bluuebunny/crossref_metadata_2025 huggingface dataset:
Multimolecule test-tube simulations of protein unfolding and aggregation
Authors: McCully Michelle E. , Beck David A. C. , Daggett Valerie
Published: October 2012

Molecular dynamics simulations of protein folding or unfolding, unlike most in vitro experimental methods, are performed on a single molecule. The effects of neighboring molecules on the unfolding/folding pathway are largely ignored experimentally and simply not modeled computationally. Here, we present two all-atom, explicit solvent molecular dynamics simulations of 32 copies of the Engrailed homeodomain (EnHD), an ultrafast-folding and -unfolding protein for which the folding/unfolding pathway is well-characterized. These multimolecule simulations, in comparison with single-molecule simulations and experimental data, show that intermolecular interactions have little effect on the folding/unfolding pathway. EnHD unfolded by the same mechanism whether it was simulated in only water or also in the presence of other EnHD molecules. It populated the same native state, transition state, and folding intermediate in both simulation systems, and was in good agreement with experimental data available for each of the three states. Unfolding was slowed slightly by interactions with neighboring proteins, which were mostly hydrophobic in nature and ultimately caused the proteins to aggregate. Protein–water hydrogen bonds were also replaced with protein–protein hydrogen bonds, additionally contributing to aggregation. Despite the increase in protein–protein interactions, the protein aggregates formed in simulation did not do so at the total exclusion of water. These simulations support the use of single-molecule techniques to study protein unfolding and also provide insight into the types of interactions that occur as proteins aggregate at high temperature at an atomic level.
Hepatitis B virus X protein targets Bcl-2 proteins to increase intracellular calcium, required for virus replication and cell death induction
Authors: Geng Xin , Huang Chenghao , Qin Yan , McCombs Janet E. , Yuan Quan , Harry Brian L. , Palmer Amy E. , Xia Ning-Shao , Xue Ding
Published: October 2012

Infection with the hepatitis B virus (HBV) promotes the development of hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) and is a leading cause of morbidity and mortality worldwide. HBV X protein (HBx) is an important effector for HBV pathogenesis, but its cellular targets and acting mechanisms remain elusive. We show here that HBx interacts with the anti-apoptotic proteins Bcl-2 and Bcl-xL through a Bcl-2 homology 3 (BH3)-like motif in mammalian cells. Importantly, mutations in the BH3-like motif that prevent HBx binding to Bcl-2 and Bcl-xL abrogate cytosolic calcium elevation and cell death induced by HBx expression in hepatocytes and severely impair HBV viral replication, which can be substantially rescued by restoring cytosolic calcium. These results suggest that HBx binding to Bcl-2 family members and subsequent elevation of cytosolic calcium are important for HBV viral replication. Consistently, RNAi knockdown of Bcl-2 or Bcl-xL results in reduced calcium elevation by HBx and decreased viral replication in hepatocytes. Our results suggest that HBx targets Bcl-2 proteins through its BH3-like motif to promote cytosolic calcium elevation, cell death, and viral replication during HBV pathogenesis, which presents an excellent therapeutic intervention point in treating patients with chronic HBV.
Benzodiazepine treatment induces subtype-specific changes in GABA
A
receptor trafficking and decreases synaptic inhibition
Authors: Jacob Tija C. , Michels Guido , Silayeva Liliya , Haydon Julia , Succol Francesca , Moss Stephen J.
Published: October 2012

Benzodiazepines potentiate γ-aminobutyric acid type A receptor (GABA
A
R) activity and are widely prescribed to treat anxiety, insomnia, and seizure disorders. Unfortunately, clinical use of benzodiazepines (BZs) is severely limited by tolerance. The mechanisms leading to BZ tolerance are unknown. BZs bind at the interface between an α and γ subunit of GABA
A
Rs, preferentially enhancing synaptic receptors largely composed of α(1–3, 5), β3, and γ2 subunits. Using confocal imaging and patch-clamp approaches, we show that treatment with the BZ flurazepam decreases GABA
A
R surface levels and the efficacy of neuronal inhibition in hippocampal neurons. A dramatic decrease in surface and total levels of α2 subunit-containing GABA
A
Rs occurred within 24 h of flurazepam treatment, whereas GABA
A
Rs incorporating α1 subunits showed little alteration. The GABA
A
R surface depletion could be reversed by treatment with the BZ antagonist Ro 15-1788. Coincident with decreased GABA
A
R surface levels, flurazepam treatment reduced miniature inhibitory postsynaptic current amplitude, which returned to control levels with acute Ro 15-1788 treatment. GABA
A
R endocytosis and insertion rates were unchanged by flurazepam treatment. Treatment with leupeptin restored flurazepam lowered receptor surface levels, strongly suggesting that flurazepam increases lysosomal degradation of GABA
A
Rs. Together, these data suggest that flurazepam exposure enhances degradation of α2 subunit-containing GABA
A
Rs after their removal from the plasma membrane, leading to a reduction in inhibitory synapse size and number along with a decrease in the efficacy of synaptic inhibition. These reported subtype-specific changes in GABA
A
R trafficking provide significant mechanistic insight into the initial neuroadaptive responses occurring with BZ treatment.
Evolutionary analyses of non-genealogical bonds produced by introgressive descent
Authors: Bapteste Eric , Lopez Philippe , Bouchard Frédéric , Baquero Fernando , McInerney James O. , Burian Richard M.
Published: October 2012

