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Diabetes mellitus (DM) is an emerging metabolic disease, and the management of diabetic bone disease poses a serious challenge worldwide. Understanding the underlying mechanisms leading to high fracture risk in DM is hence of particular interest and urgently needed to allow for diagnosis and treatment optimization. In a case-control postmortem study, the whole 12th thoracic vertebra and cortical bone from the mid-diaphysis of the femur from male individuals with type 1 diabetes mellitus (T1DM) (n = 6; 61.3 ± 14.6 years), type 2 diabetes mellitus (T2DM) (n = 11; 74.3 ± 7.9 years), and nondiabetic controls (n = 18; 69.3 ± 11.5) were analyzed with clinical and ex situ imaging techniques to explore various bone quality indices. Cortical collagen fibril deformation was measured in a synchrotron setup to assess changes at the nanoscale during tensile testing until failure. In addition, matrix composition was analyzed including determination of cross-linking and non-crosslinking advanced glycation end-products like pentosidine and carboxymethyl-lysine. In T1DM, lower fibril deformation was accompanied by lower mineralization and more mature crystalline apatite. In T2DM, lower fibril deformation concurred with a lower elastic modulus and tendency to higher accumulation of non-crosslinking advanced glycation end-products. The observed lower collagen fibril deformation in diabetic bone may be linked to altered patterns mineral characteristics in T1DM and higher advanced glycation end-product accumulation in T2DM. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Despite its clinical relevance in the context of ankle fractures, little is known about the bone microarchitecture and strength of the distal fibula, especially regarding age-, sex-, and subregion-specific effects. To address this gap of knowledge, we obtained fibulae from 30 skeletally intact donors at autopsy (each 15 male and female), which were analyzed by high-resolution peripheral quantitative computed tomography including micro-finite element analysis. Scans were performed in a 7-cm volume of interest and evaluated in three subregions according to the Danis-Weber fracture classification. Group comparisons and linear regression analyses were applied to evaluate the effects of age, sex, and subregion. From distal to proximal, we observed an increase of cortical parameters and a decrease of trabecular parameters. Age was primarily associated with a cortical decrease in all subregions (Danis-Weber type A, B, and C) in women. While women showed a greater magnitude of decline, men also exhibited an age-associated decrease for some parameters, including cortical area and cortical thickness in the type C subregion. Stiffness and failure load were highest in the type C subregion in both women and men. A critical age-related decline in bone strength parameters in the type B subregion was observed in women, providing an explanation for the increased incidence of low-traumatic type B fractures in the elderly. Together, these findings extend the current understanding of distal fibular microarchitecture, likely explaining the epidemiologic features of distal fibula fractures and emphasizing the need for age-adapted treatment algorithms.

MALT1 is a key mediator of NF-κB signaling and a main driver of B-cell lymphomas. Remarkably, MALT1 is expressed in the majority of pancreatic ductal adenocarcinomas (PDACs) as well, but absent from normal exocrine pancreatic tissue. Following, MALT1 shows off to be a specific target in cancer cells of PDAC without affecting regular pancreatic cells. Therefore, we studied the impact of pharmacological MALT1 inhibition in pancreatic cancer and showed promising effects on tumor progression. Mepazine (Mep), a phenothiazine derivative, is a known potent MALT1 inhibitor. Newly, we described that biperiden (Bip) is a potent MALT1 inhibitor with even less pharmacological side effects. Thus, Bip is a promising drug leading to reduced proliferation and increased apoptosis in PDAC cells in vitro and in vivo. By compromising MALT1 activity, nuclear translocation of c-Rel is prevented. c-Rel is critical for NF-κB-dependent inhibition of apoptosis. Hence, off-label use of Bip or Mep represents a promising new therapeutic approach to PDAC treatment. Regularly, the Anticholinergicum Bip is used to treat neurological side effects of Phenothiazines, like extrapyramidal symptoms.

