bluuebunny/crossref_metadata_2025 huggingface dataset:
Inactivation of tumor‐specific CD8+ CTLs by tumor‐infiltrating tolerogenic dendritic cells
Authors: Harimoto Hirotomo , Shimizu Masumi , Nakagawa Yohko , Nakatsuka Katsuhisa , Wakabayashi Ayako , Sakamoto Choitsu , Takahashi Hidemi
Published: September 2013

Cancer immunosurveillance failure is largely attributed to the insufficient activation of tumor‐specific class I major histocompatibility complex (MHC) molecule (MHC‐I)‐restricted CD8+ cytotoxic T lymphocytes (CTLs). DEC‐205+ dendritic cells (DCs), having the ability to cross‐present, can present captured tumor antigens on MHC‐I alongside costimulatory molecules, inducing the priming and activation of tumor‐specific CD8+ CTLs. It has been suggested that reduced levels of costimulatory molecules on DCs may be a cause of impaired CTL induction and that some tumors may induce the downregulation of costimulatory molecules on tolerogenic DCs. To examine such possibilities, we established two distinct types of murine hepatoma cell lines, named Hepa1‐6‐1 and Hepa1‐6‐2 (derived from Hepa1‐6 cells), and confirmed that they display similar antigenicities, as well as identical surface expression of MHC‐I. We found that Hepa1‐6‐1 had the ability to grow continuously after subcutaneous implantation into syngeneic C57BL/6 mice and did not prime CD8+ CTLs. In contrast, Hepa1‐6‐2 cells, which display reduced levels of adhesion molecules, such as Intercellular Adhesion Molecule 1 (ICAM‐1), failed to grow in vivo and efficiently primed CTLs. Moreover, Hepa1‐6‐1‐derived factors, such as transforming growth factor (TGF)‐β1, vascular endothelial growth factor (VEGF) and α‐fetoprotein (AFP), converted CD11chigh MHC‐IIhigh DEC‐205+ DC subsets into tolerogenic cells, displaying downregulated costimulatory molecules and having impaired cross‐presenting capacities. These immunosuppressive tolerogenic DCs appeared to inhibit the induction of tumor‐specific CD8+ CTLs and suppress their cytotoxic functions within the tumor. Together, the findings presented here provide a new method of cancer immunotherapy using the selective suppression, depletion or alteration of immunosuppressive tolerogenic DCs within tumors.
Optimal conditions required for influenza A infection‐enhanced cross‐priming of CD8+ T cells specific to cell‐associated antigens
Authors: Wei Joe , Waithman Jason , Xiao Kun , Oveissi Sara , Chen Weisan
Published: September 2013

Dendritic cells can take up exogenous tumor antigens and present their antigenic epitopes to CD8+ T cells (TCD8+), a process called cross‐presentation. Cross‐presentation is especially important in antitumor immunity because tumor cells, although carrying tumor antigens, do not activate naive T cells efficiently because of a lack of co‐stimulatory molecules. Our group has recently shown that influenza A virus (IAV) infection of allogeneic cells lead to enhanced cross‐priming of TCD8+ specific to cellular antigens. To develop this into a potential vaccine strategy, in this study, we have systematically investigated the numbers of allogeneic cells infected by IAV, IAV doses and their infectious activity, the length of in vitro infection and other associated factors. We have defined the optimal immune‐enhancing conditions and we have also shown in vivo that such enhanced cross‐priming did lead to enhanced tumor protection. The knowledge should be useful for developing more robust cancer vaccine.
A map of cell type‐specific auxin responses
Authors: Bargmann Bastiaan O R , Vanneste Steffen , Krouk Gabriel , Nawy Tal , Efroni Idan , Shani Eilon , Choe Goh , Friml Jiří , Bergmann Dominique C , Estelle Mark , Birnbaum Kenneth D
Published: September 2013

In plants, changes in local auxin concentrations can trigger a range of developmental processes as distinct tissues respond differently to the same auxin stimulus. However, little is known about how auxin is interpreted by individual cell types. We performed a transcriptomic analysis of responses to auxin within four distinct tissues of the Arabidopsis thaliana root and demonstrate that different cell types show competence for discrete responses. The majority of auxin‐responsive genes displayed a spatial bias in their induction or repression. The novel data set was used to examine how auxin influences tissue‐specific transcriptional regulation of cell‐identity markers. Additionally, the data were used in combination with spatial expression maps of the root to plot a transcriptomic auxin‐response gradient across the apical and basal meristem. The readout revealed a strong correlation for thousands of genes between the relative response to auxin and expression along the longitudinal axis of the root. This data set and comparative analysis provide a transcriptome‐level spatial breakdown of the response to auxin within an organ where this hormone mediates many aspects of development.
Barriers to transmission of transcriptional noise in a c‐fos c‐jun pathway
Authors: Shah Khyati , Tyagi Sanjay
Published: September 2013

We explored how transcriptional noise propagates in gene‐regulatory pathways by studying the induction of two downstream genes by transcription factors c‐fos and c‐jun. They are produced for a brief period following serum stimulation of cells and then activate the promoters of their target genes by binding to them as heterodimers. We found that, even though they are coordinately expressed at the population level, in individual cells the expression of c‐fos and c‐jun is noisy and uncorrelated with each other. The expression of the downstream genes is also noisy, but there is little or no effect of the noise in the upstream genes on the expression of the downstream genes. The noise is not transmitted, because the number of heterodimers present in single cells is relatively invariant, and the induction of downstream genes is insensitive to the number of heterodimers in individual cells. Sequestration of promoters of the downstream genes within compact chromatin is a likely cause of this insensitivity. These barriers to the propagation and amplification of noise are likely to be commonplace in higher eukaryotes.
Vision and air flow combine to streamline flying honeybees
Authors: Taylor Gavin J. , Luu Tien , Ball David , Srinivasan Mandyam V.
Published: September 2013

