Molecular cartography of the human skin surface in 3D
Amina Bouslimani, Carla Porto, Christopher M. Rath, Mingxun Wang, Yurong Guo, Antonio Gonzalez, Donna Berg-Lyon, Gail Ackermann, Gitte Julie Moeller Christensen, Teruaki Nakatsuji, Lingjuan Zhang, Andrew W. Borkowski, Michael J. Meehan, Kathleen Dorrestein, Richard L. Gallo, Nuno Bandeira, Rob Knight, Theodore Alexandrov, and Pieter C. Dorrestein
The paper (pp. E2120–E2129) describes the implementation of an approach to study the chemical makeup of human skin surface and correlate it to the microbes that live in the skin. We provide the translation of molecular information in high-spatial resolution 3D to understand the body distribution of skin molecules and bacteria. In addition, we use integrative analysis to interpret, at a molecular level, the large scale of data obtained from human skin samples. Correlations between molecules and microbes can be obtained to further gain insights into the chemical milieu in which these different microbial communities live.
FtsZ filament capping by MciZ, a developmental regulator of bacterial division
Alexandre W. Bisson-Filho, Karen F. Discola, Patrícia Castellen, Valdir Blasios, Alexandre Martins, Maurício L. Sforça, Wanius Garcia, Ana Carolina M. Zeri, Harold P. Erickson, Andréa Dessen, and Frederico J. Gueiros-Filho
Division of bacteria is executed by a contractile ring whose cytoskeletal framework is FtsZ (filamentation temperature-sensitive Z), a protein evolutionarily related to eukaryotic tubulin. The FtsZ ring is made of filaments of head-to-tail FtsZ subunits but its architecture and the rules governing its assembly are still poorly known. Here (pp. E2130–E2138) we show that MciZ, an inhibitor of FtsZ ring formation, functions by capping the minus end of FtsZ filaments. Capping by MciZ makes FtsZ filaments shorter than normal, likely by blocking filament annealing; this represents fundamental information to understand how FtsZ filaments grow and shrink, and attain their normal size. The powerful inhibition of Z-ring assembly by MciZ also suggests that an FtsZ ring cannot form from filaments smaller than a certain size.
Induced transcription and stability of CELF2 mRNA drives widespread alternative splicing during T-cell signaling
Michael J. Mallory, Samuel J. Allon, Jinsong Qiu, Matthew R. Gazzara, Iulia Tapescu, Nicole M. Martinez, FuXiang-Dong, and Kristen W. Lynch
Alternative splicing is a key mechanism for gene regulation that is regulated in response to developmental and antigen signaling in T cells. However, the extent and mechanisms of regulated splicing, particularly during T-cell development, have not been well characterized. Here (pp. E2139–E2148) we demonstrate that expression of the RNA binding protein CELF2 (CUGBP, Elav-like family member 2) is increased in response to T-cell signaling through the combined regulation of transcription and mRNA stability. This increase in CELF2 expression drives widespread changes in mRNA splicing in cultured T cells and correlates with changes in mRNA splicing during T-cell development. These results provide unprecedented insight into the regulation of splicing during thymic development, and reveal an important biologic role of CELF2 in human T cells.
Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs
Shuo Wang, Christos Patsis, and Antonis E. Koromilas
Stat1 functions as a tumor suppressor by inhibiting cell proliferation and mediating antitumor immune responses. Thus, Stat1 is thought to be a suitable target for the implementation of effective antitumor therapies. However, recent findings have shown that Stat1 can mediate resistance to antitumor drugs through mechanisms that are not well understood. Herein (pp. E2149–E2155), we demonstrate the ability of Stat1 to induce phosphoinositide 3-kinase γ (PI3Kγ) signaling and inhibit general protein synthesis, which results in the translation of select mRNAs encoding for proteins that inhibit cell proliferation or render cells increasingly resistant to antitumor drugs. Our work may result in the design of therapies that disarm the prosurvival function of Stat1 in tumors without compromising its ability to mount an effective antitumor immune response.
Molecular recognition of human ephrinB2 cell surface receptor by an emergent African henipavirus
Benhur Lee, Olivier Pernet, Asim A. Ahmed, Antra Zeltina, Shannon M. Beaty, and Thomas A. Bowden
African henipaviruses (HNVs) may be responsible for the misdiagnosis of encephalitis-associated outbreaks of malaria. Host-cell infection by an African HNV relies on the initial interaction between a virally encoded surface glycoprotein and a host-cell receptor. Here (pp. E2156–E2165), we provide a structural description of how a bat-borne Ghanaian HNV hijacks human ephrinB2 to facilitate cross-species transmission. We demonstrate that, although the Ghanian HNV is sequence dissimilar (<30% sequence identity) and displays a receptor-binding scaffold that differs significantly in structure to pathogenic HNV relatives from Asia, it adopts a nearly identical primary ephrinB2 binding mode. These data provide a molecular-level explanation for previously observed spillover of African HNVs into human populations.
