Kumar P, Ban HS, Kim SS, Wu H, Pearson T, Greiner DL, Laouar A, Yao J, Haridas V, Habiro K, Yang YG, Jeong JH, Lee KY, Kim YH, Kim SW, Peipp M, Fey GH, Manjunath N, Shultz LD, Lee SK, Shankar P. (2008). "T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice." Cell. Aug. 22;134(4):566-8.

Nominated by: Harry V. Flaster

Abstract: Evaluation of the therapeutic potential of RNAi for HIV infection has been hampered by the challenges of siRNA delivery and lack of suitable animal models. Using a delivery method for T cells, we show that siRNA treatment can dramatically suppress HIV infection. A CD7-specific single-chain antibody was conjugated to oligo-9-arginine peptide (scFvCD7-9R) for T cell-specific siRNA delivery in NOD/SCIDIL2rgamma-/- mice reconstituted with human lymphocytes (Hu-PBL) or CD34+ hematopoietic stem cells (Hu-HSC). In HIV-infected Hu-PBL mice, treatment with anti-CCR5 (viral coreceptor) and antiviral siRNAs complexed to scFvCD7-9R controlled viral replication and prevented the disease-associated CD4 T cell loss. This treatment also suppressed endogenous virus and restored CD4 T cell counts in mice reconstituted with HIV+ peripheral blood mononuclear cells. Moreover, scFvCD7-9R could deliver antiviral siRNAs to naive T cells in Hu-HSC mice and effectively suppress viremia in infected mice. Thus, siRNA therapy for HIV infection appears to be feasible in a preclinical animal model.

Paragraph on Why Paper is Important: In the Kumar article, RNAi was targeted specifically to T-cells using a CD7 antibody.  This therapy seemed to work very well in humanized mice. 

Perez EE, Wang J, Miller JC, Jouvenot Y, Kim KA, Liu O, Wang N, Lee G, Bartsevich VV, Lee YL, Guschin DY, Rupniewski I, Waite AJ, Carpenito C, Carroll RG, Orange JS, Urnov FD, Rebar EJ, Ando D, Gregory PD, Riley JL, Holmes MC, June CH. (2008). "Establishment of HIV-1 resistance in CD4+T cells by genome editing using zinc-finger nucleases." Nat. Biochnol. Jul;26(7):808-16.

Nominated by: Harry V. Flaster

Abstract: Homozygosity for the naturally occurring Delta32 deletion in the HIV co-receptor CCR5 confers resistance to HIV-1 infection. We generated an HIV-resistant genotype de novo using engineered zinc-finger nucleases (ZFNs) to disrupt endogenous CCR5. Transient expression of CCR5 ZFNs permanently and specifically disrupted approximately 50% of CCR5 alleles in a pool of primary human CD4(+) T cells. Genetic disruption of CCR5 provided robust, stable and heritable protection against HIV-1 infection in vitro and in vivo in a NOG model of HIV infection. HIV-1-infected mice engrafted with ZFN-modified CD4(+) T cells had lower viral loads and higher CD4(+) T-cell counts than mice engrafted with wild-type CD4(+) T cells, consistent with the potential to reconstitute immune function in individuals with HIV/AIDS by maintenance of an HIV-resistant CD4(+) T-cell population. Thus adoptive transfer of ex vivo expanded CCR5 ZFN-modified autologous CD4(+) T cells in HIV patients is an attractive approach for the treatment of HIV-1 infection.

Paragraph on Why Paper is Important: In the Perez paper, zinc-finger transcription factors were designed to specifically recognize the coding region for CCR5, an important HIV co-receptor.  They attached an endonuclease to the zinc-finger that deleted the CCR5 gene with remarkable specificity.  Mice who received this treatment were more resistant to HIV infection. 

