Stimulating neuroprotective and regenerative mechanisms in Alzheimer disease

The processes involved in neuroprotection and brain repair are an important aspect of the preservation and restoration of neuronal functions affected by pathological lesions. Mechanisms that stimulate, manage and regulate these processes thus hold potential for the development of treatment strategies for Alzheimer disease (AD). The aim of this thesis was to increase our understanding of the stimulation of neuroprotective and regenerative mechanisms, in particular with respect to amyloid-β (Aβ) accumulation and other pathological processes associated with AD. Mounting evidence suggests that the continuous loss of cholinergic neurons and nicotinic receptors (nAChRs) in the hippocampus and cerebral cortex could be mediated through an interaction between α7 nAChRs and Aβ species. In paper I, we investigated interaction of α7 nAChRs with different forms of Aβ, and the functional consequences of these interactions. We found that α7 nAChRs play an important role in mediating neuroprotective actions against Aβ-induced neurotoxicity, and that the assembly form of Aβ is important for the interaction with α7 nAChRs and the downstream effects in neuronal cells. Fibrillar Aβ appears to cause cytotoxic effects by blocking α7 nAChRs, whereas oligomeric Aβ seems to activate α7 nAChRs to modulate calcium-dependent synaptic function. In paper II, we characterized the neuroprotective and neurotrophic actions of amyloid-modulatory candidate drugs (–)- and (+)- phenserine and its primary metabolites, and investigated the primary signaling pathways responsible for mediating these effects. (+)-Phenserine increased the proliferation of mouse neural progenitor cells in culture via activation of MAPK signaling pathways, including elevated cortical levels of brain-derived neurotrophic factor in mouse brain. In paper III, we investigated the modulating effects of (+)-phenserine on the changes in brain synaptic function, hippocampal neurogenesis, and inflammatory cells at different stages of amyloid pathology. (+)-Phenserine increased proliferation of neural progenitor cells, and increased the maturation of newborn neurons in the hippocampi of young adult Tg2576 mice but not in older mice with advanced Aβ plaque pathology. In paper IV, we investigated the effects of stem cell transplantation and modulation of Aβ and α7 nAChRs on endogenous neurogenesis and astrocytosis, graft survival, and cognition. Intrahippocampi transplantation of human neural stem cells (hNSCs) improved spatial memory in young adult Tg2576 mice, and increased endogenous hippocampal neurogenesis. (+)-Phenserine increased graft survival but blocked the hNSC transplant-mediated increase in endogenous neurogenesis, indicative of interfering mechanisms of action. We found that α7 nAChR-expressing astrocytes accumulated along the needle track after transplantation, and that the numbers of these astrocytes correlated with the degree of endogenous hippocampal neurogenesis. Hence, we postulate a hitherto unexplored role for α7 nAChR-expressing astrocytes in neurogenesis and tissue remodeling. The clinical implications of stimulation of neuroprotection and brain repair in the course of AD are currently under investigation. However, it is my hope that the cumulative findings presented in this thesis will provide a better understanding of the possibilities and limitations of these therapeutic strategies that aim to change or halt the clinical progression of AD

Nutrient balancing or spring flush - What determines spruce bark stripping level by red deer?

The distribution and population density of red deer (Cervus elaphus) are increasing in several regions of Europe. The deer may cause severe damage in commercial forestry and agriculture. Bark stripping is the main problem in forests, especially on Norway spruce (Picea abies), and is thought to mostly occur during winter when other forage is scarce. It has been suggested that an imbalance in the nutrient intake, and especially a diet including high amounts of easily-digestible macronutrients, such as agricultural crops, can lead to an increased urge to consume bark. Feeding on brassicas, for example rapeseed (Brassica napus) might have this effect. The aim with this study was to investigate the relationship between intake of rapeseed and bark stripping on Norway spruce by red deer during early spring. We did this by a controlled feeding experiment with four groups of captive red deer in southern Sweden. All groups were given spruce logs every week, while only two groups had access to freshly harvested rapeseed plants. In addition, influence of air temperature and forage nutritional composition was taken into account. Our results show that red deer bark stripping can be considerable not only during winter but also during spring green-up. We found no significant influence of rapeseed on bark stripping performed by the deer. However, at a threshold temperature, deer suddenly started to ingest large amounts of bark biomass, coinciding with a significant change in the bark's concentration of starch. We suggest that the lack of effect of rapeseed feeding can partly be explained by overshadowing effects caused by such seasonal changes of bark character-istics, and partly by the fact that the rapeseed plants in our study contained lower than expected concentrations of easily-digestible macronutrients (apart from protein). We conclude that the risk of damage on spruce can be especially high during certain periods, something that is important to consider when mitigating bark stripping. However, several interactive effects are involved and must be considered in order to more efficiently mitigate damage