Insects face the challenge of integrating multi-sensory information to control their flight. Here we study a ‘streamlining’ response in honeybees, whereby honeybees raise their abdomen to reduce drag. We find that this response, which was recently reported to be mediated by optic flow, is also strongly modulated by the presence of air flow simulating a head wind. The Johnston's organs in the antennae were found to play a role in the measurement of the air speed that is used to control the streamlining response. The response to a combination of visual motion and wind is complex and can be explained by a model that incorporates a non-linear combination of the two stimuli. The use of visual and mechanosensory cues increases the strength of the streamlining response when the stimuli are present concurrently. We propose this multisensory integration will make the response more robust to transient disturbances in either modality.
Self-management activities in diabetes care: a systematic review
Authors: Coyle Meaghan E. , Francis Karen , Chapman Ysanne
Published: September 2013

Objective
To identify the range of self-management activities people diagnosed with diabetes engage in to manage their disease, the frequency of use, and whether self-management practices change over time.

Methods
A systematic review of the literature was undertaken. Thirty-two studies identified through electronic databases met the inclusion criteria and were included in the review.

Results
The study found that people living with diabetes undertake regular self-management activities and that compliance with medication regimes is high. Adherence, however, varied with respect to blood glucose testing, diet, physical activity and foot care. Levels of physical activity were not found to change over time. Evidence suggests that some people with diabetes modify their self-management practices in response to factors such as holidays.

Conclusions
The review suggests that the majority of people with diabetes self-manage, although there is variation in adherence to key self-management activities. How self-management practices change over time and whether this impacts on health outcomes is an area for future research.

What is known about the topic?
Self-management is key to diabetes control; however, many papers have described adherence as variable. Although there is a growing body of knowledge on adherence to self-management strategies, the question of whether self-management practices change over time has not been explored.

What does this paper add?
This review found that adherence to medication regimes was highest of all self-management strategies, whereas considerable variation exists for self-monitoring of blood glucose, dietary changes, physical activity and foot care. The findings suggest that adherence varies under special circumstances; however, the question of whether self-management practices change over time remains unanswered.

What are the implications for practitioners?
Continued efforts are necessary to promote awareness of the importance of diabetes self-management and adherence to regular self-care.
Development of a Translation Standard to support the improvement of health literacy and provide consistent high-quality information
Authors: Michael Jaklina , Aylen Tracy , Ogrin Rajna
Published: September 2013

Australia has a high number of people from culturally and linguistically diverse (CALD) backgrounds whose primary language is not English. CALD population groups have comparatively lower levels of education and health literacy, and poorer health outcomes compared with the Australian-born population. The delivery of consumer health information to people from CALD backgrounds usually includes the use of translated resources. Unfortunately, the quality of translated resources available on health issues is highly variable and may impact efforts to address the disparities in health outcomes. Currently applied guides to translation focus on accuracy and literalness of the translation; however, for health translations, conveying meaning and incorporating culturally relevant information is essential. Minimum standards for developing translated resources are needed to provide an indication of quality for end users, including healthcare providers, the client and carer. This paper describes the development of a Translation Standard, led by a community nursing organisation in collaboration and consultation with CALD community members and peak community organisations in Melbourne, Australia. The Translation Standard includes 10 components that have been identified as necessary to ensure a minimum standard of translation that is of high quality and caters to the health literacy levels of the target audience.

What is known about the topic?
There are many people from CALD backgrounds who have worse health outcomes than people who are Australian born. There is a gap in guidance to health professionals on how to develop high-quality translations of consumer health information that consider culture and health literacy. Higher-quality translations are needed to better inform CALD groups about their health.

What does this paper add?
The description of a new Translation Standard to guide the development of culturally relevant consumer health translations, considering the cultural needs and health literacy level of the target audience.

What are the implications for practitioners?
The Translation Standard provides assurance to practitioners that any translation that has followed this Standard is of high quality and increases the likelihood that the target audience will find the information relevant and understandable. The Translation Standard can assist consumers to make more informed choices and decisions about their health. Future translations would benefit by using such a guide.
Melanoma follow up: time to generate the evidence
Authors: Carter Drew , Afzali Hossein Haji Ali , Street Jackie , Bessen Taryn , Neuhaus Susan
Published: September 2013

Research is needed into current melanoma follow-up practices and their implications for patients and society. We highlight the need and suggest a way forward.
Anti-Leishmanial Activity of Novel Homo- and Heteroleptic Bismuth(III) Thiocarboxylates
Authors: Andrews Philip C. , Junk Peter C. , Kedzierski Lukasz , Peiris Roshani M.
Published: September 2013

