bluuebunny/crossref_metadata_2025 huggingface dataset:
Surface states and electronic structure of polar and nonpolar InN – An in situ photoelectron spectroscopy study
Authors: Eisenhardt A. , Krischok S. , Himmerlich M.
Published: June 2013

Valence band structure and surface states of InN with (0001), (000-1), (1-100), and (11-20) orientation were investigated in situ after growth using photoelectron spectroscopy. Depending on surface orientation, different occupied surface states are identified and differentiated from bulk contributions. For N-polar, m-plane, and a-plane InN, the surface states are located at the valence band maximum, while In-polar InN features surface states close to the Fermi level. The surface band alignment correlates with the position of surface states. For InN(0001), a much larger surface downward band bending is observed compared to N-polar, m-plane, and a-plane InN, where almost flat band conditions occur.
Cascaded metasurfaces for complete phase and polarization control
Authors: Pfeiffer Carl , Grbic Anthony
Published: June 2013

A metasurface lens that focuses light and controls its polarization at a wavelength of 2 μm is presented. This lens demonstrates high transmission and complete phase control within a subwavelength thickness at near-infrared frequencies. By cascading four patterned sheets, the efficiency is dramatically improved over more common single sheet designs. In addition, by utilizing anisotropic sheets, arbitrary birefringence can be achieved. A planar lens that both focuses light and converts its polarization from linear to circular is analyzed.
Al2O3/TiO2 nano-pattern antireflection coating with ultralow surface recombination
Authors: Spinelli P. , Macco B. , Verschuuren M. A. , Kessels W. M. M. , Polman A.
Published: June 2013

We present a nano-patterned dielectric coating for crystalline Si solar cells that combines excellent anti-reflection and passivation properties. The nano-patterned coating comprises an array of TiO2 nanocylinders placed on top of an ultra-thin Al2O3 layer on a flat Si(100) wafer. The antireflection effect stems from the preferential forward scattering of light through leaky Mie resonances in the TiO2 nanocylinders. The Al2O3 layer provides excellent passivation of the Si surface. We experimentally demonstrate ultralow surface recombination with carrier lifetimes above 4 ms, combined with a reflectivity of 2.8% averaged over a broad spectral range.
Cesium-doped zinc oxide as electron selective contact in inverted organic photovoltaics
Authors: Savva Achilleas , Choulis Stelios A.
Published: June 2013

Water based sol-gel processed Cesium-doped Zinc oxide (CZO) with low processing annealing temperature is introduced as an efficient electron selective contact in inverted Organic Photovoltaics (OPVs). The corresponding inverted OPVs not only demonstrate similar performance compared to the well-established sol-gel processed ZnO inverted devices but also maintain their functionality when thick layers of CZO, suitable for the up scaling scenario of OPVs have been used. The three orders of magnitude higher conductivity of CZO than ZnO in combination with the high transmittance above 80%, makes this doped oxide a suitable electron selective contact for the low-cost, roll-to-roll printing process of OPVs.
Crossover from ferroelectric to relaxor and cluster glass in BaTi1−xZrxO3 (x = 0.25–0.35) studied by non-linear permittivity
Authors: Kleemann W. , Miga S. , Dec J. , Zhai J.
Published: June 2013

The electric susceptibilities χ1, χ2, and χ3 of BaTi1−xZrxO3 ceramics with 0.25 ≤ x ≤ 0.35 are measured at 90 ≤ T ≤ 350 K and 37 ≤ f ≤ 106 Hz. Crossover from ferroelectric (x = 0.25) to relaxor behavior (x = 0.35) via coexistence of both (x = 0.30) is indicated by increasing polydispersivity and suppression of χ2 intensity and negative χ3 tails. The relaxor properties are due to weak random fields acting on dipolar Ti4+ clusters in non-polar Zr4+ environment. Frustrated interaction between blocked polar nanoregions yields a cluster glass ground state for x = 0.35.
Photovoltaic/thermal system performance utilizing thin film and nanoparticle dispersion based optical filters
Authors: Otanicar T. P. , Taylor R. A. , Telang C.
Published: June 2013

Hybrid photovoltaic/thermal (PV/T) collectors would benefit from the use of fluid based optical filters as a means to separate the useful irradiance for the PV cell from those wavelengths which are more suited to heat generation. Nanoparticle based dispersions within a working fluid can be designed/tuned to serve as optical filters for this purpose. The advantage of this concept is that the thermal part of the system is separated, allowing the photovoltaic and thermal components to operate at significantly different temperatures. Additionally, by using a fluid filter, it is relatively easy to remove heat from the thermal side. This paper theoretically investigates the performance of nanoparticle-based and conventional thin film-based optical fluid filters within a concentrating hybrid PV/T system. General results are presented to demonstrate the impact to overall efficiency when a realistic (i.e., non-ideal) filter is used at a wide-range of operating conditions. The results demonstrate that nanoparticle based filters have a slightly lower overall efficiency compared to the conventional thin film filters due to their lower performance within the window of high transmittance to the PV cell. However, nanoparticle based filters achieve up to 4% higher thermal efficiencies as a result of their significantly reduced filter thickness demonstrating their potential as a favorable compact and lower cost design.
The potential application of ultra-nanocrystalline diamond films for heavy ion irradiation detection
Authors: Chen Huang-Chin , Chen Shih-Show , Wang Wei-Cheng , Lee Chi-Young , Guo Jinghua , Lin I-Nan , Chang Ching-Lin
Published: June 2013

