Outsourcing safety - pp221 - 222

doi:10.1038/nm0309-221

With the global outsourcing of domestic drug manufacturing, the need to ensure the quality and safety of medical products has never been greater. But recent events show that the US Food and Drug Administration (FDA) is not up to the task.

Abstract - | Full Text - Outsourcing safety | PDF (106 KB) - Outsourcing safety

US drug agency blunts supply of marijuana for research - p223

Arran Frood

doi:10.1038/nm0309-223

Full Text - US drug agency blunts supply of marijuana for research | PDF (281 KB) - US drug agency blunts supply of marijuana for research

US stem cell climate improves, raising concerns elsewhere - p224

Nayanah Siva

doi:10.1038/nm0309-224a

Full Text - US stem cell climate improves, raising concerns elsewhere | PDF (213 KB) - US stem cell climate improves, raising concerns elsewhere

Tanks pose possible dengue threat - p224

Simon Grose

doi:10.1038/nm0309-224b

Full Text - Tanks pose possible dengue threat | PDF (213 KB) - Tanks pose possible dengue threat

Rare nature of mushroom poisoning means drug trials rarer still - p225

Amy Coombs

doi:10.1038/nm0309-225a

Full Text - Rare nature of mushroom poisoning means drug trials rarer still | PDF (183 KB) - Rare nature of mushroom poisoning means drug trials rarer still

Independent working group puts genetic tests under the microscope - p225

Stu Hutson

doi:10.1038/nm0309-225b

Full Text - Independent working group puts genetic tests under the microscope | PDF (183 KB) - Independent working group puts genetic tests under the microscope

Pilot projects aim to ease access to clinical data - p226

Kirsten Dorans

doi:10.1038/nm0309-226a

Full Text - Pilot projects aim to ease access to clinical data | PDF (68 KB) - Pilot projects aim to ease access to clinical data

Pfizer to disclose financial ties - p226

Kirsten Dorans

doi:10.1038/nm0309-226b

Full Text - Pfizer to disclose financial ties | PDF (68 KB) - Pfizer to disclose financial ties

Survey gauges dual-use attitudes - p226

Kirsten Dorans

doi:10.1038/nm0309-226c

Full Text - Survey gauges dual-use attitudes | PDF (68 KB) - Survey gauges dual-use attitudes

Royal Society urges integration of human and veterinary medicine - p227

Kirsten Dorans

doi:10.1038/nm0309-227a

Full Text - Royal Society urges integration of human and veterinary medicine | PDF (224 KB) - Royal Society urges integration of human and veterinary medicine

Millions put toward making polio history - p227

Kirsten Dorans

doi:10.1038/nm0309-227b

Full Text - Millions put toward making polio history | PDF (224 KB) - Millions put toward making polio history

News in brief - pp228 - 229

doi:10.1038/nm0309-228

Full Text - News in brief | PDF (747 KB) - News in brief

Straight talk with...Mac Cowell and Jason Bobe - pp230 - 231

Prashant Nair

doi:10.1038/nm0309-230

Biological innovation typically takes place within the walls of academia and industry. But a new grassroots movement to organize hobby scientists is afoot. Mac Cowell and Jason Bobe, co-founders of the organization DIYBio, spoke with Prashant Nair about their plans for amateur biology.

Abstract - | Full Text - Straight talk with...Mac Cowell and Jason Bobe | PDF (385 KB) - Straight talk with...Mac Cowell and Jason Bobe

Three's company - pp232 - 235

David F. Gruber

doi:10.1038/nm0309-232

For many years, textbooks portrayed nerve communication as a straightforward process in which a signal simply hopped from one cell to the next. This traditional view also cast cells known as glia as passive bystanders to the signaling action between neurons. But scientists increasingly regard glia as influential third players in the space where signals pass between neurons, a space they have termed the 'tripartite synapse'. On the basis of this concept, some have begun to study the involvement of glia in nervous system disorders and to develop therapeutic compounds that target these cells. David Gruber reports.

