Science Roundup


This month in Science Roundup:

NEWS FOCUS: Aging Genes: The Sirtuin Story Unravels

Summary: In 1998, MIT professor Leonard Guarente and his lab began publishing a series of influential papers that linked a set of genes to calorie restriction, which had been known for years to stretch life span in animals, suggesting the possibility that drugs could extend human life span. But other scientists failed to find what they were reporting in their experiments. The result is mass confusion over who's right and who's wrong, and a high-stakes effort to protect reputations, research money, and one of the premier theories in the biology of aging. It's also a story of science gone sour: Several principals have dug in their heels, declined to communicate, and bitterly derided one another. Tensions reached a crescendo in September, when former Guarente lab member Matt Kaeberlein and colleagues published one of their most damning papers yet, finding no effects from a key aging gene in worms and flies.
Podcast Interview


NEWS & ANALYSIS: Dispute Over Lab Notebooks Lands Researcher in Jail

Summary: Judy Mikovits, a biochemist who became world famous for her studies with chronic fatigue syndrome, was arrested and jailed on 18 November in Ventura, California, on a felony charge of possessing stolen property from her former employer—the Whittemore Peterson Institute for Neuro-Immune Disease (WPI) in Reno, Nevada—which fired her in September. The property at issue consisted of her laboratory notebooks and related data. Court documents filed by police in a criminal case and by WPI in a related but separate civil case allege that Mikovits instructed a lab assistant to steal the notebooks and other material. These astonishing—if not downright bizarre—events cap a 2-year period in which Mikovits has been mired in a topsy-turvy research debate that saw her work praised and then derided by prominent colleagues.


REPORT: Entangling Macroscopic Diamonds at Room Temperature

Abstract: Quantum entanglement in the motion of macroscopic solid bodies has implications both for quantum technologies and foundational studies of the boundary between the quantum and classical worlds. Entanglement is usually fragile in room-temperature solids, owing to strong interactions both internally and with the noisy environment. We generated motional entanglement between vibrational states of two spatially separated, millimeter-sized diamonds at room temperature. By measuring strong nonclassical correlations between Raman-scattered photons, we showed that the quantum state of the diamonds has positive concurrence with 98% probability. Our results show that entanglement can persist in the classical context of moving macroscopic solids in ambient conditions.
Supporting online material


NEWS FOCUS: Saudi Universities Offer Cash in Exchange for Academic Prestige

Summary: More than 60 top-ranked researchers from different scientific disciplines—all on the Institute for Scientific Information's (ISI's) highly cited list—have recently signed part-time employment arrangements with King Abdulaziz University in Jeddah, Saudi Arabia, in which they agree to add KAU as a second affiliation to their names on ISI's list of highly cited researchers. Meanwhile, a bigger, more prominent Saudi institution—King Saud University in Riyadh—has climbed several hundred places in international rankings in the past 4 years largely through initiatives specifically targeted toward attaching KSU's name to research publications, regardless of whether the work involved any meaningful collaboration with KSU researchers. Academics both inside and outside Saudi Arabia warn that such practices could detract from the genuine efforts that Saudi Arabia's universities are making to transform themselves into world-class research centers.


REPORT: Explaining Seasonal Fluctuations of Measles in Niger Using Nighttime Lights Imagery

Abstract: Measles epidemics in West Africa cause a significant proportion of vaccine-preventable childhood mortality. Epidemics are strongly seasonal, but the drivers of these fluctuations are poorly understood, which limits the predictability of outbreaks and the dynamic response to immunization. We show that measles seasonality can be explained by spatiotemporal changes in population density, which we measure by quantifying anthropogenic light from satellite imagery. We find that measles transmission and population density are highly correlated for three cities in Niger. With dynamic epidemic models, we demonstrate that measures of population density are essential for predicting epidemic progression at the city level and improving intervention strategies. In addition to epidemiological applications, the ability to measure fine-scale changes in population density has implications for public health, crisis management, and economic development.
Supporting online material


REPORT: Perceptual Learning Incepted by Decoded fMRI Neurofeedback Without Stimulus Presentation

Abstract: It is controversial whether the adult primate early visual cortex is sufficiently plastic to cause visual perceptual learning (VPL). The controversy occurs partially because most VPL studies have examined correlations between behavioral and neural activity changes rather than cause-and-effect relationships. With an online-feedback method that uses decoded functional magnetic resonance imaging (fMRI) signals, we induced activity patterns only in early visual cortex corresponding to an orientation without stimulus presentation or participants’ awareness of what was to be learned. The induced activation caused VPL specific to the orientation. These results suggest that early visual areas are so plastic that mere inductions of activity patterns are sufficient to cause VPL. This technique can induce plasticity in a highly selective manner, potentially leading to powerful training and rehabilitative protocols.
Supporting online material