All evolutionary biologists are familiar with evolutionary units that evolve by vertical descent in a tree-like fashion in single lineages. However, many other kinds of processes contribute to evolutionary diversity. In vertical descent, the genetic material of a particular evolutionary unit is propagated by replication inside its own lineage. In what we call introgressive descent, the genetic material of a particular evolutionary unit propagates into different host structures and is replicated within these host structures. Thus, introgressive descent generates a variety of evolutionary units and leaves recognizable patterns in resemblance networks. We characterize six kinds of evolutionary units, of which five involve mosaic lineages generated by introgressive descent. To facilitate detection of these units in resemblance networks, we introduce terminology based on two notions, P3s (subgraphs of three nodes: A, B, and C) and mosaic P3s, and suggest an apparatus for systematic detection of introgressive descent. Mosaic P3s correspond to a distinct type of evolutionary bond that is orthogonal to the bonds of kinship and genealogy usually examined by evolutionary biologists. We argue that recognition of these evolutionary bonds stimulates radical rethinking of key questions in evolutionary biology (e.g., the relations among evolutionary players in very early phases of evolutionary history, the origin and emergence of novelties, and the production of new lineages). This line of research will expand the study of biological complexity beyond the usual genealogical bonds, revealing additional sources of biodiversity. It provides an important step to a more realistic pluralist treatment of evolutionary complexity.
Capturing fleeting intermediates in a catalytic C–H amination reaction cycle
Authors: Perry Richard H. , Cahill Thomas J. , Roizen Jennifer L. , Du Bois Justin , Zare Richard N.
Published: October 2012

We have applied an ambient ionization technique, desorption electrospray ionization MS, to identify transient reactive species of an archetypal C–H amination reaction catalyzed by a dirhodium tetracarboxylate complex. Using this analytical method, we have detected previously proposed short-lived reaction intermediates, including two nitrenoid complexes that differ in oxidation state. Our findings suggest that an Rh-nitrene oxidant can react with hydrocarbon substrates through a hydrogen atom abstraction pathway and raise the intriguing possibility that two catalytic C–H amination pathways may be operative in a typical bulk solution reaction. As highlighted by these results, desorption electrospray ionization MS should have broad applicability for the mechanistic study of catalytic processes.
Modulation of voltage-gated K
+
channels by the sodium channel β1 subunit
Authors: Nguyen Hai M. , Miyazaki Haruko , Hoshi Naoto , Smith Brian J. , Nukina Nobuyuki , Goldin Alan L. , Chandy K. George
Published: October 2012

Voltage-gated sodium (Na
V
) and potassium (K
V
) channels are critical components of neuronal action potential generation and propagation. Here, we report that Na
V
β1 encoded by
SCN1b
, an integral subunit of Na
V
channels, coassembles with and modulates the biophysical properties of K
V
1 and K
V
7 channels, but not K
V
3 channels, in an isoform-specific manner. Distinct domains of Na
V
β1 are involved in modulation of the different K
V
channels. Studies with channel chimeras demonstrate that Na
V
β1-mediated changes in activation kinetics and voltage dependence of activation require interaction of Na
V
β1 with the channel’s voltage-sensing domain, whereas changes in inactivation and deactivation require interaction with the channel’s pore domain. A molecular model based on docking studies shows Na
V
β1 lying in the crevice between the voltage-sensing and pore domains of K
V
channels, making significant contacts with the S1 and S5 segments. Cross-modulation of Na
V
and K
V
channels by Na
V
β1 may promote diversity and flexibility in the overall control of cellular excitability and signaling.
Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis
Authors: Drexler Stefan K. , Bonsignore Luca , Masin Mark , Tardivel Aubry , Jackstadt Rene , Hermeking Heiko , Schneider Pascal , Gross Olaf , Tschopp Jurg , Yazdi Amir S.
Published: October 2012

A chronic inflammatory microenvironment favors tumor progression through molecular mechanisms that are still incompletely defined. In inflammation-induced skin cancers, IL-1 receptor- or caspase-1–deficient mice, or mice specifically deficient for the inflammasome adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) in myeloid cells, had reduced tumor incidence, pointing to a role for IL-1 signaling and inflammasome activation in tumor development. However, mice fully deficient for ASC were not protected, and mice specifically deficient for ASC in keratinocytes developed more tumors than controls, suggesting that, in contrast to its proinflammatory role in myeloid cells, ASC acts as a tumor-suppressor in keratinocytes. Accordingly, ASC protein expression was lost in human cutaneous squamous cell carcinoma, but not in psoriatic skin lesions. Stimulation of primary mouse keratinocytes or the human keratinocyte cell line HaCaT with UVB induced an ASC-dependent phosphorylation of p53 and expression of p53 target genes. In HaCaT cells, ASC interacted with p53 at the endogenous level upon UVB irradiation. Thus, ASC in different tissues may influence tumor growth in opposite directions: it has a proinflammatory role in infiltrating cells that favors tumor development, but it also limits keratinocyte proliferation in response to noxious stimuli, possibly through p53 activation, which helps suppressing tumors.
Genotype of a historic strain of
Mycobacterium tuberculosis
Authors: Bouwman Abigail S. , Kennedy Sandra L. , Müller Romy , Stephens Richard H. , Holst Malin , Caffell Anwen C. , Roberts Charlotte A. , Brown Terence A.
Published: October 2012

