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The lack of physical activity and overnutrition in our modern lifestyle culminates in what we now experience as the current obesity and diabetes pandemic. Medical research performed over the past 20 years identified chronic low‐grade inflammation as a mediator of these metabolic disorders. Hence, finding therapeutic strategies against this underlying inflammation and identifying molecules implicated in this process is of significant importance. Following the observation of an increased plasma concentration of interleukin‐6 (IL‐6) in obese patients, this protein, known predominantly as a pro‐inflammatory cytokine, came into focus. In an attempt to clarify its importance, several studies implicated IL‐6 as a co‐inducer of the development of obesity‐associated insulin resistance, which precedes the development of type 2 diabetes. However, the identification of IL‐6 as a myokine, a protein produced and secreted by skeletal muscle to fulfil paracrine or endocrine roles in the insulin‐sensitizing effects following exercise, provides a contrasting and hence paradoxical identity of this protein in the context of metabolism. We review here the literature considering the complex, pleiotropic role of IL‐6 in the context of metabolism in health and disease. Metabolism and pathogen defense are essential requirements for survival. Mounting an immune response requires major changes to metabolic processes, and immune mediators (such as cytokines) also dictate changes in metabolism, including endocrine regulation of substrate utilization. The April 2014 issue contains a Special Feature on Immunometabolism: The interface of immune and metabolic responses in disease. Further background information on this important topic is available through the accompanying web focus which links to related articles from across Nature Publishing Group.

CRISPR technologies have advanced cancer modelling in mice, but CRISPR activation (CRISPRa) methods have not been exploited in this context. We establish a CRISPRa mouse ( dCas9a-SAM KI ) for inducing gene expression in vivo and in vitro. Using dCas9a-SAM KI primary lymphocytes, we induce B cell restricted genes in T cells and vice versa, demonstrating the power of this system. There are limited models of aggressive double hit lymphoma. Therefore, we transactivate pro-survival BCL-2 in Eµ-Myc T/+ ;dCas9a-SAM KI/+ haematopoietic stem and progenitor cells. Mice transplanted with these cells rapidly develop lymphomas expressing high BCL-2 and MYC. Unlike standard Eµ-Myc lymphomas, BCL-2 expressing lymphomas are highly sensitive to the BCL-2 inhibitor venetoclax. We perform genome-wide activation screens in these lymphoma cells and find a dominant role for the BCL-2 protein A1 in venetoclax resistance. Here we show the potential of our CRISPRa model for mimicking disease and providing insights into resistance mechanisms towards targeted therapies. Modelling of aggressive lymphomas, such as double hit lymphoma, has been challenging. Here the authors engineer a CRISPR activation mouse to enable the generation of these aggressive lymphomas and identify the pro-survival BCL-2 protein A1 as a venetoclax resistance factor.

Identifying tumor suppressor genes is predicted to inform on the development of novel strategies for cancer therapy. To identify new lymphoma driving processes that cooperate with oncogenic MYC, which is abnormally highly expressed in ~70% of human cancers, we use a genome-wide CRISPR gene knockout screen in Eµ-Myc;Cas9 transgenic hematopoietic stem and progenitor cells in vivo. We discover that loss of any of the GATOR1 complex components - NPRL3, DEPDC5, NPRL2 - significantly accelerates c-MYC-driven lymphoma development in mice. MYC-driven lymphomas lacking GATOR1 display constitutive mTOR pathway activation and are highly sensitive to mTOR inhibitors, both in vitro and in vivo. These findings identify GATOR1 suppression of mTORC1 as a tumor suppressive mechanism in MYC-driven lymphomagenesis and suggest an avenue for therapeutic intervention in GATOR1-deficient lymphomas through mTOR inhibition. Identifying genes involved in MYC-driven lymphoma reveals therapeutic vulnerabilities. Here, the authors show by using CRISPR knockout screens in primary cells in vivo that the GATOR1 complex suppresses MYC-driven lymphomagenesis, and that GATOR1-deficient lymphomas are sensitive to mTOR inhibitors.

Liquid biopsies promise major advantages for cancer screening and diagnosis. By detecting biomarkers in peripheral blood samples, liquid biopsies reduce the need for invasive techniques and provide important genetic information integral to the emerging molecular classification of cancers. Unfortunately, the concentrations of most biomarkers, particularly circulating tumour nucleic acids, are vanishingly small—beyond the sensitivity and specificity of most assays. Clustered Regularly Interspaced Short Palindromic Repeats diagnostics (herein labelled ‘CRISPR-Dx’) use gene editing tools to detect, rather than modify, nucleic acids with extremely high specificity. These tools are commonly combined with isothermal nucleic acid amplification to also achieve sensitivities comparable to high-performance laboratory-based techniques, such as digital PCR. CRISPR assays, however, are inherently well suited to adaptation for point-of-care (POC) use, and unlike antigen-based POC assays, are significantly easier and faster to develop. In this review, we summarise current CRISPR-Dx platforms and their analytical potential for cancer biomarker discovery, with an emphasis on enhancing early diagnosis, disease monitoring, point-of-care testing, and supporting cancer therapy.