Abstract: The subventricular zone (SVZ) is a principal source of adult neural stem cells in the rodent brain, generating thousands of olfactory bulb neurons every day. If the adult human brain contains a comparable germinal region, this could have considerable implications for future neuroregenerative therapy. Stem cells have been isolated from the human brain, but the identity, organization and function of adult neural stem cells in the human SVZ are unknown. Here we describe a ribbon of SVZ astrocytes lining the lateral ventricles of the adult human brain that proliferate in vivo and behave as multipotent progenitor cells in vitro. This astrocytic ribbon has not been observed in other vertebrates studied. Unexpectedly, we find no evidence of chains of migrating neuroblasts in the SVZ or in the pathway to the olfactory bulb. Our work identifies SVZ astrocytes as neural stem cells in a niche of unique organization in the adult human brain.

Paragraph on Why Paper is Important: It is one of the first papers to show that a subpopulation of neural stem cells exist in the human adult brain that possess the ability to self-renew and differentiate. In this paper, the authors find a niche of stem cells in an area that surrounds the lateral ventricles called the subventricular zone (SVZ). They show that the stem cells are derived from a subset of GFAP+ cells in this zone. Importantly, they show that other astrocytes from other cortical locations do not possess the capability to undergo neurogenesis. This has many important implications for both neurodegerative therapy as well as understanding whether this niche is responsible for certain brain tumors like gliomas and astrocytomas that arise from areas that surround the lateral ventricles. This paper really began the search for cancer stem cells in the adult human brain as possible links to certain types of brain tumors. This is why I have chose the paper as well as because it's a simple paper with good experiments. 

Gubbels, S.P., Woessner, D.W., Mitchell, J.C., Ricci, A.J., Brigande, J.V.,.( 2008). " Functional auditory hair cells produced in the mammalian cochlea by in utero gene transfer." Nature. Sept. 25; 455(7212):537-541.

Nominated by: Taha Jan

Abstract: Sensory hair cells in the mammalian cochlea convert mechanical stimuli into electrical impulses that subserve audition. Loss of hair cells and their innervating neurons is the most frequent cause of hearing impairment. Atonal homologue 1 (encoded by Atoh1, also known as Math1) is a basic helix-loop-helix transcription factor required for hair-cell development, and its misexpression in vitro and in vivo generates hair-cell-like cells. Atoh1-based gene therapy to ameliorate auditory and vestibular dysfunction has been proposed. However, the biophysical properties of putative hair cells induced by Atoh1 misexpression have not been characterized. Here we show that in utero gene transfer of Atoh1 produces functional supernumerary hair cells in the mouse cochlea. The induced hair cells display stereociliary bundles, attract neuronal processes and express the ribbon synapse marker carboxy-terminal binding protein 2 (refs 12,13). Moreover, the hair cells are capable of mechanoelectrical transduction and show basolateral conductances with age-appropriate specializations. Our results demonstrate that manipulation of cell fate by transcription factor misexpression produces functional sensory cells in the postnatal mammalian cochlea. We expect that our in utero gene transfer paradigm will enable the design and validation of gene therapies to ameliorate hearing loss in mouse models of human deafness.

Paragraph on Why Paper is Important: I think this would be an excellent paper to discuss for a couple of reasons: First, the experiments conducted are elegantly carried out in a very anatomically complex mammalian organ.  The method of in utero gene transfer at embryonic day 11.5 using ultrasound guidance is quite fascinating.  This in utero technique brings up the idea of therapy for hereditary defects prior to the onset of degeneration.  Second, the experiments are proof of principle for the de novo generation of inner ear hair cells.  Gene therapy techniques are still relevant theraputically for the treatment of deafness given that there are many specific genetic defects that underly deafness (e.g. connexin 26).

Hopkins, A.L., (2008). "Network Pharmacology: the next paradigm in drug discovery." Nat. Chem. Biol. Nov.;4(11):682-90.

