Longitudinal Assessment of In Vivo Bone Dynamics in a Mouse Tail Model of Postmenopausal Osteoporosis

Recently, it has been shown that transient bone biology can be observed in vivo using time-lapse micro-computed tomography (μCT) in the mouse tail bone. Nevertheless, in order for the mouse tail bone to be a model for human disease, the hallmarks of any disease must be mimicked. The aim of this study was to investigate whether postmenopausal osteoporosis could be modeled in caudal vertebrae of C57Bl/6mice, considering static and dynamic bone morphometry as well as mechanical properties, and to describe temporal changes in bone remodeling rates. Twenty C57Bl/6mice were ovariectomized (OVX, n=11) or sham-operated (SHM, n=9) and monitored with in vivo μCT on the day of surgery and every 2weeks after, up to 12weeks. There was a significant decrease in bone volume fraction for OVX (−35%) compared to SHM (+16%) in trabecular bone (P<0.001). For OVX, high-turnover bone loss was observed, with the bone resorption rate exceeding the bone formation rate (P<0.001). Furthermore there was a significant decrease in whole-bone stiffness for OVX (−16%) compared to SHM (+11%, P<0.001). From these results we conclude that the mouse tail vertebra mimics postmenopausal bone loss with respect to these parameters and therefore might be a suitable model for postmenopausal osteoporosis. When evaluating temporal changes in remodeling rates, we found that OVX caused an immediate increase in bone resorption rate (P<0.001) and a delayed increase in bone formation rate (P<0.001). Monitoring transient bone biology is a promising method for future researc

Towards narrowing the reality gap in electromechanical systems: error modeling in virtual commissioning

Digital factories and smart manufacturing systems have been increasingly researched and multiple concepts were developed to cope with prevailing ever-shortening life-cycles. The ubiquitous digital twin, despite many definitions, is often praised for accurate virtual models. One key idea to improve manufacturing through such virtual models is $\textit{virtual commissioning}$ (VC), aiming at early machine code validation. VC and its virtual models are still lacking behind their real counterparts. This gap between reality and its virtual model, commonly termed $\textit{reality gap}$, increases the complexity of creating cyber-physical systems. An especially stark contrast is visible between the idealized virtual model and a real machine encountering errors. While error simulations exist in other fields of research, a thorough investigation in VC is missing. Thus, this paper addresses the task of narrowing the reality gap in VC based on two steps. First, a comprehensive body of research of possible errors encountered in virtual commissioning is analyzed. Secondly, the feasibility of error implementation is discussed. This paper lays the foundation for narrowing the reality gap and enabling test automation and digital twin-based control

The major urinary protein gene cluster knockout mouse as a novel model for translational metabolism research

Scientific evidence suggests that not only murine scent communication is regulated by major urinary proteins, but that their expression may also vary in response to metabolism via a yet unknown mechanism. Major urinary proteins are expressed mainly in the liver, showing a sexually dimorphic pattern with substantially higher expression in males. Here, we investigate the metabolic implications of a major urinary protein knockout in twelve-week-old male and female C57BL/6N mice during ad libitum feeding. Despite both sexes of major urinary protein knockout mice displayed numerically increased body weight and visceral adipose tissue proportions compared to sex-matched wildtype mice, the main genotype-specific metabolic differences were observed exclusively in males. Male major urinary protein knockout mice exhibited plasma and hepatic lipid accumulation accompanied by a hepatic transcriptome indicating an activation of lipogenesis. These findings match the higher major urinary protein expression in male compared to female wildtype mice, suggesting a more distinct reduction in energy requirements in male compared to female major urinary protein knockout mice. The observed sex-specific anabolic phenotype confirms a role of major urinary protein in metabolism and, since major urinary proteins are not expressed in humans, suggests the major urinary protein knockout mouse as a potential alternative model for translational metabolism research which needs to be further elucidated

Variations in export production, lithogenic sediment transport and iron fertilization in the Pacific sector of the Drake Passage over the past 400 kyr