Mechanically-driven phase separation in a growing bacterial colony
Pushpita Ghosh, Jagannath Mondal, Eshel Ben-Jacob, and Herbert Levine
Bacteria self-organize into a dense multicellular community known as a biofilm, in which cells are embedded in self-secreted extracellular polymeric substances (EPSs). A number of processes can contribute to spatial heterogeneity in a growing biofilm; among them, the effect of macromolecular crowding enhanced by the EPSs has largely remained unexplored. To understand the effect of macromolecular crowding in spontaneous spatial organization, we develop (pp. E2166–E2173) a computational model to investigate the explicit role of mechanical interactions in driving the collective behavior of bacterial cells in the presence of EPS particles in a colony growing on a solid substrate. Our findings demonstrate that an entropy-driven depletion interaction between bacteria and EPSs can induce significant phase separation and spatial heterogeneity in a biofilm.
Mitofusin 2 ablation increases endoplasmic reticulum–mitochondria coupling
Riccardo Filadi, Elisa Greotti, Gabriele Turacchio, Alberto Luini, Tullio Pozzan, and Paola Pizzo
The privileged interrelationship between mitochondria and the endoplasmic reticulum (ER) plays a key role in a variety of physiological functions, from lipid metabolism to Ca2+ signalling, and its modulation influences apoptotic susceptibility, mitophagy, and cellular bioenergetics. Among the several proteins known to influence ER–mitochondria interactions, mitofusin 2 (Mfn2) has been proposed to form a physical tether. In this study (pp. E2174–E2181), we demonstrate that Mfn2 instead works as an ER–mitochondria tethering antagonist preventing an excessive, potentially toxic, proximity between the two organelles. Cells in which Mfn2 is ablated or reduced have an increased number of ER–mitochondria close contacts, potentiated Ca2+ transfer between the two organelles, and greater sensitivity to cell-death stimuli that implies mitochondria Ca2+ overload toxicity.
Metatranscriptome analyses indicate resource partitioning between diatoms in the field
Harriet Alexander, Bethany D. Jenkins, Tatiana A. Rynearson, and Sonya T. Dyhrman
Nutrient availability plays a central role in driving the activities and large-scale distributions of phytoplankton, yet there are still fundamental gaps in understanding how phytoplankton metabolize nutrients, like nitrogen (N) and phosphorus (P), and how this metabolic potential is modulated in field populations. Here (pp. E2182–E2190), we show that cooccurring diatoms in a dynamic coastal marine system have apparent differences in their metabolic capacity to use N and P. Further, bioinformatic approaches enabled the identification and species-specific comparison of resource-responsive (RR) genes. Variation of these RR gene sets highlights the disparate transcriptional responses these species have to the same environment, which likely reflects the role resource partitioning has in facilitating the vast diversity of the phytoplankton.
Convergent evolution toward an improved growth rate and a reduced resistance range in Prochlorococcus strains resistant to phage
Sarit Avrani and Debbie Lindell
High abundances of the important primary producing cyanobacterium, Prochlorococcus, and its parasitic phages, inhabit vast expanses of the world’s oceans. Their coexistence is facilitated by genetic diversity that has led to an assortment of Prochlorococcus subpopulations with differences in susceptibility and resistance to co-occurring phages. Here (pp. E2191–E2200), we investigated the fate of recently emerging phage-resistant Prochlorococcus strains. We found that genetic diversification increases, as these strains evolve toward an improved growth rate and reduced resistance range, leading to phenotypes intermediary between the original susceptible and initial resistant strains. These findings suggest a continual increase in the combinatorial interactions between Prochlorococcus and its phages and that the oceans are populated with rapidly growing Prochlorococcus cells with varying degrees of phage resistance.
Increased size and cellularity of advanced atherosclerotic lesions in mice with endothelial overexpression of the human TRPC3 channel
Kathryn B. Smedlund, Lutz Birnbaumer, and Guillermo Vazquez
Atherosclerosis is a chronic disease of the arterial wall with a dominant inflammatory component. Endothelial cell inflammation and recruitment of circulating monocytes are critical processes during atherosclerotic lesion progression. In this manuscript (pp. E2201–E2206), we generated a mouse model of atherosclerosis with endothelial-specific overexpression of TRPC3, a calcium permeable channel, and provide evidence indicating that augmented expression/function of TRPC3 supports, in vivo, endothelial inflammation and increased macrophage infiltration, resulting in atherosclerotic lesions of bigger size and complexity. These findings support the notion that endothelial TRPC3 channels may represent attractive targets for development of novel therapeutic strategies in the treatment of atherosclerosis.
HCN channels enhance spike phase coherence and regulate the phase of spikes and LFPs in the theta-frequency range
Manisha Sinha and Rishikesh Narayanan
The impact of the pacemaking hyperpolarization-activated cyclic-nucleotide–gated (HCN) channels on local field potentials (LFP) has not been analyzed. Here (pp. E2207–E2216), employing a neuropil of several morphologically precise hippocampal neuronal models that received systematically randomized rhythmic synaptic inputs, we demonstrate that HCN channels alter the phase, but not the amplitude, of LFPs. Further, it is known that the spike timings of individual neurons follow the beat of the LFPs and fire at precise phases of the LFP beat. We demonstrate that the presence of HCN channels alters this phase and enhances the precision to which the spikes follow the LFP beat. These results unveil several important roles for HCN channels, extending their regulatory potential beyond single-neuron physiology.