Nominated by: Imran Haque

Abstract: The dominant paradigm in drug discovery is the concept of designing maximally selective ligands to act on individual drug targets. However, many effective drugs act via modulation of multiple proteins rather than single targets. Advances in systems biology are revealing a phenotypic robustness and a network structure that strongly suggests that exquisitely selective compounds, compared with multitarget drugs, may exhibit lower than desired clinical efficacy. This new appreciation of the role of polypharmacology has significant implications for tackling the two major sources of attrition in drug development--efficacy and toxicity. Integrating network biology and polypharmacology holds the promise of expanding the current opportunity space for druggable targets. However, the rational design of polypharmacology faces considerable challenges in the need for new methods to validate target combinations and optimize multiple structure-activity relationships while maintaining drug-like properties. Advances in these areas are creating the foundation of the next paradigm in drug discovery: network pharmacology.

Paragraph on Why Paper is Important: This recent review paper takes a higher-level view of "molecular intervention in human disease", focusing not on a treatment for a single disease, but rather on the paradigm by which we design or discover such interventions. Hopkins argues that the single molecule-single target mode of drug design is responsible for the low rate of success of candidate drugs in clinical trials. He further points to evidence from yeast chemical genetics and existing antibiotics to argue that single-protein drug perturbations are insufficient. The proposed biological-network based strategy to designing drugs is an interesting one with obvious connections to the practice of molecular intervention in human disease.

Miller, E.J., Li, J., Leng, L., McDonald, C., Atsumi, T., Bucala, R.,and Young, L.H., (2008). " Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart." Nature. Jan. 31; 451(7178): 578-82.

Nominated by: Josh Troke

Abstract: Understanding cellular response to environmental stress has broad implications for human disease. AMP-activated protein kinase (AMPK) orchestrates the regulation of energy-generating and -consuming pathways, and protects the heart against ischaemic injury and apoptosis. A role for circulating hormones such as adiponectin and leptin in the activation of AMPK has received recent attention. Whether local autocrine and paracrine factors within target organs such as the heart modulate AMPK is unknown. Here we show that macrophage migration inhibitory factor (MIF), an upstream regulator of inflammation, is released in the ischaemic heart, where it stimulates AMPK activation through CD74, promotes glucose uptake and protects the heart during ischaemia-reperfusion injury. Germline deletion of the Mif gene impairs ischaemic AMPK signalling in the mouse heart. Human fibroblasts with a low-activity MIF promoter polymorphism have diminished MIF release and AMPK activation during hypoxia. Thus, MIF modulates the activation of the cardioprotective AMPK pathway during ischaemia, functionally linking inflammation and metabolism in the heart. We anticipate that genetic variation in MIF expression may impact on the response of the human heart to ischaemia by the AMPK pathway, and that diagnostic MIF genotyping might predict risk in patients with coronary artery disease.

Paragraph on Why Paper is Important: The AMPK pathway is the major key regulator in energy metabolism responding to the cells energy balance, specifically to ratios of AMP/ATP and telling the cell when to use oxidative phosphorylation vs. glycolysis and switching on the correct pathways.  There are many chemical modulators of the AMPK pathway, most notably metformin, a anti-hyperglycemic drug used in Type II Diabetes and AICAR, and AMP analog.  This paper report for the first time a link betwwen MIF and AMPK and gives a new tool in wayst to modify energy metabolism with a focus on the ischemic heart and linking inflammation and metabolsm.  It also gives a new target for genotyping inviduals that might be at an increased risk of certain heart diseases because of SNP's in the MIF gene. 

Spivakov, M., and Fisher, A.G., (2007). "Epigenetic signatures of stem cell identity." Nat. Rev. Genet. Apr.8(4):263-71.

Nominated by: Olivia Yu-Chia Chen

Abstract: Pluripotent stem cells, similar to more restricted stem cells, are able to both self-renew and generate differentiated progeny. Although this dual functionality has been much studied, the search for molecular signatures of 'stemness' and pluripotency is only now beginning to gather momentum. While the focus of much of this work has been on the transcriptional features of embryonic stem cells, recent studies have indicated the importance of unique epigenetic profiles that keep key developmental genes 'poised' in a repressed but activatable state. Determining how these epigenetic features relate to the transcriptional signatures of ES cells, and whether they are also important in other types of stem cell, is a key challenge for the future.