The potential of utilizing the ultra-nanocrystalline (UNCD) films for detecting the Au-ion irradiation was investigated. When the fluence for Au-ion irradiation is lower than the critical value (fc = 5.0 × 1012 ions/cm2) the turn-on field for electron field emission (EFE) process of the UNCD films decreased systematically with the increase in fluence that is correlated with the increase in sp2-bonded phase (π*-band in EELS) due to the Au-ion irradiation. The EFE properties changed irregularly, when the fluence for Au-ion irradiation exceeds this critical value. The transmission electron microscopic microstructural examinations, in conjunction with EELS spectroscopic studies, reveal that the structural change preferentially occurred in the diamond-to-Si interface for the samples experienced over critical fluence of Au-ion irradiation, viz. the crystalline SiC phase was induced in the interfacial region and the thickness of the interface decreased. These observations implied that the UNCD films could be used as irradiation detectors when the fluence for Au-ion irradiation does not exceed such a critical value.
Homo- and Heteroleptic 8-Quinaldinolate Complexes From Elevated-temperature Rearrangements
Authors: Deacon Glen B. , Junk Peter C. , Turner David R. , Walker Julia A.
Published: June 2013

Three new zinc 8-quinaldinolate complexes have been obtained from rearrangement reactions at elevated temperatures including the first homoleptic zinc 8-quinaldinolate complex. The homoleptic, trinuclear complex [Zn3(MQ)6] (1) (MQ = 8-quinaldinolate) was obtained by the recrystallisation of amorphous Zn(MQ)2 from a 1,2,4,5-tetramethylbenzene flux at 270°C. The heteroleptic complexes [Zn4Cl4(MQ)4] (2) and [Zn4Cl2(MQ)6] (3) were simultaneously obtained by the reaction between Zn(MQ)2 and anhydrous ZnCl2 under the same conditions. All complexes contain quinaldinolate ligands in a mixed chelating–bridging coordination mode. The homoleptic complex adopts a V-shaped geometry whereas the heteroleptic complexes adopt closely related cyclic structures.
Ppd-B1 and Ppd-D1 and their effects in southern Australian wheat
Authors: Cane Karen , Eagles H. A. , Laurie D. A. , Trevaskis Ben , Vallance Neil , Eastwood R. F. , Gororo N. N. , Kuchel Haydn , Martin P. J.
Published: June 2013

Photoperiod and vernalisation genes are important for the adaptation of wheat to variable environments. Previously, using diagnostic markers and a large, unbalanced dataset from southern Australia, we estimated the effects on days to heading of frequent alleles of Vrn-A1, Vrn-B1, and Vrn-D1, and also two allelic classes of Ppd-D1. These genes accounted for ~45% of the genotypic variance for that trait. We now extend these analyses to further alleles of Ppd-D1, and four alleles of Ppd-B1 associated with copy number. Variation in copy number of Ppd-B1 occurred in our population, with one to four linked copies present. Additionally, in rare instances, the Ppd-B1 gene was absent (a null allele). The one-copy allele, which we labelled Ppd-B1b, and the three-copy allele, which we labelled Ppd-B1a, occurred through a century of wheat breeding, and are still frequent. With several distinct progenitors, the one-copy allele might not be homogenous. The two-copy allele, which we labelled Ppd-B1d, was generally introduced from WW15 (syn. Anza), and the four-copy allele, which we labelled Ppd-B1c, came from Chinese Spring. In paired comparisons, Ppd-B1a and Ppd-B1c reduced days to heading, but Ppd-B1d increased days to heading. Ppd-D1a, with a promoter deletion, Ppd-D1d, with a deletion in Exon 7, and Ppd-D1b, the intact allele, were frequent in modern Australian germplasm. Differences between Ppd-D1a and Ppd-D1d for days to heading under our field conditions depended on alleles of the vernalisation genes, confirming our previous report of large epistatic interactions between these classes of genes. The Ppd-D1b allele conferred a photoperiod response that might be useful for developing cultivars with closer to optimal heading dates from variable sowing dates. Inclusion of Ppd-B1 genotypes, and more precise resolution of Ppd-D1, increased the proportion of the genotypic variance attributed to these vernalisation and photoperiod genes to ~53%.
ART do not increase the risk of Y-chromosome microdeletion in 19 candidate genes at AZF regions
Authors: Liu Xiao-Hong , Yan Li-Ying , Lu Cui-Ling , Li Rong , Zhu Xiao-Hui , Jin Hong-Yan , Zhang Yan , Zhang Wen-Xin , Gao Su-Hong , Qiao Jie
Published: June 2013

Y-chromosome microdeletions (YCMs) have been found at a much higher rate in infertile men than fertile controls. A specific deletion in the azoospermia factor locus (AZF) at Yq11 is significantly associated with male infertility. Whether assisted reproductive technology (ART) increases the risk of YCM in ART-derived offspring remains unclear. In this study the occurrence of YCM in 199 fathers and their 228 sons (Chinese, Han ethnicity), including 85 offspring conceived by IVF, 73 by intra-cytoplasmic sperm injection (ICSI) and 70 by natural conception, was investigated. Nineteen candidate genes related to YCM were analysed by multiplex ligation-dependent probe amplification. We identified one de novo YCM from 70 naturally-conceived offspring and none from 158 ART-conceived offspring and found no statistical significance between these two groups. There was no statistically-significant difference in the detection rate of the father’s Y-chromosome microdeletion group: IVF 10.7% (8/75), ICSI 3.2% (2/63), natural conception 8.2% (5/61). These results suggest that ART does not increase the risk of YCM in male offspring.
Soil phosphorus responses to chronic nutrient fertilisation and seasonal drought in a humid lowland forest, Panama
Authors: Mirabello M. J. , Yavitt J. B. , Garcia M. , Harms K. E. , Turner B. L. , Wright S. J.
Published: June 2013