Glycolytic flux controls d-serine synthesis through glyceraldehyde-3-phosphate dehydrogenase in astrocytes
Masataka Suzuki, Jumpei Sasabe, Yurika Miyoshi, Kanako Kuwasako, Yutaka Muto, Kenji Hamase, Masaaki Matsuoka, Nobuaki Imanishi, and Sadakazu Aiso
Neurons require enormous energy to maintain continuous neurotransmission. To meet this requirement, astrocytes support neurons by balancing glycolytic flux with the synaptic level of an excitatory neurotransmitter, glutamate. But to control NMDA-subtype glutamate receptors, regulation of a coagonist, d-serine, as well as of glutamate, is crucial. Here (pp. E2217–E2224) we report that a glycolytic enzyme regulates d-serine synthesis as an indicator of glycolytic activity in astrocytes. This study shows how glutamatergic neurotransmission accommodates to changing energy circumstances through the coagonist.
Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans
Christopher J. Morris, Jessica N. Yang, Joanna I. Garcia, Samantha Myers, Isadora Bozzi, Wei Wang, Orfeu M. Buxton, Steven A. Shea, and Frank A. J. L. Scheer
It is established that glucose tolerance decreases from the morning to the evening, and that shift work is a risk factor for diabetes. However, the relative importance of the endogenous circadian system, the behavioral cycle (including the sleep/wake and fasting/feeding cycles), and circadian misalignment on glucose tolerance is unclear. We show (pp. E2225–E2234) that the magnitude of the effect of the endogenous circadian system on glucose tolerance and on pancreatic β-cell function was much larger than that of the behavioral cycle in causing the decrease in glucose tolerance from morning to evening. Also, independent from circadian phase and the behavioral cycle, circadian misalignment resulting from simulated night work lowered glucose tolerance—without diminishing effects upon repeated exposure—with direct relevance for shift workers.
Lag threads organize the brain’s intrinsic activity
Anish Mitra, Abraham Z. Snyder, Tyler Blazey, and Marcus E. Raichle
It is well known that slow intrinsic activity, as measured by resting-state fMRI in a variety of animals including humans, is organized into temporally synchronous networks. The question of whether intrinsic activity contains reproducible temporal sequences has received far less attention. We have previously shown that human resting-state fMRI contains a highly reproducible lag structure. Here (pp. E2235–E2244), we demonstrate that this lag structure is of high dimensionality and consists of multiple highly reproducible temporal sequences, which we term “lag threads.” Moreover, we demonstrate that the well-known zero-lag temporal correlation structure of intrinsic activity emerges as a consequence of lag structure. Thus, lag threads may represent a fundamental and previously unsuspected level of organization in resting-state activity.
Small molecule-induced oxidation of protein disulfide isomerase is neuroprotective
Anna Kaplan, Michael M. Gaschler, Denise E. Dunn, Ryan Colligan, Lewis M. Brown, Arthur G. Palmer III, Donald C. Lo, and Brent R. Stockwell
Protein disulfide isomerase (PDI) is a chaperone protein in the endoplasmic reticulum. It is up-regulated in mouse models of, and brains of patients with, neurological protein folding diseases. Irreversible inhibition of PDI activity by the small molecule 16F16 results in protection in cell and organotypic brain slice culture models of Huntington disease. Here (pp. E2245–E2252), we identified lead optimized compound (LOC)14 as a nanomolar, reversible inhibitor of PDI that protects PC12 cells and medium spiny neurons from the toxic mutant huntingtin protein. LOC14 has improved potency compared with 16F16 and displays favorable pharmaceutical properties, making it a suitable compound to evaluate the therapeutic potential of inhibiting PDI in multiple disease models.
Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury
Youn Wook Chung, Claudia Lagranha, Yong Chen, Junhui Sun, Guang Tong, Steven C. Hockman, Faiyaz Ahmad, Shervin G. Esfahani, Dahae H. Bae, Nazari Polidovitch, Jian Wu, Dong Keun Rhee, Beom Seob Lee, Marjan Gucek, Mathew P. Daniels, Christine A. Brantner, Peter H. Backx, Elizabeth Murphy, and Vincent C. Manganiello
By catalyzing the destruction of cAMP and cGMP, cyclic nucleotide phosphodiesterases (PDEs) regulate their intracellular concentrations and biological actions. Eleven distinct gene families (PDE1–PDE11) define the PDE superfamily. Most families contain several PDE genes. Two separate but related genes generate PDE3 subfamilies PDE3A and PDE3B. Although inhibition of PDE3 protects rodent heart against ischemia/reperfusion (I/R) injury, the specific PDE3 isoform involved is undetermined. Using PDE3A- and PDE3B-KO mice, we report (pp. E2253–E2262) that deletion of PDE3B, but not PDE3A, protected mouse heart from I/R injury in vivo and in vitro, via cAMP-induced preconditioning. To our knowledge, our study is the first to define a role for PDE3B in cardioprotection against I/R injury and suggests PDE3B as a target for cardiovascular therapies.