Declining vulnerability to river floods and the global benefits of adaptation
Brenden Jongman, Hessel C. Winsemius, Jeroen C. J. H. Aerts, Erin Coughlan de Perez, Maarten K. van Aalst, Wolfgang Kron, and Philip J. Ward
Understanding the vulnerability of societies around the world is crucial for understanding historical trends in flood risk and for producing accurate projections of fatalities and losses. We reproduced historical river flood occurrence using daily climate data for the period 1980–2010 and quantified the natural and socioeconomic contributions to flood risk trends. We show (pp. E2271–E2280) that the fatalities and losses as a share of the exposed population and gross domestic product are decreasing with rising income. We also show that there is a tendency of convergence in vulnerability levels between low- and high-income countries. Projections based on a wide range of climate change and socioeconomic development scenarios demonstrate that amplified adaptation efforts have the potential to largely contain losses from future floods.
Inferring epigenetic dynamics from kin correlations
Sahand Hormoz, Nicolas Desprat, and Boris I. Shraiman
Different cells in a clonal population can be in different phenotypic states, which persist for a few generations before switching to another state. Dynamics of switching between these states determines the extent of correlations between the phenotypes of related cells. Here (pp. E2281–E2289) we demonstrate—using ideas from statistical physics—that it is possible to infer simple stochastic dynamics along lineages from an instantaneous measurement of phenotypic correlations in a cell population with defined genealogy. The approach is validated using experimental observations on Pseudomonas aeruginosa colonies.
Sec17 can trigger fusion of trans-SNARE paired membranes without Sec18
Michael Zick, Amy Orr, Matthew L. Schwartz, Alexey J. Merz, and William T. Wickner
Intracellular membrane trafficking relies on SNARE proteins from apposed membranes to form trans-complexes. Sec18 (N-ethylmaleimide–sensitive factor; NSF) and its cochaperone Sec17 (soluble NSF attachment protein; α-SNAP) disassemble cis-SNARE complexes, liberating SNAREs for trans-complex assembly. We now describe an additional function of Sec17, its ability to trigger the fusion of trans-SNARE paired membranes. We propose (pp. E2290–E2297) a model in which Sec17 oligomerizes on trans-SNARE complexes, inserting apolar loops into the adjacent membranes. This precisely localized membrane interaction may disturb the lipid bilayer, lowering the energy barrier that prevents the two membranes from merging, and thereby facilitate fusion.
Highly polarized C-terminal transition state of the leucine-rich repeat domain of PP32 is governed by local stability
Thuy Phuong Dao, Ananya Majumdar, and Doug Barrick
Proteins fold to their native structure in significantly shorter timescales than expected for a random search mechanism. Rapid folding, which is likely to be important to optimize yield and avoid misfolded, aggregated states, has been proposed to result from specific folding pathways. However, mapping such pathways and understanding the principles by which they are selected remain central problems in protein science. Repeat proteins, containing tandem repeated structural units, greatly simplify folding studies. Here (pp. E2298–E2306), we exploit the linear architecture of a β-strand-containing leucine-rich repeat protein and discover that folding is highly polarized toward the C terminus. By measuring the energy distribution, we observe that polarization is guided by local stability.
The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo
Judith M. Neugebauer, Sunjong Kwon, Hyung-Seok Kim, Nathan Donley, Anup Tilak, Shailaja Sopory, and Jan L. Christian
Bone morphogenetic proteins (BMPs) are made as inactive precursor proteins that dimerize and are cleaved to generate a bioactive ligand along with prodomain fragments that lack signaling activity. BMP ligands signal as either homodimers, or as heterodimers that display significantly higher activity in vivo. Recombinant homodimeric BMP ligands are used clinically to stimulate bone healing, but this requires supraphysiological doses due to the short half-life of the implanted protein. The current studies (pp. E2307–E2316) demonstrate that properties intrinsic to the BMP4 prodomain contribute to the formation and activity of BMP homodimers and heterodimers in vivo. Understanding how the prodomain regulates the activity of the ligand when it is made in vivo may lead to changes in the way BMP ligands are used clinically.
Functional and mechanistic studies of XPC DNA-repair complex as transcriptional coactivator in embryonic stem cells
Claudia Cattoglio, Elisa T. Zhang, Ivan Grubisic, Kunitoshi Chiba, Yick W. Fong, and Robert Tjian
Because of their unique ability to self-renew and generate all cell lineages of an organism (pluripotency), embryonic stem cells represent a versatile model for developmental biology, and a promising avenue for regenerative medicine. Understanding the molecular mechanisms regulating self-renewal and pluripotency provides a productive path to effectively use embryonic stem cells, and to improve current methods for induction/differentiation of pluripotent stem cells and direct somatic cell reprogramming. This study (pp. E2317–E2326) provides novel insights into transcriptional regulation of the stem cell state by characterizing interactions between key transcription factors SOX2 and OCT4, and a recently identified, multifunctional, stem cell coactivator—the xeroderma pigmentosum, complementation group C DNA repair complex—to control pluripotency gene-expression networks.
