Tracking intracavernously injected adipose-derived stem cells to bone marrow.

The intracavernous (i.c.) injection of stem cells (SCs) has been shown to improve erectile function in various erectile dysfunction (ED) animal models. However, the tissue distribution of the injected cells remains unknown. In this study we tracked i.c.-injected adipose-derived stem cells (ADSCs) in various tissues. Rat paratesticular fat was processed for ADSC isolation and culture. The animals were then subject to cavernous nerve (CN) crush injury or sham operation, followed by i.c. injection of 1 million autologous or allogeneic ADSCs that were labeled with 5-ethynyl-2-deoxyuridine (EdU). Another group of rats received i.c. injection of EdU-labeled allogeneic penile smooth muscle cells (PSMCs). At 2 and 7 days post injection, penises and femoral bone marrow were processed for histological analyses. Whole femoral bone marrows were also analyzed for EdU-positive cells by flow cytometry. The results show that ADSCs exited the penis within days of i.c. injection and migrated preferentially to bone marrow. Allogenicity did not affect the bone marrow appearance of ADSCs at either 2 or 7 days, whereas CN injury reduced the number of ADSCs in bone marrow significantly at 7 but not 2 days. The significance of these results in relation to SC therapy for ED is discussed

A model ensemble generator to explore structural uncertainty in karst systems with unmapped conduits

Karst aquifers are characterized by high-conductivity conduits embedded in a low-conductivity fractured matrix, resulting in extreme heterogeneity and variable groundwater flow behavior. The conduit network controls groundwater flow, but is often unmapped, making it difficult to apply numerical models to predict system behavior. This paper presents a multi-model ensemble method to represent structural and conceptual uncertainty inherent in simulation of systems with limited spatial information, and to guide data collection. The study tests the new method by applying it to a well-mapped, geologically complex long-term study site: the Gottesacker alpine karst system (Austria/Germany). The ensemble generation process, linking existing tools, consists of three steps: creating 3D geologic models using GemPy (a Python package), generating multiple conduit networks constrained by the geology using the Stochastic Karst Simulator (a MATLAB script), and, finally, running multiple flow simulations through each network using the Storm Water Management Model (C-based software) to reject nonbehavioral models based on the fit of the simulated spring discharge to the observed discharge. This approach captures a diversity of plausible system configurations and behaviors using minimal initial data. The ensemble can then be used to explore the importance of hydraulic flow parameters, and to guide additional data collection. For the ensemble generated in this study, the network structure was more determinant of flow behavior than the hydraulic parameters, but multiple different structures yielded similar fits to the observed flow behavior. This suggests that while modeling multiple network structures is important, additional types of data are needed to discriminate between networks

The stochastic simulation of karst conduit network structure using anisotropic fast marching, and its application to a geologically complex alpine karst system

Anisotropic fast-marching algorithms are computationally efficient tools for generating realistic maps of karst conduit networks, constrained by both the spatial extent and the orientation of karstifiable geologic units. Existing models to generate conduit network maps are limited either by high computational requirements (for chemistry-based models) or by their inability to incorporate the effects of elevation and orientation gradients (for isotropic fast-marching models). The new anisotropic fast-marching approach described here provides a significant improvement, though it imitates rather than reproduces actual speleogenetic processes. It can rapidly generate a stochastic ensemble of plausible networks from basic geologic information, which can also be used as input to karst-appropriate flow models. This paper introduces an open-source, easy-to-use implementation through the Python package pyKasso, then describes its application to a well-mapped geologically complex long-term study site: the Gottesacker alpine karst system (Germany/Austria). Groundwater flow in this system is exceptionally well understood from speleological investigations and tracer tests. Conduit formation primarily occurs at the base of the karst aquifer, following plunging synclines. Although previous attempts to reproduce the conduit network at this site yielded implausible network maps, pyKasso quickly generated networks faithful to the known conduit system. However, the model was only able to generate these realistic networks when the inlet-outlet connections of the system were correctly assigned, highlighting the importance of pairing modeling efforts with field tracer tests. Therefore, a model ensemble method is also presented, to optimize field efforts by identifying the most informative tracer tests to perform

Efficiency of European public higher education institutions: a two-stage multicountry approach

The purpose of this study is to examine efficiency and its determinants in a set of higher education institutions (HEIs) from several European countries by means of non-parametric frontier techniques. Our analysis is based on a sample of 259 public HEIs from 7 European countries across the time period of 2001–2005. We conduct a two-stage DEA analysis (Simar and Wilson in J Economet 136:31–64, 2007), first evaluating DEA scores and then regressing them on potential covariates with the use of a bootstrapped truncated regression. Results indicate a considerable variability of efficiency scores within and between countries. Unit size (economies of scale), number and composition of faculties, sources of funding and gender staff composition are found to be among the crucial determinants of these units’ performance. Specifically, we found evidence that a higher share of funds from external sources and a higher number of women among academic staff improve the efficiency of the institution

