 4 weeks of life. Dwarfism correlates with shorter, less mineralized and functionally weaker bones that do not result from growth plate abnormalities or osteoblast dysfunction. Besides skeletal dwarfism, internal organs are correspondingly smaller, indicating proportional dwarfism and suggesting a systemic cause for the overall size reduction. In accordance with a critical role of insulin-like growth factor (IGF)-1 in growth control and bone mineralization, circulating IGF-1 levels in the sera of mice lacking either α2ß1 or α11ß1 or both integrins were sharply reduced by 39%, 64%, or 81% of normal levels, respectively. Low hepatic IGF-1 production resulted from diminished growth hormone-releasing hormone expression in the hypothalamus and, subsequently, reduced growth hormone expression in the pituitary glands of these mice. These findings point out a novel role of collagen-binding integrin receptors in the control of growth hormone/IGF-1-dependent biological activities. Thus, coupling hormone secretion to extracellular matrix signaling via integrins represents a novel concept in the control of endocrine homeostasis.

Temperature grid sensor for the measurement of spatial temperature distributions at object surfaces.

This paper presents results of the development and application of a new temperature grid sensor based on the wire-mesh sensor principle. The grid sensor consists of a matrix of 256 Pt1000 platinum chip resistors and an associated electronics that measures the grid resistances with a multiplexing scheme at high speed. The individual sensor elements can be spatially distributed on an object surface and measure transient temperature distributions in real time. The advantage compared with other temperature field measurement approaches such as infrared cameras is that the object under investigation can be thermally insulated and the radiation properties of the surface do not affect the measurement accuracy. The sensor principle is therefore suited for various industrial monitoring applications. Its applicability for surface temperature monitoring has been demonstrated through heating and mixing experiments in a vessel.

Room Temperature Light Emission from Superatom-like Ge-Core/Si-Shell Quantum Dots.

We have demonstrated the high-density formation of super-atom-like Si quantum dots with Ge-core on ultrathin SiO2 with control of high-selective chemical-vapor deposition and applied them to an active layer of light-emitting diodes (LEDs). Through luminescence measurements, we have reported characteristics carrier confinement and recombination properties in the Ge-core, reflecting the type II energy band discontinuity between the Si-clad and Ge-core. Additionally, under forward bias conditions over a threshold bias for LEDs, electroluminescence becomes observable at room temperature in the near-infrared region and is attributed to radiative recombination between quantized states in the Ge-core with a deep potential well for holes caused by electron/hole simultaneous injection from the gate and substrate, respectively. The results will lead to the development of Si-based light-emitting devices that are highly compatible with Si-ultra-large-scale integration processing, which has been believed to have extreme difficulty in realizing silicon photonics.

Insulin receptor substrate-1 and -2 mediate resistance to glucose-induced caspase-3 activation in human neuroblastoma cells.

Hyperglycemia in patients with type 2 diabetes causes multiple neuronal complications, e.g., diabetic polyneuropathy, cognitive decline, and embryonic neural crest defects due to increased apoptosis. Possible mechanisms of neuronal response to increased glucose burden are still a matter of debate. Insulin and insulin-like growth factor-1 (IGF-1) receptor signaling inhibits glucose-induced caspase-3 activation and apoptotic cell death. The insulin receptor substrates (IRS) are intracellular adapter proteins mediating insulin's and IGF-1's intracellular effects. Even though all IRS proteins have similar function and structure, recent data suggest different actions of IRS-1 and IRS-2 in mediating their anti-apoptotic effects in glucose neurotoxicity. We therefore investigated the role of IRS-1/-2 in glucose-induced caspase-3 activation using human neuroblastoma cells. Overexpression of IRS-1 or IRS-2 caused complete resistance to glucose-induced caspase-3 cleavage. Inhibition of PI3-kinase reversed this protective effect of IRS-1 or IRS-2. However, MAP-kinases inhibition had only minor impact. IRS overexpression increased MnSOD abundance as well as BAD phosphorylation while Bim and BAX levels remained unchanged. Since Akt promotes cell survival at least partially via phosphorylation and inhibition of downstream forkhead box-O (FoxO) transcription factors, we generated neuroblastoma cells stably overexpressing a dominant negative mutant of FoxO1 mimicking activation of the insulin/IGF-1 pathway on FoxO-mediated transcription. Using these cells we showed that FoxO1 is not involved in neuronal protection mediated by increased IRS-1/-2 expression. Thus, overexpression of both IRS-1 and IRS-2 induces complete resistance to glucose-induced caspase-3 activation via PI3-kinase mediated BAD phosphorylation and MnSOD expression independent of FoxO1.

Novel Mixing Relations for Determining the Effective Thermal Conductivity of Open-Cell Foams.