Changes in Southern Ocean export production have broad biogeochemical and climatic implications. Specifically, iron fertilization likely increased subantarctic nutrient utilization and enhanced the efficiency of the biological pump during glacials. However, past export production in the subantarctic southeastern Pacific is poorly documented, and its connection to Fe fertilization, potentially related to Patagonian Ice Sheet dynamics, is unknown. We report biological productivity changes over the past 400 kyr, based on a combination of 230Thxs-normalized and stratigraphy-based mass accumulation rates of biogenic barium, organic carbon, biogenic opal and calcium carbonate as indicators of paleo-export production in a sediment core upstream of the Drake Passage (57.5∘ S, 70.3∘ W). In addition, we use fluxes of iron and lithogenic material as proxies for terrigenous input, and thus potential micronutrient supply. Stratigraphy-based mass accumulation rates are strongly influenced by bottom-current dynamics, which result in variable sediment focussing or winnowing at our site. Carbonate is virtually absent in the core, except during peak interglacial intervals of the Holocene, and Marine Isotope Stages (MIS) 5 and 11, likely caused by transient decreases in carbonate dissolution. All other proxies suggest that export production increased during most glacial periods, coinciding with high iron fluxes. Such augmented glacial iron fluxes at the core site were most likely derived from glaciogenic input from the Patagonian Ice Sheet promoting the growth of phytoplankton. Additionally, glacial export production peaks are also consistent with northward shifts of the Subantarctic and Polar Fronts, which positioned our site south of the Subantarctic Front and closer to silicic acid-rich waters of the Polar Frontal Zone. However, glacial export production near the Drake Passage was lower than in the Atlantic and Indian sectors of the Southern Ocean, which may relate to complete consumption of silicic acid in the study area. Our results underline the importance of micro-nutrient fertilization through lateral terrigenous input from South America rather than eolian transport and exemplify the role of frontal shifts and nutrient limitation for past productivity changes in the Pacific entrance to the Drake Passage

The immunologic tumor microenvironment in endometrioid endometrial cancer in the morphomolecular context: mutual correlations and prognostic impact depending on molecular alterations

OBJECTIVE POLE-mutant, microsatellite-instable (MSI), p53-mutant and non-specific molecular profile (NSMP) are TCGA-defined molecular subgroups of endometrial cancer (EC). Hypothesizing that morphology and tumor immunology might differ depending on molecular background concerning composition and prognostic impact, we aimed to comprehensively interconnect morphologic, immunologic and molecular data. METHODS TCGA-defined molecular groups were determined by immunohistochemistry and sequencing in n = 142 endometrioid EC. WHO-defined histopathological grading was performed. The immunologic microenvironment (iTME) was characterised by the quantification of intraepithelial and stromal populations of tumor-infiltrating lymphocytes (TIL: overall T-cells; T-Killer cells; regulatory T-cells (Treg)). Immunologic parameters were correlated with WHO-grading, TCGA-subgroups and prognosis. RESULTS High density TIL were significantly more frequent in high-grade (G3) compared to low-grade (G1/2) EC in the whole cohort and in the subgroup of POLE-wildtype-/microsatellite-stable-EC. MSI was associated with high-level TIL-infiltration when taking into account the type of mismatch repair defect (MLH1/PMS2; MSH2/MSH6). Prognostic impact of biomarkers depended on molecular subgroups: In p53-mutant EC, Treg were independently prognostic, in NSMP, the unique independently prognostic biomarker was WHO-grading. CONCLUSIONS EC morphology and immunology differ depending on genetics. Our study delineated two molecularly distinct subgroups of immunogenic EC characterized by high-density TIL-infiltration: MSI EC and high-grade POLE-wildtype/microsatellite-stable-EC. Prognostic impact of TIL-populations relied on TCGA-subgroups indicating specific roles for TIL depending on molecular background. In NSMP, histopathological grading was the only prognostic biomarker demonstrating the relevance of WHO-grading in an era of molecular subtyping

Effects of Early Life Stress on Bone Homeostasis in Mice and Humans

Bone pathology is frequent in stressed individuals. A comprehensive examination of mechanisms linking life stress, depression and disturbed bone homeostasis is missing. In this translational study, mice exposed to early life stress (MSUS) were examined for bone microarchitecture (μCT), metabolism (qPCR/ELISA), and neuronal stress mediator expression (qPCR) and compared with a sample of depressive patients with or without early life stress by analyzing bone mineral density (BMD) (DXA) and metabolic changes in serum (osteocalcin, PINP, CTX-I). MSUS mice showed a significant decrease in NGF, NPYR1, VIPR1 and TACR1 expression, higher innervation density in bone, and increased serum levels of CTX-I, suggesting a milieu in favor of catabolic bone turnover. MSUS mice had a significantly lower body weight compared to control mice, and this caused minor effects on bone microarchitecture. Depressive patients with experiences of childhood neglect also showed a catabolic pattern. A significant reduction in BMD was observed in depressive patients with childhood abuse and stressful life events during childhood. Therefore, future studies on prevention and treatment strategies for both mental and bone disease should consider early life stress as a risk factor for bone pathologies