Two new thiocarboxylic acids, p-bromothiobenzoic BTA and thionaphthoic acid TNA, and five new homo- and heteroleptic bismuth(iii) compounds derived from thiocarboxylic acids: [Bi{S(C=O)C6H4Br}3] 1, [PhBi{S(C=O)C6H4Br}2] 2, [Bi{S(C=O)C10H7}3] 3, [PhBi{S(C=O)C10H7}2] 4, and [Ph2Bi{S(C=O)C10H7}] 5 were synthesised and fully characterised. The solid-state structure of complex [PhBi{S(C=O)C6H4Br}2] 2 was confirmed by X-ray crystallography. In complex 2, the two thiocarboxylate ligands are coordinated to the bismuth(iii) centre in a didentate fashion, forming a distorted octahedral geometry in which the phenyl group and the lone pair are oriented axial to the plane formed by the two thiocarboxylate ligands. Long-range Bi–S interactions (3.54 Å) link these monomeric units to form a one-dimensional polymer. These compounds, in addition to six previously synthesised complexes: [Bi{SC(=O)C6H5}3] 6, [PhBi{SC(=O)C6H5}2] 7, [Ph2Bi{SC(=O)C6H5}] 8, [Bi{SC(=O)C6H4NO2}3] 9, [PhBi{SC(=O)C6H4NO2}2] 10, and [PhBi{SC(=O)C6H4SO3}] 11, and the thiocarboxylic acids themselves, were assessed for their in vitro activity against Leishmania major promastigotes, and for general toxicity against human fibroblast cells. The thiocarboxylic acids, with the exception of thiobenzoic acid and sulfothiobenzoic acid, were toxic to both L. major parasites and the mammalian cells at high concentrations of 50–100 μM. The bismuth(iii) thiocarboxylate derivatives proved to be more active than the corresponding acids. Among these, the heteroleptic phenyl-substituted bismuth(iii) complexes 2, 4, 5, and 7 were highly active, showing IC50 (half maximal inhibitory concentration) values ranging from 0.39 to 4.69 μM, and a clear ligand dependence on activity.
Simulation estimates of annual yield and landed value for commercial penaeid prawns from a tropical seagrass habitat, Northern Queensland, Australia
Authors: Watson RA , Coles RG , Lee  Long WJ
Published: September 2013

Concern over the loss of seagrass habitat has prompted examination of the value of the production of
commercial prawns from such habitat. Cairns Harbour in tropical northern Queensland has 876 ha of
mixed seagrasses, dominated by Zostera capricorni and Halodule pinifolia, that support a multispecies
commercial penaeid prawn fishery offshore. Densities of juvenile commercial prawns estimated from
seagrass surveys were used to project estimates of annual yield and landed value, using a deterministic
simulation model employing lunar-period time steps. Estimates of the potential total annual yield
from Cairns Harbour seagrasses for the three major commercial prawn species (Penaeus esculentus,
P. semisulcatus and Metapenaeus endeavouri) were 178 t (range 81-316 t) year-1 with a landed value
of $A1.2 million (range $0.6 million to $2.2 million) year-1.
Dead fuel moisture research: 1991–2012
Authors: Matthews Stuart
Published: September 2013

The moisture content of dead fuels is an important determinant of many aspects of bushfire behaviour. Understanding the relationships of fuel moisture with weather, fuels and topography is useful for fire managers and models of fuel moisture are an integral component of fire behaviour models. This paper reviews research into dead fuel moisture for the period 1991–2012. The first half of the paper deals with experimental investigation of fuel moisture including an overview of the physical processes that affect fuel moisture, laboratory measurements used to quantify these processes, and field measurements of the dependence of fuel moisture on weather, vegetation structure and topography. The second set of topics examine models of fuel moisture including empirical models derived from field measurements, process-based models of vapour exchange and fuel energy and water balance, and experimental testing of both types of models. Remaining knowledge gaps and future research problems are also discussed. Opportunities for exciting research in the future exist for basic fuel moisture processes, developing new methods for applying models to fire behaviour prediction, and linking fuel moisture and weather forecast models.
Is fire severity increasing in the Sierra Nevada, California, USA?
Authors: Hanson Chad T. , Odion Dennis C.
Published: September 2013

Research in the Sierra Nevada range of California, USA, has provided conflicting results about current trends of high-severity fire. Previous studies have used only a portion of available fire severity data, or considered only a portion of the Sierra Nevada. Our goal was to investigate whether a trend in fire severity is occurring in Sierra Nevada conifer forests currently, using satellite imagery. We analysed all available fire severity data, 1984–2010, over the whole ecoregion and found no trend in proportion, area or patch size of high-severity fire. The rate of high-severity fire has been lower since 1984 than the estimated historical rate. Responses of fire behaviour to climate change and fire suppression may be more complex than assumed. A better understanding of spatiotemporal patterns in fire regimes is needed to predict future fire regimes and their biological effects. Mechanisms underlying the lack of an expected climate- and time since fire-related trend in high-severity fire need to be identified to help calibrate projections of future fire. The effects of climate change on high-severity fire extent may remain small compared with fire suppression. Management could shift from a focus on reducing extent or severity of fire in wildlands to protecting human communities from fire.
Near-optimal deterministic algorithms for volume computation via M-ellipsoids
Authors: Dadush Daniel , Vempala Santosh S.
Published: September 2013

We give a deterministic

algorithm for computing an M-ellipsoid of a convex body, matching a known lower bound. This leads to a nearly optimal deterministic algorithm for estimating the volume of a convex body and improved deterministic algorithms for fundamental lattice problems under general norms.
Inhibition of androgen receptor and β-catenin activity in prostate cancer
Authors: Lee Eugine , Madar Aviv , David Gregory , Garabedian Michael J. , DasGupta Ramanuj , Logan Susan K.
Published: September 2013