We used the Hedley sequential fractionation scheme to assess phosphorus (P) chemistry of a strongly weathered soil from a humid lowland forest in Panama. Our analyses were part of a factorial experiment of nitrogen, P, and potassium addition, with nutrients added annually, i.e. a chronic input. The aim was to examine changes in soil P chemistry with 7 years of nutrient addition for soils collected in the wet season and the dry season. The majority of P occurred in fractions extracted by NaOH (24% of the total soil P) and hot concentrated HCl (58% of the total). Organic P (Po) was ~54% of extractable P. Labile P, defined as Po plus inorganic P (Pi) extracted by NaHCO3, was largely Po (84% of the NaHCO3-extractable P). Chronic P addition increased NaHCO3-extractable Po several-fold and NaOH-extractable Pi two-fold. Seasonal variation occurred for labile P and NaOH-extractable P, whereas occluded P did not vary throughout the study period. Extractable P was ~15% higher in surface than subsurface soil. We added 350 kg P ha–1 during the 7-year period and recovered ~55% by sequential extraction. According to biogeochemical theory, added P should show up in fractions with the shortest residence times, e.g. labile P. Our finding that added P accumulated in fractions with presumably long residence times, i.e. extracted by NaOH (bound) and hot concentrated HCl (occluded), suggests that greater attention be paid to the short-term dynamics of bound and occluded P in strongly weathered tropical forest soils.
In vivo single branch axotomy induces GAP-43–dependent sprouting and synaptic remodeling in cerebellar cortex
Authors: Allegra Mascaro Anna Letizia , Cesare Paolo , Sacconi Leonardo , Grasselli Giorgio , Mandolesi Georgia , Maco Bohumil , Knott Graham W. , Huang Lieven , De Paola Vincenzo , Strata Piergiorgio , Pavone Francesco S.
Published: June 2013

Plasticity in the central nervous system in response to injury is a complex process involving axonal remodeling regulated by specific molecular pathways. Here, we dissected the role of growth-associated protein 43 (GAP-43; also known as neuromodulin and B-50) in axonal structural plasticity by using, as a model, climbing fibers. Single axonal branches were dissected by laser axotomy, avoiding collateral damage to the adjacent dendrite and the formation of a persistent glial scar. Despite the very small denervated area, the injured axons consistently reshape the connectivity with surrounding neurons. At the same time, adult climbing fibers react by sprouting new branches through the intact surroundings. Newly formed branches presented varicosities, suggesting that new axons were more than just exploratory sprouts. Correlative light and electron microscopy reveals that the sprouted branch contains large numbers of vesicles, with varicosities in the close vicinity of Purkinje dendrites. By using an RNA interference approach, we found that downregulating GAP-43 causes a significant increase in the turnover of presynaptic boutons. In addition, silencing hampers the generation of reactive sprouts. Our findings show the requirement of GAP-43 in sustaining synaptic stability and promoting the initiation of axonal regrowth.
Candidate phylum TM6 genome recovered from a hospital sink biofilm provides genomic insights into this uncultivated phylum
Authors: McLean Jeffrey S. , Lombardo Mary-Jane , Badger Jonathan H. , Edlund Anna , Novotny Mark , Yee-Greenbaum Joyclyn , Vyahhi Nikolay , Hall Adam P. , Yang Youngik , Dupont Christopher L. , Ziegler Michael G. , Chitsaz Hamidreza , Allen Andrew E. , Yooseph Shibu , Tesler Glenn , Pevzner Pavel A. , Friedman Robert M. , Nealson Kenneth H. , Venter J. Craig , Lasken Roger S.
Published: June 2013

Significance

This research highlights the discovery and genome reconstruction of a member of the globally distributed yet uncultivated candidate phylum TM6 (designated TM6SC1). In addition to the 16S rRNA gene, no other genomic information is available for this cosmopolitan phylum. This report also introduces a mini-metagenomic approach based on the use of high-throughput single-cell genomics techniques and assembly tools that address a widely recognized issue: how to effectively capture and sequence the currently uncultivated bacterial species that make up the “dark matter of life.” Amplification and sequencing random pools of 100 events enabled an estimated 90% recovery of the TM6SC1 genome.
FIGNL1-containing protein complex is required for efficient homologous recombination repair
Authors: Yuan Jingsong , Chen Junjie
Published: June 2013

The RAD51 recombinase plays a central role in homologous recombination (HR), which is critical for repair of DNA double-strand breaks, maintenance of genomic stability, and prevention of developmental disorders and cancer. Here, we report the identification of an RAD51-binding protein fidgetin-like 1 (FIGNL1). FIGNL1 specifically interacts with RAD51 through its conserved RAD51 binding domain. Cells depleted of FIGNL1 show defective HR repair. Interestingly, FIGNL1 is recruited to sites of DNA damage in a manner that is independent of breast cancer 2, early onset, RAD51, and probably, RAD51 paralogs. Conversely, FIGNL1 depletion does not affect the loading of RAD51 onto ssDNA. Our additional analysis uncovered KIAA0146, also known as scaffolding protein involved in DNA repair (SPIDR), as a binding partner of FIGNL1 and established that KIAA0146/SPIDR acts with FIGNL1 in HR repair. Collectively, our study uncovers a protein complex, which consists of FIGNL1 and KIAA0146/SPIDR, in DNA repair and provides potential directions for cancer diagnosis and therapy.
Quantifying the topography of the intrinsic energy landscape of flexible biomolecular recognition
Authors: Chu Xiakun , Gan Linfeng , Wang Erkang , Wang Jin
Published: June 2013