The use of ancient DNA in paleopathological studies of tuberculosis has largely been restricted to confirmation of disease identifications made by skeletal analysis; few attempts at obtaining genotype data from archaeological samples have been made because of the need to perform different PCRs for each genetic locus being studied in an ancient DNA extract. We used a next generation sequencing approach involving hybridization capture directed at specific polymorphic regions of the
Mycobacterium tuberculosis
genome to identify a detailed genotype for a historic strain of
M. tuberculosis
from an individual buried in the 19th century St. George’s Crypt, Leeds, West Yorkshire, England. We obtained 664,500 sequencing by oligonucleotide ligation and detection (SOLiD) reads that mapped to the targeted regions of the
M. tuberculosis
genome; the coverage included 218 of 247 SNPs, 10 of 11 insertion/deletion regions, and the repeat elements IS1081 and IS6110. The accuracy of the SOLiD data was checked by conventional PCRs directed at 11 SNPs and two insertion/deletions. The data placed the historic strain of
M. tuberculosis
in a group that is uncommon today, but it is known to have been present in North America in the early 20th century. Our results show the use of hybridization capture followed by next generation sequencing as a means of obtaining detailed genotypes of ancient varieties of
M. tuberculosis
, potentially enabling meaningful comparisons between strains from different geographic locations and different periods in the past.
Structural insights into the mechanisms of Mg
2+
uptake, transport, and gating by CorA
Authors: Guskov Albert , Nordin Nurhuda , Reynaud Aline , Engman Henrik , Lundbäck Anna-Karin , Jong Agnes Jin Oi , Cornvik Tobias , Phua Terri , Eshaghi Said
Published: October 2012

Despite the importance of Mg
2+
for numerous cellular activities, the mechanisms underlying its import and homeostasis are poorly understood. The CorA family is ubiquitous and is primarily responsible for Mg
2+
transport. However, the key questions—such as, the ion selectivity, the transport pathway, and the gating mechanism—have remained unanswered for this protein family. We present a 3.2 Å resolution structure of the archaeal CorA from
Methanocaldococcus jannaschii
, which is a unique complete structure of a CorA protein and reveals the organization of the selectivity filter, which is composed of the signature motif of this family. The structure reveals that polar residues facing the channel coordinate a partially hydrated Mg
2+
during the transport. Based on these findings, we propose a unique gating mechanism involving a helical turn upon the binding of Mg
2+
to the regulatory intracellular binding sites, and thus converting a polar ion passage into a narrow hydrophobic pore. Because the amino acids involved in the uptake, transport, and gating are all conserved within the entire CorA family, we believe this mechanism is general for the whole family including the eukaryotic homologs.
Acid–base chemical reaction model for nucleation rates in the polluted atmospheric boundary layer
Authors: Chen Modi , Titcombe Mari , Jiang Jingkun , Jen Coty , Kuang Chongai , Fischer Marc L. , Eisele Fred L. , Siepmann J. Ilja , Hanson David R. , Zhao Jun , McMurry Peter H.
Published: October 2012

Climate models show that particles formed by nucleation can affect cloud cover and, therefore, the earth's radiation budget. Measurements worldwide show that nucleation rates in the atmospheric boundary layer are positively correlated with concentrations of sulfuric acid vapor. However, current nucleation theories do not correctly predict either the observed nucleation rates or their functional dependence on sulfuric acid concentrations. This paper develops an alternative approach for modeling nucleation rates, based on a sequence of acid–base reactions. The model uses empirical estimates of sulfuric acid evaporation rates obtained from new measurements of neutral molecular clusters. The model predicts that nucleation rates equal the sulfuric acid vapor collision rate times a prefactor that is less than unity and that depends on the concentrations of basic gaseous compounds and preexisting particles. Predicted nucleation rates and their dependence on sulfuric acid vapor concentrations are in reasonable agreement with measurements from Mexico City and Atlanta.
Euler and Navier–Stokes equations on the hyperbolic plane
Authors: Khesin Boris , Misiołek Gerard
Published: October 2012

We show that nonuniqueness of the Leray–Hopf solutions of the Navier–Stokes equation on the hyperbolic plane ℍ
2
observed by Chan and Czubak is a consequence of the Hodge decomposition. We show that this phenomenon does not occur on ℍ

n

whenever
n
≥ 3. We also describe the corresponding general Hamiltonian framework of hydrodynamics on complete Riemannian manifolds, which includes the hyperbolic setting.
The ABO blood group is a trans-species polymorphism in primates
Authors: Ségurel Laure , Thompson Emma E. , Flutre Timothée , Lovstad Jessica , Venkat Aarti , Margulis Susan W. , Moyse Jill , Ross Steve , Gamble Kathryn , Sella Guy , Ober Carole , Przeworski Molly
Published: October 2012

The ABO histo-blood group, the critical determinant of transfusion incompatibility, was the first genetic polymorphism discovered in humans. Remarkably, ABO antigens are also polymorphic in many other primates, with the same two amino acid changes responsible for A and B specificity in all species sequenced to date. Whether this recurrence of A and B antigens is the result of an ancient polymorphism maintained across species or due to numerous, more recent instances of convergent evolution has been debated for decades, with a current consensus in support of convergent evolution. We show instead that genetic variation data in humans and gibbons as well as in Old World monkeys are inconsistent with a model of convergent evolution and support the hypothesis of an ancient, multiallelic polymorphism of which some alleles are shared by descent among species. These results demonstrate that the A and B blood groups result from a trans-species polymorphism among distantly related species and has remained under balancing selection for tens of millions of years—to date, the only such example in hominoids and Old World monkeys outside of the major histocompatibility complex.
AAA ATPase p97/VCP is essential for TRIM21-mediated virus neutralization
Authors: Hauler Felix , Mallery Donna L. , McEwan William A. , Bidgood Susanna R. , James Leo C.
Published: October 2012