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Silverman, J., Lu, Q., Bakker, A., To, Wayne, Duguay, A., Alba, B.M., Smith, R., Rivas, A., Li, P., Le, H., Whitehorn, E., Moore, K.W., Swimmer, C., Perlroth, V., Vogt, M., Kolkman, J., and Stemmer, W.P.C., (2005). "Multivalent avimer proteins evolved by exon shuffling of a family of human receptor domains." Nat. Biotechnol. Dec.; 23(12):1556-61.

Nominated by: Ryan Schubert

Abstract: We have developed a class of binding proteins, called avimers, to overcome the limitations of antibodies and other immunoglobulin-based therapeutic proteins. Avimers are evolved from a large family of human extracellular receptor domains by in vitro exon shuffling and phage display, generating multidomain proteins with binding and inhibitory properties. Linking multiple independent binding domains creates avidity and results in improved affinity and specificity compared with conventional single-epitope binding proteins. Other potential advantages over immunoglobulin domains include simple and efficient production of multitarget-specific molecules in Escherichia coli, improved thermostability and resistance to proteases. Avimers with sub-nM affinities were obtained against five targets. An avimer that inhibits interleukin 6 with 0.8 pM IC50 in cell-based assays is biologically active in two animal models.

Paragraph on why paper is important: I enjoyed this paper because it involved methods I hadn’t heard of before, and it offers great potential for peptide therapeutics as an alternative to antibody-based therapies.  The authors talk about one prototype drug they created for the inhibition of IL-6, an inflammatory cytokine involved several diseases.  The medical applications are wide, however, and I am interested in hearing what the group thinks about the new technique.

Poeck, H., Besch, R., Maihoefer, C., Renn, M., Tormo, D., Morskaya, S.S., Kirschnek, S., Gaffal, E., Landsberg, J., Hellmuth, J., Schmidt, A., Anz, D., Bscheider, M., Schwerd, T., Berking, C., Bourquin, C., Kalinke, U., Kremmer, E., Kato, H., Akira, S., Meyers, R., Häcker, G., Neuenhahn, M., Busch, D., Ruland, J., Rothenfusser, S., Prinz, M., Hornung, V., Endres, S., Tüting, T., and Hartmann, G. (2008). "5'-triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma." Nature Medicine. Nov. 2; 14(11):1256-63.

News:

http://www.nature.com/nm/journal/v14/n11/full/nm1108-1152.html

Nominated by: Alisa Mueller

Abstract: Genetic and epigenetic plasticity allows tumors to evade single-targeted treatments. Here we direct Bcl2-specific short interfering RNA (siRNA) with 5'-triphosphate ends (3p-siRNA) against melanoma. Recognition of 5'-triphosphate by the cytosolic antiviral helicase retinoic acid–induced protein I (Rig-I, encoded by Ddx58) activated innate immune cells such as dendritic cells and directly induced expression of interferons (IFNs) and apoptosis in tumor cells. These Rig-I–mediated activities synergized with siRNA-mediated Bcl2 silencing to provoke massive apoptosis of tumor cells in lung metastases in vivo. The therapeutic activity required natural killer cells and IFN, as well as silencing of Bcl2, as evidenced by rescue with a mutated Bcl2 target, by site-specific cleavage of Bcl2 messenger RNA in lung metastases and downregulation of Bcl-2 protein in tumor cells in vivo. Together, 3p-siRNA represents a single molecule–based approach in which Rig-I activation on both the immune- and tumor cell level corrects immune ignorance and in which gene silencing corrects key molecular events that govern tumor cell survival.

