Volume 19 Issue 4, April 2013

The Brain Activity Map is an initiative by the US National Institutes of Health to understand how thousands of neurons work in concert to control behavior and trigger disease. Miyoung Chun, vice president for science programs at The Kavli Foundation in Oxnard, California, has been developing the project since the beginning and is the self-described “glue” between its many diverse stakeholders. Chun spoke with Virginia Hughes about the evolution of the project.

Natural compounds produced by the world's microbes were once the go-to source of molecules for the drug industry before the chemistry dried up and big pharma went packing. Now, researchers hope that advances in genomics will bring companies back into the fold. Daniel Grushkin visits one startup hoping to accelerate the process.

Although cancer vaccines can induce tumor-specific cytotoxic CD8⁺ T cells, tumors treated by vaccination often fail to regress. A study in mice provides a potential explanation for this phenomenon by showing that a peptide vaccine in a water-oil adjuvant leads to the trapping of tumor-specific CD8⁺ T cells at the vaccination site, instead of promoting an effective T cell response at the tumor site (pages 465–472).

Two new studies suggest a crucial role for macrophages in boosting the number of red blood cells produced in vivo during stress, with translational implications for disease states such as β-thalassemia and polycythemia vera (pages 429–436 and 437–445).

Many HIV-infected people show impaired humoral immune responses, but it is unclear why. A new view into this conundrum may be provided with the recent discovery of altered interactions between follicular helper T (T_FH) cells and germinal center B cells from HIV-infected individuals. This leads to inadequate T_FH cell help for germinal center B cells and decreased B cell antibody responses (pages 494–499).

A new generation of target-specific inhibitors of the coagulation enzymes thrombin and factor Xa has been approved for a number of indications, but the clinical use of these drugs is hindered by the lack of a way to reverse bleeding, should it occur. An antidote to these new oral anticoagulants has now been designed and shows promise in small-animal models of blood loss (pages 446–451).

Trisomy 21 triggers multiple potential routes to intellectual disability in Down's syndrome. A new study suggests that aberrant endosomal function may contribute to the neuronal deficits behind learning and memory impairments in affected individuals (pages 473–480).

Adenovirus type 5 (Ad5) has been intensively studied as a viral vector for gene therapy, and understanding host–Ad5 interactions will be key to the safe and effective use of this vector. A recent study in mice provides new insights in this area by showing that Ad5 enlists a host coagulation factor to overcome complement-mediated blockade and infect the liver (pages 452–457).

A recent study shows that, like cancer cells, cells lacking the Pdk1 gene reprogram their metabolism to use aerobic glycolysis—the 'Warburg effect'. Targeting this pathway using a glucose analog that cannot be metabolized resulted in slower disease progression in mouse models of polycystic kidney disease. This work thus suggests a new potential therapeutic approach for autosomal dominant polycystic kidney disease (pages 488–493).

Myocardial infarction can cause irreversible heart muscle cell damage and lingering cardiac problems that can eventually lead to heart failure. For over a decade, researchers have been trying to coax stem cells to differentiate into cardiomyocytes to repair damaged heart tissue, with limited success. In 'Bedside to Bench', Christine L. Mummery and Richard T. Lee lay out a framework for re-evaluating cardiac cell therapies in the context of two recent clinical trials, in which autologous cardiac stem cells derived from heart biopsies were transferred into patients, with promising, albeit difficult to interpret, results. Results from previous clinical trials using autologous bone marrow–derived adult stem cells to induce cardiac regeneration add to the debate about how to cautiously move forward in the cardiac regeneration field and to the questions that need to be urgently answered at the bench. In 'Bench to Bedside', Young-Jae Nam, Kunhua Song and Eric N. Olson discuss a number of recent studies in rodents showing that cardiac fibroblasts can be reprogrammed, via miRNAs and a transcription factor 'cocktail', to express cardiac genes, which resulted in improved cardiac function in the animals, suggesting a new way forward for fixing damaged heart tissue.

Rifampicin and isoniazid are often used together as a co-therapy to treat tuberculosis, but their combined use often leads to hepatoxicity in humans. Xiaochao Ma and colleagues now report the mechanisms behind this side effect, thus opening a possible avenue to the safer use of these effective drugs.

Ulcerations of the oral cavity, or oral mucositis, often occur during radiation treatment for cancers of the head or neck or during bone marrow transplantation. Xiao-Jing Wang and colleagues now show that in a mouse model, Smad7 is an effective treatment for this condition, offering more hope for its clinical management.