Physical activity is associated with improvements in insulin sensitivity and muscle function. The proteoglycan decorin is increased in skeletal muscle and plasma in response to exercise, but the biological implications are unknown. We investigated the effects of decorin deficiency on obesity, glucose tolerance, and exercise adaptation in C57BL/6J mice. Decorin deficiency did not influence adiposity, insulin‐ and glucose‐ tolerance, or energy metabolism in obese, high fat diet fed mice (Dcn−/− vs. Dcn+/+). Decorin is abundant in the skeletal muscle extracellular matrix, thus we further compared the skeletal muscle of Dcn−/− and Dcn+/+ littermates. There were no effects on muscle morphology or the expression of metabolic markers. Dcn−/− mice had normal exercise capacity measured as running distance on a treadmill. To study the effects of long‐term exercise, mice were housed with access to running wheels. Overall, there were no major differences in voluntary wheel running or skeletal muscle metabolic markers, but Dcn−/− mice had a tendency for reduced running wheel activity compared to Dcn+/+ mice. This was accompanied by a smaller exercise effect on metabolic markers in muscle Dcn−/− mice. Our findings indicate that decorin does not have a major impact on glucose tolerance, metabolic adaptation, or aerobic exercise performance. Decorin deficiency does not have a major impact on glucose tolerance, metabolic adaptation, or aerobic exercise performance.

Let $f:2^X \\rightarrow \\cal R_+$ be a monotone submodular set function, and let $(X,\\cal I)$ be a matroid. We consider the problem ${\\rm max}_{S \\in \\cal I} f(S)$. It is known that the greedy algorithm yields a $1/2$-approximation [M. L. Fisher, G. L. Nemhauser, and L. A. Wolsey, Math. Programming Stud., no. 8 (1978), pp. 73-87] for this problem. For certain special cases, e.g., ${\\rm max}_{|S| \\leq k} f(S)$, the greedy algorithm yields a $(1-1/e)$-approximation. It is known that this is optimal both in the value oracle model (where the only access to f is through a black box returning $f(S)$ for a given set S) [G. L. Nemhauser and L. A. Wolsey, Math. Oper. Res., 3 (1978), pp. 177-188] and for explicitly posed instances assuming $P \\neq NP$ [U. Feige, J. ACM, 45 (1998), pp. 634-652]. In this paper, we provide a randomized $(1-1/e)$-approximation for any monotone submodular function and an arbitrary matroid. The algorithm works in the value oracle model. Our main tools are a variant of the pipage rounding technique of Ageev and Sviridenko [J. Combin. Optim., 8 (2004), pp. 307-328], and a continuous greedy process that may be of independent interest. As a special case, our algorithm implies an optimal approximation for the submodular welfare problem in the value oracle model [J. Vondrák, Proceedings of the $38$th ACM Symposium on Theory of Computing, 2008, pp. 67-74]. As a second application, we show that the generalized assignment problem (GAP) is also a special case; although the reduction requires $|X|$ to be exponential in the original problem size, we are able to achieve a $(1-1/e-o(1))$-approximation for GAP, simplifying previously known algorithms. Additionally, the reduction enables us to obtain approximation algorithms for variants of GAP with more general constraints. [PUBLICATION ABSTRACT]

c-Jun N-terminal kinase (JNK) 1-dependent signaling plays a crucial role in the development of obesity-associated insulin resistance. Here we demonstrate that JNK activation not only occurs in peripheral tissues, but also in the hypothalamus and pituitary of obese mice. To resolve the importance of JNK1 signaling in the hypothalamic/pituitary circuitry, we have generated mice with a conditional inactivation of JNK1 in nestin-expressing cells (JNK1 ΔNES mice). JNK1 ΔNES mice exhibit improved insulin sensitivity both in the CNS and in peripheral tissues, improved glucose metabolism, as well as protection from hepatic steatosis and adipose tissue dysfunction upon high-fat feeding. Moreover, JNK1 ΔNES mice also show reduced somatic growth in the presence of reduced circulating growth hormone (GH) and insulin-like growth factor 1 (IGF1) concentrations, as well as increased thyroid axis activity. Collectively, these experiments reveal an unexpected, critical role for hypothalamic/pituitary JNK1 signaling in the coordination of metabolic/endocrine homeostasis.

Obesity and associated metabolic disturbances, such as increased circulating fatty acids cause prolonged low grade activation of inflammatory signaling pathways in liver, skeletal muscle, adipose tissue and even in the CNS. Activation of inflammatory pathways in turn impairs insulin signaling, ultimately leading to obesity-associated type 2 diabetes mellitus. Conventional JNK-1 knock out mice are protected from high fat diet-induced insulin resistance, characterizing JNK-1-inhibition as a potential approach to improve glucose metabolism in obese patients. However, the cell type-specific role of elevated JNK-1 signaling as present during the course of obesity has not been fully elucidated yet. To investigate the functional contribution of altered JNK-1 activation in skeletal muscle, we have generated a ROSA26 insertion mouse strain allowing for Cre-activatable expression of a JNK-1 constitutive active construct (JNK(C)). To examine the consequence of skeletal muscle-restricted JNK-1 overactivation in the development of insulin resistance and glucose metabolism, JNK(C) mice were crossed to Mck-Cre mice yielding JNK(SM-C) mice. However, despite increased muscle-specific JNK activation, energy homeostasis and glucose metabolism in JNK(SM-C) mice remained largely unaltered compared to controls. In line with these findings, obese mice with skeletal muscle specific disruption of JNK-1, did not affect energy and glucose homeostasis. These experiments indicate that JNK-1 activation in skeletal muscle does not account for the major effects on diet-induced, JNK-1-mediated deterioration of insulin action and points towards a so far underappreciated role of JNK-1 in other tissues than skeletal muscle during the development of obesity-associated insulin resistance.