Androgen receptor (AR) is the major therapeutic target in aggressive prostate cancer. However, targeting AR alone can result in drug resistance and disease recurrence. Therefore, simultaneous targeting of multiple pathways could in principle be an effective approach to treating prostate cancer. Here we provide proof-of-concept that a small-molecule inhibitor of nuclear β-catenin activity (called C3) can inhibit both the AR and β-catenin–signaling pathways that are often misregulated in prostate cancer. Treatment with C3 ablated prostate cancer cell growth by disruption of both β-catenin/T-cell factor and β-catenin/AR protein interaction, reflecting the fact that T-cell factor and AR have overlapping binding sites on β-catenin. Given that AR interacts with, and is transcriptionally regulated by β-catenin, C3 treatment also resulted in decreased occupancy of β-catenin on the AR promoter and diminished AR and AR/β-catenin target gene expression. Interestingly, C3 treatment resulted in decreased AR binding to target genes accompanied by decreased recruitment of an AR and β-catenin cofactor, coactivator-associated arginine methyltransferase 1 (CARM1), providing insight into the unrecognized function of β-catenin in prostate cancer. Importantly, C3 inhibited tumor growth in an in vivo xenograft model and blocked renewal of bicalutamide-resistant sphere-forming cells, indicating the therapeutic potential of this approach.
Mechanism for activation of mutated epidermal growth factor receptors in lung cancer
Authors: Red Brewer Monica , Yun Cai-Hong , Lai Darson , Lemmon Mark A. , Eck Michael J. , Pao William
Published: September 2013

Significance

This is a unique report of receptor tyrosine kinase (RTK) “superacceptor” activity in which mutated EGFRs associated with lung cancer preferentially adopt the “acceptor” or “receiver” position in the presence of WT epidermal growth factor receptor (EGFR) or ErbB-2. The mechanism of superacceptor activity is defined by biochemical reconstitution data in combination with the first crystal structure of the L834R/T766M (L858R/T790M in alternate numbering) mutant EGFR kinase asymmetric dimer in an active conformation. The data imply that mutant/wild-type interactions play a key role in tumorigenesis as well as sensitivity of cells to various EGFR tyrosine kinase inhibitors, which could be therapeutically important. Notably, none of the previous studies involving mutated EGFR have studied the contribution of WT EGFRs in heterogeneous cell populations, although in nearly all instances wild-type EGFR alleles are preserved within EGFR mutant tumor cells.
Polyclonal hyper-IgE mouse model reveals mechanistic insights into antibody class switch recombination
Authors: Misaghi Shahram , Senger Kate , Sai Tao , Qu Yan , Sun Yonglian , Hamidzadeh Kajal , Nguyen Allen , Jin Zhaoyu , Zhou Meijuan , Yan Donghong , Lin Wei Yu , Lin Zhonghua , Lorenzo Maria N. , Sebrell Andrew , Ding Jiabing , Xu Min , Caplazi Patrick , Austin Cary D. , Balazs Mercedesz , Roose-Girma Merone , DeForge Laura , Warming Søren , Lee Wyne P. , Dixit Vishva M. , Zarrin Ali A.
Published: September 2013

Significance

Switch (S) regions are repetitive DNA sequences. During an immune response, one of several S regions recombine with a donor switch (Sμ) that is constitutively “on,” resulting in the production of antibodies with new functions. Donor Sμ is large and very repeat-rich, while another switch, Sε, is less than half its size with a low density of repeats. We replaced Sε with Sμ in mice. These mice switch to Sε more effectively and produce high levels of IgE antibodies implicated in asthma, making this a useful model to study disease. In addition, placing Sμ outside of its native context revealed insights into how switches work.
Broad-scale predictability of carbohydrates and exopolymers in Antarctic and Arctic sea ice
Authors: Underwood Graham J. C. , Aslam Shazia N. , Michel Christine , Niemi Andrea , Norman Louiza , Meiners Klaus M. , Laybourn-Parry Johanna , Paterson Harriet , Thomas David N.
Published: September 2013

Significance

Many marine microalgae and bacteria secrete polysaccharide gels (exopolymers) in response to environmental stresses, such as the freezing temperatures and salt concentrations that organisms experience when in sea ice. This study of sea ice cores from both the Antarctic and Arctic identified compelling relationships between ice thickness and salinity, algal biomass, and the concentration of polysaccharides in the ice. Knowing the first three parameters, we were able to predict the polysaccharide concentrations of the ice. This predictability is the first step in estimating the importance of such secretions to the organic carbon content of the millions of square kilometers of the ice-covered Arctic and Southern Oceans.
Ets-1 facilitates nuclear entry of NFAT proteins and their recruitment to the IL-2 promoter
Authors: Tsao Hsiao-Wei , Tai Tzong-Shyuan , Tseng William , Chang Hui-Hsin , Grenningloh Roland , Miaw Shi-Chuen , Ho I-Cheng
Published: September 2013