RESEARCH ARTICLE: Detecting Novel Associations in Large Data Sets

Abstract: Identifying interesting relationships between pairs of variables in large data sets is increasingly important. Here, we present a measure of dependence for two-variable relationships: the maximal information coefficient (MIC). MIC captures a wide range of associations both functional and not, and for functional relationships provides a score that roughly equals the coefficient of determination (R2) of the data relative to the regression function. MIC belongs to a larger class of maximal information-based nonparametric exploration (MINE) statistics for identifying and classifying relationships. We apply MIC and MINE to data sets in global health, gene expression, major-league baseball, and the human gut microbiota and identify known and novel relationships.
Supporting online material


REPORT: Peak External Photocurrent Quantum Efficiency Exceeding 100% via MEG in a Quantum Dot Solar Cell

Abstract: Multiple exciton generation (MEG) is a process that can occur in semiconductor nanocrystals, or quantum dots (QDs), whereby absorption of a photon bearing at least twice the bandgap energy produces two or more electron-hole pairs. Here, we report on photocurrent enhancement arising from MEG in lead selenide (PbSe) QD-based solar cells, as manifested by an external quantum efficiency (the spectrally resolved ratio of collected charge carriers to incident photons) that peaked at 114 ± 1% in the best device measured. The associated internal quantum efficiency (corrected for reflection and absorption losses) was 130%. We compare our results with transient absorption measurements of MEG in isolated PbSe QDs and find reasonable agreement. Our findings demonstrate that MEG charge carriers can be collected in suitably designed QD solar cells, providing ample incentive to better understand MEG within isolated and coupled QDs as a research path to enhancing the efficiency of solar light harvesting technologies.
Supporting online material


PERSPECTIVE: A Correlation for the 21st Century

Summary: Most scientists will be familiar with the use of Pearson's correlation coefficient r to measure the strength of association between a pair of variables: for example, between the height of a child and the average height of their parents (r ˜ 0.5; see the figure, panel A), or between wheat yield and annual rainfall (r ˜ 0.75, panel B). However, Pearson's r captures only linear association, and its usefulness is greatly reduced when associations are nonlinear. What has long been needed is a measure that quantifies associations between variables generally, one that reduces to Pearson's in the linear case, but that behaves as we'd like in the nonlinear case. On page 1518 of the 16 December 2011 issue, Reshef et al. (1) introduce the maximal information coefficient, or MIC, that can be used to determine nonlinear correlations in data sets equitably.



REPORT: From Flat Foot to Fat Foot: Structure, Ontogeny, Function, and Evolution of Elephant "Sixth Toes"

Abstract: Several groups of tetrapods have expanded sesamoid (small, tendon-anchoring) bones into digit-like structures ("predigits"), such as pandas’ "thumbs." Elephants similarly have expanded structures in the fat pads of their fore- and hindfeet, but for three centuries these have been overlooked as mere cartilaginous curiosities. We show that these are indeed massive sesamoids that employ a patchy mode of ossification of a massive cartilaginous precursor and that the predigits act functionally like digits. Further, we reveal clear osteological correlates of predigit joint articulation with the carpals/tarsals that are visible in fossils. Our survey shows that basal proboscideans were relatively "flat-footed" (plantigrade), whereas early elephantiforms evolved the more derived "tip-toed" (subunguligrade) morphology, including the predigits and fat pad, of extant elephants. Thus, elephants co-opted sesamoid bones into a role as false digits and used them for support as they changed their foot posture.
Supporting online material


REPORT: Fear Erasure in Mice Requires Synergy Between Antidepressant Drugs and Extinction Training

Abstract: Antidepressant drugs and psychotherapy combined are more effective in treating mood disorders than either treatment alone, but the neurobiological basis of this interaction is unknown. To investigate how antidepressants influence the response of mood-related systems to behavioral experience, we used a fear-conditioning and extinction paradigm in mice. Combining extinction training with chronic fluoxetine, but neither treatment alone, induced an enduring loss of conditioned fear memory in adult animals. Fluoxetine treatment increased synaptic plasticity, converted the fear memory circuitry to a more immature state, and acted through local brain-derived neurotrophic factor. Fluoxetine-induced plasticity may allow fear erasure by extinction-guided remodeling of the memory circuitry. Thus, the pharmacological effects of antidepressants need to be combined with psychological rehabilitation to reorganize networks rendered more plastic by the drug treatment.
Supporting online material


NEWS FOCUS: America's Lost City

Summary: A millennium ago, what is now East St. Louis, Illinois, was an affluent neighborhood of Native Americans, set amid the largest concentration of people and monumental architecture north of what is now Mexico. To the east was another concentration of enormous earthen mounds and people—the settlement called Cahokia by today's archaeologists—and to the west across the Mississippi was a third center of mounds and houses at what is modern St. Louis. Cahokia proper was the only pre-Columbian city north of the Rio Grande, and it was large even by European and Mesoamerican standards of the day. Now new excavations suggest a far larger, complex metropolis. But a new highway and a bridge over the Mississippi will soon destroy the remnants of the site. The $2.5 million dig is yielding big surprises for researchers, who had thought that the 19th century industrial city here wiped out the ancient remains.