Tripartite motif-containing 21 (TRIM21) is a cytosolic IgG receptor that mediates intracellular virus neutralization by antibody. TRIM21 targets virions for destruction in the proteasome, but it is unclear how a substrate as large as a viral capsid is degraded. Here, we identify the ATPase p97/valosin-containing protein (VCP), an enzyme with segregase and unfoldase activity, as a key player in this process. Depletion or catalytic inhibition of VCP prevents capsid degradation and reduces neutralization. VCP is required concurrently with the proteasome, as addition of inhibitor after proteasomal degradation has no effect. Moreover, our results suggest that it is the challenging nature of virus as a substrate that necessitates involvement of VCP, since intracellularly expressed IgG Fc is degraded in a VCP-independent manner. These results implicate VCP as an important host factor in antiviral immunity.
Structural and functional characterization of the nitrite channel NirC from
Salmonella typhimurium
Authors: Lü Wei , Schwarzer Nikola J. , Du Juan , Gerbig-Smentek Elke , Andrade Susana L. A. , Einsle Oliver
Published: October 2012

Nitrite (NO
2
−
) is a central intermediate in the nitrogen metabolism of microorganisms and plants, and is used as a cytotoxin by macrophages as part of the innate immune response. The bacterial membrane protein NirC acts as a specific channel to facilitate the transport of nitrite anions across lipid bilayers for cytoplasmic detoxification. Despite NirC’s importance in nitrogen metabolism and in the pathogenicity of enteric bacteria, available biochemical data are scarce. Here we present a functional and structural characterization of NirC from
Salmonella typhimurium
by lipid bilayer electrophysiology and X-ray crystallography. NirC is a pentameric member of the formate/nitrite transporter family of membrane proteins that operates as a channel with high conductance. Single-channel measurements reveal fast and slow gating events but, in contrast to the related FocA formate channel, no pH-dependent gating. A 2.4Å crystal structure of NirC at pH 5 shows similarity to FocA and aquaporins, but lacks the structural asymmetry observed in the formate channel at similarly low pH. Resolved water molecules in the protomers suggest a transport mechanism that also permits a facultative NO
2
−
/H
+
symport.
Structural insight into HIV-1 capsid recognition by rhesus TRIM5α
Authors: Yang Haitao , Ji Xiaoyun , Zhao Gongpu , Ning Jiying , Zhao Qi , Aiken Christopher , Gronenborn Angela M. , Zhang Peijun , Xiong Yong
Published: October 2012

Tripartite motif protein isoform 5 alpha (TRIM5α) is a potent antiviral protein that restricts infection by HIV-1 and other retroviruses. TRIM5α recognizes the lattice of the retrovirus capsid through its B30.2 (PRY/SPRY) domain in a species-specific manner. Upon binding, TRIM5α induces premature disassembly of the viral capsid and activates the downstream innate immune response. We have determined the crystal structure of the rhesus TRIM5α PRY/SPRY domain that reveals essential features for capsid binding. Combined cryo-electron microscopy and biochemical data show that the monomeric rhesus TRIM5α PRY/SPRY, but not the human TRIM5α PRY/SPRY, can bind to HIV-1 capsid protein assemblies without causing disruption of the capsid. This suggests that the PRY/SPRY domain alone constitutes an important pattern-sensing component of TRIM5α that is capable of interacting with viral capsids of different curvatures. Our results provide molecular insights into the mechanisms of TRIM5α-mediated retroviral restriction.
One-shot NMR analysis of microbial secretions identifies highly potent proteasome inhibitor
Authors: Stein Martin L. , Beck Philipp , Kaiser Markus , Dudler Robert , Becker Christian F. W. , Groll Michael
Published: October 2012

Natural products represent valuable lead structures for drug discovery. However, for most bioactive compounds no cellular target is yet identified and many substances predicted from genome analysis are inaccessible due to their life stage-dependent biosynthesis, which is not reflected in common isolation procedures. In response to these issues, an NMR-based and target-directed protease assay for inhibitor detection of the proteasome was developed. The methodology is suitable for one-shot identification of inhibitors in conglomerates and crude culture broths. The technique was applied for analysis of the different life stages of the bacterium
Photorhabdus luminescens
, which resulted in the isolation and characterization of cepafungin I (CepI), the strongest proteasome inhibitor described to date. Its biosynthesis is strictly regulated and solely induced by the specific environmental conditions determined by our methodology. The transferability of the developed technique to other drug targets may disclose an abundance of novel compounds applicable for drug development.
Regulation of actin-myosin interaction by conserved periodic sites of tropomyosin
Authors: Barua Bipasha , Winkelmann Donald A. , White Howard D. , Hitchcock-DeGregori Sarah E.
Published: October 2012