Significance

Biomolecular binding, which controls the realization of biomolecular function, is ubiquitous and fundamental to many cellular processes. We quantified the intrinsic energy landscapes of flexible biomolecular recognition—i.e., the binding–folding. Our findings reveal that the energy landscape topography determines the thermodynamics, kinetics, and the association mechanism of the binding–folding dynamics. These three aspects are closely related to feasibility, efficiency, and the ways of realizing biomolecular function, respectively. Our results provide a unique way to address the long-standing debate of the “structure–dynamics–function” relationship using landscape topography and establish the connections between recognition landscape theory and experimental measurements.
Discovery of positive allosteric modulators and silent allosteric modulators of the μ-opioid receptor
Authors: Burford Neil T. , Clark Mary J. , Wehrman Tom S. , Gerritz Samuel W. , Banks Martyn , O’Connell Jonathan , Traynor John R. , Alt Andrew
Published: June 2013

μ-Opioid receptors are among the most studied G protein-coupled receptors because of the therapeutic value of agonists, such as morphine, that are used to treat chronic pain. However, these drugs have significant side effects, such as respiratory suppression, constipation, allodynia, tolerance, and dependence, as well as abuse potential. Efforts to fine tune pain control while alleviating the side effects of drugs, both physiological and psychological, have led to the development of a wide variety of structurally diverse agonist ligands for the μ-opioid receptor, as well as compounds that target κ- and δ-opioid receptors. In recent years, the identification of allosteric ligands for some G protein-coupled receptors has provided breakthroughs in obtaining receptor subtype-selectivity that can reduce the overall side effect profiles of a potential drug. However, positive allosteric modulators (PAMs) can also have the specific advantage of only modulating the activity of the receptor when the orthosteric agonist occupies the receptor, thus maintaining spatial and temporal control of receptor signaling in vivo. This second advantage of allosteric modulators may yield breakthroughs in opioid receptor research and could lead to drugs with improved side-effect profiles or fewer tolerance and dependence issues compared with orthosteric opioid receptor agonists. Here, we describe the discovery and characterization of μ-opioid receptor PAMs and silent allosteric modulators, identified from high-throughput screening using a β-arrestin–recruitment assay.
Evolution of working memory
Authors: Carruthers Peter
Published: June 2013

Working memory (WM) is fundamental to many aspects of human life, including learning, speech and text comprehension, prospection and future planning, and explicit “system 2” forms of reasoning, as well as overlapping heavily with fluid general intelligence. WM has been intensively studied for many decades, and there is a growing consensus about its nature, its components, and its signature limits. Remarkably, given its central importance in human life, there has been very little comparative investigation of WM abilities across species. Consequently, much remains unknown about the evolution of this important human capacity. Some questions can be tentatively answered from the existing comparative literature. Even studies that were not intended to do so can nonetheless shed light on the WM capacities of nonhuman animals. However, many questions remain.
The evolution of episodic memory
Authors: Allen Timothy A. , Fortin Norbert J.
Published: June 2013

One prominent view holds that episodic memory emerged recently in humans and lacks a “(neo)Darwinian evolution” [Tulving E (2002)
Annu Rev Psychol
53:1–25]. Here, we review evidence supporting the alternative perspective that episodic memory has a long evolutionary history. We show that fundamental features of episodic memory capacity are present in mammals and birds and that the major brain regions responsible for episodic memory in humans have anatomical and functional homologs in other species. We propose that episodic memory capacity depends on a fundamental neural circuit that is similar across mammalian and avian species, suggesting that protoepisodic memory systems exist across amniotes and, possibly, all vertebrates. The implication is that episodic memory in diverse species may primarily be due to a shared underlying neural ancestry, rather than the result of evolutionary convergence. We also discuss potential advantages that episodic memory may offer, as well as species-specific divergences that have developed on top of the fundamental episodic memory architecture. We conclude by identifying possible time points for the emergence of episodic memory in evolution, to help guide further research in this area.
Neuroethology of primate social behavior
Authors: Chang Steve W. C. , Brent Lauren J. N. , Adams Geoffrey K. , Klein Jeffrey T. , Pearson John M. , Watson Karli K. , Platt Michael L.
Published: June 2013

A neuroethological approach to human and nonhuman primate behavior and cognition predicts biological specializations for social life. Evidence reviewed here indicates that ancestral mechanisms are often duplicated, repurposed, and differentially regulated to support social behavior. Focusing on recent research from nonhuman primates, we describe how the primate brain might implement social functions by coopting and extending preexisting mechanisms that previously supported nonsocial functions. This approach reveals that highly specialized mechanisms have evolved to decipher the immediate social context, and parallel circuits have evolved to translate social perceptual signals and nonsocial perceptual signals into partially integrated social and nonsocial motivational signals, which together inform general-purpose mechanisms that command behavior. Differences in social behavior between species, as well as between individuals within a species, result in part from neuromodulatory regulation of these neural circuits, which itself appears to be under partial genetic control. Ultimately, intraspecific variation in social behavior has differential fitness consequences, providing fundamental building blocks of natural selection. Our review suggests that the neuroethological approach to primate behavior may provide unique insights into human psychopathology.
Synaptogenesis and development of pyramidal neuron dendritic morphology in the chimpanzee neocortex resembles humans
Authors: Bianchi Serena , Stimpson Cheryl D. , Duka Tetyana , Larsen Michael D. , Janssen William G. M. , Collins Zachary , Bauernfeind Amy L. , Schapiro Steven J. , Baze Wallace B. , McArthur Mark J. , Hopkins William D. , Wildman Derek E. , Lipovich Leonard , Kuzawa Christopher W. , Jacobs Bob , Hof Patrick R. , Sherwood Chet C.
Published: June 2013