In Science Signaling


RESEARCH ARTICLE: Neuronal Growth Cone Retraction Relies on Proneurotrophin Receptor Signaling Through Rac

Abstract: Growth of axons and dendrites is a dynamic process that involves guidance molecules, adhesion proteins, and neurotrophic factors. Although neurite extension is stimulated by the neurotrophin nerve growth factor (NGF), we found that the precursor of NGF, proNGF, induced acute collapse of growth cones of cultured hippocampal neurons. This retraction was initiated by an interaction between the p75 neurotrophin receptor (p75NTR) and the sortilin family member SorCS2 (sortilin-related VPS10 domain–containing receptor 2). Binding of proNGF to the p75NTR-SorCS2 complex induced growth cone retraction by initiating the dissociation of the guanine nucleotide exchange factor Trio from the p75NTR-SorCS2 complex, resulting in decreased Rac activity and, consequently, growth cone collapse. The actin-bundling protein fascin was also inactivated, contributing to the destabilization and collapse of actin filaments. These results identify a bifunctional signaling mechanism by which proNGF regulates actin dynamics to acutely modulate neuronal morphology.
Supplementary Materials


PRESPECTIVES: Is the Regulation of Insulin Signaling Multi-Organismal?

Abstract: The sustained health of an individual animal depends on the composition and activities of its resident microbiota. A major challenge is to identify the processes by which the microbiota and animal interact, recognizing that this research should lead ultimately to novel strategies to promote human health. Drosophila is emerging as a tractable model system to investigate these interactions. New evidence reveals that the gut microbiota promotes insulin signaling in Drosophila, leading to increased growth and development rates. Different gut bacteria and bacterial effectors were implicated: acetic acid produced by Acetobacter pomorum and branched-chain amino acids produced by Lactobacillus plantarum, respectively. These findings raise the possibility that multiple bacterial effectors may interact with signaling networks to shape animal health.


RESEARCH ARTICLE: Human Regulatory T Cells Rapidly Suppress T Cell Receptor–Induced Ca2+, NF-?B, and NFAT Signaling in Conventional T Cells

Abstract: CD4+CD25hiFoxp3+ regulatory T cells (Tregs) are critical mediators of self-tolerance, which is crucial for the prevention of autoimmune disease, but Tregs can also inhibit antitumor immunity. Tregs inhibit the proliferation of CD4+CD25– conventional T cells (Tcons), as well as the ability of these cells to produce effector cytokines; however, the molecular mechanism of suppression remains unclear. Here, we showed that human Tregs rapidly suppressed the release of calcium ions (Ca2+) from intracellular stores in response to T cell receptor (TCR) activation in Tcons. The inhibition of Ca2+ signaling resulted in decreased dephosphorylation, and thus decreased activation, of the transcription factor nuclear factor of activated T cells 1 (NFAT1) and reduced the activation of nuclear factor ?B (NF-?B). In contrast, Ca2+-independent events in Tcons, such as TCR-proximal signaling and activation of the transcription factor activator protein 1 (AP-1), were not affected during coculture with Tregs. Despite suppressing intracellular Ca2+-mobilization, coculture with Tregs did not block the generation of inositol 1,4,5-trisphosphate in TCR-stimulated Tcons. The Tregs-induced suppression of the activity of NFAT and NF-?B and of the expression of the gene encoding the cytokine interleukin-2 was reversed in Tcons by increasing the concentration of intracellular Ca2+. Our results elucidate a previously unrecognized and rapid mechanism of Tregs-mediated suppression. This increased understanding of Tregs function may be exploited to generate possible therapies for the treatment of autoimmune diseases and cancer.
Supplementary Materials


In Science Translational Medicine


RESEARCH ARTICLE: Age-Related Intimal Stiffening Enhances Endothelial Permeability and Leukocyte Transmigration