Cooperative activation of actin-myosin interaction by tropomyosin (Tm) is central to regulation of contraction in muscle cells and cellular and intracellular movements in nonmuscle cells. The steric blocking model of muscle regulation proposed 40 y ago has been substantiated at both the kinetic and structural levels. Even with atomic resolution structures of the major players, how Tm binds and is designed for regulatory function has remained a mystery. Here we show that a set of periodically distributed evolutionarily conserved surface residues of Tm is required for cooperative regulation of actomyosin. Based on our results, we propose a model of Tm on a structure of actin-Tm-myosin in the “open” (on) state showing potential electrostatic interactions of the residues with both actin and myosin. The sites alternate with a second set of conserved surface residues that are important for actin binding in the inhibitory state in the absence of myosin. The transition from the closed to open states requires the sites identified here, even when troponin + Ca
2+
is present. The evolutionarily conserved residues are important for actomyosin regulation, a universal function of Tm that has a common structural basis and mechanism.
Size and complexity in model financial systems
Authors: Arinaminpathy Nimalan , Kapadia Sujit , May Robert M.
Published: October 2012

The global financial crisis has precipitated an increasing appreciation of the need for a systemic perspective toward financial stability. For example: What role do large banks play in systemic risk? How should capital adequacy standards recognize this role? How is stability shaped by concentration and diversification in the financial system? We explore these questions using a deliberately simplified, dynamic model of a banking system that combines three different channels for direct transmission of contagion from one bank to another: liquidity hoarding, asset price contagion, and the propagation of defaults via counterparty credit risk. Importantly, we also introduce a mechanism for capturing how swings in “confidence” in the system may contribute to instability. Our results highlight that the importance of relatively large, well-connected banks in system stability scales more than proportionately with their size: the impact of their collapse arises not only from their connectivity, but also from their effect on confidence in the system. Imposing tougher capital requirements on larger banks than smaller ones can thus enhance the resilience of the system. Moreover, these effects are more pronounced in more concentrated systems, and continue to apply, even when allowing for potential diversification benefits that may be realized by larger banks. We discuss some tentative implications for policy, as well as conceptual analogies in ecosystem stability and in the control of infectious diseases.
Optical tweezers reveal relationship between microstructure and nanoparticle penetration of pulmonary mucus
Authors: Kirch Julian , Schneider Andreas , Abou Bérengère , Hopf Alexander , Schaefer Ulrich F. , Schneider Marc , Schall Christian , Wagner Christian , Lehr Claus-Michael
Published: October 2012

In this study, the mobility of nanoparticles in mucus and similar hydrogels as model systems was assessed to elucidate the link between microscopic diffusion behavior and macroscopic penetration of such gels. Differences in particle adhesion to mucus components were strongly dependent on particle coating. Particles coated with 2 kDa PEG exhibited a decreased adhesion to mucus components, whereas chitosan strongly increased the adhesion. Despite such mucoinert properties of PEG, magnetic nanoparticles of both coatings did not penetrate through native respiratory mucus, resisting high magnetic forces (even for several hours). However, model hydrogels were, indeed, penetrated by both particles in dependency of particle coating, obeying the theory of particle mobility in an external force field. Comparison of penetration data with cryogenic scanning EM images of mucus and the applied model systems suggested particularly high rigidity of the mucin scaffold and a broad pore size distribution in mucus as reasons for the observed particle immobilization. Active probing of the rigidity of mucus and model gels with optical tweezers was used in this context to confirm such properties of mucus on the microscale, thus presenting the missing link between micro- and macroscopical observations. Because of high heterogeneity in the size of the voids and pores in mucus, on small scales, particle mobility will depend on adhesive or inert properties. However, particle translocation over distances larger than a few micrometers is restricted by highly rigid structures within the mucus mesh.
Somatic cell lineage is required for differentiation and not maintenance of germline stem cells in
Drosophila
testes
Authors: Lim Jaclyn G. Y. , Fuller Margaret T.
Published: October 2012

Adult stem cells are believed to be maintained by a specialized microenvironment, the niche, which provides short-range signals that either instruct stem cells to self-renew or inhibit execution of preprogrammed differentiation pathways. In
Drosophila
testes, somatic cyst stem cells (CySCs) and the apical hub form the niche for neighboring germline stem cells (GSCs), with CySCs as the proposed source of instructive self-renewal signals [Leatherman JL, Dinardo S (2010)
Nat Cell Biol
12(8):806–811]. In contrast to this model, we show that early germ cells with GSC characteristics can be maintained over time after ablation of CySCs and their cyst cell progeny. Without CySCs and cyst cells, early germ cells away from the hub failed to initiate differentiation. Our results suggest that CySCs do not have a necessary instructive role in specifying GSC self-renewal and that the differentiated progeny of CySCs provide an environment necessary to trigger GSC differentiation. This work highlights the complex interaction between different stem cell populations in the same niche and how the state of one stem cell population can influence the fate of the other.
Linking water quality and well-being for improved assessment and valuation of ecosystem services
Authors: Keeler Bonnie L. , Polasky Stephen , Brauman Kate A. , Johnson Kris A. , Finlay Jacques C. , O’Neill Ann , Kovacs Kent , Dalzell Brent
Published: October 2012