How Reliable Is Ki-67 Immunohistochemistry in Grade 2 Breast Carcinomas? A QA Study of the Swiss Working Group of Breast- and Gynecopathologists

Adjuvant chemotherapy decisions in breast cancer are increasingly based on the pathologist's assessment of tumor proliferation. The Swiss Working Group of Gyneco- and Breast Pathologists has surveyed inter- and intraobserver consistency of Ki-67-based proliferative fraction in breast carcinomas. Methods Five pathologists evaluated MIB-1-labeling index (LI) in ten breast carcinomas (G1, G2, G3) by counting and eyeballing. In the same way, 15 pathologists all over Switzerland then assessed MIB-1-LI on three G2 carcinomas, in self-selected or pre-defined areas of the tumors, comparing centrally immunostained slides with slides immunostained in the different laboratoires. To study intra-observer variability, the same tumors were re-examined 4 months later. Results The Kappa values for the first series of ten carcinomas of various degrees of differentiation showed good to very good agreement for MIB-1-LI (Kappa 0.56–0.72). However, we found very high inter-observer variabilities (Kappa 0.04–0.14) in the read-outs of the G2 carcinomas. It was not possible to explain the inconsistencies exclusively by any of the following factors: (i) pathologists' divergent definitions of what counts as a positive nucleus (ii) the mode of assessment (counting vs. eyeballing), (iii) immunostaining technique, and (iv) the selection of the tumor area in which to count. Despite intensive confrontation of all participating pathologists with the problem, inter-observer agreement did not improve when the same slides were re-examined 4 months later (Kappa 0.01–0.04) and intra-observer agreement was likewise poor (Kappa 0.00–0.35). Conclusion Assessment of mid-range Ki-67-LI suffers from high inter- and intra-observer variability. Oncologists should be aware of this caveat when using Ki-67-LI as a basis for treatment decisions in moderately differentiated breast carcinomas

Elite Influence? Religion, Economics, and the Rise of the Nazis

Adolf Hitler's seizure of power was one of the most consequential events of the twentieth century. Yet, our understanding of which factors fueled the astonishing rise of the Nazis remains highly incomplete. This paper shows that religion played an important role in the Nazi party's electoral success -- dwarfing all available socioeconomic variables. To obtain the first causal estimates we exploit plausibly exogenous variation in the geographic distribution of Catholics and Protestants due to a peace treaty in the sixteenth century. Even after allowing for sizeable violations of the exclusion restriction, the evidence indicates that Catholics were significantly less likely to vote for the Nazi Party than Protestants. Consistent with the historical record, our results are most naturally rationalized by a model in which the Catholic Church leaned on believers to vote for the democratic Zentrum Party, whereas the Protestant Church remained politically neutral

Differentiation of human adipose-derived stem cells into neuron/motoneuron-like cells for cell replacement therapy of spinal cord injury

Human adipose-derived stem cells (hADSCs) are increasingly presumed to be a prospective stem cell source for cell replacement therapy in various degenerative and/or traumatic diseases. The potential of trans-differentiating hADSCs into motor neuron cells indisputably provides an alternative way for spinal cord injury (SCI) treatment. In the present study, a stepwise and efficient hADSC trans-differentiation protocol with retinoic acid (RA), sonic hedgehog (SHH), and neurotrophic factors were developed. With this protocol hADSCs could be converted into electrophysiologically active motoneuron-like cells (hADSC-MNs), which expressed both a cohort of pan neuronal markers and motor neuron specific markers. Moreover, after being primed for neuronal differentiation with RA/SHH, hADSCs were transplanted into SCI mouse model and they survived, migrated, and integrated into injured site and led to partial functional recovery of SCI mice. When ablating the transplanted hADSC-MNs harboring HSV-TK-mCherry overexpression system with antivirial Ganciclovir (GCV), functional relapse was detected by motor-evoked potential (MEP) and BMS assays, implying that transplanted hADSC-MNs participated in rebuilding the neural circuits, which was further confirmed by retrograde neuronal tracing system (WGA). GFP-labeled hADSC-MNs were subjected to whole-cell patch-clamp recording in acute spinal cord slice preparation and both action potentials and synaptic activities were recorded, which further confirmed that those pre-conditioned hADSCs indeed became functionally active neurons in vivo. As well, transplanted hADSC-MNs largely prevented the formation of injury-induced cavities and exerted obvious immune-suppression effect as revealed by preventing astrocyte reactivation and favoring the secretion of a spectrum of anti-inflammatory cytokines and chemokines. Our work suggests that hADSCs can be readily transformed into MNs in vitro, and stay viable in spinal cord of the SCI mouse and exert multi-therapeutic effects by rebuilding the broken circuitry and optimizing the microenvironment through immunosuppression