Neocortical development in humans is characterized by an extended period of synaptic proliferation that peaks in mid-childhood, with subsequent pruning through early adulthood, as well as relatively delayed maturation of neuronal arborization in the prefrontal cortex compared with sensorimotor areas. In macaque monkeys, cortical synaptogenesis peaks during early infancy and developmental changes in synapse density and dendritic spines occur synchronously across cortical regions. Thus, relatively prolonged synapse and neuronal maturation in humans might contribute to enhancement of social learning during development and transmission of cultural practices, including language. However, because macaques, which share a last common ancestor with humans ∼25 million years ago, have served as the predominant comparative primate model in neurodevelopmental research, the paucity of data from more closely related great apes leaves unresolved when these evolutionary changes in the timing of cortical development became established in the human lineage. To address this question, we used immunohistochemistry, electron microscopy, and Golgi staining to characterize synaptic density and dendritic morphology of pyramidal neurons in primary somatosensory (area 3b), primary motor (area 4), prestriate visual (area 18), and prefrontal (area 10) cortices of developing chimpanzees (
Pan troglodytes
). We found that synaptogenesis occurs synchronously across cortical areas, with a peak of synapse density during the juvenile period (3–5 y). Moreover, similar to findings in humans, dendrites of prefrontal pyramidal neurons developed later than sensorimotor areas. These results suggest that evolutionary changes to neocortical development promoting greater neuronal plasticity early in postnatal life preceded the divergence of the human and chimpanzee lineages.
APE2 is required for ATR-Chk1 checkpoint activation in response to oxidative stress
Authors: Willis Jeremy , Patel Yogin , Lentz Barry L. , Yan Shan
Published: June 2013

The base excision repair pathway is largely responsible for the repair of oxidative stress-induced DNA damage. However, it remains unclear how the DNA damage checkpoint is activated by oxidative stress at the molecular level. Here, we provide evidence showing that hydrogen peroxide (H
2
O
2
) triggers checkpoint kinase 1 (Chk1) phosphorylation in an ATR [ataxia-telangiectasia mutated (ATM) and Rad3-related]-dependent but ATM-independent manner in
Xenopus
egg extracts. A base excision repair protein, Apurinic/apyrimidinic (AP) endonuclease 2 (APE2, APN2, or APEX2), is required for the generation of replication protein A (RPA)-bound single-stranded DNA, the recruitment of a checkpoint protein complex [ATR, ATR-interacting protein (ATRIP), and Rad9] to damage sites, and H
2
O
2
-induced Chk1 phosphorylation. A conserved proliferating cell nuclear antigen interaction protein box of APE2 is important for the recruitment of APE2 to H
2
O
2
-damaged chromatin. APE2 3′-phosphodiesterase and 3′-5′ exonuclease activity is essential for single-stranded DNA generation in the 3′–5′ direction from single-stranded breaks, referred to as single-stranded break end resection. In addition, APE2 associates with Chk1, and a serine residue (S86) in the Chk1-binding motif of APE2 is essential for Chk1 phosphorylation, indicating a Claspin-like but distinct role for APE2 in ATR-Chk1 signaling. Our data indicate that APE2 plays a vital and previously unexpected role in ATR-Chk1 checkpoint signaling in response to oxidative stress. Thus, our findings shed light on a distinct mechanism of how an ATR-Chk1–dependent DNA damage checkpoint is mediated by APE2 in the oxidative stress response.
Functional interplay between a virus and the ESCRT machinery in Archaea
Authors: Snyder Jamie C. , Samson Rachel Y. , Brumfield Susan K. , Bell Stephen D. , Young Mark J.
Published: June 2013

Recently it has been discovered that a number of eukaryotic viruses, including HIV, coopt the cellular Endosomal Sorting Complex Required for Transport (ESCRT) machinery to affect egress from infected cells. Strikingly, the ESCRT apparatus is conserved in a subset of Archaea, including members of the genus
Sulfolobus
where it plays a role in cytokinesis. In the current work, we reveal that the archaeal virus
Sulfolobus
turreted icosahedral virus isolated from Yellowstone National Park's acidic hot springs also exploits the host ESCRT machinery in its replication cycle. Moreover, perturbation of normal ESCRT function abrogates viral replication and, thus, prevents establishment of a productive
Sulfolobus
turreted icosahedral virus infection. We propose that the
Sulfolobus
ESCRT machinery is involved in viral assembly within the cytoplasm and in escape from the infected cell by using a unique lysis mechanism. Our results support an ancient origin for viruses “hijacking” ESCRT proteins to complete their replication cycle and thus identify a critical host–virus interaction conserved between two domains of life.
Differential control of seed primary dormancy in
Arabidopsis
ecotypes by the transcription factor SPATULA
Authors: Vaistij Fabián E. , Gan Yinbo , Penfield Steven , Gilday Alison D. , Dave Anuja , He Zhesi , Josse Eve-Marie , Choi Giltsu , Halliday Karen J. , Graham Ian A.
Published: June 2013