Cartilage calcification (CC) is associated with degeneration in non-vertebral joints, but little is known about CC and lumbar vertebral joints. The goal of this study was to analyze the prevalence of CC in lumbar facet joints (FJ) and intervertebral discs (IVD) and its relation to cartilage degeneration and age in a non-selected cohort of the general population. The segment L4/5 of 85 consecutive donors (mean age 61.9 years) was analyzed by high-resolution imaging digital-contact radiography (DCR). Quantification was achieved by measuring CC in % of total cartilage area. Histological degeneration of FJs and IVDs was determined by OARSI and Boos scores. Prevalence of CC was 36.5% for FJ (95%CI (0.26, 0.48)) and 100% for IVD (95%CI (0.96, 1.00)). The amount of IVD CC (3.36% SD ± 7.14) was 16.3 times higher (p

The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one‐third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling‐centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes., The current article reviews the most up‐to‐date literature on Endoplasmic Reticulum (ER) biology and articulates this information from a signalling perspective. Not only do we cover the basic cell biology aspects of adaptive ER signalling but also provide information about the latest discoveries on ER stress targeting drugs and their potential use in the clinic.

Articular cartilage calcification is considered a pathological albeit incompletely understood process which is known to be associated with osteoarthritis of the knee and hip. The goal of this study was to determine the prevalence of articular cartilage calcification of the shoulder as a non-weight-bearing joint and to analyze the interrelationship of calcification with age and histological severity of shoulder osteoarthritis in the general population. In a cross-sectional study of 180 humeral heads from 90 donors (n = 49 male, n = 41 female; mean age 62.7 years [20-93]), cartilage calcification of the humeral head was quantified by digital contact radiography (DCR). Histological OA grade (OARSI) was determined and structural equation modeling (SEM) was used to analyze the interrelationship of cartilage calcification, OARSI and age. The prevalence of articular cartilage calcification was 98.9% (95%CI: [93.96%, 99.97%]) and was independent of gender (p = 0.55). Cartilage calcification of one shoulder correlated significantly with that of the contralateral side (r = 0.61, 95%CI: [0.46, 0.73], p

An extensive field trial was established on a fly ash deposit (1) to evaluate whether the inoculation with arbuscular mycorrhizal fungi (AMF) and/or ectomycorrhizal fungi (EcMF) improves growth and survival of 13 planted tree species and (2) to trace the inoculated mycorrhizal fungi in tree roots after one growing season. Molecular methods were applied to characterize AMF and EcMF entering the studied system (inocula, native soil, and roots of nursery seedlings). Biometric parameters and mortality of the trees were recorded and the presence of AMF and EcMF in sampled trees was determined both microscopically and genetically. Mycorrhizal inoculation did not improve survival or growth of any tree species. Most AMF-host and all EcMF-host seedlings were highly precolonized already from the nursery. An abundant and diverse AMF community was also found in the field soil. The AMF inoculum taxa partially overlapped with AMF in the native soil and in the precolonized roots. After one season, the only two inoculum-unique AMF taxa were detected in host species non-precolonized or only partially precolonized from the nursery. The components of EcMF inoculum were not detected in any sampled tree. After the season, the ectomycorrhizal hosts maintained most of their original EcMF taxa gathered in nursery, some tree species were additionally colonized by EcMF probably originating from the soil. Our results show considerable self-restoration potential of nature on the target site. Mycorrhizal inoculation thus did not bring any conclusive advantage to the planted trees and seems superfluous for reclamation practice on the fly ash deposit.

Objective: The aim was to analyze the relationship between scapular form and function in hominoids by using geometric morphometrics (GM) and finite element analysis (FEA).Methods: FEA was used to analyze the biomechanical performance of different hominoid scapulae by simulating static postural scenarios. GM was used to quantify scapular shape differences and the relationship between form and function was analyzed by applying both multivariate-multiple regressions and phylogenetic generalized least- squares regressions (PGLS).Results: Although it has been suggested that primate scapular morphology is mainly a product of function rather than phylogeny, our results showed that shape has a significant phylogenetic signal. There was a significant rela- tionship between scapular shape and its biomechanical performance; hence at least part of the scapular shape varia- tion is due to non-phylogenetic factors, probably related to functional demands.Discussion: This study has shown that a combined approach using GM and FEA was able to cast some light regarding the functional and phylogenetic contributions in hominoid scapular morphology, thus contributing to a better insight of the association between scapular form and function. Am J Phys Anthropol 000:000?000, 2015. VC 2015 Wiley Periodicals, Inc.

