This study aims to evaluate the incidence of breast cancer after risk-reducing mastectomy (RRM) in healthy BRCA mutation carriers. This study is a long-term follow-up of 307 BRCA mutation carriers of whom 96 chose RRM. None of the study participants had a previous history of breast or ovarian cancer nor had they undergone RRM or risk-reducing bilateral salpingo-oophorectomy (BSO) prior to the time of BRCA testing. The annual incidence of post-mastectomy breast cancer was 0.8% compared with 1.7% in the non-operated group. Implications of these findings in relation to genetic counseling and future management are discussed.

Insects, like the model species Drosophila melanogaster, lose neuromuscular function and enter a state of paralysis (chill coma) at a population- and species-specific low temperature threshold that is decreased by cold acclimation. Entry into this coma is related to a spreading depolarization in the central nervous system, while recovery involves restoration of electrochemical gradients across muscle cell membranes. The Na+/K+-ATPase helps maintain ion balance and membrane potential in both the brain and hemolymph (surrounding muscles), and changes in thermal tolerance traits have therefore been hypothesized to be closely linked to variation in the expression and/or activity of this pump in multiple tissues. Here, we tested this hypothesis by measuring activity and thermal sensitivity of the Na+/K+-ATPase at the tagma-specific level (head, thorax and abdomen) in warm-(25°C) and cold-acclimated (15°C) flies by Na+/K+-ATPase activity at 15, 20, and 25°C. We relate differences in pump activity to differences in chill coma temperature, spreading depolarization temperature, and thermal dependence of muscle cell polarization. Differences in pump activity and thermal sensitivity induced by cold acclimation varied in a tissue-specific manner: While cold-acclimated flies had decreased thermal sensitivity of Na+/K+-ATPase that maintains activity at low temperatures in the thorax (mainly muscle), activity instead decreased in the heads (mainly brain). We argue that these changes may assist in maintenance of K+ homeostasis and membrane potential across muscle membranes and discuss how reduced Na+/K+-ATPase activity in the brain may counterintuitively help insects delay coma onset in the cold.

Finding an efficient framework for estimating total narrow-sense heritability in admixedpopulations remains an open question. In this work, we used extensive simulations to evaluate existing linear mixed model frameworks in estimating total narrow-sense heritability in two population-based cohorts from Greenland and compared the results to data from unadmixed individuals from Denmark. When our analysis focused on Greenlandic sib pairs, the model with two relationship matrices, one capturing identity by descent and one capturing identity by state, returned heritability estimates close to the true simulated value, while using each of the two matrices alone led to downward biases. When phenotypes correlated with ancestry, heritability estimates were inflated. Based on these observations, we propose a post-estimation PCA-based adjustment that recovers successfully the true simulated heritability. We use this knowledge to estimate the heritability of ten quantitative traits from the two Greenlandic cohorts and report differences such as lower heritability for height in Greenlanders compared to Europeans. In conclusion, narrow-sense heritability in admixed populations is best estimated using a mixture of genetic relationship matrices on individuals with at least one first-degree relative included in the sample.

Maintaining extracellular osmotic and ionic homeostasis is crucial to maintain organismal function. In insects, hemolymph volume and ion content is regulated by the combined actions of the secretory Malpighian tubules and reabsorptive hindgut. When exposed to stressful cold, homeostasis is gradually disrupted, characterized by a debilitating increase in extracellular K+ concentration (hyperkalemia). In accordance with this paradigm, studies have found a strong link between the cold tolerance of insect species and their ability to maintain ion and water homeostasis at low temperature. This is also the case for drosophilids where studies have already established how inter- and intra-specific differences in cold tolerance are linked to the secretory capacity of Malpighian tubules. However, presently there is little information on the effects of temperature on the reabsorptive capacity of the hindgut in Drosophila. To address this question we developed a novel method that allows for continued measurements of hindgut ion and fluid reabsorption in Drosophila. Firstly we demonstrate that this assay is temporally stable (> 3 hours) and that the preparation is responsive to humoral stimulation and pharmacological intervention of active and passive transport in accordance with the current insect hindgut reabsorption model. Using this method at benign (24°C) and low temperature (3°C) we investigated how cold acclimation or cold adaptation affected the thermal sensitivity of osmoregulatory function. We found that cold tolerant Drosophila species and cold-acclimated D. melanogaster are innately better at maintaining rates of fluid and Na+ reabsorption at low temperature. Furthermore, cold adaptation and acclimation causes a relative reduction in K+ reabsorption at low temperature. These characteristic responses of cold adapted/acclimated Drosophila will act to promote maintenance of ion and water homeostasis at low temperature and therefore provide further links between adaptations in osmoregulatory capacity of insects and their ability to tolerate cold exposure.