Freshly matured seeds exhibit primary dormancy, which prevents germination until environmental conditions are favorable. The establishment of dormancy occurs during seed development and involves both genetic and environmental factors that impact on the ratio of two antagonistic phytohormones: abscisic acid (ABA), which promotes dormancy, and gibberellic acid, which promotes germination. Although our understanding of dormancy breakage in mature seeds is well advanced, relatively little is known about the mechanisms involved in establishing dormancy during seed maturation. We previously showed that the SPATULA (SPT) transcription factor plays a key role in regulating seed germination. Here we investigate its role during seed development and find that, surprisingly, it has opposite roles in setting dormancy in Landsberg
erecta
and Columbia
Arabidopsis
ecotypes. We also find that SPT regulates expression of five transcription factor encoding genes:
ABA-INSENSITIVE4
(
ABI4
) and
ABI5
, which mediate ABA signaling;
REPRESSOR-OF-GA
(
RGA
) and
RGA-LIKE3
involved in gibberellic acid signaling; and
MOTHER-OF-FT-AND-TFL1
(
MFT
) that we show here promotes
Arabidopsis
seed dormancy. Although
ABI4
,
RGA
, and
MFT
are repressed by SPT,
ABI5
and
RGL3
are induced. Furthermore, we show that
RGA
,
MFT
, and
ABI5
are direct targets of SPT in vivo. We present a model in which SPT drives two antagonistic “dormancy-repressing” and “dormancy-promoting” routes that operate simultaneously in freshly matured seeds. Each of these routes has different impacts and this in turn explains the opposite effect of SPT on seed dormancy of the two ecotypes analyzed here.
mitoBK
Ca
is encoded by the
Kcnma1
gene, and a splicing sequence defines its mitochondrial location
Authors: Singh Harpreet , Lu Rong , Bopassa Jean C. , Meredith Andrea L. , Stefani Enrico , Toro Ligia
Published: June 2013

The large-conductance Ca
2+
- and voltage-activated K
+
channel (BK
Ca,
MaxiK), which is encoded by the
Kcnma1
gene, is generally expressed at the plasma membrane of excitable and nonexcitable cells. However, in adult cardiomyocytes, a BK
Ca
-like channel activity has been reported in the mitochondria but not at the plasma membrane. The putative opening of this channel with the BK
Ca
agonist, NS1619, protects the heart from ischemic insult. However, the molecular origin of mitochondrial BK
Ca
(mitoBK
Ca
) is unknown because its linkage to
Kcnma1
has been questioned on biochemical and molecular grounds. Here, we unequivocally demonstrate that the molecular correlate of mitoBK
Ca
is the
Kcnma1
gene, which produces a protein that migrates at ∼140 kDa and arranges in clusters of ∼50 nm in purified mitochondria. Physiological experiments further support the origin of mitoBK
Ca
as a
Kcnma1
product because NS1619-mediated cardioprotection was absent in
Kcnma1
knockout mice. Finally, BK
Ca
transcript analysis and expression in adult cardiomyocytes led to the discovery of a 50-aa C-terminal splice insert as essential for the mitochondrial targeting of mitoBK
Ca
.
Hypoxic survival requires a 2-on-2 hemoglobin in a process involving nitric oxide
Authors: Hemschemeier Anja , Düner Melis , Casero David , Merchant Sabeeha S. , Winkler Martin , Happe Thomas
Published: June 2013

Hemoglobins are recognized today as a diverse family of proteins present in all kingdoms of life and performing multiple reactions beyond O2chemistry. The physiological roles of most hemoglobins remain elusive. Here, we show that a 2-on-2 (“truncated”) hemoglobin, termed THB8, is required for hypoxic growth and the expression of anaerobic genes inChlamydomonas reinhardtii. THB8 is 1 of 12 2-on-2 hemoglobins in this species. It belongs to a subclass within the 2-on-2 hemoglobin class I family whose members feature a remarkable variety of domain arrangements and lengths. Posttranscriptional silencing of theTHB8gene results in the mis-regulation of several genes and a growth defect under hypoxic conditions. The latter is intensified in the presence of an NO scavenger, which also impairs growth of wild-type cells. As recombinant THB8 furthermore reacts with NO, the results of this study indicate that THB8 is part of an NO-dependent signaling pathway.
Symmetry breaking in self-assembled M
4
L
6
cage complexes
Authors: Meng Wenjing , Ronson Tanya K. , Nitschke Jonathan R.
Published: June 2013

Here we describe the phenomenon of symmetry breaking within a series of M
4
L
6
container molecules. These containers were synthesized using planar rigid bis-bidentate ligands based on 2,6-substituted naphthalene, anthracene, or anthraquinone spacers and Fe
II
ions. The planarity of the ligand spacer favors a stereochemical configuration in which each cage contains two metal centers of opposite handedness to the other two, which would ordinarily result in an
S
4
-symmetric, achiral configuration. Reduction of symmetry from
S
4
to
C
1
is achieved by the spatial offset between each ligand’s pair of binding sites, which breaks the
S
4
symmetry axis. Using larger Cd
II
or Co
II
ions instead of Fe
II
resulted, in some cases, in the observation of dynamic motion of the symmetry-breaking ligands in solution. NMR spectra of these dynamic complexes thus reflected apparent
S
4
symmetry owing to rapid interconversion between energetically degenerate, enantiomeric
C
1
-symmetric conformations.
Filter gate closure inhibits ion but not water transport through potassium channels
Authors: Hoomann Torben , Jahnke Nadin , Horner Andreas , Keller Sandro , Pohl Peter
Published: June 2013

