Panopharma

[Perspectives] Dodging Drug-Resistant Cancer with Diamonds

Merkel, T. J., DeSimone, J. M

• Locust Heaven
  Locust outbreaks have severe consequences for agriculture, but the conditions that promote an outbreak are unknown. Cease et al. (p. 467) investigated aspects of the locust diet and found that … [Read more]
• Natural Selection Caught in the Act
  Understanding how new functions evolve has been of long-standing interest. However, the number of mutations needed to evolve a key innovation is rarely known, or whether other sets of mutations … [Read more]
• Potassium Permeation
  Two–pore domain potassium (K2P) channels conduct K+ ions across the plasma membrane of eukaryotic cells. They help to maintain the cellular resting potential and their modulation can tune cellular excitability … [Read more]
• Porous Membranes
  Thin semi-permeable membranes are commonly used as chemical barriers or for filtration purposes. While the size of the pores will influence which molecules are able to pass, other factors—including the … [Read more]
• Boxing in Peroxide
  Hydrogen peroxide (H2O2) is a powerful oxidant, and its reactivity is exploited in numerous biological, as well as synthetic, contexts. Lopez et al. (p. 450) have now managed to capture … [Read more]
• Centrosome Center Stage?
  The centrosome is a major organizer of the cytoskeleton in animal cells. The precise duplication of this organelle at each cell cycle ensures proper organization of the mitotic apparatus and … [Read more]
• Magnetic Moon
  It has long been suspected that the Moon once had a core-dynamo magnetic field. Shea et al. (p. 453) describe a lunar basalt brought back by Apollo 11 that records … [Read more]
• Forest Diversification
  The relative role of neutral and deterministic processes in generating species richness in ecological communities (particularly tropical trees) has dominated recent discussions about patterns of diversity and abundance of species. … [Read more]
• A Good Judge of Distance
  Jumping spiders actively pursue their prey, often jumping relatively long distances in order to catch them. Such feats require accurate depth perception. Nagata et al. (p. 469; see the Perspective … [Read more]
• A Passive Optical Diode
  Electrical diodes are at the core of microelectronics. The optical equivalent, however, has been difficult to realize owing to the time-reversal symmetry of Maxwell's equations that describe electromagnetic propagation. Usually, … [Read more]