Atmosphere-ocean changes in the Pacific Southern Ocean over the past 1 Million years and implications for global climate

Atmosphere-ocean interactions play an important role for understanding processes and feedbacks in the Southern Ocean (SO) and are relevant for changes in Antarctic ice-sheets and atmospheric CO2 concentrations. The most important atmospheric forcing at high and mid-latitudes of the Southern Hemisphere is the westerly wind belt (SWW), which strongly affects the strength and extension of the Antarctic Circumpolar Current (ACC), upwelling of deep-water masses, and controls the back-flow of intermediate waters to the tropics. In order to address orbital and millennial-scale changes of the SWW and the ACC, we present sediment proxy records from the Pacific SO including the Chilean Margin and the Drake Passage. The Drake Passage (DP) represents the most important oceanic gateway along the ACC. Based on grain-size and geochemical properties of sediment records from the southernmost continental margin of South America, we reconstruct changes in DP throughflow dynamics over the past 65,000 years. In combination with published sediment records from the Scotia Sea and preliminary sediment records from the central Drake Passage (Polarstern cruise PS97, 2016), we argue for a considerable total reduction of DP transport and reveal an up to ~40% decrease in flow speed along the northernmost ACC pathway entering the DP during glacial times. Superimposed on this long-term decrease are high-amplitude millennial-scale variations, which parallel Southern Ocean and Antarctic temperature patterns. The glacial intervals of strong weakening of the ACC entering the DP imply a reduced Pacific-Atlantic exchange via the DP (“cold-water route”). The reduced Drake Passage glacial throughflow was accompanied by a pronounced northward extension of the Antarctic cold-water sphere in the Southeast Pacific sector and stronger export of northern ACC water into the South Pacific gyre. These oceanographic changes are consistent with reduced SWW within the modern maximum wind strength zone over the subantarctic ACC and reduced wind forcing due to extended sea-ice further south. Despite this reduction in winds in the core of the westerlies, we observe 3-fold higher dust deposition during glacial periods in Past Antarctic Ice Sheet Dynamics (PAIS) Conference September 10-15th 2017, Trieste - Italy the Pacific Southern Ocean (SO). This observation may be explained by a combination of factors including more expanded arid dust source areas in Australia and a northward extent or enhancement of the SWW over Southeast Australia during glacials that would plausibly increase the dust uptake and export into the Pacific SO. Such scenario would imply stronger SWW at the present northernmost margin of the wind belt coeval with weaker core westerlies in the south and reduced ACC strength, including Drake Passage throughflow during glacials. We conclude that changes in DP throughflow play a critical role for the global meridional overturning circulation and interbasin exchange in the Southern Ocean, most likely regulated by variations in the westerly wind field and changes in Antarctic sea-ice extent. Keywords: Pelagic Southern Ocean, Antarctic Circumpolar Current, Southern Westerlies, Teleconnections

DNA Vaccines against Dengue Virus Type 2 Based on Truncate Envelope Protein or Its Domain III

Two DNA vaccines were constructed encoding the ectodomain (domains I, II and III) of the DENV2 envelope protein (pE1D2) or only its domain III (pE2D2), fused to the human tissue plasminogen activator signal peptide (t-PA). The expression and secretion of recombinant proteins was confirmed in vitro in BHK cells transfected with the two plasmids, detected by immunofluorescence or immunoprecipitation of metabolically labeled gene products, using polyclonal and monoclonal antibodies against DENV2. Besides, results reveal that the ectodomain of the E protein can be efficiently expressed in vivo, in a mammalian system, without the prM protein that is hypothesized to act as a chaperonin during dengue infection. Balb/c mice were immunized with the DNA vaccines and challenged with a lethal dose of DENV2. All pE1D2-vaccinated mice survived challenge, while 45% of animals immunized with the pE2D2 died after infection. Furthermore, only 10% of pE1D2-immunized mice presented some clinical signs of infection after challenge, whereas most of animals inoculated with the pE2D2 showed effects of the disease with high morbidity degrees. Levels of neutralizing antibodies were significantly higher in pE1D2-vaccinated mice than in pE2D2-immunized animals, also suggesting that the pE1D2 vaccine was more protective than the pE2D2