How breast cancer cells respond to the stress of endocrine therapies determines whether they acquire a resistant phenotype or execute a cell death pathway. A successfully executed survival signal then requires determination of whether or not to replicate. How these cell fate decisions are regulated is unclear but evidence suggests that the signals determining these outcomes are highly integrated. Central to the final cell fate decision is signaling from the unfolded protein response, which can be activated following the sensing of stress within the endoplasmic reticulum. Duration of the response to stress is partly mediated by the duration of inositol requiring enzyme-1 (IRE1; ERN) activation following its release from heat shock protein A5 (HSPA5). The resulting signaling appears to use several B-cell lymphoma-2 (BCL2) family members to both suppress apoptosis and activate autophagy. Changes in metabolism induced by cellular stress are key components of this regulatory system, and further adaptation of the metabolome is affected in response to stress. Here we describe the unfolded protein response, autophagy and apoptosis, and how their regulation is integrated. Central topological features of the signaling network that integrate cell fate regulation and decision execution are discussed.

Hosts of avian brood parasites can avoid the reproductive costs of raising genetically unrelated offspring by rejecting parasitic eggs. The perceptual cues and controls mediating parasitic egg discrimination and ejection are well studied: hosts are thought to use differences in egg color, brightness, maculation, size and shape to discriminate between their own and foreign eggs. Most theories of brood parasitism implicitly assume that the primary criteria to which hosts attend when discriminating eggs are differences between the eggs themselves. However, this assumption is confounded by the degree to which chromatic and achromatic characteristics of the nest lining co-vary with egg coloration, so that egg-nest contrast per se might be the recognition cue driving parasitic egg detection. Here, we systematically tested whether and how egg-nest contrast itself contributes to foreign egg discrimination. In an artificial parasitism experiment, we independently manipulated egg color and nest lining color of the egg-ejector American robin (Turdus migratorius), a host of the obligate brood parasitic brown-headed cowbird (Molothrus ater). We hypothesized that the degree of contrast between foreign eggs and the nest background would affect host egg rejection behavior. We predicted that experimentally decreasing egg-nest chromatic and achromatic contrast (i.e. rendering parasitic eggs more cryptic against the nest lining) would decrease rejection rates, while increasing egg-nest contrast would increase rejection rates. In contrast to our predictions, egg-nest contrast was not a significant predictor of egg ejection patterns. Instead, egg color significantly predicted responses to parasitism. We conclude that eggegg differences are the primary drivers of egg rejection in this system. Future studies should test for the effects of egg-nest contrast per se in predicting parasitic egg recognition in other host-parasite systems, including those hosts building enclosed nests and those parasites laying cryptic eggs, as an alternative to hypothesized effects of egg-egg contrast.

Background Prediabetes affects 1 in 3 US adults. Most are not receiving evidence-based interventions, so understanding how providers discuss prediabetes with patients will inform how to improve their care. Objective This study aimed to develop a natural language processing (NLP) algorithm using machine learning techniques to identify discussions of prediabetes in narrative documentation. Methods We developed and applied a keyword search strategy to identify discussions of prediabetes in clinical documentation for patients with prediabetes. We manually reviewed matching notes to determine which represented actual prediabetes discussions. We applied 7 machine learning models against our manual annotation. Results Machine learning classifiers were able to achieve classification results that were close to human performance with up to 98% precision and recall to identify prediabetes discussions in clinical documentation. Conclusions We demonstrated that prediabetes discussions can be accurately identified using an NLP algorithm. This approach can be used to understand and identify prediabetes management practices in primary care, thereby informing interventions to improve guideline-concordant care.

In addition to the continuous low levels of neurogenesis typical of adult vertebrates to replace damaged chemoreceptor cells, red-backed salamanders (Plethodon cinereus) experience an up-regulation of chemoreceptor epithelial cell proliferation on a seasonal basis. Significantly more cell division occurs in late spring than at any other time of the year, and we investigated the fate and life span of these newly generated cells. We used 5-bromo-2′-deoxyuridine (BrdU) immunocytochemical cell birth dating to examine cell proliferation and cell migration in the main olfactory and vomeronasal epithelia of red-backed salamanders collected in late spring who were allowed to survive for one hour or three, four, 25, 28, 42, 49 and 100 days post-injection. We examined new neuron growth in the vomeronasal and olfactory epithelia using antibodies against Growth Associated Protein-43 (GAP-43), a protein whose synthesis is up-regulated during axon growth. We also tracked apoptosis within both types of chemosensory epithelia using terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL). BrdU-immunoreactive cells were located extensively throughout the vomeronasal epithelia, particularly in the area posterior to the entrance of the nasolacrimal duct, not only after three days of survival, but also all of the longer experimental survival periods as well; BrdU-ir cells within the olfactory epithelia were rarely located after longer survival periods. Salamanders collected in late spring displayed extensive GAP-43 labeling in the vomeronasal epithelia posterior to the entrance of the nasolacrimal duct, indicating a large population of young vomeronasal receptor neurons. Finally, apoptotic cells were evident in this same post-nasolacrimal-duct-area of the vomeronasal organ and in the olfactory epithelium. We suggest that vomeronasal receptor neurons born in late spring function throughout the summer and may be associated with the animals’ extensive territoriality during that period.