Abstract: Age is the most significant risk factor for atherosclerosis; however, the link between age and atherosclerosis is poorly understood. During both aging and atherosclerosis progression, the blood vessel wall stiffens owing to alterations in the extracellular matrix. Using in vitro and ex vivo models of vessel wall stiffness and aging, we show that stiffening of extracellular matrix within the intima promotes endothelial cell permeability—a hallmark of atherogenesis. When cultured on hydrogels fabricated to match the elasticity of young and aging intima, endothelial monolayers exhibit increased permeability and disrupted cell-cell junctions on stiffer matrices. In parallel experiments, we showed a corresponding increase in cell-cell junction width with age in ex vivo aortas from young (10 weeks) and old (21 to 25 months) healthy mice. To investigate the mechanism by which matrix stiffening alters monolayer integrity, we found that cell contractility increases with increased matrix stiffness, mechanically destabilizing cell-cell junctions. This increase in endothelial permeability results in increased leukocyte extravasation, which is a critical step in atherosclerotic plaque formation. Mild inhibition of Rho-dependent cell contractility using Y-27632, an inhibitor of Rho-associated kinase, or small interfering RNA restored monolayer integrity in vitro and in vivo. Our results suggest that extracellular matrix stiffening alone, which occurs during aging, can lead to endothelial monolayer disruption and atherosclerosis pathogenesis. Because previous therapeutics designed to decrease vascular stiffness have been met with limited success, our findings could be the basis for the design of therapeutics that target the Rho-dependent cellular contractile response to matrix stiffening, rather than stiffness itself, to more effectively prevent atherosclerosis progression.
Supplementary material


RESEARCH ARTICLE: Amelioration of Type 2 Diabetes by Antibody-Mediated Activation of Fibroblast Growth Factor Receptor 1

Abstract: Clinical use of recombinant fibroblast growth factor 21 (FGF21) for the treatment of type 2 diabetes and other disorders linked to obesity has been proposed; however, its clinical development has been challenging owing to its poor pharmacokinetics. Here, we describe an alternative antidiabetic strategy using agonistic anti-FGFR1 (FGF receptor 1) antibodies (R1MAbs) that mimic the metabolic effects of FGF21. A single injection of R1MAb into obese diabetic mice induced acute and sustained amelioration of hyperglycemia, along with marked improvement in hyperinsulinemia, hyperlipidemia, and hepatosteatosis. R1MAb activated the mitogen-activated protein kinase pathway in adipose tissues, but not in liver, and neither FGF21 nor R1MAb improved glucose clearance in lipoatrophic mice, which suggests that adipose tissues played a central role in the observed metabolic effects. In brown adipose tissues, both FGF21 and R1MAb induced phosphorylation of CREB (cyclic adenosine 5'-monophosphate response element–binding protein), and mRNA expression of PGC-1a (peroxisome proliferator–activated receptor-? coactivator 1a) and the downstream genes associated with oxidative metabolism. Collectively, we propose FGFR1 in adipose tissues as a major functional receptor for FGF21, as an upstream regulator of PGC-1a, and as a compelling target for antibody-based therapy for type 2 diabetes and other obesity-associated disorders.
Supplementary material


RESEARCH ARTICLE: Pathogenesis of Lethal Cardiac Arrhythmias in Mecp2 Mutant Mice: Implication for Therapy in Rett Syndrome

Abstract: Rett syndrome is a neurodevelopmental disorder typically caused by mutations in methyl-CpG–binding protein 2 (MECP2) in which 26% of deaths are sudden and of unknown cause. To explore the hypothesis that these deaths may be due to cardiac dysfunction, we characterized the electrocardiograms in 379 people with Rett syndrome and found that 18.5% show prolongation of the corrected QT interval (QTc), an indication of a repolarization abnormality that can predispose to the development of an unstable fatal cardiac rhythm. Male mice lacking MeCP2 function, Mecp2Null/Y, also have prolonged QTc and show increased susceptibility to induced ventricular tachycardia. Female heterozygous null mice, Mecp2Null/+, show an age-dependent prolongation of QTc associated with ventricular tachycardia and cardiac-related death. Genetic deletion of MeCP2 function in only the nervous system was sufficient to cause long QTc and ventricular tachycardia, implicating neuronally mediated changes to cardiac electrical conduction as a potential cause of ventricular tachycardia in Rett syndrome. The standard therapy for prolonged QTc in Rett syndrome, ß-adrenergic receptor blockers, did not prevent ventricular tachycardia in Mecp2Null/Y mice. To determine whether an alternative therapy would be more appropriate, we characterized cardiomyocytes from Mecp2Null/Y mice and found increased persistent sodium current, which was normalized when cells were treated with the sodium channel–blocking anti-seizure drug phenytoin. Treatment with phenytoin reduced both QTc and sustained ventricular tachycardia in Mecp2Null/Y mice. These results demonstrate that cardiac abnormalities in Rett syndrome are secondary to abnormal nervous system control, which leads to increased persistent sodium current. Our findings suggest that treatment in people with Rett syndrome would be more effective if it targeted the increased persistent sodium current to prevent lethal cardiac arrhythmias.


IMAGE CREDITS (In order of appearance): J. COHEN/SCIENCE; COURTESY OF VENTURA COUNTY SHERIFF'S OFFICE, AMMAR SHAKER/WIKIMEDIA COMMONS, (A) F. GALTON