Regulation of mesenchymal stromal cell culture in 3D collagen and NiTi scaffolds by inflammatory and biomechanical factors

The processes of bone fracture healing and bone development share certain similarities and are affected by mechanical loads, the local microenvironment and other factors. In this thesis, an established in vitro fracture callus model was further developed through the introduction of mechanical loading. This system allows for the investigation of the effects of physiological mechanical loads on fracture calluses (engineered endochondral constructs), NiTi-reinforced endochondral constructs and native tissues. Exploring the benefits of rapid-prototyping, shape-memory-alloys and mechanical loading the introduction of a novel, in vitro model for mechanically modulated endochondral ossification is intended. Inflammatory cytokines, which are present in the environment of the fracture site, are important modulators of fracture healing. Thus, the effect of IL-1β on glycosaminoglycan (GAG) production and BMP-2 expression during chondrogenesis and ECM calcification during the hypertrophic phase of in vitro cultures was investigated. These constructs depict an in vitro model for fracture calluses and are therefore used to investigate the effect of IL-1β on the remodeling process, which occurs upon in vivo implantation. It has been demonstrated that IL-1β finely modulates early and late events of the endochondral bone formation by MSC. Controlling the inflammatory environment could enhance the success of therapeutic approaches for the treatment of fractures by resident MSC as well as improve the engineering of implantable tissues. Secondary bone fracture healing is a physiological process, which leads to functional tissue regeneration recapitulating endochondral bone formation. Besides other factors, mechanical loading is known to modulate the process of fracture healing. Therefore, a novel perfused compression bioreactor system (PCB) is demonstrated for the investigation of the effect of dynamic mechanical loading on the mineralization process of engineered, hypertrophic constructs. The results obtained demonstrate that dynamic mechanical loading enhances the maturation process of MSC towards late hypertrophic chondrocytes and the mineralization of the extracellular matrix. Moreover, the system possibly allows for the identification of suitable loading regimes to accelerate the process of fracture healing. In order to improve primary implant stability and to upscale endochondral constructs, selective laser melting (SLM)-based NiTi constructs are foreseen to be utilized as a backbone for hypertrophic cartilage templates. NiTi alloys possess a unique combination of mechanical properties including a relatively low elastic modulus, pseudoelasticity, and high damping capacity, matching the properties of bone. Hence, we demonstrated biocompatibility of NiTi-based constructs. Moreover, MSC adhesion, proliferation and differentiation along the osteogenic lineage were similar to MSC cultured on clinically used Ti. When seeded and cultured on porous 3D SLM-NiTi scaffolds, MSC homogeneously colonized the scaffold, and following osteogenic induction, filled the scaffold’s pore volume with extracellular matrix. The combination of bone-related mechanical properties of SLM-NiTi with its cytocompatibility and support of osteogenic properties by MSC highlights its potential as a superior bone substitute as compared to Ti. In conclusion, MSC based chondrogenic and hypertrophic constructs depict in vitro models for soft and hard fracture calluses, respectively. This constructs are responsive to both inflammatory cytokines (IL-1β modulating early and late events of the endochondral bone formation) and dynamic mechanical loading (increased degree of maturation of both MSC and ECM). Moreover, it has been shown that the PCB serves as a promising tool for further systematic studies in an in vitro setting leading to a reduction of animal experiments within the field. Nevertheless, the established models (including mechanically loaded constructs) are not capable of supporting load-bearing fracture sites. Therefore, to overcome the lack of mechanical stability a NiTi-based approach is intended. SLM-NiTi was shown to be biocompatible and MSC do colonize these constructs and differentiate along the osteogenic lineage. Using SLM-NiTi scaffolds as a backbone supporting initial load-bearing, MSC could be used to colonize it and fill the scaffolds pores with a chondrogenic and/or hypertrophic ECM. This construct depicts a NiTi-reinforced, mechanically stable endochondral implant intended for orthotopic implantation

an ion mobility-mass spectrometry study

Coordinative halogen bonds have recently gained interest for the assembly of supramolecular capsules. Ion mobility-mass spectrometry and theoretical calculations now reveal the well-defined gas-phase structures of dimeric and hexameric [N⋯I+⋯N] halogen-bonded capsules with counterions located inside their cavities as guests. The solution reactivity of the large hexameric capsule shows the intriguing solvent-dependent equilibrium between the hexamer and an unprecedented pentameric [N⋯I+⋯N] halogen-bonded capsule, when the solvent is changed from chloroform to dichloromethane. The intrinsic flexibility of the cavitands enables this novel structure to adopt a pseudo-trigonal bipyramidal geometry with nine [N⋯I+⋯N] bonds along the edges and two pyridine binding sites uncomplexed

Cryogenic infrared spectroscopy reveals remarkably short NH+⋯F hydrogen bonds in fluorinated phenylalanines

In past decades, hydrogen bonds involving organic fluorine have been a highly disputed topic. Obtaining clear evidence for the presence of fluorine-specific interactions is generally difficult because of their weak nature. Today, the existence of hydrogen bonds with organic fluorine is widely accepted and supported by numerous studies. However, strong bonds with short H⋯F distances remain scarce and are primarily found in designed model compounds. Using a combination of cryogenic gas-phase infrared spectroscopy and density functional theory, we here analyze a series of conformationally unrestrained fluorinated phenylalanine compounds as protonated species. The results suggest proximal NH+⋯F hydrogen bonds with an exceptionally close H⋯F distance (1.79 Å) in protonated ortho-fluorophenylalanine

Decoding the Fucose Migration Product during Mass-Spectrometric analysis of Blood Group Epitopes