Significance

IL-2 plays critical roles in many immune responses. However, its transcriptional regulation is still not fully understood. Data described in this paper demonstrate that the transcriptional factor E26 transformation-specific sequence 1 (Ets-1) promotes the expression of IL-2 by nuclear factor of activated T-cells (NFAT)-dependent mechanisms. Nuclear Ets-1 synergizes with NFAT in the transcription of IL-2. Ets-1 is also translocated to the cytoplasm in response to calcium-induced signals and facilitates the release of NFAT from noncoding RNA repressor of NFAT complex, which traps NFAT in the cytoplasm. This paper not only advances our understanding of the transcriptional regulation of IL-2 but also depicts a unique mechanism of action of Ets-1.
Presynaptic gating of excitation in the dorsal raphe nucleus by GABA
Authors: Soiza-Reilly Mariano , Anderson Wayne B. , Vaughan Christopher W. , Commons Kathryn G.
Published: September 2013

Significance

Using a combination of approaches, a unique organization of the synaptic architecture of the dorsal raphe nucleus is revealed. That is, presynaptic GABAergic and glutamatergic boutons often pair with each other and converge on a single postsynaptic target, forming synaptic triads.
Phase behavior and critical activated dynamics of limited-valence DNA nanostars
Authors: Biffi Silvia , Cerbino Roberto , Bomboi Francesca , Paraboschi Elvezia Maria , Asselta Rosanna , Sciortino Francesco , Bellini Tommaso
Published: September 2013

Significance

At atomic and molecular levels, particles interact via the immutable laws of quantum mechanics, whereas at nanoscopic and microscopic levels, interactions between colloidal particles can be determined by human design. We exploit DNA self-assembly to produce nanoscopic particles with a controlled number of interacting terminations, providing the particles with valence. Experimental investigation of the collective behavior of such colloids shows that reducing the number of interacting sites results in a significant shrinkage of the gas–liquid coexistence region, with critical parameters decreasing as the valence is reduced. We also observe an unconventional dynamic behavior in the proximity of the critical point. Such findings are relevant to answer fundamental physics issues and potentially to determine the stability region of new DNA-based materials.
Seed shattering in a wild sorghum is conferred by a locus unrelated to domestication
Authors: Tang Haibao , Cuevas Hugo E. , Das Sayan , Sezen Uzay U. , Zhou Chengbo , Guo Hui , Goff Valorie H. , Ge Zhengxiang , Clemente Thomas E. , Paterson Andrew H.
Published: September 2013

Suppression of seed shattering was a key step during crop domestication that we have previously suggested to be convergent among independent cereal lineages. Positional, association, expression, and mutant complementation data all implicate a WRKY transcription factor,
SpWRKY
, in conferring shattering to a wild sorghum relative,
Sorghum propinquum
. We hypothesize that
SpWRKY
functions in a manner analogous to
Medicago
and
Arabidopsis
homologs that regulate cell wall biosynthesis genes, with low expression toward the end of floral development derepressing downstream cell wall biosynthesis genes to allow deposition of lignin that initiates the abscission zone in the seed–pedicel junction. The recent discovery of a YABBY locus that confers shattering within
Sorghum bicolor
and other cereals validated our prior hypothesis that some parallel domestication may have been convergent. Ironically, however, the shattering allele of
SpWRKY
appears to be recently evolved in
S. propinquum
and illustrates a case in which the genetic control of a trait in a wild relative fails to extrapolate even to closely related crops. Remarkably, the
SpWRKY
and YABBY loci lie only 300 kb apart and may have appeared to be a single genetic locus in some sorghum populations.
Regional and seasonal response of a West Nile virus vector to climate change
Authors: Morin Cory W. , Comrie Andrew C.
Published: September 2013

Significance

The potential impacts of climate change on human health are possibly large and not yet well understood, especially for vector-borne diseases. This study provides projections of how climate change may affect the population of a West Nile virus mosquito vector across the southern United States. Using a climate-driven mosquito population model, we simulate vector abundance under base and future climate. Under future climate, many locations exhibit a lengthening of the mosquito season with a decrease in summer populations. These impacts are not uniform geographically and vary with local temperature and precipitation conditions. The results imply that disease-transmission studies and vector-control programs must be targeted locally to maximize their effectiveness.
Supramolecular polymers with tunable topologies via hierarchical coordination-driven self-assembly and hydrogen bonding interfaces
Authors: Yan Xuzhou , Li Shijun , Pollock James Bryant , Cook Timothy R. , Chen Jianzhuang , Zhang Yanyan , Ji Xiaofan , Yu Yihua , Huang Feihe , Stang Peter J.
Published: September 2013

A powerful strategy to obtain complex supramolecular materials is the bottom-up construction of noncovalently bound materials by hierarchical self-assembly. This assembly process involves stepwise, uniform increases to the architectural complexity of a substrate, starting from discrete precursors and growing in dimensionality through controlled reactivity to a final product. Herein, two orthogonal processes are exploited: coordination-driven self-assembly and hydrogen bonding. The former relies on the predictable formation of metal–ligand bonds wherein the directionalities of the rigid precursors used determines the structural outcome. The latter uses 2-ureido-4-pyrimidinone interfaces that are structurally robust by virtue of the quadruple hydrogen bonding that can occur between subunits. By combining these two processes into a single system, it is possible to generate hierarchical materials that preserve the attractive tunability associated with discrete supramolecular coordination complexes. For instance, the synthesis of a one-dimensional chain comprising linked metalla-rhomboids is readily adapted to a 2D cross-linked hexagonal network by simply selecting a different metal acceptor precursor as an assembly component. The specific interactions between subunits, in this case platinum(II)-pyridyl bonds and the quadruple H-bonding of ureidopyrimidinone, are unchanged, establishing a unique strategy to obtain supramolecular polymers with marked topological differences with minimal synthetic redesign. In addition, the structural rigidity imposed by the inclusion of the platinum metallacycles serves to minimize the formation of cyclic oligomers, increasing the efficacy of formation and improving the properties of the resultant materials. Furthermore, this study taps the potential of organoplatinum(II) metallacycles in materials science.
Semisynthetic K
+
channels show that the constricted conformation of the selectivity filter is not the C-type inactivated state
Authors: Devaraneni Prasanna K. , Komarov Alexander G. , Costantino Corey A. , Devereaux Jordan J. , Matulef Kimberly , Valiyaveetil Francis I.
Published: September 2013