Paragraph on why paper is important: This paper is particularly intriguing because of the authors' two-pronged approach in their treatment strategy and the potential applicability of this therapy to a wide range of tumors. Although previous studies have used Bcl2-specific siRNA as a potential tumor therapy, these endeavors ultimately potentiated the anti-tumor effect with other drugs or dodged activation of the innate immune system by using chemical derivatives of the siRNA. In contrast, the authors in this paper use the immune system to their advantage by designing an siRNA molecule that not only lowers expression of an anti-apoptotic protein, but also employs a 3'-triphosphate that activates innate immune mechanisms against the tumors.  Moreover, they demonstrate that the combination of the two effects more effectively hampers tumor growth than either effect singly. That being said, several issues with respect to the applicability and the practicality of this treatment strategy could be discussed in section. In particular, although they attained tumor-specific induction of apoptosis, the authors acknowledge that RNA delivery is not specific. What are the potential side effects of this feature and how might we target delivery?  Another issue we could discuss is whether it is more valuable to have a single molecule with two functions or two molecules with single functions. As mentioned in the associated news article, the two separate types of receptors for this siRNA may compete for binding, leading to different effects in different cell types.  This study gives us a platform to evaluate RNA-based therapies in terms of their advantages and disadvantages over other strategies as well as their potential in terms of selectivity, efficacy, and safety.

Kain, R., Exner, M., Brandes, R., Ziebermayr, R., Cunningham, D., Alderson, C.A., Davidovits, A., Raab, I., Jahn, R., Ashour, O., Spitzauer, S., Sunder-Plassmann, G., Fukuda, M., Klemm, P., Rees, A.J., and Kerjasckhki, D., (2008). “Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis.” Nature Medicine. Oct.;14(10):1088-96.

Nominated by: David Craig

Abstract: Pauci-immune focal necrotizing glomerulonephritis (FNGN) is a severe inflammatory disease associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA). Here we characterize autoantibodies to lysosomal membrane protein-2 (LAMP-2) and show that they are a new ANCA subtype present in almost all individuals with FNGN. Consequently, its prevalence is nearly twice that of the classical ANCAs that recognize myeloperoxidase or proteinase-3. Furthermore, antibodies to LAMP-2 cause pauci-immune FNGN when injected into rats, and a monoclonal antibody to human LAMP-2 (H4B4) induces apoptosis of human microvascular endothelium in vitro. The autoantibodies in individuals with pauci-immune FNGN commonly recognize a human LAMP-2 epitope (designated P(41-49)) with 100% homology to the bacterial adhesin FimH, with which they cross-react. Rats immunized with FimH develop pauci-immune FNGN and also develop antibodies to rat and human LAMP-2. Finally, we show that infections with fimbriated pathogens are common before the onset of FNGN. Thus, FimH-triggered autoimmunity to LAMP-2 provides a previously undescribed clinically relevant molecular mechanism for the development of pauci-immune FNGN.

Paragraph on why paper is important: The glomerulonephritides (GN) are devastating diseases that can destroy kidney function past the point of recovery, necessitating transplant. This is especially true for accute presentations. Additionally, many of these glomeruli-destroying diseases are poorly understood, and therapy often comes down to "do we give corticosteroids for immunosuppression or will they not help?" In this paper, Kain et al. present compelling evidence in support of bacterial molecular mimicry as the basis of one type of glomerulonephritis, pauci-immune FNGN. As the name suggests, pauci-immune FNGN does not have many readily-identifiable immune deposits, as other GN diseases do, and its pathogenesis is unclear. Now, we see that antibodies against LAMP-2 are present in almost all disease cases, absent in controls, and capable of recapitulating the disease. Additionally, these antibodes are formed naturally against a segment of LAMP-2 that is homologous to a bacterial fimbriae protein, and immunization with this protein leads to development of pauci-immune FNGN in rats. In the future, therapies against LAMP-2 autoantibodies could treat pauci-immune FNGN without the need for broad-spectrum immunosuppression (possible example therapy: free LAMP-2 cytosolic domain injection).

I think this paper merits discussion because renal disease is devastating and underappreciated. End-stage renal disease patients are a very serious subject in medicine and policy, to the point where they are one of the only groups that qualifies for medicare benefits regardless of age.

The paper also merits discussion because it seems to be a pretty well-defended and plausible example of molecular mimicry as it is hypothesized in textbooks. To date, there aren't many great examples of this, so it's interesting to see one that seems possible.

