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The reversible phosphorylation of tyrosine residues is an important mechanism for modulating biological processes such as cellular signaling, differentiation, and growth, and if deregulated, can result in various types of cancer. Therefore, an understanding of these dynamic cellular processes at the molecular level requires the ability to assess changes in the sites of tyrosine phosphorylation across numerous proteins simultaneously as well as over time. Here we describe a sensitive approach based on multidimensional liquid chromatography/mass spectrometry that enables the rapid identification of numerous sites of tyrosine phosphorylation on a number of different proteins from human whole cell lysates. We used this methodology to follow changes in tyrosine phosphorylation patterns that occur over time during either the activation of human T cells or the inhibition of the oncogenic BCR-ABL fusion product in chronic myelogenous leukemia cells in response to treatment with ST1571 (Gleevec). Together, these experiments rapidly identified 64 unique sites of tyrosine phosphorylation on 32 different proteins. Half of these sites have been documented in the literature, validating the merits of our approach, whereas motif analysis suggests that a number of the undocumented sites are also potentially involved in biological pathways. This methodology should enable the rapid generation of new insights into signaling pathways as they occur in states of health and disease.

Background There are several indications that the composition of the tumor stroma can contribute to the malignancy of a tumor. Here we utilized expression data sets to identify metagenes that may serve as surrogate marker for the extent of matrix production and vascularization of a tumor and to characterize prognostic molecular components of the stroma. Methods TCGA data sets from six cancer forms, two breast cancer microarray sets and one mRNA data set of xenografted tumors were downloaded. Using the mean correlation as distance measure compact clusters with genes representing extracellular matrix production (ECM metagene) and vascularization (endothelial metagene) were defined. Explorative Cox modeling was used to identify prognostic stromal gene sets. Results Clustering of stromal genes in six cancer data sets resulted in metagenes, each containing three genes, representing matrix production and vascularization. The ECM metagene was associated with poor prognosis in renal clear cell carcinoma and in lung adenocarcinoma but not in other cancers investigated. Explorative Cox modeling using gene pairs identified gene sets that in multivariate models were prognostic in breast cancer. This was validated in two microarray sets. Two notable genes are TCF4 and P4HA3 which were included in the sets associated with positive and negative prognosis, respectively. Data from laser-microdissected tumors, a xenografted tumor data set and from correlation analyses demonstrate the stroma specificity of the genes. Conclusions It is possible to construct ECM and endothelial metagenes common for several cancer forms. The molecular composition of matrix-producing cells, rather than the extent of matrix production seem to be important for breast cancer prognosis.

Understanding how the nutritional properties of food resources drive foraging choices is important for the management and conservation of wildlife populations. For moose (Alces alces), recent experimental and observational studies during the winter have shown macronutrient balancing between available protein (AP) and highly metabolizable macronutrients (total non‐structural carbohydrates [TNC] and lipids). Here, we combined the use of continuous‐recording camera collars with plant nutrient analyses and forage availability measurements to obtain a detailed insight into the food and nutritional choices of three wild moose in Norway over a 5‐day period in summer. We found that moose derived their macronutrient energy primarily from carbohydrates (74.2%), followed by protein (13.1%), and lipids (12.7%). Diets were dominated by deciduous tree browse (71%). Willows (Salix spp.) were selected for and constituted 51% of the average diet. Moose consumed 25 different food items during the study period of which 9 comprised 95% of the diet. Moose tightly regulated their intake of protein to highly metabolizable macronutrients (AP:TNC + lipids) to a ratio of 1:2.7 (0.37 ± 0.002SD). They did this by feeding on foods that most closely matched the target macronutrient ratio such as Salix spp., or by combining nutritionally imbalanced foods (complementary feeding) in a non‐random manner that minimized deviations from the intake target. The observed patterns of macronutrient balancing aligned well with the findings of winter studies. Differential feeding on nutritionally balanced downy birch (Betula pubescens) leaves versus imbalanced twigs+leaves across moose individuals indicated that macronutrient balancing may occur on as fine a scale as foraging bites on a single plant species. Utilized forages generally met the suggested requirement thresholds for the minerals calcium, phosphorus, copper, molybdenum, and magnesium but tended to be low in sodium. Our findings offer new insights into the foraging behavior of a model species in ungulate nutritional ecology and contribute to informed decision‐making in wildlife and forest management. Understanding how the nutritional properties of food resources influence foraging decisions is crucial for wildlife management and conservation. Using a combination of camera collars with plant nutrient analyses and forage availability measurements, we show that moose used macronutrient balancing for tightly regulating their intake of protein to highly metabolizable macronutrients (non‐structural carbohydrates and lipids) during summer. Our findings provide novel contributions to ungulate nutritional ecology and inform decision‐making in wildlife and forest management.