Chow et al. report a crucial role for macrophages in erythroblast development in mice. Under conditions that induce new red blood cell formation, macrophage depletion impaired red blood cell recovery. Conversely, macrophage depletion normalized red blood cell counts in a mouse model of polycythemia vera, pointing to a potential new therapeutic strategy for this disease. Findings similar to these are reported in an accompanying paper by Ramos et al.

Ramos et al. report a crucial role for macrophages in erythroblast development in mice. Under conditions that induce new red blood cell formation, macrophage depletion impaired red blood cell recovery. Conversely, macrophage depletion normalized red blood cell counts in mouse models of polycythemia vera and ®-thalassemia, pointing to a potential new therapeutic strategy for these diseases. Findings similar to these are reported in an accompanying paper by Chow et al.

Coagulation factor Xa is targeted by a new generation of antithrombotic drugs such as rivaroxaban. However, as excessive factor Xa inhibition can cause bleeding, the clinical use of factor Xa inhibitors would be enhanced by the availability of a specific antidote. Uma Sinha and her colleagues devise such an antidote, an inactive form of recombinant factor Xa that can bind to and neutralize factor Xa inhibitors, and demonstrate its efficacy in animal models.

Understanding how adenoviruses transduce cells is important for their use and development as vaccine vectors. Adenovirus type 5 (Ad5) is known to bind coagulation factor X (FX), and FX is thought to act as a bridge between the virus and its receptor on hepatocytes. Andrew Byrnes and his colleagues now report that the major role of FX binding to Ad5 is actually to protect Ad5 from neutralization by complement and natural antibodies, and in the absence of B cells, Ad5 does not require FX binding for effective liver transduction.

Different types of neurons are differentially susceptible to West Nile virus (WNV) infection. Michael Diamond and colleagues now show that cerebellar granule cell neurons (GCN) have a higher basal level of expression of type I interferon–inducible genes than cortical neurons, making GCN more resistant to infection by a variety of positive-stranded RNA viruses, including WNV.

Cancer vaccines have had limited success in eliminating tumors in patients. Here Willem Overwijk and colleagues report that one reason for the failure of peptide-based vaccines may be their formulation. Their research shows that peptides formulated in incomplete Freund's adjuvant sequester CD8+ T cells at the site of injection, leading to T cell dysfunction and eventual apoptosis. A peptide and adjuvant formulation that did not persist long term at the injection site showed superior ability to induce a functional antitumor T cell response.

Synaptic abnormalities and learning dysfunction are prominent characteristics of Down's syndrome. Now Huaxi Xu and colleagues show that expression of the protein SNX27 is reduced in Down's syndrome brains and that restoring its expression can ameliorate learning dysfunction in a mouse model of the disease.

Focal and segmental glomerulosclerosis, or renal scarring, is a debilitating disease. The identification of the molecular mechanisms of its initiation and progression has been limited, thus hampering the development of proper animal models. Dontscho Kerjaschki and his colleagues now report that microRNA-193a is elevated in human cases of the disease and that transgenic expression in mice is sufficient to cause the condition.

Polycystic kidney disease is marked by progressive growth of renal tubular epithelia and thus the formation of pathological cysts in the organ over time. Alessandra Boletta and her colleagues now show that this cystic growth has the hallmarks of the Warburg effect (that is, the primary reliance of cells on glycolysis for their energy demands) and that blocking this effect in vivo is sufficient to improve disease progression in two mouse models.

B cell responses are impaired in HIV-infected individuals. Elias Haddad and colleagues now report that follicular helper T (T_FH) cells, which are crucial for the maturation of B cell memory and development of high-affinity antibodies, are functionally impaired upon interaction with lymph node germinal center B cells from HIV-infected individuals. The interaction of the inhibitory molecule PD-1 on T_FH cells with its ligand PD-L1, which is elevated on germinal center B cells in HIV-infected lymph nodes, impairs T_FH cell proliferation and antibody production by B cells, thus providing insight into humoral dysfunction in HIV infection.

The noninvasive detection of myeloperoxidase (MPO)-mediated oxidative stress in deep tissue inflammatory foci has been hampered by poor penetration of luminol-emitted short wavelength light due to tissue absorption and scattering. To circumvent this, Daniel Ansaldi and his colleagues have adopted a chemiluminescence resonance energy transfer approach whereby near-infrared (NIR) nanoparticles are used to red-shift luminol-emitted blue light to the NIR. Improved in vivo detectability of MPO is demonstrated in a lipopolysaccharide-induced pulmonary inflammation model, as well as in deep tissue tumor metastases.