This paper proposes a new approach to relate the effective thermal conductivity of open-cell solid foams to their porosity. It is based on a recently published approach for estimating the dielectric permittivity of isotropic porous media. A comprehensive assessment was performed comparing the proposed mixing relation with published experimental data for thermal conductivity and with numerical data from state-of-the-art relations. The mixing relation for the estimation of thermal conductivities based on dodecahedrons as building blocks shows good agreement with experimental data over a wide range of porosity.

Experimental Study of a Compact Microwave Applicator for Evaporation of Airflow-Entrained Droplets.

In many energy and process engineering systems where fluids are processed, droplet-laden gas flows may occur. As droplets are often detrimental to the system's operation, they need to be removed. Compact engineering solutions for the removal of entrained droplets are difficult to achieve with conventional flow control and heat transfer approaches and thus droplet removal devices are hence often costly and bulky. In this study, we analyzed the potential of a compact technology based on droplet capture and in situ evaporation by microwave heating. For that, we designed a microwave applicator containing a porous droplet separator for capturing and evaporating droplets. The application of open-cell ceramic foams as filter medium reduced 99.9% of the volumetric flow of droplets, while additional microwave exposure increases reduction to 99.99%. In addition, microwave-heated foams prevent droplet re-entrainment and structure-borne liquid accumulation within foams, thus avoiding water clogging and flooding.

Towards the Growth of Hexagonal Boron Nitride on Ge(001)/Si Substrates by Chemical Vapor Deposition.

The growth of hexagonal boron nitride (hBN) on epitaxial Ge(001)/Si substrates via high-vacuum chemical vapor deposition from borazine is investigated for the first time in a systematic manner. The influences of the process pressure and growth temperature in the range of 10-7-10-3 mbar and 900-980 °C, respectively, are evaluated with respect to morphology, growth rate, and crystalline quality of the hBN films. At 900 °C, nanocrystalline hBN films with a lateral crystallite size of ~2-3 nm are obtained and confirmed by high-resolution transmission electron microscopy images. X-ray photoelectron spectroscopy confirms an atomic N:B ratio of 1 ± 0.1. A three-dimensional growth mode is observed by atomic force microscopy. Increasing the process pressure in the reactor mainly affects the growth rate, with only slight effects on crystalline quality and none on the principle growth mode. Growth of hBN at 980 °C increases the average crystallite size and leads to the formation of 3-10 well-oriented, vertically stacked layers of hBN on the Ge surface. Exploratory ab initio density functional theory simulations indicate that hBN edges are saturated by hydrogen, and it is proposed that partial de-saturation by H radicals produced on hot parts of the set-up is responsible for the growth.

Modeling of the Effective Permittivity of Open-Cell Ceramic Foams Inspired by Platonic Solids.

Open-cell solid foams are rigid skeletons that are permeable to fluids, and they are used as direct heaters or thermal dissipaters in many industrial applications. Using susceptors, such as dielectric materials, for the skeleton and exposing them to microwaves is an efficient way of heating them. The heating performance depends on the permittivity of the skeleton. However, generating a rigorous description of the effective permittivity is challenging and requires an appropriate consideration of the complex skeletal foam morphology. In this study, we propose that Platonic solids act as building elements of the open-cell skeletal structures, which explains their effective permittivity. The new, simplistic geometrical relation thus derived is used along with electromagnetic wave propagation calculations of models that represent real foams to obtain a geometrical, parameter-free relation, which is based only on foam porosity and the material's permittivity. The derived relation facilitates an efficient and reliable estimation of the effective permittivity of open-cell foams over a large range of porosity.

Neuronal IGF-1 resistance reduces Abeta accumulation and protects against premature death in a model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by progressive neurodegeneration leading to loss of cognitive abilities and ultimately to death. Postmortem investigations revealed decreased expression of cerebral insulin-like growth factor (IGF)-1 receptor (IGF-1R) and insulin receptor substrate (IRS) proteins in patients with AD. To elucidate the role of insulin/IGF-1 signaling in AD, we crossed mice expressing the Swedish mutation of amyloid precursor protein (APP(SW), Tg2576 mice) as a model for AD with mice deficient for either IRS-2, neuronal IGF-1R (nIGF-1R(-/-)), or neuronal insulin receptor (nIR(-/-)), and analyzed survival, glucose, and APP metabolism. In the present study, we show that IRS-2 deficiency in Tg2576 mice completely reverses premature mortality in Tg2576 females and delays beta-amyloid (Abeta) accumulation. Analysis of APP metabolism suggested that delayed Abeta accumulation resulted from decreased APP processing. To delineate the upstream signal responsible for IRS-2-mediated disease protection, we analyzed mice with nIGF-1R or nIR deficiency predominantly in the hippocampus. Interestingly, both male and female nIGF-1R(-/-)Tg2576 mice were protected from premature death in the presence of decreased Abeta accumulation specifically in the hippocampus formation. However, neuronal IR deletion had no influence on lethality of Tg2576 mice. Thus, impaired IGF-1/IRS-2 signaling prevents premature death and delays amyloid accumulation in a model of AD.