Despite broad recognition of the value of the goods and services provided by nature, existing tools for assessing and valuing ecosystem services often fall short of the needs and expectations of decision makers. Here we address one of the most important missing components in the current ecosystem services toolbox: a comprehensive and generalizable framework for describing and valuing water quality-related services. Water quality is often misrepresented as a final ecosystem service. We argue that it is actually an important contributor to many different services, from recreation to human health. We present a valuation approach for water quality-related services that is sensitive to different actions that affect water quality, identifies aquatic endpoints where the consequences of changing water quality on human well-being are realized, and recognizes the unique groups of beneficiaries affected by those changes. We describe the multiple biophysical and economic pathways that link actions to changes in water quality-related ecosystem goods and services and provide guidance to researchers interested in valuing these changes. Finally, we present a valuation template that integrates biophysical and economic models, links actions to changes in service provision and value estimates, and considers multiple sources of water quality-related ecosystem service values without double counting.
Conformation of receptor-bound visual arrestin
Authors: Kim Miyeon , Vishnivetskiy Sergey A. , Van Eps Ned , Alexander Nathan S. , Cleghorn Whitney M. , Zhan Xuanzhi , Hanson Susan M. , Morizumi Takefumi , Ernst Oliver P. , Meiler Jens , Gurevich Vsevolod V. , Hubbell Wayne L.
Published: October 2012

Arrestin-1 (visual arrestin) binds to light-activated phosphorylated rhodopsin (P-Rh*) to terminate G-protein signaling. To map conformational changes upon binding to the receptor, pairs of spin labels were introduced in arrestin-1 and double electron–electron resonance was used to monitor interspin distance changes upon P-Rh* binding. The results indicate that the relative position of the N and C domains remains largely unchanged, contrary to expectations of a “clam-shell” model. A loop implicated in P-Rh* binding that connects β-strands V and VI (the “finger loop,” residues 67–79) moves toward the expected location of P-Rh* in the complex, but does not assume a fully extended conformation. A striking and unexpected movement of a loop containing residue 139 away from the adjacent finger loop is observed, which appears to facilitate P-Rh* binding. This change is accompanied by smaller movements of distal loops containing residues 157 and 344 at the tips of the N and C domains, which correspond to “plastic” regions of arrestin-1 that have distinct conformations in monomers of the crystal tetramer. Remarkably, the loops containing residues 139, 157, and 344 appear to have high flexibility in both free arrestin-1 and the P-Rh*complex.
Logical meaning, interdependency and the linking particle {na/-ng} in Tagalog
Authors: Martin J.R.
Published: October 2012

In this paper the linking particle {nal-ng} in Tagalog is interpreted from the perspective of systemic functional linguistics. It is suggested that Tagalog's deployment of this particle to depend one unit on another across a range of grammatical environments argues for a grammatical theory in which constituency and interdependency are seen as complementary structuring principles, reflecting the experiential and logical subcomponents of Halliday's ideational meta-function. In addition, the challenge posed by Tagalog's apparently interpersonal deployments of the linking particle is addressed.
Use of Illicit Substances among Schoolchildren in Colombo District, Sri Lanka
Authors: Liyanage Isurujith Kongala , Wickramasinghe Kremlin , Ratnayake Himali Erandathie , Palmer Paula , Matthews David R. , Katulanda Prasad
Published: October 2012

Objective: This study aimed to understand the usage patterns and correlates of illicit drug use among schoolchildren in Colombo district, Sri Lanka. Methods: A cross-sectional study was carried out among grade 10 and 12 students using a self-administered questionnaire. Results: From the 6000 students selected, 5353(89.22%) responded. Betel chewing with tobacco was seen in 28.48% males and 10.44% females. Substances such as Barbul, Madana Modaka, and cough syrups that are not established as illicit drugs were used as psychoactive substances. Ingredients of some of these compounds are not fully understood or regulated. Prevalence of cannabis use was 3.85% in males and 0.24% in females. Studying nonscience subjects for Advanced Level, doing sports, low academic performance, and peer smoking significantly increased the odds of using one or more substances ( P < .05). Conclusions: Many types of illicit substances were used by schoolchildren. More strategies to prevent further aggravation of these behaviors are needed. Constituents of some compounds are not understood and need further evaluation. Recognized high-risk groups can be targets for preventive and cessation programs.
Incidence, Secular Trends, and Outcomes of Prosthetic Joint Infection: A Population-Based Study, Olmsted County, Minnesota, 1969–2007
Authors: Tsaras Geoffrey , Osmon Douglas R. , Mabry Tad , Lahr Brian , Sauveur Jennifer St. , Yawn Barbara , Kurland Robert , Berbari Elie F.
Published: October 2012

Context.

The epidemiology of prosthetic joint infection (PJI) in a population-based cohort has not been studied in the United States.

Objectives.

To provide an accurate assessment of the true incidence, secular trends, clinical manifestations, microbiology, and treatment outcomes of PJI in a population-based cohort.

Design.

Historical cohort study.

Setting.

Olmsted County, Minnesota.

Participants.

Residents who underwent total knee arthroplasty (TKA) or total hip arthroplasty (THA) between January 1, 1969, and December 31, 2007.

Methods.

Incidence rates and trends in PJI were assessed using the Kaplan-Meier method and log-rank test, as were treatment outcomes among PJI case patients.

Results.

A total of 7,375 THAs or TKAs were implanted in residents of Olmsted County during the study period. Seventy-five discrete joints in 70 individuals developed PJI, during a mean ± SD follow-up of 6.8 ± 6.1 years. The cumulative incidence of PJI was 0.5%, 0.8%, and 1.4% after 1, 5, and 10 years after arthroplasty, respectively. Overall, the rate of survival free of clinical failure after treatment of PJI was 76.8% (95% confidence interval [CI], 64.3–85.2) and 65.2% (95% CI, 33.1–76.2) at 3 and 5 years, respectively. The incidence and treatment outcomes did not significantly differ by decade of implantation, patient age at implantation, gender, or joint location.

