Close relation between quantum interference in molecular conductance and diradical existence
Yuta Tsuji, Roald Hoffmann, Mikkel Strange, and Gemma C. Solomon
It might seem that the existence of a dramatic diminution in molecular conductance across a hydrocarbon (quantum interference, QI) would be unrelated to the existence of an important class of organic molecules with two electrons in two orbitals, diradicals. However, if you add two carbons to a planar π-electron hydrocarbon, you get a diradical if and only if there is a QI feature in conductance when two electrodes are attached to the molecule at the same sites. When you remove the two carbons where the electrodes are attached, you also generate a diradical. The connection, first empirically observed, is proven. Two kinds of diradicals, with different ground state spin consequences, are also easily distinguished by the relationship. (See pp. E413–E419.)
Attention promotes episodic encoding by stabilizing hippocampal representations
Mariam Aly and Nicholas B. Turk-Browne
Why does the brain store memories of some things but not others? At a cognitive level, attention provides an explanation: What aspects of an experience we focus on determines what information is perceived and available for encoding. But the mechanism of how attention alters memory formation at the neural level is unknown. With high-resolution neuroimaging, we show that attention alters the state of a key brain structure for memory, the hippocampus, and that the extent to which this occurs predicts whether the attended information gets stored in memory. The dependence of hippocampal encoding on attentional states reveals the broad involvement of the hippocampus in multiple cognitive processes, and highlights that the workings of the hippocampus are under our control. (See pp. E420–E429.)
Identification of a mammalian glycerol-3-phosphate phosphatase: Role in metabolism and signaling in pancreatic β-cells and hepatocytes
Yves Mugabo, Shangang Zhao, Annegrit Seifried, Sari Gezzar, Anfal Al-Mass, Dongwei Zhang, Julien Lamontagne, Camille Attane, Pegah Poursharifi, José Iglesias, Erik Joly, Marie-Line Peyot, Antje Gohla, S. R. Murthy Madiraju, and Marc Prentki
Glycerol-3-phosphate (Gro3P) lies at the crossroads of glucose, lipid, and energy metabolism in mammalian cells and is thought to participate in glycolysis or in gluconeogenesis, lipid synthesis, and Gro3P electron transfer shuttle to mitochondria. We now report a previously unidentified pathway of Gro3P metabolism in mammalian cells with the identification of Gro3P phosphatase (G3PP) that can directly hydrolyze Gro3P to glycerol. We observed that G3PP expression level controls glycolysis, lipogenesis, lipolysis, fatty acid oxidation, cellular redox, and mitochondrial energy metabolism in β-cells and hepatocytes, as well as glucose-induced insulin secretion and the response to metabolic stress in β-cells, and in gluconeogenesis in hepatocytes. G3PP is a previously unknown player in metabolic regulation and signaling and offers a potential target for cardiometabolic disorders. (See pp. E430–E439.)
Distance from sub-Saharan Africa predicts mutational load in diverse human genomes
Brenna M. Henn, Laura R. Botigué, Stephan Peischl, Isabelle Dupanloup, Mikhail Lipatov, Brian K. Maples, Alicia R. Martin, Shaila Musharoff, Howard Cann, Michael P. Snyder, Laurent Excoffier, Jeffrey M. Kidd, and Carlos D. Bustamante
Human genomes carry hundreds of mutations that are predicted to be deleterious in some environments, potentially affecting the health or fitness of an individual. We characterize the distribution of deleterious mutations among diverse human populations, modeled under different selection coefficients and dominance parameters. Using a new dataset of diverse human genomes from seven different populations, we use spatially explicit simulations to reveal that classes of deleterious alleles have very different patterns across populations, reflecting the interaction between genetic drift and purifying selection. We show that there is a strong signal of purifying selection at conserved genomic positions within African populations, but most predicted deleterious mutations have evolved as if they were neutral during the expansion out of Africa. (See pp. E440–E449.)