During Drosophila disc regeneration, JAK/STAT coordinates cell proliferation with Dilp8-mediated developmental delay
Tomonori Katsuyama, Federico Comoglio, Makiko Seimiya, Erik Cabuy, and Renato Paro
The larval imaginal discs of the fruit fly are capable of fully regenerating mechanically damaged parts. Wound healing is initiated by the JNK signaling pathway. We followed the subsequent formation of the regenerating blastema by transcriptome profiling and identified the JAK/STAT pathway as a central regulatory node controlling local cellular and global physiological responses (pp. E2327–E2336). This signaling cascade induces, together with the Wingless pathway, proliferation of cells forming the blastema. However, JAK/STAT also up-regulates Drosophila insulin-like peptide 8 (Dilp8), a paracrine factor involved in organismal developmental delay, thereby allowing regenerative recovery.
Heightened potency of human pluripotent stem cell lines created by transient BMP4 exposure
Ying Yang, Katsuyuki Adachi, Megan A. Sheridan, Andrei P. Alexenko, Danny J. Schust, Laura C. Schulz, Toshihiko Ezashi, and R. Michael Roberts
Human ES cells (ESCs) and induced pluripotent stem cells (iPSCs) can differentiate along all the major cell lineages of the embryo proper, but there is evidence that they can also give rise to extraembryonic placental trophoblast. This observation is controversial because human ESCs (hESCs) are considered to arise from a part of the embryo that does not contribute to trophoblast. Here (pp. E2337–E2346), we describe stable, self-renewing stem cell lines derived from hESCs and iPSCs by brief exposure to bone morphogenetic protein 4 (BMP4) that appear poised to differentiate readily along all the main developmental cell lineages, including placental trophoblast. BMP4 signaling may thus play a role in the early embryo by establishing a cell state permissive for trophoblast development.
Periodic retinoic acid–STRA8 signaling intersects with periodic germ-cell competencies to regulate spermatogenesis
Tsutomu Endo, Katherine A. Romer, Ericka L. Anderson, Andrew E. Baltus, Dirk G. de Rooij, and David C. Page
As male sex cells mature into sperm, two pivotal transitions are spermatogonial differentiation (exit from the stem cell pool) and meiotic initiation. These transitions occur in physical proximity, with 8.6-d periodicity. We report (pp. E2347–E2356) that the gene Stra8, essential for meiotic initiation, also promotes (but is not required for) spermatogonial differentiation. Moreover, injected RA induces both transitions to occur precociously. We conclude that a periodic RA signal, acting instructively through the common target Stra8, coordinates these transitions. This RA signal intersects with two distinct windows of sex-cell competency, which both begin while RA levels are low; sex cells respond quickly to rising RA. These mechanisms help account for the elaborate organization of sperm production, and its prodigious output.
Hybrid apomicts trapped in the ecological niches of their sexual ancestors
Martin Mau, John T. Lovell, José M. Corral, Christiane Kiefer, Marcus A. Koch, Olawale M. Aliyu, and Timothy F. Sharbel
Ecological-niche differentiation in diploid sexual–polyploid asexual complexes has been observed within and among many taxa, yet the relative contributions of reproductive system and ploidy are not fully understood. Here, we assess niche characteristics of sexual diploid, apomictic (asexual) diploid, and triploid Boechera (Brassicaceae) lineages. We find strong evidence for widespread hybridization and, to a lesser degree, ploidy variation as factors that together overcome the adaptive disadvantages of apomictic (i.e., asexual) reproduction (pp. E2357–E2365). When controlling for ploidy, we find only modest evidence for putatively asexually driven ecological-niche divergence among reproductive systems, a finding that contradicts the well-supported patterns of geographic parthenogenesis.