Conclusions.

The incidence of PJI is relatively low in a population-based cohort and is a function of age of the prosthesis. Incidence trends and outcomes have not significantly changed over the past 40 years.
Impact of Vancomycin Minimum Inhibitory Concentration on Mortality among Critically Ill Patients witn Methicillin-Resistant Staphylococcus aureus Bacteremia
Authors: Woods Christian J. , Chowdhury Anindita , Patel Vinay M. , Shorr Andrew F.
Published: October 2012

We retrospectively evaluated 99 intensive care unit patients with methicillin-resistant Staphylococcus aureus bacteremia to determine whether having a vancomycin minimum inhibitory concentration (MIC) of 2 mg/L affected mortality. This MIC was found in 5.1% of patients and was associated with the probability of death (adjusted odds ratio, 13.9 [95% confidence interval, 1.1–171.2]) independent of other factors.
Experimental investigation of formation time in single-gap pseudospark discharge
Authors: Hu Jing , Rovey Joshua L
Published: October 2012

Experiment results on the formation of pseudospark discharge in single-gap device are presented. The formation process is investigated by capacitive probes and shows two phases: a slow ignition phase and a fast current increasing phase. The ignition of the discharge is found to be synchronous with a high speed ionization wave propagating from cathode to anode. Transition to the high current phase is initiated when the ionization front reaches the anode side. The experimental results on four different gap widths are presented under different pressures. The characteristic time of the ignition phase of the discharge is decreased with increasing pressure in all four gap widths. The mean velocity of the observed ionization front varies from 5.4 × 10 to 1.7 × 103 cm µs−1 under the investigated pressures. In four gap widths, the velocity of the ionization front can be fitted by one given curve as an exponential decline function of E/P.
High-power piezoelectric characteristics of manganese-modified BiScO3–PbTiO3 high-temperature piezoelectric ceramics
Authors: Chen Jianguo , Hu Zhongqiang , Shi Huaduo , Li Meiya , Dong Shuxiang
Published: October 2012

Hard piezoelectric ceramics of manganese (Mn)-modified 0.36BiScO3–0.64PbTiO3 (0.36BS–0.64PTM) with a high Curie temperature were prepared using the traditional solid-state reaction method. The effects of different concentrations of Mn on the structure, dielectric and piezoelectric properties of the 0.36BS–0.64PTM ceramics were investigated. X-ray diffraction results indicated that the 0.36BS–0.64PTM ceramics showed a single perovskite structure with tetragonal symmetry and the c/a ratio decreased slightly with increasing Mn content. The grain sizes of the 0.36BS–0.64PTM ceramics were enlarged by Mn addition, and their distributions were uniform. The dielectric loss tan δ decreased clearly with the increase in Mn content, and the mechanical quality factor Q
m and vibration velocity v
0 were improved significantly at the same time. The Curie temperature T
c, the planar electromechanical coupling factor k
p, dielectric loss tan δ, mechanical quality factor Q
m and vibration velocity v
0 of the 0.36BS–0.64PTM ceramics with 3 mol% Mn were about 431 °C, 0.57, 0.007, 134 and 1.05 m s−1, respectively. The maximum vibration velocity v
0 of the 0.36BS–0.64PTM ceramics is much superior to those of PZT (0.4 m s−1) ceramics and PZT–PZM (0.72 m s−1). These results indicated that the 0.36BS–0.64PTM ceramics are promising candidates for high-temperature and high-power piezoelectric applications.
Predictions for cooling a solid to its ground state
Authors: Troy William
Published: October 2012

A major goal of quantum computing research is to drain all quanta(q)(q)of thermal energy from a solid at a positive temperatureT0>0,T_{0}>0,leaving the object in its ground state. In 2010 the first complete success was reported when a quantum drum was cooled to its ground state atT0=20mK.T_{0}=20\textrm {mK.}However, current theory, which is based on the Bose-Einstein equation, predicts that the temperatureT→0T \to 0asq→0.q \to 0.We prove that this discrepancy between experiment and theory is due to previously unobserved errors in low temperature predictions of the Bose-Einstein equation. We correct this error and derive a new formula for temperature which proves thatT→T0>0T \to T_{0}>0asq→0.q \to 0.Simultaneously, the energy decreases to its ‘supersolid’ ground state level asq→0+.q \to 0^{+}.For experimental data our temperature formula predicts thatT0=9.8mK,T_{0}= 9.8\textrm {mK,}in close agreement with the20mK20\textrm {mK}experimental result. Our results form a first step towards bridging the gap between existing theory and the construction of useful quantum computing devices.
Treatment of Thoracolumbar Spinal Infections through Anterolateral Approaches Using Expandable Titanium Mesh Cage for Spine Reconstruction
Authors: Roberto Tarantino , Daniele Marruzzo , Martina Cappelletti , Tiziano De Giacomo , Roberto Delfini
Published: October 2012