The selectivity filter of K
+
channels is conserved throughout all kingdoms of life. Carbonyl groups of highly conserved amino acids point toward the lumen to act as surrogates for the water molecules of K
+
hydration. Ion conductivity is abrogated if some of these carbonyl groups flip out of the lumen, which happens (
i
) in the process of C-type inactivation or (
ii
) during filter collapse in the absence of K
+
. Here, we show that K
+
channels remain permeable to water, even after entering such an electrically silent conformation. We reconstituted fluorescently labeled and constitutively open mutants of the bacterial K
+
channel KcsA into lipid vesicles that were either C-type inactivating or noninactivating. Fluorescence correlation spectroscopy allowed us to count both the number of proteoliposomes and the number of protein-containing micelles after solubilization, providing the number of reconstituted channels per proteoliposome. Quantification of the per-channel increment in proteoliposome water permeability with the aid of stopped-flow experiments yielded a unitary water permeability
p
f
of (6.9 ± 0.6) × 10
−13
cm
3
⋅s
−1
for both mutants. “Collapse” of the selectivity filter upon K
+
removal did not alter
p
f
and was fully reversible, as demonstrated by current measurements through planar bilayers in a K
+
-containing medium to which K
+
-free proteoliposomes were fused. Water flow through KcsA is halved by 200 mM K
+
in the aqueous solution, which indicates an effective K
+
dissociation constant in that range for a singly occupied channel. This questions the widely accepted hypothesis that multiple K
+
ions in the selectivity filter act to mutually destabilize binding.
Langerin
neg
conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice
Authors: Wohn Christian , Ober-Blöbaum Julia L. , Haak Stefan , Pantelyushin Stanislav , Cheong Cheolho , Zahner Sonja P. , Onderwater Sabina , Kant Marius , Weighardt Heike , Holzmann Bernhard , Reizis Boris , Becher Burkhard , Prens Errol P. , Clausen Björn E.
Published: June 2013

Psoriasis is an autoinflammatory skin disease of unknown etiology. Topical application of Aldara cream containing the Toll-like receptor (TLR)7 agonist Imiquimod (IMQ) onto patients induces flares of psoriasis. Likewise, in mice IMQ triggers pathological changes closely resembling psoriatic plaque formation. Key cytokines like IL-23 and type-I IFN (IFN-I), both being produced mainly by dendritic cells (DCs), have been implicated in psoriasis. Although plasmacytoid DCs (pDCs) are the main source of IFNα and thought to initiate disease, conventional DCs (cDCs) appear to maintain the psoriatic lesions. Any role of cDCs during lesion formation remains elusive. Here, we report that selective activation of TLR7 signaling specifically in CD11c
+
DCs was sufficient to induce psoriasiform skin disease in mice. Intriguingly, both pDCs and the IFN-I pathway were dispensable for the development of local skin inflammation. Selective TLR7 triggering of Langerin
+
DCs resulted in attenuated disease, whereas their depletion did not alter the severity of skin lesions. Moreover, after IMQ-painting, IL-23 was exclusively produced by Langerin
neg
DCs in vivo. In conclusion, TLR7-activated Langerin
neg
cDCs trigger psoriatic plaque formation via IL-23–mediated activation of innate IL-17/IL-22–producing lymphocytes, independently of pDCs or IFN-I. These results suggest therapeutic targeting of IL-23 production by cDCs to refine current treatment strategies for psoriasis.
TLR-independent neutrophil-derived IFN-γ is important for host resistance to intracellular pathogens
Authors: Sturge Carolyn R. , Benson Alicia , Raetz Megan , Wilhelm Cara L. , Mirpuri Julie , Vitetta Ellen S. , Yarovinsky Felix
Published: June 2013

IFN-γ is a major cytokine that is critical for host resistance to a broad range of intracellular pathogens. Production of IFN-γ by natural killer and T cells is initiated by the recognition of pathogens by Toll-like receptors (TLRs). In an experimental model of toxoplasmosis, we have identified the presence of a nonlymphoid source of IFN-γ that was particularly evident in the absence of TLR-mediated recognition ofToxoplasma gondii. Genetically altered mice lacking all lymphoid cells due to deficiencies in Recombination Activating Gene 2 and IL-2Rγcgenes also produced IFN-γ in response to the protozoan parasite. Flow-cytometry and morphological examinations of non-NK/non-T IFN-γ+cells identified neutrophils as the cell type capable of producing IFN-γ. Selective elimination of neutrophils in TLR11−/−mice infected with the parasite resulted in acute susceptibility similar to that observed in IFN-γ–deficient mice. Similarly,Salmonella typhimuriuminfection of TLR-deficient mice induces the appearance of IFN-γ+neutrophils. Thus, neutrophils are a crucial source for IFN-γ that is required for TLR-independent host protection against intracellular pathogens.
Double deletion of melanocortin 4 receptors and SAPAP3 corrects compulsive behavior and obesity in mice
Authors: Xu Pin , Grueter Brad A. , Britt Jeremiah K. , McDaniel Latisha , Huntington Paula J. , Hodge Rachel , Tran Stephanie , Mason Brittany L. , Lee Charlotte , Vong Linh , Lowell Bradford B. , Malenka Robert C. , Lutter Michael , Pieper Andrew A.
Published: June 2013

Compulsive behavior is a debilitating clinical feature of many forms of neuropsychiatric disease, including Tourette syndrome, obsessive-compulsive spectrum disorders, eating disorders, and autism. Although several studies link striatal dysfunction to compulsivity, the pathophysiology remains poorly understood. Here, we show that both constitutive and induced genetic deletion of the gene encoding the melanocortin 4 receptor (MC4R), as well as pharmacologic inhibition of MC4R signaling, normalize compulsive grooming and striatal electrophysiologic impairments in synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3)-null mice, a model of human obsessive-compulsive disorder. Unexpectedly, genetic deletion of SAPAP3 restores normal weight and metabolic features of MC4R-null mice, a model of human obesity. Our findings offer insights into the pathophysiology and treatment of both compulsive behavior and eating disorders.
Random fluctuation of selection coefficients and the extent of nucleotide variation in human populations
Authors: Miura Sayaka , Zhang Zhenguo , Nei Masatoshi
Published: June 2013