Caenorhabditis elegans microRNAs of the let-7 family act in innate immune response circuits and confer robust developmental timing against pathogen stress
Zhiji Ren and Victor R. Ambros
Proper animal development requires the robust execution of cell fates under stressful conditions. In Caenorhabditis elegans, reciprocal interactions between heterochronic genes and the p38 innate immune pathway help to coordinate development with pathogen defense. Importantly, the robustness of developmental cell fate expression during infection depends on functional redundancy among genes encoding microRNAs (miRNAs) of the let-7 family. These findings (pp. E2366–E2375) underscore the importance of miRNA pathways in conferring robustness to developmental programs under stressful conditions and highlight roles for heterochronic genes not only as developmental timers but also as modulators of innate immune responses. The let-7 family miRNAs and p38 innate immune pathway are evolutionarily conserved; therefore, this study presents implications for similar integration of these two pathways in other animal systems.
NK cells require IL-28R for optimal in vivo activity
Fernando Souza-Fonseca-Guimaraes, Arabella Young, Deepak Mittal, Ludovic Martinet, Claudia Bruedigam, Kazuyoshi Takeda, Christopher E. Andoniou, Mariapia A. Degli-Esposti, Geoffrey R. Hill, and Mark J. Smyth
Natural killer (NK) cells are naturally circulating innate lymphocytes that sense altered cells, including pathogen-activated and early-transformed cells. The signals that prime the NK cell to respond are not completely understood, but cytokines, such as IL-12, IL-18, and type I interferon (IFN-αβ) from antigen-presenting cells, are appreciated to be key to NK cell effector functions in response to bacteria, viruses, and tumors. In this light, another class of IFN, IFN type III (IFN-λ), has been described that shares some common functions with IFN-αβ, but with a more restricted cellular expression. Here (pp. E2376–E2384), we demonstrate for the first time, to our knowledge, the ability of IFN-λ to directly regulate NK cell effector functions in vivo, alone and in the context of IFN-αβ.
Protection in antibody- and T cell-mediated autoimmune diseases by antiinflammatory IgG Fcs requires type II FcRs
Benjamin M. Fiebiger, Jad Maamary, Andrew Pincetic, and Jeffrey V. Ravetch
IgG molecules are capable of inducing pro- and antiinflammatory responses dependent on their fragment crystallizable domain (Fc) glycan composition. Antiinflammatory responses are specifically triggered upon Fc sialylation, which decreases the binding affinity for type I Fc receptors but enhances binding to type II Fc receptors such as SIGN-R1, CD23, or human DC-SIGN. Structural analyses revealed that sialylation induces conformational changes in the Fc portion, which is a prerequisite for the selective binding to type II Fc receptors. Here (pp. E2385–E2394) we generated an Fc variant, F241A, that mimics the conformational state of sialylated Fc. F241A, even when nonsialylated, mediated protection from autoantibody- and T cell-mediated inflammation in a type II Fc receptor-dependent manner.
Quantitative optical coherence tomography angiography of vascular abnormalities in the living human eye
Yali Jia, Steven T. Bailey, Thomas S. Hwang, Scott M. McClintic, Simon S. Gao, Mark E. Pennesi, Christina J. Flaxel, Andreas K. Lauer, David J. Wilson, Joachim Hornegger, James G. Fujimoto, and David Huang
Retinal vascular diseases are a leading cause of blindness. Optical coherence tomography (OCT) has become the standard imaging modality for evaluating fluid accumulation in these diseases and for guiding treatment. However, fluorescein angiography (FA) is still required for initial evaluation of retinal ischemia and choroidal neovascularization, which are not visible in conventional structural OCT. The limitations of FA include poor penetration of fluorescence through blood and pigment, inability to determine the depth of the pathology due to its two-dimensional nature, and some uncommon but potentially severe complications. As a noninvasive three-dimensional alternative, OCT angiography may be used in routine screening and monitoring to provide new information for clinical diagnosis and management (pp. E2395–E2402).
Olfactory receptor genes expressed in distinct lineages are sequestered in different nuclear compartments
Kyoung-hye Yoon, Tobias Ragoczy, Zhonghua Lu, Kunio Kondoh, Donghui Kuang, Mark Groudine, and Linda B. Buck
Odorants are detected in the mouse nose by 1,000 different odorant receptors (ORs) and 14 TAARs. Each olfactory sensory neuron (OSN) expresses one receptor allele. While ORs generate diverse odor perceptions, some TAARs appear to be involved in innate responses, raising questions about mechanisms that could segregate ORs and TAARs in functionally distinct OSN subsets. Here (pp. E2403–E2409), we identify two OSN subsets with different epithelial expression patterns that express different subgroups of TAARs rather than ORs. Our studies show that Taar and Olfr genes localize in different nuclear compartments, suggesting a physical substrate for their differential regulation. We further find that activation of a Taar allele is accompanied by its escape from peripheral repressive heterochromatin to a permissive interior chromatin environment.