Look before you leap: is risk of injury a foraging cost?

Theory states that an optimal forager should exploit a patch so long as its harvest rate of resources from the patch exceeds its energetic, predation, and missed opportunity costs for foraging. However, for many foragers, predation is not the only source of danger they face while foraging. Foragers also face the risk of injuring themselves. To test whether risk of injury gives rise to a foraging cost, we offered red foxes pairs of depletable resource patches in which they experienced diminishing returns. The resource patches were identical in all respects, save for the risk of injury. In response, the foxes exploited the safe patches more intensively. They foraged for a longer time and also removed more food (i.e., had lower giving up densities) in the safe patches compared to the risky patches. Although they never sustained injury, video footage revealed that the foxes used greater care while foraging from the risky patches and removed food at a slower rate. Furthermore, an increase in their hunger state led foxes to allocate more time to foraging from the risky patches, thereby exposing themselves to higher risks. Our results suggest that foxes treat risk of injury as a foraging cost and use time allocation and daring—the willingness to risk injury—as tools for managing their risk of injury while foraging. This is the first study, to our knowledge, which explicitly tests and shows that risk of injury is indeed a foraging cost. While nearly all foragers may face an injury cost of foraging, we suggest that this cost will be largest and most important for predators

Malonyl coenzymeA decarboxylase regulates lipid and glucose metabolism in human skeletal muscle

Objective: malonyl coenzyme A (CoA) decarboxylase (MCD) is a key enzyme responsible for malonyl-CoA turnover and functions in the control of the balance between lipid and glucose metabolism. We utilized RNA interference (siRNA)-based gene silencing to determine the direct role of MCD on metabolic responses in primary human skeletal muscle. Research design and methods: we used siRNA to silence MCD gene expression in cultured human myotubes from healthy volunteers (seven male and seven female) with no known metabolic disorders. Thereafter, we determined lipid and glucose metabolism and signal transduction under basal and insulin-stimulated conditions. Results: RNA interference-based silencing of MCD expression (75% reduction) increased malonyl-CoA levels twofold and shifted substrate utilization from lipid to glucose oxidation. RNA interference-based depletion of MCD reduced basal palmitate oxidation. In parallel with this reduction, palmitate uptake was decreased under basal (40%) and insulin-stimulated (49%) conditions compared with myotubes transfected with a scrambled sequence. MCD silencing increased basal and insulin-mediated glucose oxidation 1.4- and 2.6-fold, respectively, compared with myotubes transfected with a scrambled sequence. In addition, glucose transport and cell-surface GLUT4 content was increased. In contrast, insulin action on IRS-1 tyrosine phosphorylation, tyrosine-associated phosphatidylinositol (PI) 3-kinase activity, Akt, and glycogen synthase kinase (GSK) phosphorylation was unaltered between myotubes transfected with siRNA against MCD versus a scrambled sequence. Conclusions: these results provide evidence that MCD silencing suppresses lipid uptake and enhances glucose uptake in primary human myotubes. In conclusion, MCD expression plays a key reciprocal role in the balance between lipid and glucose metabolism

A Genome-Wide siRNA Screen to Identify Modulators of Insulin Sensitivity and Gluconeogenesis