It is well known that the selection coefficient of a mutant allele varies from generation to generation, and the effect of this factor on genetic variation has been studied by many theoreticians. However, no consensus has been reached. One group of investigators believes that fluctuating selection has an effect of enhancing genetic variation, whereas the other group contends that it has a diversity-reducing effect. In recent years, it has become possible to study this problem by using single nucleotide polymorphisms (SNPs) as well as exome sequence data. In this article we present the theoretical distributions of mutant nucleotide frequencies for the two models of fluctuating selection and then compare the distributions with the empirical distributions obtained from SNP and exome sequence data in human populations. Interestingly, both SNP and exome sequence data showed that the neutral mutation model fits the empirical distribution quite well. Furthermore, the mathematical models with diversity-enhancing and diversity-reducing effects also fit the empirical distribution reasonably well. This result implies that there is no need of distinguishing between the diversity-enhancing and diversity-reducing models of fluctuating selection and the nucleotide polymorphism in human populations can be explained largely by neutral mutations when long-term evolution is considered.
Roles of different pools of the mitotic checkpoint complex and the mechanisms of their disassembly
Authors: Eytan Esther , Sitry-Shevah Danielle , Teichner Adar , Hershko Avram
Published: June 2013

The mitotic (or spindle assembly) checkpoint system prevents premature separation of sister chromatids in mitosis. When the checkpoint is turned on, the mitotic checkpoint complex (MCC) inhibits the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C). MCC is composed of the checkpoint proteins BubR1, Bub3, and Mad2 associated with the APC/C activator Cdc20. The mechanisms of the assembly of MCC when the checkpoint is turned on, and of its disassembly when the checkpoint is inactivated, are not sufficiently understood. Previous reports indicated that APC/C-mediated polyubiquitylation of Cdc20 in MCC is required for the dissociation of APC/C-associated MCC, but not of free MCC. The pool of free MCC is disassembled by an ATP-dependent process stimulated by the Mad2-binding protein p31
comet
. It remained unknown whether free MCC is the precursor or the dissociation product of APC/C-bound MCC. By characterizing the mechanisms of the disassembly of APC/C-bound MCC in a purified system, we find that it cannot be the source of free MCC, because it is bound at high affinity and is released only in ubiquitylated or partially disassembled forms. By the use of a cell-free system from
Xenopus
eggs that reproduces the mitotic checkpoint, we show that MCC can be assembled in the absence of APC/C in a checkpoint-dependent manner. We propose that when the checkpoint is turned on, free MCC is the precursor of APC/C-bound MCC. When the mitotic checkpoint is extinguished, both APC/C-bound and free MCC pools have to be disassembled to release APC/C from inhibition.
Crystal structure of the Golgi casein kinase
Authors: Xiao Junyu , Tagliabracci Vincent S. , Wen Jianzhong , Kim Soo-A , Dixon Jack E.
Published: June 2013

The family with sequence similarity 20 (Fam20) kinases phosphorylate extracellular substrates and play important roles in biomineralization. Fam20C is the Golgi casein kinase that phosphorylates secretory pathway proteins within Ser-x-Glu/pSer motifs. Mutations in Fam20C cause Raine syndrome, an osteosclerotic bone dysplasia. Here we report the crystal structure of the Fam20C ortholog from
Caenorhabditis elegans.
The nucleotide-free and Mn/ADP-bound structures unveil an atypical protein kinase-like fold and highlight residues critical for activity. The position of the regulatory αC helix and the lack of an activation loop indicate an architecture primed for efficient catalysis. Furthermore, several distinct elements, including the presence of disulfide bonds, suggest that the Fam20 family diverged early in the evolution of the protein kinase superfamily. Our results reinforce the structural diversity of protein kinases and have important implications for patients with disorders of biomineralization.
AP4 is a mediator of epithelial–mesenchymal transition and metastasis in colorectal cancer
Authors: Jackstadt Rene , Röh Simone , Neumann Jens , Jung Peter , Hoffmann Reinhard , Horst David , Berens Christian , Bornkamm Georg W. , Kirchner Thomas , Menssen Antje , Hermeking Heiko
Published: June 2013

The basic helix-loop-helix transcription factor AP4/TFAP4/AP-4 is encoded by a c-MYC target gene and displays up-regulation concomitantly with c-MYC in colorectal cancer (CRC) and numerous other tumor types. Here a genome-wide characterization of AP4 DNA binding and mRNA expression was performed using a combination of microarray, genome-wide chromatin immunoprecipitation, next-generation sequencing, and bioinformatic analyses. Thereby, hundreds of induced and repressed AP4 target genes were identified. Besides many genes involved in the control of proliferation, the AP4 target genes included markers of stemness (LGR5 and CD44) and epithelial–mesenchymal transition (EMT) such as SNAIL, E-cadherin/CDH1, OCLN, VIM, FN1, and the Claudins 1, 4, and 7. Accordingly, activation of AP4 induced EMT and enhanced migration and invasion of CRC cells. Conversely, down-regulation of AP4 resulted in mesenchymal–epithelial transition and inhibited migration and invasion. In addition, AP4 induction was required for EMT, migration, and invasion caused by ectopic expression of c-MYC. Inhibition of AP4 in CRC cells resulted in decreased lung metastasis in mice. Elevated AP4 expression in primary CRC significantly correlated with liver metastasis and poor patient survival. These findings imply AP4 as a new regulator of EMT that contributes to metastatic processes in CRC and presumably other carcinomas.