Significance

C-type inactivation is a conformational change at the selectivity filter, the ion binding site in a K
+
channel that renders it nonconductive. C-type inactivation is important in modulating cellular excitability. Previous studies have suggested a “constricted conformation” for the selectivity filter in the C-type inactivated state. Here, we use protein semisynthesis to introduce unnatural amino acids into the selectivity filter to block it from attaining the constricted conformation. We show that blocking the constricted conformation does not affect C-type inactivation. This study therefore suggests that the constricted conformation of the selectivity filter is not the C-type inactivated state in a K
+
channel. The study also highlights ways in which chemical synthesis can be used to manipulate large integral membrane proteins.
Thirst-dependent risk preferences in monkeys identify a primitive form of wealth
Authors: Yamada Hiroshi , Tymula Agnieszka , Louie Kenway , Glimcher Paul W.
Published: September 2013

Significance

We show that monkeys display similar risk preferences and rationality to those of humans, suggesting that despite concerns raised by earlier reports, they can serve as a model for human behavior. Standard experimental economic techniques have long allowed us to evaluate human risk attitudes, but we do not know how they relate to wealth levels, a critical variable in economic models. We find thirsty monkeys to be more risk averse and discuss implications for the role of wealth in human decision making.
Herbivore exploits orally secreted bacteria to suppress plant defenses
Authors: Chung Seung Ho , Rosa Cristina , Scully Erin D. , Peiffer Michelle , Tooker John F. , Hoover Kelli , Luthe Dawn S. , Felton Gary W.
Published: September 2013

Significance

The role of herbivore-associated microbes in modifying plant defenses has received scant attention. The Colorado potato beetle secretes symbiotic bacteria to wounds to manipulate plant defenses. The bacteria elicit salicylic acid (SA)-regulated defenses, and because SA signaling often negatively cross-talks with jasmonate signaling, plants are unable to fully activate their jasmonate-mediated resistance against the herbivore. From the plants’ perspective, they recognize herbivores not as such, but as microbial threats. We identified the specific bacteria from the beetle secretions and also characterized one of the bacterial effectors responsible for defense suppression. This clever, deceptive strategy for suppressing defenses has not been previously documented. Our results add a significant, unique concept to plant–insect interactions and how herbivores hijack plant defense signaling.
Hydrogen sulphide pathway contributes to the enhanced human platelet aggregation in hyperhomocysteinemia
Authors: d’Emmanuele di Villa Bianca Roberta , Mitidieri Emma , Di Minno Matteo N. D. , Kirkby Nicholas S. , Warner Timothy D. , Di Minno Giovanni , Cirino Giuseppe , Sorrentino Raffaella
Published: September 2013

Significance

Here we have demonstrated that the
l
-cysteine/H
2
S pathway contributes to the increased thrombotic events associated with hyperhomocysteinemia. In particular, by using platelets harvested from hyperhomocysteinemic patients, H
2
S generated within the platelets in turn activates the arachidonic acid cascade by phosphorylating phospholipase A
2
. This cascade of events primes the platelet that becomes more responsive (reactive) to endogenous stimuli. Finally, our study also suggests that H
2
S could represent a unique biomarker in patients affected with hyperhomocystinemia to define the susceptibility of a cardiovascular event driven by platelets.
Processing of meteoritic organic materials as a possible analog of early molecular evolution in planetary environments
Authors: Pizzarello Sandra , Davidowski Stephen K. , Holland Gregory P. , Williams Lynda B.
Published: September 2013

Significance

The data reported here suggest a far larger availability of meteoritic organic materials for planetary environments than previously assumed and that molecular evolution on the early Earth could have benefited from accretion of carbonaceous meteorites both directly with soluble compounds and, for a more protracted time, through alteration, processing, and release from their insoluble organic materials.
Coalescence and genetic diversity in sexual populations under selection
Authors: Neher Richard A. , Kessinger Taylor A. , Shraiman Boris I.
Published: September 2013

Significance

Many populations are genetically diverse, and genomes of individuals can differ at millions of loci, some of which affect the fitness of the organism. Although recombination will separate distant loci rapidly, nearby loci are inherited together and stay linked for long times. Selected alleles at linked loci influence each other’s dynamics in complex ways that are poorly understood. We present an analysis of the coupled histories of linked loci subject to selection and recombination and make predictions for the resulting genetic diversity. We show that simple patterns emerge from the collective effect of many loci and that these patterns can be used to infer evolutionary parameters from sequence data.
Regulation of GDF-11 and myostatin activity by GASP-1 and GASP-2
Authors: Lee Yun-Sil , Lee Se-Jin
Published: September 2013