Strong Electron-Phonon Interaction in 2D Vertical Homovalent III-V Singularities.

Highly polar materials are usually preferred over weakly polar ones to study strong electron-phonon interactions and its fascinating properties. Here, we report on the achievement of simultaneous confinement of charge carriers and phonons at the vicinity of a 2D vertical homovalent singularity (antiphase boundary, APB) in an (In,Ga)P/SiGe/Si sample. The impact of the electron-phonon interaction on the photoluminescence processes is then clarified by combining transmission electron microscopy, X-ray diffraction, ab initio calculations, Raman spectroscopy, and photoluminescence experiments. 2D localization and layer group symmetry properties of homovalent electronic states and phonons are studied by first-principles methods, leading to the prediction of a type-II band alignment between the APB and the surrounding semiconductor matrix. A Huang-Rhys factor of 8 is finally experimentally determined for the APB emission line, underlining that a large and unusually strong electron-phonon coupling can be achieved by 2D vertical quantum confinement in an undoped III-V semiconductor. This work extends the concept of an electron-phonon interaction to 2D vertically buried III-V homovalent nano-objects and therefore provides different approaches for material designs, vertical carrier transport, heterostructure design on silicon, and device applications with weakly polar semiconductors.

Timetable of effects of testosterone administration to hypogonadal men on variables of sex and mood.

INTRODUCTION: The effects of testosterone have been extensively characterized, but little attention has been given to the timetable of occurrence of the various effects of testosterone. METHODS: The timetables of effects on sexual and psychological variables in 40 hypogonadal men receiving treatment with either parenteral testosterone enanthate (TE) or undecanoate (TU). RESULTS: Sexual thoughts/fantasies and sexual interest/desire/spontaneous morning erections emerged quickly and plateaued after 3 weeks. Total erections rose to a maximum over 9 weeks and then plateaued. Ejaculations per week/satisfaction with sex life rose over the first 3 weeks, increasing steadily to a plateau at 12 weeks. Depression scores decreased to reach a plateau after 6 weeks. Aggressiveness did not change. Scores of concentration improved and reached a plateau after 3 weeks in the group treated with TE and after 9 weeks in the group treated with TU. Good mood improved after 6-9 weeks. Positive effects on self-confidence appeared between 3-6 weeks and on fatigue after 9-12 weeks. CONCLUSION: Insight into the emergence of effects may be useful information for the patient and for the attending physician in monitoring clinical effects of testosterone treatment of hypogonadal men.

IRS-2 branch of IGF-1 receptor signaling is essential for appropriate timing of myelination.

Insulin-like growth factor (IGF)-1 increases proliferation, inhibits apoptosis and promotes differentiation of oligodendrocytes and their precursor cells, indicating an important function for IGF-1 receptor (IGF-1R) signaling in myelin development. The insulin receptor substrates (IRS), IRS-1 and -2 serve as intracellular IGF-1R adaptor proteins and are expressed in neurons, oligodendrocytes and their precursors. To address the role of IRS-2 in myelination, we analyzed myelination in IRS-2 deficient (IRS-2(-/-)) mice and age-matched controls during postnatal development. Interestingly, expression of the most abundant myelin proteins, myelin basic protein and proteolipid protein was reduced in IRS-2(-/-) brains at postnatal day 10 (P10) as compared to controls. myelin basic protein immunostaining in P10-IRS-2(-/-) mice revealed a reduced immunostaining, but an unchanged regional distribution pattern. In cerebral myelin isolates at P10 unaltered relative expression of different myelin proteins was found, indicating quantitatively reduced but not qualitatively altered myelination. Interestingly, up-regulation of IRS-1 expression and increased IGF-1R signaling were observed in IRS-2(-/-) mice at P10-14, indicating a compensatory mechanism to overcome IRS-2 deficiency. Adult IRS-2(-/-) mice showed unaltered myelination and motor function. Furthermore, in neuronal/brain-specific insulin receptor knockout mice myelination was unchanged. Thus, our experiments reveal that IGF-1R/IRS-2 mediated signals are critical for appropriate timing of myelination in vivo.

Thin Film on CMOS Active Pixel Sensor for Space Applications.

A 664 x 664 element Active Pixel image Sensor (APS) with integrated analog signal processing, full frame synchronous shutter and random access for applications in star sensors is presented and discussed. A thick vertical diode array in Thin Film on CMOS (TFC) technology is explored to achieve radiation hardness and maximum fill factor.