Fucose is a signaling carbohydrate that is attached at the end of glycan processing. It is involved in a range of processes, such as the selectin-dependent leukocyte adhesion or pathogen-receptor interactions. Mass-spectrometric techniques, which are commonly used to determine the structure of glycans, frequently show fucose-containing chimeric fragments that obfuscate the analysis. The rearrangement leading to these fragments—often referred to as fucose migration—has been known for more than 25 years, but the chemical identity of the rearrangement product remains unclear. In this work, we combine ion-mobility spectrometry, radical-directed dissociation mass spectrometry, cryogenic IR spectroscopy of ions, and density-functional theory calculations to deduce the product of the rearrangement in the model trisaccharides Lewis x and blood group H2. The structural search yields the fucose moiety attached to the galactose with an α(1→6) glycosidic bond as the most likely product

Emergence of low-symmetry foldamers from single monomers

Self-assembly is a powerful method to obtain large discrete functional molecular architectures. When using a single building block, self-assembly generally yields symmetrical objects in which all the subunits relate similarly to their neighbours. Here we report the discovery of a family of self-constructing cyclic macromolecules with stable folded conformations of low symmetry, which include some with a prime number (13, 17 and 23) of units, despite being formed from a single component. The formation of these objects amounts to the production of polymers with a perfectly uniform length. Design rules for the spontaneous emergence of such macromolecules include endowing monomers with a strong potential for non-covalent interactions that remain frustrated in competing entropically favoured yet conformationally restrained smaller cycles. The process can also be templated by a guest molecule that itself has an asymmetrical structure, which paves the way to molecular imprinting techniques at the level of single polymer chains

Pogorszenie kontroli ciśnienia tętniczego skojarzone ze znaczną progresją przewlekłej choroby nerek u 68-letniej kobiety z przewlekłym zamknięciem lewej tętnicy nerkowej — opis przypadku

Atherosclerotic renal artery stenosis is important etiology of secondary hypertension. Optimal treatment in this disease has been widely discussed for the recent 30 years. Authors present a case of a patient with a history of arterial hypertension, chronic closure of left renal artery, left kidney atrophy and chronic kidney disease with significant blood pressure control and kidney function deterioration in a short period of time. Miażdżycowe zwężenie tętnicy nerkowej stanowi ważną przyczynę wtórnego nadciśnienia tętniczego. W ostatnich 30 latach szeroko dyskutowano optymalne postępowanie w tej jednostce chorobowej. Autorzy prezentują przypadek pacjentki obciążonej nadciśnieniem tętniczym, przewlekle zamkniętą lewą tętnicą nerkową i z zanikową lewą nerką oraz przewlekłą chorobą nerek, u której w krótkim czasie doszło do znacznego pogorszenia kontroli ciśnienia tętniczego i parametrów funkcji nerek.

Moderate-to-High Intensity Physical Exercise in Patients with Alzheimer's Disease:A Randomized Controlled Trial

Background: Studies of physical exercise in patients with Alzheimer’s disease (AD) are few and results have been inconsistent. Objective: To assess the effects of a moderate-to-high intensity aerobic exercise program in patients with mild AD. Methods: In a randomized controlled trial, we recruited 200 patients with mild AD to a supervised exercise group (60-min sessions three times a week for 16 weeks) or to a control group. Primary outcome was changed from baseline in cognitive performance estimated by Symbol Digit Modalities Test (SDMT) in the intention-to-treat (ITT) group. Secondary outcomes included changes in quality of life, ability to perform activities of daily living, and in neuropsychiatric and depressive symptoms. Results: The ITT analysis showed no significant differences between intervention and control groups in change from baseline of SDMT, other cognitive tests, quality of life, or activities of daily living. The change from baseline in Neuropsychiatric Inventory differed significantly in favor of the intervention group (mean: –3.5, 95% confidence interval (CI) –5.8 to –1.3, p = 0.002). In subjects who adhered to the protocol, we found a significant effect on change from baseline in SDMT as compared with the control group (mean: 4.2, 95% CI 0.5 to 7.9, p = 0.028), suggesting a dose-response relationship between exercise and cognition. Conclusions: This is the first randomized controlled trial with supervised moderate-to-high intensity exercise in patients with mild AD. Exercise reduced neuropsychiatric symptoms in patients with mild AD, with possible additional benefits of preserved cognition in a subgroup of patients exercising with high attendance and intensity.</jats:p

Impacts of climate change adaptation options on soil functions: A review of European case‐studies

Soils are vital for supporting food security and other ecosystem services. Climate change can affect soil functions both directly and indirectly. Direct effects include temperature, precipitation, and moisture regime changes. Indirect effects include those that are induced by adaptations such as irrigation, crop rotation changes, and tillage practices. Although extensive knowledge is available on the direct effects, an understanding of the indirect effects of agricultural adaptation options is less complete. A review of 20 agricultural adaptation case‐studies across Europe was conducted to assess implications to soil threats and soil functions and the link to the Sustainable Development Goals (SDGs). The major findings are as follows: (a) adaptation options reflect local conditions; (b) reduced soil erosion threats and increased soil organic carbon are expected, although compaction may increase in some areas; (c) most adaptation options are anticipated to improve the soil functions of food and biomass production, soil organic carbon storage, and storing, filtering, transforming, and recycling capacities, whereas possible implications for soil biodiversity are largely unknown; and (d) the linkage between soil functions and the SDGs implies improvements to SDG 2 (achieving food security and promoting sustainable agriculture) and SDG 13 (taking action on climate change), whereas the relationship to SDG 15 (using terrestrial ecosystems sustainably) is largely unknown. The conclusion is drawn that agricultural adaptation options, even when focused on increasing yields, have the potential to outweigh the negative direct effects of climate change on soil degradation in many European regions