In 2011, a large outbreak of Shiga toxin-producing enterohemorrhagic Escherichia coli (EHEC) infections occurred in northern Germany, which mainly affected adults. Out of 3842 patients, 104 experienced a complicated course comprising hemolytic uremic syndrome and neurological complications, including cognitive impairment, aphasia, seizures and coma. T2 hyperintensities on magnet resonance imaging (MRI) bilateral in the thalami and in the dorsal pons were found suggestive of a metabolic toxic effect. Five of the 104 patients died because of toxic heart failure. In the present study, the post-mortem neuropathological findings of the five EHEC patients are described. Histological investigation of 13 brain regions (frontal, temporal, occipital cortex, corpora mammillaria, thalamus, frontal operculum, corona radiata, gyrus angularis, pons, medulla oblongata, cerebellar vermis and cerebellar hemisphere) showed no thrombosis, ischemic changes or fresh infarctions. Further, no changes were found in electron microscopy. In comparison with five age-matched controls, slightly increased activation of microglia and a higher neuronal expression of interleukin-1β and of Shiga toxin receptor CD77/globotriaosylceramide 3 was observed. The findings were confirmed by Western blot analyses. It is suggested that CD77/globotriaosylceramide upregulation may be a consequence to Shiga toxin exposure, whereas increased interleukin-1β expression may point to activation of inflammatory cascades.

Optimizing illumination is essential for optimizing the growth of phototrophic cells and their production of desired metabolites and/or biomass. This requires appropriate modulation of light and other key inputs and continuous online monitoring of their metabolic activities. Powerful noninvasive systems for cultivating heterotrophic organisms include shake flasks in online monitoring units, but they are rarely used for phototrophs because they lack the appropriate illumination design and necessary illuminatory power. This study presents the design and characterization of a photosynthetic shake flask unit, illuminated from below by warm white light-emitting diodes with variable light intensities up to 2300 μmol m−2 s−1. The photosynthetic unit was successfully used, in combination with online monitoring of oxygen production, to cultivate Arthrospira platensis. In phototrophic growth under continuous light and a 16 h light/8 h dark cycle (light intensity: 180 μmol m−2 s−1), the oxygen transfer rate and biomass-related oxygen production were −1.5 mmol L−1 h−1 and 0.18 mmol O2 gx−1 h−1, respectively. The maximum specific growth rate was 0.058 h−1, during the exponential growth phase, after which the biomass concentration reached 0.75 g L−1.

The validity of dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) measurements as predictors of pertrochanteric and femoral neck fracture loads was compared in an experimental simulation of a fall on the greater trochanter. 65 proximal femora were harvested from patients at autopsy. All specimens were scanned with use of DXA for areal bone mineral density and pQCT for volumetric densities at selected sites of the proximal femur. A three-point bending test simulating a side-impact was performed to determine fracture load and resulted in 16 femoral neck and 49 pertrochanteric fractures. Regression analysis revealed that DXA BMD trochanter was the best variable at predicting fracture load of pertrochanteric fractures with an adjusted R2 of 0.824 (p