BACKGROUND: Hepatic insulin resistance impairs insulin's ability to suppress hepatic glucose production (HGP) and contributes to the development of type 2 diabetes (T2D). Although the interests to discover novel genes that modulate insulin sensitivity and HGP are high, it remains challenging to have a human cell based system to identify novel genes. METHODOLOGY/PRINCIPAL FINDINGS: To identify genes that modulate hepatic insulin signaling and HGP, we generated a human cell line stably expressing beta-lactamase under the control of the human glucose-6-phosphatase (G6PC) promoter (AH-G6PC cells). Both beta-lactamase activity and endogenous G6PC mRNA were increased in AH-G6PC cells by a combination of dexamethasone and pCPT-cAMP, and reduced by insulin. A 4-gene High-Throughput-Genomics assay was developed to concomitantly measure G6PC and pyruvate-dehydrogenase-kinase-4 (PDK4) mRNA levels. Using this assay, we screened an siRNA library containing pooled siRNA targeting 6650 druggable genes and identified 614 hits that lowered G6PC expression without increasing PDK4 mRNA levels. Pathway analysis indicated that siRNA-mediated knockdown (KD) of genes known to positively or negatively affect insulin signaling increased or decreased G6PC mRNA expression, respectively, thus validating our screening platform. A subset of 270 primary screen hits was selected and 149 hits were confirmed by target gene KD by pooled siRNA and 7 single siRNA for each gene to reduce G6PC expression in 4-gene HTG assay. Subsequently, pooled siRNA KD of 113 genes decreased PEPCK and/or PGC1alpha mRNA expression thereby demonstrating their role in regulating key gluconeogenic genes in addition to G6PC. Last, KD of 61 of the above 113 genes potentiated insulin-stimulated Akt phosphorylation, suggesting that they suppress gluconeogenic gene by enhancing insulin signaling. CONCLUSIONS/SIGNIFICANCE: These results support the proposition that the proteins encoded by the genes identified in our cell-based druggable genome siRNA screen hold the potential to serve as novel pharmacological targets for the treatment of T2D

Habituated, Tolerant, or Salt-conditioned Mountain Goats and Human Safety

Interactions between humans and wildlife include a number of consumptive and non-consumptive forms. In some cases, the increased demand for wildlife viewing can precipitate new human–wildlife conflicts. Mountain goats (Oreamnos americanus; goats) are native to a number of North American mountain ranges from southeastern Alaska to southwestern Montana, USA. Goat habitat typically consists of steep terrain and cold weather habitats, which has left them particularly vulnerable to climate change. Their alpine environments also make them vulnerable to disturbance by aircraft and land-based motorized human activity. We reviewed and characterized situations in which goats in close proximity to humans on foot may become a nuisance or dangerous to people. We identify how such interactions might occur, focusing on the array of intensity observed in different settings. We summarize and evaluate interventions that have been attempted and may warrant additional research. Goats that tolerate people along hiking trails, perhaps through a habituation-like process, can typically be kept at a safe distance simply by shouting, clapping hands, or vigorous gestures. Goats that have learned to associate people with a salt reward (e.g., typically urine deposited on the ground, less frequently sweat obtained directly by licking) are more likely to be successfully hazed by tossing small stones, hitting the animal in the flank or rear. Salt-conditioned goats sometimes come within touching distance of humans; we strongly advise against prodding or poking these animals with sharp objects such as trekking poles. The recreating public that ventures into goat habitat is the ultimate source of these conflicts. Education, compliance, and possibly some infrastructure improvements can lessen the potential for conflicts and provide new and safer opportunities to view goats

Is there an optimal minimally invasive technique for left anterior descending coronary artery bypass?

<p>Abstract</p> <p>Background</p> <p>The aim of this retrospective study was to evaluate the clinical outcome of three different minimally invasive surgical techniques for left anterior descending (LAD) coronary artery bypass grafting (CABG): Port-Access surgery (PA-CABG), minimally invasive direct CABG (MIDCAB) and off-pump totally endoscopic CABG (TECAB).</p> <p>Methods</p> <p>Over a decade, 160 eligible patients for elective LAD bypass were referred to one of the three techniques: 48 PA-CABG, 53 MIDCAB and 59 TECAB. In MIDCAB group, Euroscore was higher and target vessel quality was worse. In TECAB group, early patency was systematically evaluated using coronary CT scan. During follow-up (mean 2.7 ± 0.1 years, cumulated 438 years) symptom-based angiography was performed.</p> <p>Results</p> <p>There was no conversion from off-pump to on-pump procedure or to sternotomy approach. In TECAB group, there was one hospital cardiac death (1.7%), reoperation for bleeding was higher (8.5% vs 3.7% in MIDCAB and 2% in PA-CABG) and 3-month LAD reintervention was significantly higher (10% vs 1.8% in MIDCAB and 0% in PA-CABG). There was no difference between MIDCAB and PA-CABG groups. During follow-up, symptom-based angiography (n = 12) demonstrated a good patency of LAD bypass in all groups and 4 patients underwent a no LAD reintervention. At 3 years, there was no difference in survival; 3-year angina-free survival and reintervention-free survival were significantly lower in TECAB group (TECAB, 85 ± 12%, 88 ± 8%; MIDCAB, 100%, 98 ± 5%; PA-CABG, 94 ± 8%, 100%; respectively).</p> <p>Conclusions</p> <p>Our study confirmed that minimally invasive LAD grafting was safe and effective. TECAB is associated with a higher rate of early bypass failure and reintervention. MIDCAB is still the most reliable surgical technique for isolated LAD grafting and the least cost effective.</p