• [Commentary] Triggers for Research Ethics Consultation
  Research ethics consultation services are designed to help scientists address ethical and societal issues that may not be considered in the context of existing regulatory frameworks, such as institutional review boards. Here, we identify some types of biomedical research for which the research process can benefit from consultation with ethicists.
  Havard, M., Cho, M. K., Magnus, D.
• [Commentary] A Virtual National Laboratory for Reengineering Clinical Translational Science
  Clinical research is burdened by inefficiencies and complexities, with a poor record of trial completion, none of which is desirable. The Clinical and Translational Science Award (CTSA) Consortium, including more than 60 clinical research institutions, supports a unified national effort to become, in effect, a virtual national laboratory designed to identify, implement, evaluate, and extend process improvements across all parts of clinical research, from conception to completion. If adequately supported by academic health centers, industry, and funding agencies, the Consortium could become a test bed for improvements that can dramatically reduce wasteful complexity, thus increasing the likelihood of clinical trial completion.
  Dilts, D. M., Rosenblum, D., Trochim, W. M.
• [Research Articles] Molecular Diagnosis of Infantile Mitochondrial Disease with Targeted Next-Generation Sequencing
  Advances in next-generation sequencing (NGS) promise to facilitate diagnosis of inherited disorders. Although in research settings NGS has pinpointed causal alleles using segregation in large families, the key challenge for clinical diagnosis is application to single individuals. To explore its diagnostic use, we performed targeted NGS in 42 unrelated infants with clinical and biochemical evidence of mitochondrial oxidative phosphorylation disease. These devastating mitochondrial disorders are characterized by phenotypic and genetic heterogeneity, with more than 100 causal genes identified to date. We performed "MitoExome" sequencing of the mitochondrial DNA (mtDNA) and exons of ~1000 nuclear genes encoding mitochondrial proteins and prioritized rare mutations predicted to disrupt function. Because patients and healthy control individuals harbored a comparable number of such heterozygous alleles, we could not prioritize dominant-acting genes. However, patients showed a fivefold enrichment of genes with two such mutations that could underlie recessive disease. In total, 23 of 42 (55%) patients harbored such recessive genes or pathogenic mtDNA variants. Firm diagnoses were enabled in 10 patients (24%) who had mutations in genes previously linked to disease. Thirteen patients (31%) had mutations in nuclear genes not previously linked to disease. The pathogenicity of two such genes, NDUFB3 and AGK, was supported by complementation studies and evidence from multiple patients, respectively. The results underscore the potential and challenges of deploying NGS in clinical settings.
  Calvo, S. E., Compton, A. G., Hershman, S. G., Lim, S. C., Lieber, D. S., Tucker, E. J., Laskowski, A., Garone, C., Liu, S., Jaffe, D. B., Christodoulou, J., Fletcher, J. M., Bruno, D. L., Goldblatt, J., DiMauro, S., Thorburn, D. R., Mootha, V. K.
• [Research Articles] Surgical Stress Resistance Induced by Single Amino Acid Deprivation Requires Gcn2 in Mice
  Dietary restriction, or reduced food intake without malnutrition, increases life span, health span, and acute stress resistance in model organisms from yeast to nonhuman primates. Although dietary restriction is beneficial for human health, this treatment is not widely used in the clinic. Here, we show that short-term, ad libitum feeding of diets lacking essential nutrients increased resistance to surgical stress in a mouse model of ischemia reperfusion injury. Dietary preconditioning by 6 to 14 days of total protein deprivation, or removal of the single essential amino acid tryptophan, protected against renal and hepatic ischemic injury, resulting in reduced inflammation and preserved organ function. Pharmacological treatment with halofuginone, which activated the amino acid starvation response within 3 days by mimicking proline deprivation, was also beneficial. Both dietary and pharmacological interventions required the amino acid sensor and eIF2α (eukaryotic translation initiation factor 2α) kinase Gcn2 (general control nonderepressible 2), implicating the amino acid starvation response and translational control in stress protection. Thus, short-term dietary or pharmacological interventions that modulate amino acid sensing can confer stress resistance in models of surgical ischemia reperfusion injury.
  Peng, W., Robertson, L., Gallinetti, J., Mejia, P., Vose, S., Charlip, A., Chu, T., Mitchell, J. R.
• [Editors' Choice] Bidirectional Dance of Glutamine
  Emadi, A.
• [Research Articles] Teplizumab Induces Human Gut-Tropic Regulatory Cells in Humanized Mice and Patients
  The development and optimization of immune therapies in patients has been hampered by the lack of preclinical models in which their effects on human immune cells can be studied. As a result, observations that have been made in preclinical studies have suggested mechanisms of drug action in murine models that have not been confirmed in clinical studies. Here, we used a humanized mouse reconstituted with human hematopoietic stem cells to study the mechanism of action of teplizumab, an Fc receptor nonbinding humanized monoclonal antibody to CD3 being tested in clinical trials for the treatment of patients with type 1 diabetes mellitus. In this model, human gut-tropic CCR6+ T cells exited the circulation and secondary lymph organs and migrated to the small intestine. These cells then produced interleukin-10 (IL-10), a regulatory cytokine, in quantities that could be detected in the peripheral circulation. Blocking T cell migration to the small intestine with natalizumab, which prevents cellular adhesion by inhibiting α4 integrin binding, abolished the treatment effects of teplizumab. Moreover, IL-10 expression by CD4+CD25highCCR6+FoxP3 cells returning to the peripheral circulation was increased in patients with type 1 diabetes treated with teplizumab. These findings demonstrate that humanized mice may be used to identify novel immunologic mechanisms that occur in patients treated with immunomodulators.
  Waldron-Lynch, F., Henegariu, O., Deng, S., Preston-Hurlburt, P., Tooley, J., Flavell, R., Herold, K. C.
• [Editors' Choice] When Fat Gets on Your Nerves
  Mashour, G. A.
• [Editors' Choice] Just Be "pH"-tient
  Rytting, E.
• [Editors' Choice] Smoking Out a New Therapy for Lung Disease
  Shum, A. K.