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Cathepsin D (CTSD) is a lysosomal protease and a marker of poor prognosis in breast cancer. However, the cells responsible for this association and the function of CTSD in cancer are still incompletely understood. By using a conditional CTSD knockout mouse crossed to the transgenic MMTV-PyMT breast cancer model we demonstrate that CTSD deficiency in the mammary epithelium, but not in myeloid cells, blocked tumor development in a cell-autonomous manner. We show that lack of CTSD impaired mechanistic Target of Rapamycin Complex 1 (mTORC1) signaling and induced reversible cellular quiescence. In line, CTSD-deficient tumors started to grow with a two-month delay and quiescent Ctsd -/- tumor cells re-started proliferation upon long-term culture. This was accompanied by rewiring of oncogenic gene expression and signaling pathways, while mTORC1 signaling remained permanently disabled in CTSD-deficient cells. Together, these studies reveal a tumor cell-autonomous effect of CTSD deficiency, and establish a pivotal role of this protease in the cellular response to oncogenic stimuli. The lysosomal aspartic protease Cathepsin D (CTSD) is associated with breast cancer progression. Here the authors show that selective inactivation of CTSD in mammary epithelium delays tumor onset due to impaired mTORC1 signaling, but resumes malignant growth due to compensatory oncogenic pathways

The Solomon Islands Government and its development partners are heavily investing in road maintenance programmes to promote development in the small islands least developed state. Based on 12 months of ethnographic fieldwork, this article challenges the future orientation of these programmes. Instead it emphasises rural Solomon Islanders' past and present experiences with road-based mobilities and state-sponsored road maintenance projects. These experiences reveal roads and road repairs as a source of insecurity, immorality, and potential state violence that sideline, if not obstruct, hopes for any imagined future that a maintained road may (or may not) bring.

Mimicking research and practice that demonstrates the importance of seemingly mundane acts for resolving protracted conflicts, this article enquires into the potential contributions of food-related practices to post-conflict reconciliation. Based on fieldwork with a Japanese-South Korean reconciliation initiative (Koinonia), the argument is made that food-related practices can create the spatio-temporal conditions necessary to mitigate successfully situations that may otherwise be characterised by misunderstandings, animosity and an unwillingness to move beyond dividing lines. It is demonstrated that food-related practices have the capacity to influence reconciliation positively throughout the three stages that are perceived as vital for building lasting relationships between conflicting parties: encouragement of participation in reconciliation events (stage 1), encouragement of positive interaction during reconciliation events (stage 2) and sustainability of reconciliation events after participants re-enter daily life and the likely negative perceptions of the Other therein (stage 3).

We critically reflect on a conservation project in the Ecuadorian Amazon that was designed to promote biodiversity conservation among lowland indigenous communities involved in eco-tourism initiatives by teaching them how to knit a particular set of local animals. We use interpretive qualitative research and draw on social practice theory to examine the ways that participants’ engagement with new knitting in participatory knitting workshops changed the understanding of environmental conservation and social entrepreneurship within an eco-tourism context. Eventually, the intervention pushed participants to adopt new and difficult-to-sustain conservation and entrepreneurial practices. The introduction of these new practices and a focus on a specific list of local species turned animals into commodities and created unsustainable connections with new materials and a disconnect between local and traditional know-how.

Precise control of transgene expression through novel enhancer-promoter combinations is a promising strategy for advancing gene therapy mediated by adeno-associated virus (AAV). We present STARR-CRAAVT, a novel STARR-Seq-derived platform to screen for enhancers in the AAV context. Using HepG2 and HaCaT cells as screening models, we applied STARR-CRAAVT for the identification of cell type-specific enhancers. We integrated epigenetic datasets into an in-silico library of putative HepG2 enhancers and captured corresponding fragments from genomic DNA. The fragments were processed into AAV libraries and applied to HepG2 and HaCaT cells. STARR-CRAAVT analysis revealed a selective activity of the libraries confirming the HepG2-directed in-silico design and the specificity of single enhancer-promoter combinations could be validated using luciferase reporter assays. In addition, we scrutinized the impact of key experimental parameters on enhancer identification and found that the used promoter type had significant influence on the ability of candidates to act as enhancers. Furthermore, switching the location of identified enhancers in reporter assays revealed that the level of enhancer activity is highly dependent on the position in the AAV genome. Taken together, our study yields novel insights into enhancer function and demonstrates that STARR-CRAAVT can be employed to identify cell type-specific enhancers, highlighting promoter preference and enhancer positioning as key considerations for enhancer screening campaigns.