Proangiogenic contribution of adiponectin toward mammary tumor growth in vivo

PURPOSE: Adipocytes represent one of the most abundant constituents of the mammary gland. They are essential for mammary tumor growth and survival. Metabolically, one of the more important fat-derived factors (“adipokines”) is adiponectin (APN). Serum concentrations of APN negatively correlate with body mass index and insulin resistance. To explore the association of APN with breast cancer and tumor angiogenesis, we took an in vivo approach aiming to study its role in the mouse mammary tumor virus (MMTV)-polyoma middle T antigen (PyMT) mammary tumor model. EXPERIMENTAL DESIGN: We compared the rates of tumor growth in MMTV-PyMT mice in wild-type and APN-null backgrounds. RESULTS: Histology and micro-positron emission tomography imaging show that the rate of tumor growth is significantly reduced in the absence of APN at early stages. PyMT/APN knockout mice exhibit a reduction in their angiogenic profile resulting in nutrient deprivation of the tumors and tumor-associated cell death. Surprisingly, in more advanced malignant stages of the disease, tumor growth develops more aggressively in mice lacking APN, giving rise to a larger tumor burden, an increase in the mobilization of circulating endothelial progenitor cells, and a gene expression fingerprint indicative of more aggressive tumor cells. CONCLUSIONS: These observations highlight a novel important contribution of APN in mammary tumor development and angiogenesis, indicating that APN has potent angio-mimetic properties in tumor vascularization. However, in tumors deprived of APN, this antiangiogenic stress results in an adaptive response that fuels tumor growth through mobilization of circulating endothelial progenitor cells and the development of mechanisms enabling massive cell proliferation despite a chronically hypoxic micro-environment

Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines.

To provide evidence-based guidelines for early enteral nutrition (EEN) during critical illness. We aimed to compare EEN vs. early parenteral nutrition (PN) and vs. delayed EN. We defined "early" EN as EN started within 48 h independent of type or amount. We listed, a priori, conditions in which EN is often delayed, and performed systematic reviews in 24 such subtopics. If sufficient evidence was available, we performed meta-analyses; if not, we qualitatively summarized the evidence and based our recommendations on expert opinion. We used the GRADE approach for guideline development. The final recommendations were compiled via Delphi rounds. We formulated 17 recommendations favouring initiation of EEN and seven recommendations favouring delaying EN. We performed five meta-analyses: in unselected critically ill patients, and specifically in traumatic brain injury, severe acute pancreatitis, gastrointestinal (GI) surgery and abdominal trauma. EEN reduced infectious complications in unselected critically ill patients, in patients with severe acute pancreatitis, and after GI surgery. We did not detect any evidence of superiority for early PN or delayed EN over EEN. All recommendations are weak because of the low quality of evidence, with several based only on expert opinion. We suggest using EEN in the majority of critically ill under certain precautions. In the absence of evidence, we suggest delaying EN in critically ill patients with uncontrolled shock, uncontrolled hypoxaemia and acidosis, uncontrolled upper GI bleeding, gastric aspirate &gt;500 ml/6 h, bowel ischaemia, bowel obstruction, abdominal compartment syndrome, and high-output fistula without distal feeding access

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts