J. Andrew Pospisilik, Claude Knauf, Nicholas Joza, Paule Benit, Michael Orthofer, Patrice D. Cani, Ingo Ebersberger, Tomoki Nakashima, Renu Sarao, Gregory Neely, Harald Esterbauer, Andrey Kozlov, C. Ronald Kahn, Guido Kroemer, Pierre Rustin, Remy Burcelin and Josef M. Penninger (2007). "Targeted Deletion of AIF Decreases Mitochondrial Oxidative Phosphorylation and Protects from Obesity and Diabetes". Cell Nov 2; 131 (3): 476-491.

Nominated by: Anna Chen Arroyo

Abstract:

Type-2 diabetes results from the development of insulin resistance and a concomitant impairment of insulin secretion. Recent studies place altered mitochondrial oxidative phosphorylation (OxPhos) as an underlying genetic element of insulin resistance. However, the causative or compensatory nature of these OxPhos changes has yet to be proven. Here, we show that muscle- and liver-specific AIF ablation in mice initiates a pattern of OxPhos deficiency closely mimicking that of human insulin resistance, and contrary to current expectations, results in increased glucose tolerance, reduced fat mass, and increased insulin sensitivity. These results are maintained upon high- fat feeding and in both genetic mosaic and ubiquitous OxPhos-deficient mutants. Importantly, the effects of AIF on glucose metabolism are acutely inducible and reversible. These findings establish that tissue- specific as well as global OxPhos defects in mice can counteract the development of insulin resistance, diabetes, and obesity.

Paragraph on Why Paper is Important:

I'm proposing this paper because its findings contradict the current ideas about the development of insulin resistance by reduced mitochondrial oxidative metabolism. It would be interesting to discuss this paper about mechanisms in insulin resistance as a follow-up to our diabetes discussion.

Kiel MJ, He S, Ashkenazi R, Gentry SN, Teta M, Kushner JA, Jackson TL, Morrison SJ. "Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU." Nature. 2007 Sep 13;449(7159):238-42. Epub 2007 Aug 29.

Nominated by: Agnieszka Czechowicz

Abstract:

Stem cells are proposed to segregate chromosomes asymmetrically during self-renewing divisions so that older ('immortal') DNA strands are retained in daughter stem cells whereas newly synthesized strands segregate to differentiating cells. Stem cells are also proposed to retain DNA labels, such as 5-bromo-2-deoxyuridine (BrdU), either because they segregate chromosomes asymmetrically or because they divide slowly. However, the purity of stem cells among BrdU-label-retaining cells has not been documented in any tissue, and the 'immortal strand hypothesis' has not been tested in a system with definitive stem cell markers. Here we tested these hypotheses in haematopoietic stem cells (HSCs), which can be highly purified using well characterized markers. We administered BrdU to newborn mice, mice treated with cyclophosphamide and granulocyte colony-stimulating factor, and normal adult mice for 4 to 10 days, followed by 70 days without BrdU. In each case, less than 6% of HSCs retained BrdU and less than 0.5% of all BrdU-retaining haematopoietic cells were HSCs, revealing that BrdU has poor specificity and poor sensitivity as an HSC marker. Sequential administration of 5-chloro-2-deoxyuridine and 5-iodo-2-deoxyuridine indicated that all HSCs segregate their chromosomes randomly. Division of individual HSCs in culture revealed no asymmetric segregation of the label. Thus, HSCs cannot be identified on the basis of BrdU-label retention and do not retain older DNA strands during division, indicating that these are not general properties of stem cells.

Paragraph on Why Paper is Important:

This paper elegantly disproves the long believed hypotheses of quiescence and asymmetric division of stem cells in the best defined stem cell system, hematopoeitic stem cells. This paper is short, clear and easy to understand, and nicely demonstrates these principles. It causes one to rethink the literature and encourages the testing of long believed hypotheses in other systems. It also uses some interesting, useful, common techniques that everyone should know about.

Lee, N. K., Sowa, H., Hinoi, E., Ferron, M., Ahn, J. D.; Confavreux, C., Dacquin, R., Mee, P. J., McKee, M. D., Jung, D. Y., Zhang, Z., Kim, J. K., Mauvaid-Jarvis, F., Ducy, P., Karsenty, G. (2007). Endocrine regulation of energy metabolism by the skeleton. Cell 130, 456-469.

Nominated by: James (J. T.) Link

Abstract:

The regulation of bone remodeling by an adipocyte-derived hormone implies that bone may exert a feedback control of energy homeostasis. To test this hypothesis we looked for genes expressed in osteoblasts, encoding signaling molecules and affecting energy metabolism. We show here that mice lacking the protein tyrosine phosphatase OST-PTP are hypoglycemic and are protected from obesity and glucose intolerance because of an increase in beta-cell proliferation, insulin secretion, and insulin sensitivity. In contrast, mice lacking the osteoblast-secreted molecule osteocalcin display decreased beta-cell proliferation, glucose intolerance, and insulin resistance. Removing one Osteocalcin allele from OST-PTP-deficient mice corrects their metabolic phenotype. Ex vivo, osteocalcin can stimulate CyclinD1 and Insulin expression in beta-cells and Adiponectin, an insulin-sensitizing adipokine, in adipocytes; in vivo osteocalcin can improve glucose tolerance. By revealing that the skeleton exerts an endocrine regulation of sugar homeostasis this study expands the biological importance of this organ and our understanding of energy metabolism.

Paragraph on Why Paper is Important:

The paper by Karsenty et. al. explores a novel mechanism by which the skeleton participates in endocrine regulation of glucose homeostasis. Perhaps a better understanding of glucose homeostasis will lead to new targets for therapeutic intervention for the treatment of metabolic syndrome, diabetes, and/or obesity.

Patil ST et al. (2007). Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nature Medicine 13, 1102 - 1107.

Nominated by: Matt Pianko

Abstract:

Schizophrenia is a chronic, complex and heterogeneous mental disorder, with pathological features of disrupted neuronal excitability and plasticity within limbic structures of the brain. These pathological features manifest behaviorally as positive symptoms (including hallucinations, delusions and thought disorder), negative symptoms (such as social withdrawal, apathy and emotional blunting) and other psychopathological symptoms (such as psychomotor retardation, lack of insight, poor attention and impulse control)1. Altered glutamate neurotransmission has for decades been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors2. LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors3 and has shown antipsychotic potential in animal studies. With data from rodents, we provide new evidence that mGlu2/3 receptor agonists work by a distinct mechanism different from that of olanzapine. To clinically test this mechanism, an oral prodrug of LY404039 (LY2140023) was evaluated in schizophrenic patients with olanzapine as an active control in a randomized, three-armed, double-blind, placebo-controlled study. Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo (P < 0.001 at week 4). Notably, patients treated with LY2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain. These data suggest that mGlu2/3 receptor agonists have antipsychotic properties and may provide a new alternative for the treatment of schizophrenia.

Paragraph on Why Paper is Important:

I thought this paper was interesting because it shows data from a clinical trial examining an entirely new class of antipsychotic drug used to treat schizophrenia based on activated on metabotropic glutamate receptors, rather than the other classical approach currently used that modify the serotonergic and dopaminergic systems in the brain. The new approach targets schizophrenia susceptibility gene products, the mGlu2/3 receptors, and shows none of the typical side effects of the drugs currently used. I was interested in this paper because it is an example of rational drug design that takes advantage of recently identified genetic targets involved in a complex psychiatric disorder.

Maskos U, Molles BE, Pons S, Besson M, Guiard BP, Guilloux JP, Evrard A, Cazala P, Cormier A, Mameli-Engvall M, Dufour N, Cloez-Tayarani I, Bemelmans AP, Mallet J, Gardier AM, David V, Faure P, Granon S, Changeux JP. “Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors.” Nature. 2005 Jul 7;436(7047):103-7.

Nominated by: Robert Mair

Abstract:

Worldwide, 100 million people are expected to die this century from the consequences of nicotine addiction, but nicotine is also known to enhance cognitive performance. Identifying the molecular mechanisms involved in nicotine reinforcement and cognition is a priority and requires the development of new in vivo experimental paradigms. The ventral tegmental area (VTA) of the midbrain is thought to mediate the reinforcement properties of many drugs of abuse. Here we specifically re-expressed the beta2-subunit of the nicotinic acetylcholine receptor (nAChR) by stereotaxically injecting a lentiviral vector into the VTA of mice carrying beta2-subunit deletions. We demonstrate the efficient re-expression of electrophysiologically responsive, ligand-binding nicotinic acetylcholine receptors in dopamine-containing neurons of the VTA, together with the recovery of nicotine-elicited dopamine release and nicotine self-administration. We also quantified exploratory behaviours of the mice, and showed that beta2-subunit re-expression restored slow exploratory behaviour (a measure of cognitive function) to wild-type levels, but did not affect fast navigation behaviour. We thus demonstrate the sufficient role of the VTA in both nicotine reinforcement and endogenous cholinergic regulation of cognitive functions.

Paragraph on Why Paper is Important:

This paper presents a surprisingly simple mechanism for nicotine addiction, showing that the expression of a single receptor subunit in the VTA is necessary and sufficient for the self-administration of nicotine in mice. It’s pretty amazing how addiction researchers are beginning to understand the biology behind such a mysterious disease. Don’t be a chicken, vote for the smoking paper. All the cool kids are doing it.

Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, Karin M. (2007). Gender Disparity in Liver Cancer Due to Sex Differences in MyD88-Dependent IL-6 Production. Science. 317, 121-124.

Nominated by: Gary Green

Abstract:

Hepatocellular carcinoma (HCC), the most common liver cancer, occurs mainly in men. Similar gender disparity is seen in mice given a chemical carcinogen, diethylnitrosamine (DEN). DEN administration caused greater increases in serum interleukin-6 (IL-6) concentration in males than it did in females. Furthermore, ablation of IL-6 abolished the gender differences in hepatocarcinogenesis in mice. DEN exposure promoted production of IL-6 in Kupffer cells (KCs) in a manner dependent on the Toll-like receptor adaptor protein MyD88, ablation of which also protected male mice from DEN-induced hepatocarcinogenesis. Estrogen inhibited secretion of IL-6 from KCs exposed to necrotic hepatocytes and reduced circulating concentrations of IL-6 in DEN-treated male mice. We propose that estrogen-mediated inhibition of IL-6 production by KCs reduces liver cancer risk in females, and these findings may be used to prevent HCC in males.

Paragraph on Why Paper is Important:

Hepatocellular carcinoma, like many cancers, affects men at a significantly greater rate than women. These sex-based risk factors are currently not well understood. The paper by Naugler and colleagues seeks to identify a molecular basis for this by looking at the influence of estrogen signaling on IL-6 expression in a mouse model of liver cancer. IL-6 is already known to be involved in the progression of prostate and ovarian cancers and may be an attractive target for clinical intervention in men and post-menopausal women with liver cancer. Antibodies directed against IL-6 are already in use for rheumatoid arthritis and are in clinical trials for certain cancers. This paper was ghost written by David Sedaris, who is much funnier than this Naugler guy.

Larsen CC et al.(2007). A biomimetic peptide fluorosurfactant polymer for endothelialization of ePTFE with limited platelet adhesion. Biomaterials.Aug;28(24):3537-48.

Nominated by: Chad Tang

Abstract:

Endothelialization of expanded polytetrafluoroethylene (ePTFE) has the potential to improve long-term patency for small-diameter vascular grafts. Successful endothelialization requires ePTFE surface modification to permit cell attachment to this otherwise non-adhesive substrate. We report here on a peptide fluorosurfactant polymer (FSP) biomimetic construct that promotes endothelial cell (EC)-selective attachment, growth, shear stability, and function on ePTFE. The peptide FSP consists of a flexible poly(vinyl amine) backbone with EC-selective peptide ligands for specific cell adhesion and pendant fluorocarbon branches for stable anchorage to underlying ePTFE. The EC-selective peptide (primary sequence: Cys?Arg?Arg?Glu?Thr?Ala?Trp?Ala?Cys, CRRETAWAC) has demonstrated high binding affinity for the ?5?1 integrin found on ECs. Here, we demonstrate low affinity of CRRETAWAC for platelets and platelet integrins, thus providing it with EC-selectivity. This EC-selectivity could potentially facilitate rapid in vivo endothelialization and healing without thrombosis for small-diameter ePTFE vascular grafts.

Paragraph on Why Paper is Important:

This paper addresses vascular disease by creating a novel polymer scaffold which self-assembles onto a vascular graft surface and presents peptides which specifically adheres endothelial cells. I thought this paper would be interesting because it presents a relatively simple and interesting tissue engineering approach to improve the outcome of patients undergoing vascular bypass surgery.

Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L,Chorianopoulos E, Liesenborghs L, Koch M, De Mol M, Autiero M, Wyns S,Plaisance S, Moons L, van Rooijen N, Giacca M, Stassen JM, Dewerchin M, Collen D, Carmeliet P. (2007). Anti-PlGF Inhibits Growth of VEGF(R)-Inhibitor-Resistant Tumors without Affecting Healthy Vessels. Cell.Nov 2;131(3):463-75.

Nominated by: Sergio Arroyo

Abstract:

Novel antiangiogenic strategies with complementary mechanisms are needed to maximize efficacy and minimize resistance to current angiogenesis inhibitors. We explored the therapeutic potential and mechanisms of alphaPlGF, an antibody against placental growth factor (PlGF), a VEGF homolog, which regulates the angiogenic switch in disease, but not in health. alphaPlGF inhibited growth and metastasis of various tumors, including those resistant to VEGF(R) inhibitors (VEGF(R)Is), and enhanced the efficacy of chemotherapy and VEGF(R)Is. alphaPlGF inhibited angiogenesis, lymphangiogenesis, and tumor cell motility. Distinct from VEGF(R)Is, alphaPlGF prevented infiltration of angiogenic macrophages and severe tumor hypoxia, and thus, did not switch on the angiogenic rescue program responsible for resistance to VEGF(R)Is. Moreover, it did not cause or enhance VEGF(R)I-related side effects. The efficacy and safety of alphaPlGF, its pleiotropic and complementary mechanism to VEGF(R)Is, and the negligible induction of an angiogenic rescue program suggest that alphaPlGF may constitute a novel approach for cancer treatment.

Paragraph on why paper is important:

We talked some about proteasome inhibitors in cancer chemotherapy; this paper represents a different therapeutic approach, investigating the effects of an antibody against a VEFG homolog that (relatively specifically) inhibits the growth of tumors and not healthy vessels.

Zuo T, Wang L, Morrison C, Chang X, Zhang H, Li W, Liu Y, Wang Y, Liu X, Chan MW, Liu JQ, Love R, Liu CG, Godfrey V, Shen R, Huang TH, Yang T, Park BK, Wang CY, Zheng P, Liu Y. "FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene." Cell. 2007 Jun 29;129(7):1275-86.

Nominated by: Eric A. Davalos

Abstract:

The X-linked Foxp3 is a member of the forkhead/winged helix transcription factor family. Germline mutations cause lethal autoimmune diseases in males. Serendipitously, we observed that female mice heterozygous for the "scurfin" mutation of the Foxp3 gene (Foxp3(sf/+)) developed cancer at a high rate. The majority of the cancers were mammary carcinomas in which the wild-type Foxp3 allele was inactivated and HER-2/ErbB2 was overexpressed. Foxp3 bound and repressed the HER-2/ErbB2 promoter. Deletion, functionally significant somatic mutations, and downregulation of the FOXP3 gene were commonly found in human breast cancer samples and correlated significantly with HER-2/ErbB2 overexpression, regardless of the status of HER-2 amplification. Our data demonstrate that FOXP3 is an X-linked breast cancer suppressor gene and an important regulator of the HER-2/ErbB2 oncogene.

Paragraph on why paper is important:

This paper by Zuo et al. presents the role of Foxp3 as an X-linked breast cancer suppressor gene. This paper adds to our understanding of breast cancer development and I also think that this cancer suppressor gene being X-linked is pretty interesting.

C. Fischer, B. Jonckx, M. Mazzone, S. Zacchigna, S. Loges, L. Pattarini, E. Chorianopoulos, L. Liesenborghs, M. Koch, M. De Mol Anti-PlGF Inhibits Growth of VEGF(R)-Inhibitor-Resistant Tumors without Affecting Healthy Vessels. Cell, 2007. 131(3): p. 463-75.

Nominated by: Raymond Choi

Abstract:

Novel antiangiogenic strategies with complementary mechanisms are needed to maximize efficacy and minimize resistance to current angiogenesis inhibitors. We explored the therapeutic potential and mechanisms of alphaPlGF, an antibody against placental growth factor (PlGF), a VEGF homolog, which regulates the angiogenic switch in disease, but not in health. alphaPlGF inhibited growth and metastasis of various tumors, including those resistant to VEGF(R) inhibitors (VEGF(R)Is), and enhanced the efficacy of chemotherapy and VEGF(R)Is. alphaPlGF inhibited angiogenesis, lymphangiogenesis, and tumor cell motility. Distinct from VEGF(R)Is, alphaPlGF prevented infiltration of angiogenic macrophages and severe tumor hypoxia, and thus, did not switch on the angiogenic rescue program responsible for resistance to VEGF(R)Is. Moreover, it did not cause or enhance VEGF(R)I-related side effects. The efficacy and safety of alphaPlGF, its pleiotropic and complementary mechanism to VEGF(R)Is, and the negligible induction of an angiogenic rescue program suggest that alphaPlGF may constitute a novel approach for cancer treatment.

Paragraph on why paper is important:

I thought this paper was interesting because it suggests an antiangiogenic agent that could potentially have little side effects if this research was eventually translated to the bedside. The experimental design was thorough and there is quite a bit of data for the class to discuss. It's also a really nice start up paper and a lot of projects/future experiments can be proposed from it.

Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Red Eagle A, Vats D, Brombacher F, Ferrante AW, Chawla A. (2007) "Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance." Nature.; Jun 28;447(7148):1116-20.

Nominated by: Shyam Raghavan

Abstract:

Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity. These findings together suggest a correlation between macrophage content in adipose tissue and insulin resistance. However, resident macrophages in tissues display tremendous heterogeneity in their activities and functions, primarily reflecting their local metabolic and immune microenvironment. While Mcp1 directs recruitment of pro-inflammatory classically activated macrophages to sites of tissue damage, resident macrophages, such as those present in the adipose tissue of lean mice, display the alternatively activated phenotype. Despite their higher capacity to repair tissue, the precise role of alternatively activated macrophages in obesity-induced insulin resistance remains unknown. Using mice with macrophage-specific deletion of the peroxisome proliferator activated receptor-gamma (PPARgamma), we show here that PPARgamma is required for maturation of alternatively activated macrophages. Disruption of PPARgamma in myeloid cells impairs alternative macrophage activation, and predisposes these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, gene expression profiling revealed that downregulation of oxidative phosphorylation gene expression in skeletal muscle and liver leads to decreased insulin sensitivity in these tissues. Together, our findings suggest that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggest that macrophage polarization towards the alternative state might be a useful strategy for treating type 2 diabetes.

Paragraph on why paper is important:

This paper would be interesting to read, not only because it involves a topic we discussed earlier in the term, but because it explores a unique (or what I think is unique) relationship between diabetes, immunology, and inflammation. It also involves one of the orphan receptors (PPAR gamma) which we all know so much about. Finally, it teaches us about yet another role macrophages play in our bodies.

Liu Y, Teige I, Birnir B, Issazadeh-Navikas S.(2006). "Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE." Nat Med. May;12(5):518-25.

Nominated by:Pearl Chang

Abstract:

Neurons have been neglected as cells with a major immune-regulatory function because they do not express major histocompatibility complex class II. Our data show that neurons are highly immune regulatory, having a crucial role in governing T-cell response and central nervous system (CNS) inflammation. Neurons induce the proliferation of activated CD4+ T cells through B7-CD28 and transforming growth factor (TGF)-beta1-TGF-beta receptor signaling pathways, resulting in amplification of T-cell receptor signaling through phosphorylated ZAP-70, interleukin (IL)-2 and IL-9. The interaction between neurons and T cells results in the conversion of encephalitogenic T cells to CD25+ TGF-beta1+ CTLA-4+ FoxP3+ T regulatory (Treg) cells that suppress encephalitogenic T cells and inhibit experimental autoimmune encephalomyelitis. Suppression is dependent on cytotoxic T lymphocyte antigen (CTLA)-4 but not TGF-beta1. Autocrine action of TGF-beta1, however, is important for the proliferative arrest of Treg cells. Blocking the B7 and TGF-beta pathways prevents the CNS-specific generation of Treg cells. These findings show that generation of neuron-dependent Treg cells in the CNS is instrumental in regulating CNS inflammation.

Paragraph on why paper is important:

It is only relatively recently that the idea of peripheral tolerance playing a key role in preventing autoimmunity has been accepted. Regulatory T cells are now believed to be important in preventing autoimmunity, and this paper demonstrates that neurons, not often thought of as an immune function cell, is involved in suppressing CNS inflammation and EAE (model of multiple sclerosis) via generation of Tregs. These findings could lead to better understanding and treatment of CNS diseases like multiple sclerosis.

Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW. (2007) "Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas." Nature. Feb 8;445(7128):656-60.

Nominated by: Jennifer Hong

Abstract:

Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.

Paragraph on why paper is important:

I liked that this paper was able to apply novel technologies such as RNAi to solving a clinical problem like liver cancer, whose molecular basis has been well worked out. I thought the experiments were clear, and easy to understand and the data was compelling.

Livet J, Weissman TA, Kang H, Draft RW, Lu J, Bennis RA, Sanes JR, Lichtman JW.(2007). "Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system." Nature. Nov 1;450(7166):56-62.

Nominated by: Jennifer Hong

Abstract:

Detailed analysis of neuronal network architecture requires the development of new methods. Here we present strategies to visualize synaptic circuits by genetically labelling neurons with multiple, distinct colours. In Brainbow transgenes, Cre/lox recombination is used to create a stochastic choice of expression between three or more fluorescent proteins (XFPs). Integration of tandem Brainbow copies in transgenic mice yielded combinatorial XFP expression, and thus many colours, thereby providing a way to distinguish adjacent neurons and visualize other cellular interactions. As a demonstration, we reconstructed hundreds of neighbouring axons and multiple synaptic contacts in one small volume of a cerebellar lobe exhibiting approximately 90 colours. The expression in some lines also allowed us to map glial territories and follow glial cells and neurons over time in vivo. The ability of the Brainbow system to label uniquely many individual cells within a population may facilitate the analysis of neuronal circuitry on a large scale.

Paragraph on why paper is important:

I thought this was a great "cutting-edge" basic science paper which applied smart genetic manipulations to solving the problem of mapping out neural networks in the brain. Though this paper isn't explicitly about human disease, I can think of a number of diseases that could potentially benefit from insights from this technology. Also, I really like the figures.

Lamarre D. et al. (2003) "An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus" Nature Nov. 13:426, 186-189.

Nominated by: Wei Gu

Abstract:

Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality1, 2, 3. Current interferon-based therapies4 are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics5, 6. The HCV-encoded NS3 protease is essential for viral replication7, 8 and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.

Paragraph on why paper is important:

This is a comprehensive paper covering the development of a protease inhibitor (BILN 2061) against Hepatitis C from test tube to patient . Since HCV is a leading cause of hepatitis and current treatments with interferon have a lot of side effects, new drugs proven to work against HCV would be high impact. With the structure of the virus's NS3 protease in hand, the researchers used rational drug design to develop BILN 2061 from surrogate enzymatic and cell culture assays. Then they looked at the pharmacokinetics in animals, toxicity in humans, and even antiviral effects in HCV patients. BILN 2061 seems to reduce viral load about 3 orders of magnitude or more after a brief dose.

Salick, D. A., Kretsinger, J. K., Pochan, D. J., Scheider, J. P.(2007). "Inherent Antibacterial Activity of a Peptide-Based beta-Hairpin Hydrogel." J Am Chem Soc. Nov. 7.

Nominated by: A. Sloan Devlin

Abstract:

Among several important considerations for implantation of a biomaterial, a main concern is the introduction of infection. We have designed a hydrogel scaffold from the self-assembling peptide, MAX1, for tissue regeneration applications whose surface exhibits inherent antibacterial activity. In experiments where MAX1 gels are challenged with bacterial solutions ranging in concentrations from 2  103 colony forming units (CFUs)/dm2 to 2  109 CFUs/dm2, gel surfaces exhibit broad-spectrum antibacterial activity. Results show that the hydrogel surface is active against Gram-positive (Staphylococcus epidermidis, Staphylococcus aureus, and Streptococcus pyogenes) and Gram-negative (Klebsiella pneumoniae and Escherichia coli) bacteria, all prevalent in hospital settings. Live-dead assays employing laser scanning confocal microscopy show that bacteria are killed when they engage the surface. In addition, the surface of MAX1 hydrogels was shown to cause inner and outer membrane disruption in experiments that monitor the release of â-galactosidase from the cytoplasm of lactose permease-deficient E. coli ML-35. These data suggest a mechanism of antibacterial action that involves membrane disruption that leads to cell death upon cellular contact with the gel surface. Although the hydrogel surface exhibits bactericidal activity, co-culture experiments indicate hydrogel surfaces show selective toxicity to bacterial versus mammalian cells. Additionally, gel surfaces are nonhemolytic toward human erythrocytes, which maintain healthy morphologies when in contact with the surface. These material attributes make MAX1 gels attractive candidates for use in tissue regeneration, even in nonsterile environments.