Abstract - | Full Text - Three's company | PDF (2,217 KB) - Three's company

Stromal signature identifies basal breast cancers - pp237 - 238

Kristian Wennmalm, Arne Östman & Jonas Bergh

doi:10.1038/nm0309-237

Full Text - Stromal signature identifies basal breast cancers | PDF (258 KB) - Stromal signature identifies basal breast cancers | Supplementary information

Stromal signature identifies basal breast cancers - p238

Greg Finak, Nicholas Bertos, Michael Hallett & Morag Park

doi:10.1038/nm0309-238a

Full Text - Stromal signature identifies basal breast cancers | PDF (82 KB) - Stromal signature identifies basal breast cancers

The preimplantation embryo and Jewish law - p238

Arthur I. Eidelman & Mordechai Halperin

doi:10.1038/nm0309-238b

Full Text - The preimplantation embryo and Jewish law | PDF (86 KB) - The preimplantation embryo and Jewish law

The boundaries of medicine - p241

Dave E Marcotte reviews Comfortably Numb: How Psychiatry is Medicating a Nation by Charles Barber

doi:10.1038/nm0309-241

Full Text - The boundaries of medicine | PDF (102 KB) - The boundaries of medicine

NO may prompt calcium leakage in dystrophic muscle - pp243 - 244

James G Tidball & S Armando Villalta

doi:10.1038/nm0309-243

A remote, downstream event in the pathology of muscular dystrophy may have a key role in the disease (pages 325–330). It seems that induction of nitric oxide synthase causes calcium to leak inside the cell through ryanodine receptors. The findings provide new options for therapeutic interventions.

Abstract - | Full Text - NO may prompt calcium leakage in dystrophic muscle | PDF (409 KB) - NO may prompt calcium leakage in dystrophic muscle

See also: Letter by Bellinger et al.

Choosing the right memory T cell for HIV - pp244 - 246

Genoveffa Franchini

doi:10.1038/nm0309-244

An experimental simian immunodeficiency virus vaccine boosts production of memory T cells at the site where the virus first contacts the body—in the mucosa (pages 293–299). The approach has the potential to result in more effective HIV vaccines than those currently under development.

Abstract - | Full Text - Choosing the right memory T cell for HIV | PDF (113 KB) - Choosing the right memory T cell for HIV

See also: Letter by Hansen et al.

Oxygen sensor boosts growth factor signaling - pp246 - 247

Mien-Chie Hung, Gordon B Mills & Dihua Yu

doi:10.1038/nm0309-246

Activation of hypoxia-inducible factor, a molecule central to oxygen sensing, can promote the survival and growth of tumor cells. New experiments dissect a pathway behind this effect—upregulation of the epidermal growth factor receptor (pages 319–324).

Abstract - | Full Text - Oxygen sensor boosts growth factor signaling | PDF (302 KB) - Oxygen sensor boosts growth factor signaling

See also: Letter by Wang et al.

Intolerant of glucose and gasping for oxygen - pp247 - 249

Fiona M Gribble

doi:10.1038/nm0309-247

Findings in knockout mice indicate that hypoxia-sensitive pathways modulate the glucose-sensing machinery of pancreatic beta cells. Conditions that mimic hypoxia severely impair glucose-stimulated insulin release.

Abstract - | Full Text - Intolerant of glucose and gasping for oxygen | PDF (597 KB) - Intolerant of glucose and gasping for oxygen

When integrins fail to integrate - pp249 - 250

Andrés Hidalgo & Paul S Frenette

doi:10.1038/nm0309-249

Three studies implicate Kindlin-3, a molecule that mediates signaling through integrins, in a rare disorder characterized by spontaneous bleeding and susceptibility to infection (pages 300–305, 306–312 and 313–318).

Abstract - | Full Text - When integrins fail to integrate | PDF (550 KB) - When integrins fail to integrate

See also: Letter by Moser et al. | Letter by Svensson et al. | Letter by Malinin et al.

Moving closer to a mouse model for hepatitis C - p251

doi:10.1038/nm0309-251

Full Text - Moving closer to a mouse model for hepatitis C | PDF (134 KB) - Moving closer to a mouse model for hepatitis C

Getting a handle on Huntington's disease: silencing neurodegeneration - pp252 - 253

Albert R La Spada

doi:10.1038/nm0309-252

Inherited neurodegenerative conditions such as Huntington's disease have proximal causes (a defective gene) and downstream causes (pathological events caused by that gene). Albert R. La Spada examines efforts to target bad genes with gene knockdown approaches on the eve of a clinical trial designed to silence the causative gene in familial amyotrophic lateral sclerosis. Masahisa Katsuno, Hiroaki Adachi and Gen Sobue examine the possibility of targeting a potentially damaging downstream event in Huntington's disease—dysregulated cholesterol metabolism in the brain.