Phillips, B., Nylander, K., Harnaha, J., Machen, J., Lakomy, R., Styche, A., Gillis, K, Brown, L., Lafreniere, D., Gallo, M., Knox, J., Hogeland, K., Trucco, M., and Giannoukakis, N., (2008). “A microsphere-based vaccine prevents and reverses new-onset autoimmune diabetes.” Diabetes. Jun.;57(6):1544-55.

Nominated by: Kim Dang

Abstract: This study was aimed at ascertaining the efficacy of antisense oligonucleotide-formulated microspheres to prevent type 1 diabetes and to reverse new-onset disease. RESEARCH DESIGN AND METHODS: Microspheres carrying antisense oligonucleotides to CD40, CD80, and CD86 were delivered into NOD mice. Glycemia was monitored to determine disease prevention and reversal. In recipients that remained and/or became diabetes free, spleen and lymph node T-cells were enriched to determine the prevalence of Foxp3(+) putative regulatory T-cells (Treg cells). Splenocytes from diabetes-free microsphere-treated recipients were adoptively cotransferred with splenocytes from diabetic NOD mice into NOD-scid recipients. Live-animal in vivo imaging measured the microsphere accumulation pattern. To rule out nonspecific systemic immunosuppression, splenocytes from successfully treated recipients were pulsed with beta-cell antigen or ovalbumin or cocultured with allogeneic splenocytes. RESULTS: The microspheres prevented type 1 diabetes and, most importantly, exhibited a capacity to reverse clinical hyperglycemia, suggesting reversal of new-onset disease. The microspheres augmented Foxp3(+) Treg cells and induced hyporesponsiveness to NOD-derived pancreatic beta-cell antigen, without compromising global immune responses to alloantigens and nominal antigens. T-cells from successfully treated mice suppressed adoptive transfer of disease by diabetogenic splenocytes into secondary immunodeficient recipients. Finally, microspheres accumulated within the pancreas and the spleen after either intraperitoneal or subcutaneous injection. Dendritic cells from spleen of the microsphere-treated mice exhibit decreased cell surface CD40, CD80, and CD86. CONCLUSIONS: This novel microsphere formulation represents the first diabetes-suppressive and reversing nucleic acid vaccine that confers an immunoregulatory phenotype to endogenous dendritic cells.

Paragraph on why paper is important: The only current method to achieve insulin independence for type 1 diabetics is pancreatic islet transplantation. However, islet transplantation suffers from severe limitations: There is an extremely limited supply of suitable cadaveric donors, recipients are susceptible to graft rejection, and subsequent life-long immunosuppressive drugs are both costly and are associated with additional morbidity themselves (EG: nephrotoxicity).  A recent report by Phillips et al. shows another putative method to reverse new onset or pre-clinical autoimmune diabetes in mice using anti-sense oligonucelotide therapy to preserve residual functioning beta islet cells. Furthermore, Phillips et al. employed a water-soluble polymer microsphere vehicle to administer the oligonucleotides, thus circumventing the use of controversial viral vectors while maintaining delivery feasibility.

Orlic, D., Kajstura, J., Chimenti, S., Limana, F., Jakoniuk, I., Quaini, F., Nadal-Ginard, B., Bodine, D.M., Leri, A., and Anversa, P., (2001). “Mobilized bone marrow cells repair the infarcted heart, improving function and survival.” Proc. Natl. Acad. Sci. Aug. 28;98(18):10344-9.