Paragraph on why paper is important:

Hydrogel materials present a novel treatment for wound healing. However, the same environment that promotes host cell growth also provides a site for bacterial infection. This papers reports the development of a so-called MAX1, peptide-based hydrogel whose surface is inherently antibacterial, showing broad activity against both Gram-positive and Gram-negative strains while still allowing for mammalian cell proliferation. The authors discuss both the molecular-level details of the hydrogel's composition, in which the peptides self-assemble into B-sheet fibrils when placed in cell culture media, as well as the practicality of these gels, which they have tested at colony forming unit (CFU) concentrations higher than are found in a typical clinic setting. The authors also delve into these gels' mode of action by performing assays (including a live-dead assay using laser scanning confocal microscopy to visualize the gel surface, and a B-galactosidase activity to measure enzyme leakage and thus loss of cell membrane integrity), which suggest that the gel's surface is bactericidal, causing cell death by cell membrane disruption. Finally, a co-culture experiment that mimics a clinical setting in which both bacterial and mammalian cells are present shows that bacteria die while fibroblasts proliferate on the gel's surface. This paper presents the development of an idea from chemical synthesis to in vivo testing and presents a novel solution to the practical problem of bacterial infection - very cool!

Alirio J Melendez, Margaret M Harnett, Peter N Pushparaj, WS Fred Wong, Hwee Kee Tay, Charles P McSharry, and William Harnett.(2007). "Inhibition of FcepsilonRI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes." Nature Med. Oct. 21:13;1375-1381.

Nominated by: AbdulRasheed Alabi

Abstract:

Atopic allergy is characterized by an increase in IgE antibodies that signal through the high-affinity Fcepsilon receptor (FcepsilonRI) to induce the release of inflammatory mediators from mast cells. For unknown reasons, the prevalence of allergic diseases has recently increased steeply in the developed world1. However, this increase has not been mirrored in developing countries2, even though IgE concentrations are often greatly elevated in individuals from these countries, owing to nonspecific IgE induction by universally present parasitic worms3. Here we offer one explanation for this paradox based on the properties of ES-62, a molecule secreted by filarial nematodes4. We found that highly purified, endotoxin-free ES-62 directly inhibits the FcepsilonRI-induced release of allergy mediators from human mast cells by selectively blocking key signal transduction events, including phospholipase D–coupled, sphingosine kinase–mediated calcium mobilization and nuclear factor-kappaB activation. ES-62 mediates these effects by forming a complex with Toll-like receptor 4, which results in the sequestration of protein kinase C-alpha (PKC-alpha). This causes caveolae/lipid raft–mediated, proteasome-independent degradation of PKC-alpha, a molecule important for the coupling of FcepsilonRI to phospholipase D and mast cell activation. We also show that ES-62 is able to protect mice from mast cell–dependent hypersensitivity in the skin and lungs, indicating that it has potential as a novel therapeutic for allergy.

Paragraph on why paper is important:

I think this paper is a great example of how a relatively simple physiological response (allergy) involves a complex cognate molecular cascade that involves immune cells, second messengers, transcriptional activaters et cetera. The authors motivate this paper as trying to understand a paradoxical difference in allergic response in developing versus developed countries. They characterize a molecule produced by filarial nematodes (ES-62) that inhibits the release of allergy mediators and point to ES-62 as a potential therapeutic for allergy because of its ability to protect against mast cell-dependent hypersensitivity in skin and lungs. The paper utilizes a number of wide ranging scientific techniques and provides nice mechanistic detail. It is also timely for many first years in the class who will be taking immunology next quarter.

Markus Weckmann, Adam Collison, Jodie L Simpson, Matthias V Kopp, Peter A B Wark, Mark J Smyth4, Hideo Yagita, Klaus I Matthaei, Nicole Hansbro, Bruce Whitehead, Peter G Gibson, Paul S Foster,and Joerg Mattes.(2007). "Critical link between TRAIL and CCL20 for the activation of TH2 cells and the expression of allergic airway disease." Nature Med. Oct. 14:13;1308-1315.

Nominated by: AbdulRasheed Alabi

Abstract:

The role of tumor necrosis factor?related apoptosis-inducing ligand (TRAIL) in immune responses mediated by T-helper 2 (TH2) lymphocytes is unknown. Here we characterize the development of allergic airway disease in TRAIL-deficient (Tnfsf10-/-) mice and in mice exposed to short interfering RNA targeting TRAIL. We show that TRAIL is abundantly expressed in the airway epithelium of allergic mice and that inhibition of signaling impairs production of the chemokine CCL20 and homing of myeloid dendritic cells and T cells expressing CCR6 and CD4 to the airways. Attenuated homing limits TH2 cytokine release, inflammation, airway hyperreactivity and expression of the transcriptional activator STAT6. Activation of STAT6 by interleukin-13 restores airway hyperreactivity in Tnfsf10-/- mice. Recombinant TRAIL induces pathognomic features of asthma and stimulates the production of CCL20 in primary human bronchial epithelium cells. TRAIL is also increased in sputum of asthmatics. The function of TRAIL in the airway epithelium identifies this molecule as a target for the treatment of asthma.