Background and Purpose Recent studies suggested a role for PGE2 in the expression of the chemokine IL-8. PGE2 signals via four different GPCRs, EP1-EP4. The role of EP1 and EP4 receptors for IL-8 induction was studied in HEK293 cells, overexpressing EP1 (HEK-EP1), EP4 (HEK-EP4) or both receptors (HEK-EP1 + EP4). Experimental Approach IL-8 mRNA and protein induction and IL-8 promoter and NF-κB activation were assessed in EP expressing HEK cells. Key Results In HEK-EP1 and HEK-EP1 + EP4 but not HEK or HEK-EP4 cells, PGE2 activated the IL-8 promoter and induced IL-8 mRNA and protein synthesis. Stimulation of HEK-EP1 + EP4 cells with an EP1-specific agonist activated IL-8 promoter and induced IL-8 mRNA and protein, whereas a specific EP4 agonist neither activated the IL-8 promoter nor induced IL-8 mRNA and protein synthesis. Simultaneous stimulation of HEK- EP1 + EP4 cells with both agonists activated IL-8 promoter and induced IL-8 mRNA to the same extent as PGE2. In HEK-EP1 + EP4 cells, PGE2-mediated IL-8 promoter activation and IL-8 mRNA induction were blunted by inhibition of IκB kinase. PGE2 activated NF-κB in HEK-EP1, HEK-EP4 and HEK-EP1 + EP4 cells. In HEK-EP1 + EP4 cells, simultaneous activation of both receptors was needed for maximal PGE2-induced NF-κB activation. PGE2-stimulated NF-κB activation by EP1 was blocked by inhibitors of PLC, calcium-signalling and Src-kinase, whereas that induced by EP4 was only blunted by Src-kinase inhibition. Conclusions and Implications These findings suggest that PGE2-mediated NF-κB activation by simultaneous stimulation of EP1 and EP4 receptors induces maximal IL-8 promoter activation and IL-8 mRNA and protein induction.

Background and Objective Preclinical studies suggest an increased vaporization rate and speed of the 532 nm 180-W XPS GreenLight laser (180-W) compared with the 120-W HPS GreenLight laser (120-W) and the 80-W PV GreenLight laser (80-W). To test the clinical relevance of this observation we analyzed intraoperative data and early postoperative results after photoselective vaporization of the prostate (PVP) with the 180-W, 120-W, and 80-W laser. Study Design/Materials and Methods A retrospective pair-to-pair comparison was performed including 80 consecutive patients who underwent PVP for the treatment of benign prostate enlargement with the 180-W, 120-W, and 80-W laser. The groups matched concerning age, prostate volume, PSA-value, and preoperative catheterization. Primary study outcome measurement was PSA-value reduction at 3 months; intraoperative data, perioperative complications, and early postoperative functional course were secondary study outcome measurements. Results Energy application per case (kJ), preoperative prostate volume (kJ/ml) operating time (kJ/minute), and lasing time (kJ/minute) was significantly higher with the 180-W laser. Prevalence of impaired visibility due to bleeding was comparable between the 180-W and the 120-W laser but significantly lower with 80-W. Duration of hospitalization was shorter with the 180-W laser compared to the former laser systems. During the postoperative course of 3 months voiding parameters and micturition symptoms significantly improved in all groups, the incidence of postoperative dysuria was comparable. Postoperative PSA-value reduction was significantly higher after treatment with the 180-W laser. Conclusions With the 180-W laser, higher energy application and higher speed of tissue vaporization leads to increased tissue vaporization compared to the former 120-W and 80-W laser systems. Clinical efficacy and perioperative safety are maintained with the higher powered laser. Lasers Surg. Med. 45: 28–33, 2013. © 2012 Wiley Periodicals, Inc.

Demographische und historische Analyse der Hamburger Hornhautbank uber 30 Jahre Purpose: To evaluate donor demographics, trends in donor tissue procurement and tissue storage over a long period. Methods: A retrospective, longitudinal, descriptive analysis was undertaken of data from the Hamburg Eye Bank Data Base (HEB-DB) that had been collected between 1981 and 2010. Data on 54 parameters of cornea donors [including clinical history, age, death cause, gender and death-to-explantation interval (DEI)]and of cultivated corneas (endothelial quality and development in culture, cultivation period, microbiological contamination) were retrieved. These data were analysed statistically, focusing on the historical development of the eye bank. Results: At the time of retrieval (June 2010), the HEB-DB contained data on 10 943 corneas (5503 donors). Most donors were men (65%) and had died from cardiopulmonary (n = 801) ⁄ cerebral (n = 261) failure or as the result of a polytraumatic accident ⁄ suicide (n = 602). Within these years, donor age,DEI and storage time increased. The percentage of stored corneas suitable forntransplantation displayed a variable but increasing trend; in 2007, almost 75% of the stored corneas were transplanted. Between 1995 and June 2010, the median microbiological contamination rate was 5.3%. A change in the procurement procedure from enucleation to corneoscleral explantation in 2008 led to a briefly increased contamination rate. Conclusion: Donor demographic data run parallel to the general demographic development. Our analysis indicates a dynamic development of the eye bank over the last 30 years and emphasizes the need for an active quality management in coping with the challenges of modern eye banking.

