Inactivation of TNF signaling by rationally designed dominant-negative TNF variants

Tumor necrosis factor (TNF) is a key regulator of inflammatory responses and has been implicated in many pathological conditions. We used structure-based design to engineer variant TNF proteins that rapidly form heterotrimers with native TNF to give complexes that neither bind to nor stimulate signaling through TNF receptors. Thus, TNF is inactivated by sequestration. Dominant-negative TNFs represent a possible approach to anti-inflammatory biotherapeutics, and experiments in animal models show that the strategy can attenuate TNF-mediated pathology. Similar rational design could be used to engineer inhibitors of additional TNF superfamily cytokines as well as other multimeric ligands.     

Molecular hydrogen as an energy source for Helicobacter pylori

The gastric pathogen Helicobacter pylori is known to be able to use molecular hydrogen as a respiratory substrate when grown in the laboratory. We found that hydrogen is available in the gastric mucosa of mice and that its use greatly increased the stomach colonization by H. pylori. Hydrogenase activity in H. pylori is constitutive but increased fivefold upon incubation with hydrogen. Hydrogen concentrations measured in the stomachs of live mice were found to be 10 to 50 times as high as the H. pylori affinity for hydrogen. A hydrogenase mutant strain is much less efficient in its colonization of mice. Therefore, hydrogen present in animals as a consequence of normal colonic flora is an energy-yielding substrate that can facilitate the maintenance of a pathogenic bacterium.     

High-accuracy ab initio rotation-vibration transitions for water

The spectrum of water vapor is of fundamental importance for a variety of processes, including the absorption and retention of sunlight in Earth's atmosphere. Therefore, there has long been an urgent need for a robust and accurate predictive model for this spectrum. In our work on the high-resolution spectrum of water, we report first-principles calculations that approach experimental accuracy. To achieve this, we performed exceptionally large electronic structure calculations and considered a variety of effects, including quantum electrodynamics, which have routinely been neglected in studies of small many-electron molecules. The high accuracy of the resulting ab initio procedure is demonstrated for the main isotopomers of water.     

Grasping primate origins

The evolutionary history that led to Eocene-and-later primates of modern aspect (Euprimates) has been uncertain. We describe a skeleton of Paleocene plesiadapiform Carpolestes simpsoni that includes most of the skull and many postcranial bones. Phylogenetic analyses indicate that Carpolestidae are closely related to Euprimates. C. simpsoni had long fingers and an opposable hallux with a nail. It lacked orbital convergence and an ankle specialized for leaping. We infer that the ancestor of Euprimates was primitively an arboreal grasper adapted for terminal branch feeding rather than a specialized leaper or visually directed predator.     

Increase in the Asian southwest monsoon during the past four centuries

Climate reconstructions reveal unprecedented warming in the past century; however, little is known about trends in aspects such as the monsoon. We reconstructed the monsoon winds for the past 1000 years using fossil Globigerina bulloides abundance in box cores from the Arabian Sea and found that monsoon wind strength increased during the past four centuries as the Northern Hemisphere warmed. We infer that the observed link between Eurasian snow cover and the southwest monsoon persists on a centennial scale. Alternatively, the forcing implicated in the warming trend (volcanic aerosols, solar output, and greenhouse gases) may directly affect the monsoon. Either interpretation is consistent with the hypothesis that the southwest monsoon strength will increase during the coming century as greenhouse gas concentrations continue to rise and northern latitudes continue to warm.     

White fat progenitor cells reside in the adipose vasculature

White adipose (fat) tissues regulate metabolism, reproduction, and life span. Adipocytes form throughout life, with the most marked expansion of the lineage occurring during the postnatal period. Adipocytes develop in coordination with the vasculature, but the identity and location of white adipocyte progenitor cells in vivo are unknown. We used genetically marked mice to isolate proliferating and renewing adipogenic progenitors. We found that most adipocytes descend from a pool of these proliferating progenitors that are already committed, either prenatally or early in postnatal life. These progenitors reside in the mural cell compartment of the adipose vasculature, but not in the vasculature of other tissues. Thus, the adipose vasculature appears to function as a progenitor niche and may provide signals for adipocyte development.     

Anterior cingulate conflict monitoring and adjustments in control

Conflict monitoring by the anterior cingulate cortex (ACC) has been posited to signal a need for greater cognitive control, producing neural and behavioral adjustments. However, the very occurrence of behavioral adjustments after conflict has been questioned, along with suggestions that there is no direct evidence of ACC conflict-related activity predicting subsequent neural or behavioral adjustments in control. Using the Stroop color-naming task and controlling for repetition effects, we demonstrate that ACC conflict-related activity predicts both greater prefrontal cortex activity and adjustments in behavior, supporting a role of ACC conflict monitoring in the engagement of cognitive control.     

Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation

Phospholipase A(2)(PLA(2)) enzymes are considered the primary source of arachidonic acid for cyclooxygenase (COX)-mediated biosynthesis of prostaglandins. Here, we show that a distinct pathway exists in brain, where monoacylglycerol lipase (MAGL) hydrolyzes the endocannabinoid 2-arachidonoylglycerol to generate a major arachidonate precursor pool for neuroinflammatory prostaglandins. MAGL-disrupted animals show neuroprotection in a parkinsonian mouse model. These animals are spared the hemorrhaging caused by COX inhibitors in the gut, where prostaglandins are instead regulated by cytosolic PLA(2). These findings identify MAGL as a distinct metabolic node that couples endocannabinoid to prostaglandin signaling networks in the nervous system and suggest that inhibition of this enzyme may be a new and potentially safer way to suppress the proinflammatory cascades that underlie neurodegenerative disorders.