Paragraph on why paper is important:

I think this is a good example of examining phenotype and the development of disease from a cellular physiological standpoint. The authors attempt to examine the role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in immune responses mediated by T-helper 2 lymphocytes. They begin by charaterizing TRAIL-null mice and mice in which TRAIL is knocked down using siRNA. They then define the downstream effects of impaired TRAIL signaling from the release and homing of immune cells/molecules to the activation of a transcription factor STAT6. They show that activating STAT6 in TRAIL-null mice is sufficient to restore a wild-type phenotype. They further relate TRAIL expression in airway epithelia to asthma and point to TRAIL as a molecular target for asthma treatment/therapy. The paper displays a logical pattern (and set of experiments) from phenotype to characterization of the gene product which is deficient to identifying and characterizing other downstream effects; steps which help identify several potential layers of therapeutic intervention and are also important in linking pathophysiology to molecular and cellular defects in any human disease.

Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; the TRITON–TIMI 38 Investigators., (2007). "Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes." N Engl J Med. Nov 15;357(20):2001-2015.

Nominated by: Gene Ma

Abstract:

Dual-antiplatelet therapy with aspirin and a thienopyridine is a cornerstone of treatment to prevent thrombotic complications of acute coronary syndromes and percutaneous coronary intervention. Methods: To compare prasugrel, a new thienopyridine, with clopidogrel, we randomly assigned 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key safety end point was major bleeding. Results: The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). We also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P=0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P=0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P=0.23) and fatal bleeding (0.4% vs. 0.1%; P=0.002). Conclusions: In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups.

Paragraph on why paper is important:

This is a recent article that offers a new treatment to prevent thrombosis, which is normally prevented with aspirin or other anti-platelet therapies. Since the major side effect of these drugs is bleeding, a new drug that does not have that side effect would be extremely beneficial to patients suffering from acute coronary syndromes.

Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim R, Lin WM, Province MA, Kraja A, Johnson LA, Shah K, Sato M, Thomas RK, Barletta JA, Borecki IB, Broderick S, Chang AC, Chiang DY, Chirieac LR, Cho J, Fujii Y, Gazdar AF, Giordano T, Greulich H, Hanna M, Johnson BE, Kris MG, Lash A, Lin L, Lindeman N, Mardis ER, McPherson JD, Minna JD, Morgan MB, Nadel M, Orringer MB, Osborne JR, Ozenberger B, Ramos AH, Robinson J, Roth JA, Rusch V, Sasaki H, Shepherd F, Sougnez C, Spitz MR, Tsao MS, Twomey D, Verhaak RG, Weinstock GM, Wheeler DA, Winckler W, Yoshizawa A, Yu S, Zakowski MF, Zhang Q, Beer DG, Wistuba II, Watson MA, Garraway LA, Ladanyi M, Travis WD, Pao W, Rubin MA, Gabriel SB, Gibbs RA, Varmus HE, Wilson RK, Lander ES, Meyerson M. (2007). "Characterizing the cancer genome in lung adenocarcinoma." Nature. Nov. 4;doi:10.1038.

Nominated by: Hersh Sagreiya

Abstract:

Somatic alterations in cellular DNA underlie almost all human cancers. The prospect of targeted therapies and the development of high-resolution, genome-wide approaches are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in ~ 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.

Paragraph on why paper is important:

This recent Nature paper is a large-scale, genome wide effort to characterize copy number alterations via analysis of a collection of primary lung adenocarcinomas. The paper identified common instances of copy-number gain or loss, and the most common amplification was in chromosome 14q13.3, which was not previously associated with a particular gene. Importantly, they found that the target gene was the potential proto-oncogene, NKX2-1, which is involved in lung development. This paper uses a variety of techniques, including GISTIC analysis, sequencing, genotype validation, tissue microarray FISH, and RNAi. Finally, this paper shows what is possible through the use of systemic copy-number analysis using SNP arrays, a technique that could be applied to other cancer-related diseases.