Bystanders play a vital role in public access defibrillation (PAD) in out-of-hospital cardiac arrest (OHCA). Dual dispatch of first responders (FR) alongside emergency medical services (EMS) can reduce time to first defibrillation. The aim of this study was to describe the use of automated external defibrillators (AEDs) in OHCAs before EMS arrival. All OHCA cases with a shockable rhythm in which an AED was used prior to the arrival of EMS between 2008 and 2015 in western Sweden were eligible for inclusion. Data from the Swedish Register for Cardiopulmonary Resuscitation (SRCR) were used for analysis, on-site bystander and FR defibrillation were compared with EMS defibrillation in the final analysis. Of the reported 6675 cases, 24% suffered ventricular fibrillation (VF), 162 patients (15%) of all VF cases were defibrillated before EMS arrival, 46% with a public AED on site. The proportion of cases defibrillated before EMS arrival increased from 5% in 2008 to 20% in 2015 (p<0.001). During this period, 30-day survival increased in patients with VF from 22% to 28% (p=0.04) and was highest when an AED was used on site (68%), with a median delay of 6.5min from collapse to defibrillation. Adjusted odds ratio for on-site defibrillation versus dispatched defibrillation for 30-day survival was 2.45 (95% CI: 1.02–5.95). The use of AEDs before the arrival of EMS increased over time. This was associated with an increased 30-day survival among patients with VF. Thirty-day survival was highest when an AED was used on site before EMS arrival.

Understanding how the nutritional properties of food resources drive foraging choicesis important for the management and conservation of wildlife populations. For moose(Alces alces), recent experimental and observational studies during the winter haveshown macronutrient balancing between available protein (AP) and highly metaboliz-able macronutrients (total non-structural carbohydrates [TNC] and lipids). Here, wecombined the use of continuous-recording camera collars with plant nutrient analysesand forage availability measurements to obtain a detailed insight into the food andnutritional choices of three wild moose in Norway over a 5-day period in summer. Wefound that moose derived their macronutrient energy primarily from carbohydrates(74.2%), followed by protein (13.1%), and lipids (12.7%). Diets were dominated bydeciduous tree browse (71%). Willows (Salix spp.) were selected for and constituted51% of the average diet. Moose consumed 25 different food items during the studyperiod of which 9 comprised 95% of the diet. Moose tightly regulated their intake ofprotein to highly metabolizable macronutrients (AP:TNC + lipids) to a ratio of 1:2.7(0.37 ± 0.002SD). They did this by feeding on foods that most closely matched thetarget macronutrient ratio such as Salix spp., or by combining nutritionally imbalancedfoods (complementary feeding) in a non-random manner that minimized deviationsfrom the intake target. The observed patterns of macronutrient balancing alignedwell with the findings of winter studies. Differential feeding on nutritionally balanceddowny birch (Betula pubescens) leaves versus imbalanced twigs+leaves across mooseindividuals indicated that macronutrient balancing may occur on as fine a scale asforaging bites on a single plant species. Utilized forages generally met the suggestedrequirement thresholds for the minerals calcium, phosphorus, copper, molybdenum,and magnesium but tended to be low in sodium. Our findings offer new insights intothe foraging behavior of a model species in ungulate nutritional ecology and contrib-ute to informed decision-making in wildlife and forest management. cervid, deer, large herbivore, macronutrient balancing, nutritional ecology

Understanding how the nutritional properties of food resources drive foraging choicesis important for the management and conservation of wildlife populations. For moose(Alces alces), recent experimental and observational studies during the winter haveshown macronutrient balancing between available protein (AP) and highly metaboliz-able macronutrients (total non-structural carbohydrates [TNC] and lipids). Here, wecombined the use of continuous-recording camera collars with plant nutrient analysesand forage availability measurements to obtain a detailed insight into the food andnutritional choices of three wild moose in Norway over a 5-day period in summer. Wefound that moose derived their macronutrient energy primarily from carbohydrates(74.2%), followed by protein (13.1%), and lipids (12.7%). Diets were dominated bydeciduous tree browse (71%). Willows (Salix spp.) were selected for and constituted51% of the average diet. Moose consumed 25 different food items during the studyperiod of which 9 comprised 95% of the diet. Moose tightly regulated their intake ofprotein to highly metabolizable macronutrients (AP:TNC + lipids) to a ratio of 1:2.7(0.37 ± 0.002SD). They did this by feeding on foods that most closely matched thetarget macronutrient ratio such as Salix spp., or by combining nutritionally imbalancedfoods (complementary feeding) in a non-random manner that minimized deviationsfrom the intake target. The observed patterns of macronutrient balancing alignedwell with the findings of winter studies. Differential feeding on nutritionally balanceddowny birch (Betula pubescens) leaves versus imbalanced twigs+leaves across mooseindividuals indicated that macronutrient balancing may occur on as fine a scale asforaging bites on a single plant species. Utilized forages generally met the suggestedrequirement thresholds for the minerals calcium, phosphorus, copper, molybdenum,and magnesium but tended to be low in sodium. Our findings offer new insights intothe foraging behavior of a model species in ungulate nutritional ecology and contrib-ute to informed decision-making in wildlife and forest management. cervid, deer, large herbivore, macronutrient balancing, nutritional ecology