Abstract - | Full Text - Getting a handle on Huntington's disease: silencing neurodegeneration | PDF (91 KB) - Getting a handle on Huntington's disease: silencing neurodegeneration

Getting a handle on Huntington's disease: the case for cholesterol - pp253 - 254

Masahisa Katsuno, Hiroaki Adachi & Gen Sobue

doi:10.1038/nm0309-253

Full Text - Getting a handle on Huntington's disease: the case for cholesterol | PDF (261 KB) - Getting a handle on Huntington's disease: the case for cholesterol

Research Highlights - pp256 - 257

doi:10.1038/nm0309-256

Full Text - Research Highlights | PDF (204 KB) - Research Highlights

Coordination of PGC-1 and iron uptake in mitochondrial biogenesis and osteoclast activation - pp259 - 266

Kiyo-aki Ishii, Toshio Fumoto, Kazuhiro Iwai, Sunao Takeshita, Masako Ito, Nobuyuki Shimohata, Hiroyuki Aburatani, Shigeru Taketani, Christopher J Lelliott, Antonio Vidal-Puig & Kyoji Ikeda

doi:10.1038/nm.1910

Bone is resorbed by osteoclasts, and too much activity by these cells leads to disease, such as osteoporosis. Here Kyoji Ikeda and colleagues show that the combined action of iron uptake and a key transcription factor involved in mitochondrial biogenesis are required for the proper functioning of these cells and that in cases of increased bone loss, iron chelation may be beneficial by inhibiting these cells.

Abstract - | Full Text - Coordination of PGC-1 and iron uptake in mitochondrial biogenesis and osteoclast activation | PDF (640 KB) - Coordination of PGC-1 and iron uptake in mitochondrial biogenesis and osteoclast activation | Supplementary information

Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells - pp267 - 276

Chinnaswamy Jagannath, Devin R Lindsey, Subramanian Dhandayuthapani, Yi Xu, Robert L Hunter Jr & N Tony Eissa

doi:10.1038/nm.1928

During autophagy, cytosolic proteins and damaged organelles are delivered via autophagosomes to lysosomes, where they are degraded before presentation at the cell surface. Agents that induce autophagy have previously been shown to boost antigen presentation in vitro. Here Chinnaswamy Jagannath and colleagues show in mice that autophagy can be exploited to boost the efficacy of a dendritic cell vaccine for Mycobacterium tuberculosis.

Abstract - | Full Text - Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells | PDF (933 KB) - Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells | Supplementary information

Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10 - pp277 - 284

Jie Sun, Rajat Madan, Christopher L Karp & Thomas J Braciale

doi:10.1038/nm.1929

Interleukin-10 is known to dampen immune responses and contribute to the persistence of chronic viruses and parasites. Thomas Braciale and his colleagues show in mice that the anti-inflammatory cytokine is produced, along with proinflammatory cytokines, by effector CD4⁺ and CD8⁺ T cells during an acute virus infection of the lung, thereby helping to regulate the extent of inflammatory lung damage in response to the virus.

Abstract - | Full Text - Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10 | PDF (610 KB) - Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10 | Supplementary information

Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34⁺ cells - pp285 - 292

Ronald T Mitsuyasu, Thomas C Merigan, Andrew Carr, Jerome A Zack, Mark A Winters, Cassy Workman, Mark Bloch, Jacob Lalezari, Stephen Becker, Lorna Thornton, Bisher Akil, Homayoon Khanlou, Robert Finlayson, Robert McFarlane, Don E Smith, Roger Garsia, David Ma, Matthew Law, John M Murray, Christof von Kalle, Julie A Ely, Sharon M Patino, Alison E Knop, Philip Wong, Alison V Todd, Margaret Haughton, Caroline Fuery, Janet L Macpherson, Geoff P Symonds, Louise A Evans, Susan M Pond & David A Cooper

doi:10.1038/nm.1932

The first phase 2 gene therapy trial for HIV-1 has shown some promising signs. There's a long way to go before this would be a viable approach in people with HIV—this trial did not show a statistically significant difference in viral load at the primary end point–but other analyses did reveal that the gene therapy seemed to have a modest, but statistically significant, effect at reducing viral load in the treated subjects versus the placebo arm. The study also provides some clues about what to improve in the future.