Significance

The TGF-β family encompasses a large number of secreted proteins that regulate embryonic development and adult tissue homeostasis. Growth and differentiation factor (GDF) -associated serum protein-1 (GASP-1) and GASP-2 are related proteins capable of binding and inhibiting two family members, myostatin and GDF-11. Here, we show that mice genetically engineered to lack GASP-1 and/or GASP-2 exhibit muscle and skeletal phenotypes consistent with overactivity of myostatin and/or GDF-11. These studies also reveal the enormous complexity of this regulatory system in vivo and the delicate balance that must be maintained between signaling molecules and their inhibitory proteins for proper levels of signaling to be achieved.
Sensitive periods for the functional specialization of the neural system for human face processing
Authors: Röder Brigitte , Ley Pia , Shenoy Bhamy H. , Kekunnaya Ramesh , Bottari Davide
Published: September 2013

Significance

Sensitive periods in human functional brain development were tested in humans who had been blind from birth and whose sight was restored as long as 14 y later. In investigating this rare population, our data demonstrate a general principle of brain development: rather than being born with highly specialized neural systems (e.g., for specific object categories such as faces), the functional differentiation of neural circuits seems to depend on early (visual) experience involving a decrease in responsiveness to certain events during sensitive periods. The functional tuning of neural systems seems necessary to achieve high processing proficiency.
Protein domain mimetics as in vivo modulators of hypoxia-inducible factor signaling
Authors: Kushal Swati , Lao Brooke Bullock , Henchey Laura K. , Dubey Ramin , Mesallati Hanah , Traaseth Nathaniel J. , Olenyuk Bogdan Z. , Arora Paramjit S.
Published: September 2013

Significance

Protein–protein interactions are attractive targets for interfering with processes leading to disease states. Proteins often use folded domains or secondary structures to contact partner proteins. Synthetic molecules that mimic these domains could disrupt protein–protein contacts, thereby inhibiting formation of multiprotein complexes. This article describes protein domain mimetics (PDMs) that modulate interactions between two proteins that control expression of a multitude of genes under hypoxic environments, such as those found inside tumors. The low-oxygen conditions promote angiogenesis—process of formation of new blood vessels—that together with invasion and altered energy metabolism facilitates tumor growth. We find that the PDMs can control expression of target hypoxia-inducible genes in cell culture and reduce tumor burden in mice.
Functional and structural architecture of the human dorsal frontoparietal attention network
Authors: Szczepanski Sara M. , Pinsk Mark A. , Douglas Malia M. , Kastner Sabine , Saalmann Yuri B.
Published: September 2013

Significance

Everyday actions require us to represent attentional priorities in different reference frames. For example, to pick up a cup of coffee, we need to know where the cup is relative to our body, and where the handle is relative to the cup (i.e., body-centered and object-centered reference frames). Multiple brain areas in frontal and parietal cortex help process attentional priorities. Although these areas are commonly conceptualized as an attentional network, it is not clear what neural pathways connect these areas, nor the pathways’ functions. We demonstrate that two pathways link these areas in frontal and parietal cortex. The pathways help represent attentional priorities in different reference frames, enabling us to flexibly interact with objects in our environment.
Complete mitochondrial genome sequence of a Middle Pleistocene cave bear reconstructed from ultrashort DNA fragments
Authors: Dabney Jesse , Knapp Michael , Glocke Isabelle , Gansauge Marie-Theres , Weihmann Antje , Nickel Birgit , Valdiosera Cristina , García Nuria , Pääbo Svante , Arsuaga Juan-Luis , Meyer Matthias
Published: September 2013

Significance

Outside of permafrost, no contiguous DNA sequences have been generated from material older than ∼120,000 y. By improving our ability to sequence very short DNA fragments, we have recovered the mitochondrial genome sequence of a >300,000-y-old cave bear from Sima de los Huesos, a Spanish cave site that is famous for its rich collection of Middle Pleistocene human fossils. This finding demonstrates that DNA can survive for hundreds of thousands of years outside of permafrost and opens the prospect of making more samples from this time period accessible to genetic studies.
CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo
Authors: Zhu Jinge G. , Ochalek Justin T. , Kaufmann Martin , Jones Glenville , DeLuca Hector F.
Published: September 2013

Significance

Although the vitamin D endocrine system has been well defined and the enzyme responsible for converting 25-hydroxyvitamin D to the final hormone, 1α,25-dihydroxyvitamin D
3
, is well understood, the enzyme responsible for the conversion of vitamin D to the blood form, 25-hydroxyvitamin D, has not been clearly identified. A case has been made for vitamin D 25-hydroxylase CYP2R1 as the responsible enzyme, but proof is lacking. We have produced a null mutant mouse lacking CYP2R1. With this model, we have shown that CYP2R1 is the major but not exclusive 25-hydroxylase and that there remains another significant enzyme responsible for this step in vitamin D activation that has yet to be identified.
Protein hydrogen exchange at residue resolution by proteolytic fragmentation mass spectrometry analysis
Authors: Kan Zhong-Yuan , Walters Benjamin T. , Mayne Leland , Englander S. Walter
Published: September 2013

Significance

This paper shows how hydrogen exchange–mass spectrometry data can be deconvolved to obtain direct protein structural information at amino acid resolution. The solution to this problem has eluded prior efforts and is considered to be of fundamental importance for the rapidly expanding hydrogen exchange–MS field.
SnoN facilitates ALK1–Smad1/5 signaling during embryonic angiogenesis
Authors: Zhu Qingwei , Kim Yong Hwan , Wang Douglas , Oh S. Paul , Luo Kunxin
Published: September 2013