Automated lesion detection of breast cancer in [18F] FDG PET/CT using a novel AI-Based workflow

UNLABELLED: Applications based on artificial intelligence (AI) and deep learning (DL) are rapidly being developed to assist in the detection and characterization of lesions on medical images. In this study, we developed and examined an image-processing workflow that incorporates both traditional image processing with AI technology and utilizes a standards-based approach for disease identification and quantitation to segment and classify tissue within a whole-body [ METHODS: One hundred thirty baseline PET/CT studies from two multi-institutional preoperative clinical trials in early-stage breast cancer were semi-automatically segmented using techniques based on PERCIST v1.0 thresholds and the individual segmentations classified as to tissue type by an experienced nuclear medicine physician. These classifications were then used to train a convolutional neural network (CNN) to automatically accomplish the same tasks. RESULTS: Our CNN-based workflow demonstrated Sensitivity at detecting disease (either primary lesion or lymphadenopathy) of 0.96 (95% CI [0.9, 1.0], 99% CI [0.87,1.00]), Specificity of 1.00 (95% CI [1.0,1.0], 99% CI [1.0,1.0]), DICE score of 0.94 (95% CI [0.89, 0.99], 99% CI [0.86, 1.00]), and Jaccard score of 0.89 (95% CI [0.80, 0.98], 99% CI [0.74, 1.00]). CONCLUSION: This pilot work has demonstrated the ability of AI-based workflow using DL-CNNs to specifically identify breast cancer tissue as determined by

Female-Oriented Male-Male Erotica: Comparison of the Engaged Anglophone Demographic and That of the Greater China Area

Our aim is to compare comprehensive data on the engaged demographics of female-oriented male-male erotica in Anglophone regions and that of the greater China area. Our study constitutes the largest such data set in each region (Anglophone N = 1707; Chinese N = 1498). Data were analysed from our online Boys’ Love (BL) fandom survey: one version in English and an almost identical version in Chinese. We confirm that the engaged Anglophone demographic includes more men, people with a wider range of sexual orientations, lower proportion of heterosexual identification, and a wider and older age range. We provide greater detail than ever before and demonstrate engagement with BL by young straight men and questioning of sexual identity by female fans, at least in the Anglophone West. Finally, we provide novel evidence that a broad demographic of young people in the greater China area is familiar with BL as a casual interest in contrast to Anglophone regions where it is more of an intense and niche pass-time. We offer important insights into a global erotic entertainment by-and-for women which is influencing the mainstream but under increasing legislative scrutiny

Common variants upstream of KDR encoding VEGFR2 and in TTC39B associate with endometriosis.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.We conducted a genome-wide association scan (GWAS) of endometriosis using 25.5 million sequence variants detected through whole-genome sequencing (WGS) of 8,453 Icelanders and imputed into 1,840 cases and 129,016 control women, followed by testing of associated variants in Danish samples. Here we report the discovery of a new endometriosis susceptibility locus on 4q12 (rs17773813[G], OR=1.28; P=3.8 × 10(-11)), upstream of KDR encoding vascular endothelial growth factor receptor 2 (VEGFR2). The variant correlates with disease severity (P=0.0046) when moderate/severe endometriosis cases are tested against minimal/mild cases. We further report association of rs519664[T] in TTC39B on 9p22 with endometriosis (P=4.8 × 10(-10); OR=1.29). The involvement of KDR in endometriosis risk highlights the importance of the VEGF pathway in the pathogenesis of the disease.e Danish National Research Foundation. Additional support for the DNBC has been obtained from the Danish Pharmacists’ Fund, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation and the Health Fund of the Danish Health Insurance Societies. B.F. is supported by an Oak Foundation fellowshi

Clonal analysis of Notch1-expressing cells reveals the existence of unipotent stem cells that retain long-term plasticity in the embryonic mammary gland.