Nominated by: Andrew Lee

Abstract: Attempts to repair myocardial infarcts by transplanting cardiomyocytes or skeletal myoblasts have failed to reconstitute healthy myocardium and coronary vessels integrated structurally and functionally with the remaining viable portion of the ventricular wall. The recently discovered growth and transdifferentiation potential of primitive bone marrow cells (BMC) prompted us, in an earlier study, to inject in the border zone of acute infarcts Lin(-) c-kit(POS) BMC from syngeneic animals. These BMC differentiated into myocytes and vascular structures, ameliorating the function of the infarcted heart. Two critical determinants seem to be required for the transdifferentiation of primitive BMC: tissue damage and a high level of pluripotent cells. On this basis, we hypothesized here that BMC, mobilized by stem cell factor and granulocyte-colony stimulating factor, would home to the infarcted region, replicate, differentiate, and ultimately promote myocardial repair. We report that, in the presence of an acute myocardial infarct, cytokine-mediated translocation of BMC resulted in a significant degree of tissue regeneration 27 days later. Cytokine-induced cardiac repair decreased mortality by 68%, infarct size by 40%, cavitary dilation by 26%, and diastolic stress by 70%. Ejection fraction progressively increased and hemodynamics significantly improved as a consequence of the formation of 15 x 10(6) new myocytes with arterioles and capillaries connected with the circulation of the unaffected ventricle. In conclusion, mobilization of primitive BMC by cytokines might offer a noninvasive therapeutic strategy for the regeneration of the myocardium lost as a result of ischemic heart disease and, perhaps, other forms of cardiac pathology.

Paragraph on why paper is important: This is one of the three seminal papers published in 2001 that led to the large number of phase I trials in cardiac cell replacement therapy currently underway (and many of which have been completed).
 
In this paper, the investigators present seemingly incontrovertible proof that bone marrow stem cells can transdifferentiate into myoblasts and integrate with host myocardium upon transplantation into a murine model of infarction. This is supplemented by a much elevated ejection fraction in mice that receive cell transplantation as compared to those that did not.

At many steps of the paper there are false assumptions and errors made however. It has since been shown in human trials, see NEJM editorial also attached, that bone marrow stem cells do not transdifferentiate and do not contribute to recovery following infarction for long periods of time.

Autism Genome Project Consortium, Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ, Vincent JB, Skaug JL, Thompson AP, Senman L, Feuk L, Qian C, Bryson SE, Jones MB, Marshall CR, Scherer SW, Vieland VJ, Bartlett C, Mangin LV, Goedken R, Segre A, Pericak-Vance MA, Cuccaro ML, Gilbert JR, Wright HH, Abramson RK, Betancur C, Bourgeron T, Gillberg C, Leboyer M, Buxbaum JD, Davis KL, Hollander E, Silverman JM, Hallmayer J, Lotspeich L, Sutcliffe JS, Haines JL, Folstein SE, Piven J, Wassink TH, Sheffield V, Geschwind DH, Bucan M, Brown WT, Cantor RM, Constantino JN, Gilliam TC, Herbert M, Lajonchere C, Ledbetter DH, Lese-Martin C, Miller J, Nelson S, Samango-Sprouse CA, Spence S, State M, Tanzi RE, Coon H, Dawson G, Devlin B, Estes A, Flodman P, Klei L, McMahon WM, Minshew N, Munson J, Korvatska E, Rodier PM, Schellenberg GD, Smith M, Spence MA, Stodgell C, Tepper PG, Wijsman EM, Yu CE, Rogé B, Mantoulan C, Wittemeyer K, Poustka A, Felder B, Klauck SM, Schuster C, Poustka F, Bölte S, Feineis-Matthews S, Herbrecht E, Schmötzer G, Tsiantis J, Papanikolaou K, Maestrini E, Bacchelli E, Blasi F, Carone S, Toma C, Van Engeland H, de Jonge M, Kemner C, Koop F, Langemeijer M, Hijmans C, Staal WG, Baird G, Bolton PF, Rutter ML, Weisblatt E, Green J, Aldred C, Wilkinson JA, Pickles A, Le Couteur A, Berney T, McConachie H, Bailey AJ, Francis K, Honeyman G, Hutchinson A, Parr JR, Wallace S, Monaco AP, Barnby G, Kobayashi K, Lamb JA, Sousa I, Sykes N, Cook EH, Guter SJ, Leventhal BL, Salt J, Lord C, Corsello C, Hus V, Weeks DE, Volkmar F, Tauber M, Fombonne E, Shih A, Meyer KJ. (2007). “Mapping autism risk loci using genetic linkage and chromosomal rearrangements.” Nat. Genet. Mar.;39(3):319-28.

Nominated by: Anna Krawisz

Abstract: Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.

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