In endothelial cells, two type I receptors of the transforming growth factor β (TGF-β) family, ALK1 and ALK5, coordinate to regulate embryonic angiogenesis in response to BMP9/10 and TGF-β. Whereas TGF-β binds to and activates ALK5, leading to Smad2/3 phosphorylation and inhibition of endothelial cell proliferation and migration, BMP9/10 and TGF-β also bind to ALK1, resulting in the activation of Smad1/5. SnoN is a negative regulator of ALK5 signaling through the binding and repression of Smad2/3. Here we uncover a positive role of SnoN in enhancing Smad1/5 activation in endothelial cells to promote angiogenesis. Upon ligand binding, SnoN directly bound to ALK1 on the plasma membrane and facilitated the interaction between ALK1 and Smad1/5, enhancing Smad1/5 phosphorylation. Disruption of this SnoN–Smad interaction impaired Smad1/5 activation and up-regulated Smad2/3 activity. This resulted in defective angiogenesis and arteriovenous malformations, leading to embryonic lethality at E12.5. Thus, SnoN is essential for TGF-β/BMP9-dependent biological processes by its ability to both positively and negatively modulate the activities of Smad-dependent pathways.
Phosphatidylserine flipping enhances membrane curvature and negative charge required for vesicular transport
Authors: Xu Peng , Baldridge Ryan D. , Chi Richard J. , Burd Christopher G. , Graham Todd R.
Published: September 2013

Vesicle-mediated protein transport between organelles of the secretory and endocytic pathways is strongly influenced by the composition and organization of membrane lipids. In budding yeast, protein transport between the trans-Golgi network (TGN) and early endosome (EE) requires Drs2, a phospholipid translocase in the type IV P-type ATPase family. However, downstream effectors of Drs2 and specific phospholipid substrate requirements for protein transport in this pathway are unknown. Here, we show that the Arf GTPase-activating protein (ArfGAP) Gcs1 is a Drs2 effector that requires a variant of the ArfGAP lipid packing sensor (+ALPS) motif for localization to TGN/EE membranes. Drs2 increases membrane curvature and anionic phospholipid composition of the cytosolic leaflet, both of which are sensed by the +ALPS motif. Using mutant forms of Drs2 and the related protein Dnf1, which alter their ability to recognize phosphatidylserine, we show that translocation of this substrate to the cytosolic leaflet is essential for +ALPS binding and vesicular transport between the EE and the TGN.
aPKCλ controls epidermal homeostasis and stem cell fate through regulation of division orientation
Authors: Niessen Michaela T. , Scott Jeanie , Zielinski Julia G. , Vorhagen Susanne , Sotiropoulou Panagiota A. , Blanpain Cédric , Leitges Michael , Niessen Carien M.
Published: September 2013

The atypical protein kinase C (aPKC) is a key regulator of polarity and cell fate in lower organisms. However, whether mammalian aPKCs control stem cells and fate in vivo is not known. Here we show that loss of aPKCλ in a self-renewing epithelium, the epidermis, disturbed tissue homeostasis, differentiation, and stem cell dynamics, causing progressive changes in this tissue. This was accompanied by a gradual loss of quiescent hair follicle bulge stem cells and a temporary increase in proliferating progenitors. Lineage tracing analysis showed that loss of aPKCλ altered the fate of lower bulge/hair germ stem cells. This ultimately led to loss of proliferative potential, stem cell exhaustion, alopecia, and premature aging. Inactivation of aPKCλ produced more asymmetric divisions in different compartments, including the bulge. Thus, aPKCλ is crucial for homeostasis of self-renewing stratifying epithelia, and for the regulation of cell fate, differentiation, and maintenance of epidermal bulge stem cells likely through its role in balancing symmetric and asymmetric division.
Targeting antigens to CD180 rapidly induces antigen-specific IgG, affinity maturation, and immunological memory
Authors: Chaplin Jay W. , Chappell Craig P. , Clark Edward A.
Published: September 2013

Antigen (Ag) targeting is an efficient way to induce immune responses. Ag is usually coupled to an antibody (Ab) specific for a receptor expressed on dendritic cells (DCs), and then the Ag–anti-receptor is inoculated with an adjuvant. Here we report that targeting Ag to a receptor expressed on both B cells and DCs, the TLR orphan receptor CD180, in the absence of adjuvant rapidly induced IgG responses that were stronger than those induced by Ag in alum. Ag conjugated to anti-CD180 (Ag-αCD180) induced affinity maturation and Ab responses that were partially T cell independent, as Ag-specific IgGs were generated in CD40- and T cell–deficient mice. After preimmunization with Ag-αCD180 and boosting with soluble Ag, both WT and CD40 knockout (KO) mice rapidly produced Ag-specific IgG-forming cells, demonstrating that Ag–anti-CD180 induces immunological memory. The potent adjuvant effect of Ag-αCD180 required Ag to be coupled to anti-CD180 and the responsive B cells to express both CD180 and an Ag-specific B cell receptor. Surprisingly, CD180 Ag targeting also induced IgG Abs in BAFF-R KO mice lacking mature B cells and in mice deficient in interferon signaling. Targeting Ag to CD180 may be useful for therapeutic vaccination and for vaccinating the immune compromised.