Versatile strategy for controlling the specificity and activity of engineered T cells
Jennifer S. Y. Ma, Ji Young Kim, Stephanie A. Kazane, Sei-hyun Choi, Hwa Young Yun, Min Soo Kim, David T. Rodgers, Holly M. Pugh, Oded Singer, Sophie B. Sun, Bryan R. Fonslow, James N. Kochenderfer, Timothy M. Wright, Peter G. Schultz, Travis S. Young, Chan Hyuk Kim, and Yu Cao
Despite the unprecedented antileukemic response demonstrated in recent clinical trials, the inability to control the potent chimeric antigen receptor (CAR)—T-cell activity has resulted in several serious adverse incidents. Herein, we demonstrate that a switch-mediated CAR-T approach enables the titration of engineered T-cell antitumor activity, which was observed to be highly advantageous in reducing treatment-related toxicities in vivo. Moreover, we show that the use of optimized antibody-based switches readily enables a single CAR construct to target different antigens, indicating its potential application to treat tumor escape variants and heterogeneous tumors expressing distinct tumor antigens. Our data support the safe application of this potent immune cell-based therapy to target other types of cancer, including solid tumors, as well as nononcology indications. (See pp. E450–E458.)
Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies
David T. Rodgers, Magdalena Mazagova, Eric N. Hampton, Yu Cao, Nitya S. Ramadoss, Ian R. Hardy, Andrew Schulman, Juanjuan Du, Feng Wang, Oded Singer, Jennifer Ma, Vanessa Nunez, Jiayin Shen, Ashley K. Woods, Timothy M. Wright, Peter G. Schultz, Chan Hyuk Kim, and Travis S. Young
Chimeric antigen receptor T (CAR-T) cell therapy has produced promising results in clinical trials but has been challenged by the inability to control engineered cells once infused into the patient. Here we present a generalizable method of controlling CAR-T cells using peptide-engrafted antibody-based molecular switches that act as a bridge between the target cell and CAR-T cell. We show that switches specific for CD19 govern the activity, tissue-homing, cytokine release, and phenotype of switchable CAR-T cells in a dose-titratable manner using xenograft mouse models of B-cell leukemia. We expect that this method of tuning CAR-T cell responses will provide improved safety and versatility of CAR–T-cell therapy in the clinic. (See pp. E459–E468.)
Transcriptional profiles of supragranular-enriched genes associate with corticocortical network architecture in the human brain
Fenna M. Krienen, B. T. Thomas Yeo, Tian Ge, Randy L. Buckner, and Chet C. Sherwood
The human cerebral cortex is patterned with distributed networks that connect disproportionately enlarged association zones across the frontal, temporal, and parietal lobes. We asked herein whether the expansion of the cortical surface, with the concomitant emergence of long-range connectivity networks, might be accompanied by changes to the underlying molecular architecture. We focused on the supragranular layers of the cortex, where most corticocortical connections originate. Genes that are enriched in supragranular layers in the human cerebral cortex relative to mouse are expressed in a topography that reflects broad cortical classes (sensory/motor, paralimbic, associational) and their associated network properties. Molecular innovations of upper cortical layers may be an important component in the evolution of increased long-range corticocortical projections. (See pp. E469–E478.)
Neuregulin1 displayed on motor axons regulates terminal Schwann cell-mediated synapse elimination at developing neuromuscular junctions
Young il Lee, Yue Li, Michelle Mikesh, Ian Smith, Klaus-Armin Nave, Markus H. Schwab, and Wesley J. Thompson
Refinement of synaptic connections occurs throughout the nervous system and is essential for its proper function. Significant gaps remain in our understanding of the mechanisms that mediate pruning of synaptic connections—a form of synaptic plasticity known as synapse elimination. Recently it has become clear there is significant glial cell involvement. The present study of the rodent neuromuscular junction addresses two outstanding questions involving this glial involvement: which molecules determine the Schwann cell behavior present during pruning, and whether these behaviors actually alter synaptic structure. Our findings identify axon-tethered neuregulin1 as a molecular determinant for Schwann cell-driven neuromuscular synaptic plasticity. (See pp. E479–E487.)