Fat and physical inactivity are the most evident factors in the pathogenesis of obesity, and fat quality seems to play a crucial role for measures of glucose homeostasis. However, the impact of dietary fat quality on brain function, behavior, and sleep is basically unknown. In this study, mice were fed a diet supplemented with either monounsaturated fatty acids (MUFAs) or saturated fatty acids (SFAs) and their impact on glucose homeostasis, locomotion, brain activity, and sleep behavior was evaluated. MUFAs and SFAs led to a significant increase in fat mass but only feeding of SFAs was accompanied by glucose intolerance in mice. Radiotelemetry revealed a significant decrease in cortical activity in SFA-mice whereas MUFAs even improved activity. SFAs decreased wakefulness and increased non-rapid eye movement sleep. An intracerebroventricular application of insulin promoted locomotor activity in MUFA-fed mice, whereas SFA-mice were resistant. In humans, SFA-enriched diet led to a decrease in hippocampal and cortical activity determined by functional magnetic resonance imaging techniques. Together, dietary intake of MUFAs promoted insulin action in the brain with its beneficial effects for cortical activity, locomotion, and sleep, whereas a comparable intake of SFAs acted as a negative modulator of brain activity in mice and humans.

Aim: There is accumulating evidence that food consumption is controlled by a wide range of brain circuits outside of the homeostatic system. Activation in these brain circuits may override the homeostatic system and also contribute to the enormous increase of obesity. However, little is known about the influence of hormonal signals on the brain's non-homeostatic system. Thus, selective insulin action in the brain was investigated by using intranasal application. Methods: We performed ‘resting-state' functional magnetic resonance imaging in 17 healthy lean female subjects to assess intrinsic brain activity by fractional amplitude of low-frequency fluctuations (fALFF) before, 30 and 90 min after application of intranasal insulin. Results: Here, we showed that insulin modulates intrinsic brain activity in the hypothalamus and orbitofrontal cortex. Furthermore, we could show that the prefrontal and anterior cingulate cortex response to insulin is associated with body mass index. Conclusion: This demonstrates that hormonal signals as insulin may reduce food intake by modifying the reward and prefrontal circuitry of the human brain, thereby potentially decreasing the rewarding properties of food. Due to the alarming increase in obesity worldwide, it is of great importance to identify neural mechanisms of interaction between the homeostatic and non-homeostatic system to generate new targets for obesity therapy.

Background Many research projects in general practice face problems when recruiting patients, often resulting in low recruitment rates and an unknown selection bias, thus limiting their value for health services research. The objective of the study is to evaluate the recruitment performance of the practice staff in 25 participating general practices when using a clinical trial alert (CTA) tool. Methods The CTA tool was developed for an osteoporosis survey of patients at risk for osteoporosis and fractures. The tool used data from electronic patient records (EPRs) to automatically identify the population at risk (net sample), to apply eligibility criteria, to contact eligible patients, to enrol and survey at least 200 patients per practice. The effects of the CTA intervention were evaluated on the basis of recruitment efficiency and selection bias. Results The CTA tool identified a net sample of 16,067 patients (range 162 to 1,316 per practice), of which the practice staff reviewed 5,161 (32%) cases for eligibility. They excluded 3,248 patients and contacted 1,913 patients. Of these, 1,526 patients (range 4 to 202 per practice) were successfully enrolled and surveyed. This made up 9% of the net sample and 80% of the patients contacted. Men and older patients were underrepresented in the study population. Conclusion Although the recruitment target was unreachable for most practices, the practice staff in the participating practices used the CTA tool successfully to identify, document and survey a large patient sample. The tool also helped the research team to precisely determine a slight selection bias.

There is growing evidence that excessive body weight correlates with impaired cognitive performance like executive function, attention and memory. In our study, we applied a visual working memory task to quantify associations between body weight and executive function. In total, 34 lean (BMI 22±2.1kg/m2) and 34 obese (BMI 30.4±3.2kg/m2) subjects were included. Magnetic brain activity and behavioral responses were recorded during a one-back visual memory task with food and non-food pictures, which were matched for color, size and complexity. Behavioral responses (reaction time and accuracy) were reduced in obese subjects independent of the stimulus category. Neuronal activity at the source level showed a positive correlation between the right dorsolateral prefrontal cortex (DLPFC) activity and BMI only for the food category. In addition, a negative correlation between BMI and neuronal activity was observed in the occipital area for both categories. Therefore we conclude that increased body weight is associated with reduced task performance and specific neuronal changes. This altered activity is probably related to executive function as well as encoding and retrieval of information. ► Reduced behavioral performance during working memory task is BMI dependent. ► Obese subjects have reduced neural activity during retrieve and encode of information. ► Correlation of activity in dorsolateral prefrontal cortex and BMI is food dependent.