Abstract - | Full Text - Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells | PDF (533 KB) - Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells | Supplementary information

Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge - pp293 - 299

Scott G Hansen, Cassandra Vieville, Nathan Whizin, Lia Coyne-Johnson, Don C Siess, Derek D Drummond, Alfred W Legasse, Michael K Axthelm, Kelli Oswald, Charles M Trubey, Michael Piatak Jr, Jeffrey D Lifson, Jay A Nelson, Michael A Jarvis & Louis J Picker

doi:10.1038/nm.1935

Issue:Vaccines that induce T cell responses to simian immunodeficiency virus are able to reduce virus load in infected macaques. Such vaccines typically induce central memory T cells that must expand before gaining full antiviral functions. Picker and his colleagues show that a new replicating anti-SIV vaccine, based on the persistently infecting cytomegalovirus, which preferentially induces effector memory T cells in mucosal tissues, can reduce the likelihood that the macaques become infected in the first place (pages 244–246).

First Paragraph - | Full Text - Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge | PDF (948 KB) - Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge | Supplementary information

See also: News and Views by Franchini

Kindlin-3 is required for ₂ integrin–mediated leukocyte adhesion to endothelial cells - pp300 - 305

Markus Moser, Martina Bauer, Stephan Schmid, Raphael Ruppert, Sarah Schmidt, Michael Sixt, Hao-Ven Wang, Markus Sperandio & Reinhard Fässler

doi:10.1038/nm.1921

Kindlin-3 interacts with ₁ and ₃ integrins on platelets, and Kindlin-3–deficient mice have defects in platelet activation and blood clotting. Moser et al. now show that these mice also have defects in ₂ integrin activation on leukocytes, leading to severely compromised leukocyte adhesion to the endothelium. The combined platelet and leukocyte defects of these mice resemble those seen in individuals with the leukocyte adhesion deficiency syndrome LAD-III. Other papers in this issue by Malinin et al. and Svensson et al. provide evidence that KINDLIN-3 dysfunction does indeed underlie this type of human disease syndrome (pages 249–250, 306–312 and 313–318).

First Paragraph - | Full Text - Kindlin-3 is required for 2 integrin–mediated leukocyte adhesion to endothelial cells | PDF (497 KB) - Kindlin-3 is required for 2 integrin–mediated leukocyte adhesion to endothelial cells | Supplementary information

See also: News and Views by Hidalgo & Frenette | Letter by Svensson et al. | Letter by Malinin et al.

Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation - pp306 - 312

Lena Svensson, Kimberley Howarth, Alison McDowall, Irene Patzak, Rachel Evans, Siegfried Ussar, Markus Moser, Ayse Metin, Mike Fried, Ian Tomlinson & Nancy Hogg

doi:10.1038/nm.1931

In this issue, three reports show that Kindlin-3 is crucial for activation of multiple classes of integrins in several types of hematopoietic cells. In mice, Kindlin-3 was previously shown to be important for platelet activation and blood clotting, and Moser et al. now show its importance in leukocytes for adhesion to the endothelium. In humans, Svensson et al. and Malinin et al. show that mutation of the gene encoding Kindlin-3 is associated with a disease syndrome involving severe bleeding, infection and osteopetrosis, which Malinin et al. showed could be corrected by bone marrow transplantation (pages 249–250, 300–305 and 313–318).

First Paragraph - | Full Text - Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation | PDF (523 KB) - Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation | Supplementary information

See also: News and Views by Hidalgo & Frenette | Letter by Moser et al. | Letter by Malinin et al.

A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans - pp313 - 318

Nikolay L Malinin, Li Zhang, Jeongsuk Choi, Alieta Ciocea, Olga Razorenova, Yan-Qing Ma, Eugene A Podrez, Michael Tosi, Donald P Lennon, Arnold I Caplan, Susan B Shurin, Edward F Plow & Tatiana V Byzova

doi:10.1038/nm.1917

In this issue, three reports show that Kindlin-3 is crucial for activation of multiple classes of integrins in several types of hematopoietic cells. In mice, Kindlin-3 was previously shown to be important for platelet activation and blood clotting, and Moser et al. now show its importance in leukocytes for adhesion to the endothelium. In humans, Svensson et al. and Malinin et al. show that mutation of the gene encoding Kindlin-3 is associated with a disease syndrome involving severe bleeding, infection and osteopetrosis, which Malinin et al. showed could be corrected by bone marrow transplantation (pages 249–250, 300–305 and 306–312).

First Paragraph - | Full Text - A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans | PDF (517 KB) - A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans | Supplementary information

See also: News and Views by Hidalgo & Frenette | Letter by Moser et al. | Letter by Svensson et al.

Regulation of endocytosis via the oxygen-sensing pathway - pp319 - 324

Yi Wang, Olga Roche, Mathew S Yan, Greg Finak, Andrew J Evans, Julie L Metcalf, Bridgid E Hast, Sara C Hanna, Bill Wondergem, Kyle A Furge, Meredith S Irwin, William Y Kim, Bin T Teh, Sergio Grinstein, Morag Park, Philip A Marsden & Michael Ohh

doi:10.1038/nm.1922

Hypoxia promotes tumor growth by stimulating angiogenesis, glycolysis, resistance to apoptosis and cell invasion. Wang et al. now report that hypoxia also increases the duration of growth factor signaling in tumor cells. They show that hypoxia-inducible factor downregulates the expression of an effector of early endosome fusion, slowing the endocytic recycling of epidermal growth factor receptor and thereby extending its activation and potential to enhance tumor cell proliferation and survival (pages 246–247).

First Paragraph - | Full Text - Regulation of endocytosis via the oxygen-sensing pathway | PDF (669 KB) - Regulation of endocytosis via the oxygen-sensing pathway | Supplementary information

See also: News and Views by Hung et al.

Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle - pp325 - 330

Andrew M Bellinger, Steven Reiken, Christian Carlson, Marco Mongillo, Xiaoping Liu, Lisa Rothman, Stefan Matecki, Alain Lacampagne & Andrew R Marks

doi:10.1038/nm.1916

Increased calcium levels in dystrophic muscle have damaging consequences. In this report, Bellinger et al. show that nitrosylation of the ryanodine receptor calcium channel, leading to calcium leak through the channel, is an underlying cause of increased calcium levels in the muscle of dystrophic mdx mice. Treatment of the mice with a compound that inhibits calcium leak increases their muscle function and physical activity, pointing to a potential new treatment for muscular dystrophy (pages 243–244).

First Paragraph - | Full Text - Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle | PDF (496 KB) - Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle | Supplementary information

See also: News and Views by Tidball & Villalta

Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease - pp331 - 337

Alan H Nagahara, David A Merrill, Giovanni Coppola, Shingo Tsukada, Brock E Schroeder, Gideon M Shaked, Ling Wang, Armin Blesch, Albert Kim, James M Conner, Edward Rockenstein, Moses V Chao, Edward H Koo, Daniel Geschwind, Eliezer Masliah, Andrea A Chiba & Mark H Tuszynski

doi:10.1038/nm.1912

Mark Tuszynski and his colleagues show that brain-derived neurotrophic factor is neuroprotective and can improve cognition in rodent and primate models of Alzheimer's disease.

First Paragraph - | Full Text - Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease | PDF (597 KB) - Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease | Supplementary information

Sensitive in vivo imaging of T cells using a membrane-bound Gaussia princeps luciferase - pp338 - 344

Elmer B Santos, Raymond Yeh, James Lee, Yan Nikhamin, Blesida Punzalan, Blesserene Punzalan, Krista La Perle, Steven M Larson, Michel Sadelain & Renier J Brentjens

doi:10.1038/nm.1930

A research team led by Renier Brentjens offers a new approach to monitor in vivo trafficking of T cells by tagging them for bioluminescence imaging using a membrane-anchored form of the humanized Gaussia luciferase enzyme. The set-up provides a high bioluminescent signal and should be useful for studying in vivo T cell function in mouse models of disease investigating mouse or human primary T cells.

Abstract - | Full Text - Sensitive in vivo imaging of T cells using a membrane-bound Gaussia princeps luciferase | PDF (757 KB) - Sensitive in vivo imaging of T cells using a membrane-bound Gaussia princeps luciferase | Supplementary information