Recent lineage tracing studies have revealed that mammary gland homeostasis relies on unipotent stem cells. However, whether and when lineage restriction occurs during embryonic mammary development, and which signals orchestrate cell fate specification, remain unknown. Using a combination of in vivo clonal analysis with whole mount immunofluorescence and mathematical modelling of clonal dynamics, we found that embryonic multipotent mammary cells become lineage-restricted surprisingly early in development, with evidence for unipotency as early as E12.5 and no statistically discernable bipotency after E15.5. To gain insights into the mechanisms governing the switch from multipotency to unipotency, we used gain-of-function Notch1 mice and demonstrated that Notch activation cell autonomously dictates luminal cell fate specification to both embryonic and basally committed mammary cells. These functional studies have important implications for understanding the signals underlying cell plasticity and serve to clarify how reactivation of embryonic programs in adult cells can lead to cancer.Wellcome Trus

Variants in the fetal genome near FLT1 are associated with risk of preeclampsia.

Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10-11) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes

High Temperature Triggers Latent Variation among Individuals: Oviposition Rate and Probability for Outbreaks

It is anticipated that extreme population events, such as extinctions and outbreaks, will become more frequent as a consequence of climate change. To evaluate the increased probability of such events, it is crucial to understand the mechanisms involved. Variation between individuals in their response to climatic factors is an important consideration, especially if microevolution is expected to change the composition of populations.Here we present data of a willow leaf beetle species, showing high variation among individuals in oviposition rate at a high temperature (20 °C). It is particularly noteworthy that not all individuals responded to changes in temperature; individuals laying few eggs at 20 °C continued to do so when transferred to 12 °C, whereas individuals that laid many eggs at 20 °C reduced their oviposition and laid the same number of eggs as the others when transferred to 12 °C. When transferred back to 20 °C most individuals reverted to their original oviposition rate. Thus, high variation among individuals was only observed at the higher temperature. Using a simple population model and based on regional climate change scenarios we show that the probability of outbreaks increases if there is a realistic increase in the number of warm summers. The probability of outbreaks also increased with increasing heritability of the ability to respond to increased temperature.If climate becomes warmer and there is latent variation among individuals in their temperature response, the probability for outbreaks may increase. However, the likelihood for microevolution to play a role may be low. This conclusion is based on the fact that it has been difficult to show that microevolution affect the probability for extinctions. Our results highlight the urge for cautiousness when predicting the future concerning probabilities for extreme population events

Genetic insight into sick sinus syndrome

Aims. The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. Methods and results. We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1–1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10⁻²⁰), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). Conclusion. We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS

A modest start, but a steady rise in research use: a longitudinal study of nurses during the first five years in professional life

<p>Abstract</p> <p>Background</p> <p>Newly graduated nurses are faced with a challenging work environment that may impede their ability to provide evidence-based practice. However, little is known about the trajectory of registered nurses' use of research during the first years of professional life. Thus, the aim of the current study was to prospectively examine the extent of nurses' use of research during the first five years after undergraduate education and specifically assess changes over time.</p> <p>Method</p> <p>Survey data from a prospective cohort of 1,501 Swedish newly graduated nurses within the national LANE study (Longitudinal Analyses of Nursing Education and Entry in Worklife) were used to investigate perceived use of research over the first five years as a nurse. The dependent variables consisted of three single items assessing instrumental, conceptual, and persuasive research use, where the nurses rated their use on a five-point scale, from 'never' (1) to 'on almost every shift' (5). These data were collected annually and analyzed both descriptively and by longitudinal growth curve analysis.</p> <p>Results</p> <p>Instrumental use of research was most frequently reported, closely followed by conceptual use, with persuasive use occurring to a considerably lower extent. The development over time showed a substantial general upward trend, which was most apparent for conceptual use, increasing from a mean of 2.6 at year one to 3.6 at year five (unstandardized slope +0.25). However, the descriptive findings indicated that the increase started only after the second year. Instrumental use had a year one mean of 2.8 and a year five mean of 3.5 (unstandardized slope +0.19), and persuasive use showed a year one mean of 1.7 and a year five mean of 2.0 (unstandardized slope +0.09).</p> <p>Conclusion</p> <p>There was a clear trend of increasing research use by nurses during their first five years of practice. The level of the initial ratings also indicated the level of research use in subsequent years. However, it took more than two years of professional development before this increase 'kicked in.' These findings support previous research claiming that newly graduated nurses go through a 'transition shock,' reducing their ability to use research findings in clinical work.</p