Pyogenic vertebral osteomyelitis (PVO) is still a rare pathology. However, its incidence is on the rise. This is due to an increasing population with predisposing factors. Also, the availability of more effective diagnostic tools has brought it increasingly to the surgeon’s attention. In this study the patients were treated in the Neurosurgery Division of the Department of Neurological Sciences and Psychiatry of the Sapienza University of Rome, between 2001 and 2009. They had thoracolumbar pyogenic spondylitis. This study was undertaken in order to identify the correct diagnostic and therapeutic treatment needed in such cases. From the cases studied here, it is evident that spinal infections can be extremely insidious and that diagnosis tends to be reached late. Surgery, along with the antibiotic treatment, allows for eradication of the causes of the pathology by the reclamation of the affected region. Surgery is also fundamental in helping to recover vital functions and in restoring as much as possible the correct curvature of the rachises. The use of an anterolateral approach is dictated by the necessity of obtaining 360° stability as well as by the need to clear away extensive infections, which are not always reachable using a posterior approach.
A fivefold interpenetrating diamond-like three-dimensional metal–organic framework: poly[(μ2-benzene-1,4-diacetato)[μ2-1,6-bis(1,2,4-triazol-1-yl)hexane]zinc(II)]
Authors: Wang Jun , Xu Xiao-Juan , Tao Jian-Qing , Tan Chun-Yun
Published: October 2012

In the mixed-ligand metal–organic title polymeric compound, [Zn(C10H8O4)(C10H16N6)]nor [Zn(PBEA)(BTH)]n[H2PBEA is benzene-1,4-diacetic acid and BTH is 1,6-bis(1,2,4-triazol-1-yl)hexane], the asymmetric unit contains a ZnIIatom, one half of a BTH ligand and one half of a doubly deprotonated H2PBEA ligand. Each ZnIIcentre lies on a crystallographic twofold rotation axis and is four-coordinated by two O atoms from two distinct PBEA2−ligands and two N atoms from two different BTH ligands in a {ZnO2N2} coordination environment. The three-dimensional topology of the title compound corresponds to that of a fivefold interpenetrating diamond-like metal–organic framework.
Structures of four polymorphs of the pesticide dithianon solved from X-ray powder diffraction data
Authors: Halasz Ivan , Dinnebier Robert , Chiodo Tiziana , Saxell Heidi
Published: October 2012

The crystal structures of four polymorphs of the pesticide dithianon (5,10-dihydro-5,10-dioxonaphtho[2,3-b]-1,4-dithiine-2,3-dicarbonitrile) have been solved from powder diffraction data and refined using the Rietveld method. Three polymorphs crystallize in non-centrosymmetric space groups. Two polymorphs have Z′ > 1. The structures are assembled via interactions between carbonyl groups of quinoid fragments into layers which further interact only by weak interactions.
Dominant Learning Processes in Emergency Response Organizations: A Case Study of a Joint Rescue Coordination Centre
Authors: Sommer Morten , Njå Ove
Published: October 2012

Research on decision‐making and expert performance in operational settings generally considers extensive personal experience and deliberate practice to be decisive for development of expertise. Learning and development of decision‐making abilities therefore tend to be explained in terms of human cognition. This study examines the dominant learning processes in a Joint Rescue Coordination Centre, revealing that personal experience, individual problem‐solving, knowledge accumulation, and collective reflection are the key processes in the individual development of decision‐making abilities. These findings show that both individual and contextual (including organisational) aspects need to be considered if we are to fully understand the development of decision‐making abilities and consequently be better able to explain and analyse decision‐making and expert performance in natural settings.
Root internalization, transport and in‐planta survival of Salmonella enterica serovar Newport in sweet basil
Authors: Gorbatsevich Elena , Sela (Saldinger) Shlomo , Pinto Riky , Bernstein Nirit
Published: October 2012

It is now acknowledged that food‐borne pathogens present in the irrigation water or soil can become associated with crop plants in the field, penetrate internal plant tissues via the root, translocate and survive inside plants. Only little information is available concerning interaction between enteric pathogens and plants. The present study evaluated the potential for contamination of the aromatic plant, sweet basil during cultivation, by Salmonella enterica serovar Newport. Root internalization was plant‐age‐dependent, with the highest susceptibility occurring at the beginning of the rapid growth phase of the root. Higher incidence of internalization was detected in vegetative than reproductive plant organs, pointing at bacterial transport in the transpiration stream. Internalized Salmonella survived only < 30 h in the phyllosphere. In contrast, survival of Salmonella on the leaf surface was much pronounced (at least 8 days), and the initial decay rate was lower at the abaxial (lower) compared with the adaxial (upper) side of the leaf. Although the experiments were conducted with high concentration of Salmonella unlikely to happen in the field, internalization occurred at a low frequency and in‐planta survival was limited to less than 30 h. These findings imply that leaf surface contamination, rather than root internalization, may pose higher risk for human infection following consumption of contaminated basil.
Casein phosphopeptide‐amorphous calcium phosphate: a remineralizing agent of enamel
Authors: Gurunathan D , Somasundaram S , Kumar SA
Published: October 2012

The pathogenesis of enamel caries involves a succession of demineralization and remineralization activities. The net effect can result in lesion consolidation when the redeposited minerals improve the resistance of the surface to the extent that the usual level of cariogenic activity cannot cause mineral dissolution. Since it has been established that the caries process is a continuum, albeit one that is interrupted numerous times daily, it is therefore possible to intervene at any stage with a therapeutic product or an intervention methodology. Incorporation of remineralizing treatments into routine dental care programmes will have a strong impact on the public health aspects of caries control. A recent advancement in the phenomenon of remineralization is the casein phosphopeptides. These casein phosphopeptides localize the amorphous calcium phosphate and are proved to be anticariogenic. This review discusses the mechanism of remineralization by casein phosphopeptide‐amorphous calcium phosphate and its incorporation into various products.