Formation of the mammalian primitive streak appears to rely on cell proliferation to a minor extent only, but compensating cell movements have not yet been directly observed. This study analyses individual cell migration and proliferation simultaneously, using multiphoton and differential interference contrast time-lapse microscopy of late pregastrulation rabbit blastocysts. Epiblast cells in the posterior gastrula extension area accumulated medially and displayed complex planar movements including U-turns and a novel type of processional cell movement. In the same area metaphase plates tended to be aligned parallel to the anterior-posterior axis, and statistical analysis showed that rotations of metaphase plates causing preferred orientation were near-complete 8 min before anaphase onset; in some cases, rotations were strikingly rapid, achieving up to 45° per min. The mammalian primitive streak appears to be formed initially with its typically minimal anteroposterior elongation by a combination of oriented cell divisions with dedicated planar cell movements.

An agricultural use of reclaimed coal-mine spoil banks is limited to nonfood crop uses and provides potential for biofuel crops. Two high-biomass crops—Galega orientalis and Helianthus tuberosus—were cultivated in a greenhouse pot experiment conducted in sterilized and nonsterile spoil bank clay. We aimed (1) to determine the possibility of reducing the applied rate of organic amendments (thus decreasing the costs of spoil-bank reclamation) and (2) to assess whether the inoculation with arbuscular mycorrhizal fungi (AMF) can improve plant growth and biomass accumulation of bioenergy crops even in nonsterile soil containing naturally occurring AMF. The spoil substrate was either unamended or treated with a mixture of composted urban waste and ligno-cellulose at a rate corresponding to 40 t ha–1. Three native AMF isolates or three isolates from the International Bank of Glomeromycota (BEG) originating from man-made ecosystems were used for inoculation. Generally, both plant species positively responded to both mycorrhizal inoculation and organic amendment. While G. orientalis did not show any preferences towards the AMF inoculum origin in the nonsterile soil, for H. tuberosus the specific combination of organic amendment and BEG isolates resulted in highest yields of shoot biomass. The study shows that the successful planting of both tested crops requires the organic amendment. However, its dosage can be substantially reduced. The effectiveness of mycorrhizal inoculation can vary for the combination of plant species and the origin of the applied AMF.

The prevention of hip fractures is a desirable goal to reduce morbidity, mortality, and socio-economic burden. We evaluated the influence on femoral strength of different clinically applicable cementing techniques as “femoroplasty.” Twenty-eight human cadaveric femora were augmented by means of four clinically applicable percutaneous cementing techniques and then tested biomechanically against their native contralateral control to determine fracture strength in an established biomechanical model mimicking a fall on the greater trochanter. The energy applied until fracture could be significantly increased by two of the methods by 160% (53.1 Nm vs. 20.4 Nm, p

This study focused on the application of native strains of arbuscular mycorrhizal fungi (AMF) and Sinorhizobium in effective crop production during reclamation of coal-mine spoil banks. Two greenhouse experiments were conducted in spoil-bank clay with a low dose of organic amendment to determine whether the microbial inoculation improves growth and utility qualities of two cultivars of Linum usitatissimum L. (oil and fiber flax). Inoculation with two native AMF isolates (Glomus mosseae, G. intraradices, and their mixture) significantly increased growth and shoot phosphorus (P) concentration of both flax cultivars. Inoculated fiber flax plants produced fivefold more fibers than the uninoculated ones. In oil flax, mycorrhizal inoculation significantly but quantitatively to a minor degree decreased the concentration of nonsaturated fatty acids in the seed oil. A mixture of five native Sinorhizobium sp. strains supported growth and P uptake of oil flax only in the absence of AMF. However, these beneficial effects of the bacteria were significantly lower as compared to AMF. No synergic action of Sinorhizobium strains and AMF was observed, and their interactions were often even antagonistic. Inoculation with AMF significantly decreased population density of Sinorhizobium in the soil. These results suggest that a careful selection of suitable bacterial strains is necessary to provide effective AMF combinations and maximize flax-growth support.