bluuebunny/crossref_metadata_2025 huggingface dataset:
Retrogression and Reaging Applied to Warm Forming of High-Strength Aluminum Alloy AA7075-T6 Sheet
Authors: Ivanoff Thomas A. , Carter Jon T. , Hector Louis G. , Taleff Eric M.
Published: January 2019

This study introduces retrogression forming, a new warm-forming methodology for high-strength aluminum alloys such as AA7075-T6. Retrogression forming combines a retrogression heat treatment with simultaneous warm forming at approximately 200 °C to improve upon the room-temperature ductility of AA7075-T6, approximately 10 pct in tension, and can then use the automotive paint-bake cycle to restore nearly peak-aged strength. Experimental data indicate that retrogression forming at 200 °C provides a tensile ductility of 20 pct, approximately double that of room temperature, and that subsequent reaging by a simulated paint bake restores hardness to within 10 pct of the original peak-aged (T6) hardness. To explore the retrogression-forming concept, the retrogression behaviors of two AA7075-T6 sheet materials from different suppliers are characterized between 200 °C and 350 °C. The times and temperatures of retrogression treatments suitable for simultaneous warm forming are determined, and tensile ductilities under these conditions are measured. Tensile ductilities during high-temperature deformation (up to 520 °C) are measured and compared to those possible under retrogression-forming conditions. Plastic flow at temperatures of 460 °C to 520 °C is governed by dislocation-climb-controlled creep, a mechanism different from the behaviors observed under retrogression-forming conditions.
High surface-area carbon microcantilevers
Authors: Noyce Steven G. , Vanfleet Richard R. , Craighead Harold G. , Davis Robert C.
Published: January 2019

Fully-porous carbon resonators were formed with precise microscale dimension and characterized for sensitive detection of vapors.
Template assisted preparation of high surface area macroporous supports with uniform and tunable nanocrystal loadings
Authors: Paul Michael T. Y. , Yee Brenden B. , Zhang Xin , Alford Eiji H. , Pilapil Brandy K. , Gates Byron D.
Published: January 2019

The preparation of nanocrystals coated macroporous supports with tunable compositions, catalyst loading densities, and feature dimensions.
Glycosylated naphthalimides and naphthalimide Tröger's bases as fluorescent aggregation probes for Con A
Authors: Calatrava-Pérez Elena , Delente Jason M. , Shanmugaraju Sankarasekaran , Hawes Chris S. , Williams Clive D. , Gunnlaugsson Thorfinnur , Scanlan Eoin M.
Published: January 2019

We report the synthesis of glycosylated naphthalimide compounds and their application as fluorescent probes for Concanavalin A (Con A) lectin.
Branched polystyrenes from suspension “Strathclyde” polymerization using a vulcanization accelerator as a chain transfer agent
Authors: Yong Haiyang , Miao Yongpeng , A Sigen , Quan Dong , Ivankovic Alojz , Singh Krutika , Zhang Jing , Zhou Dezhong , Wang Wenxin
Published: January 2019

Branched polymers exhibit a unique three-dimensional (3D) molecular architecture and distinctive physical/chemical properties, and thus have been applied in a wide variety of fields.
Perylene diimide based star-shaped small molecular acceptors for high efficiency organic solar cells
Authors: Wang Hang , Li Miao , Liu Yahui , Song Jinsheng , Li Cuihong , Bo Zhishan
Published: January 2019

High efficiency organic solar cells based on perylene diimide based small molecular acceptors can be achieved by holding the balance between nanoscale phase separation and charge mobilities.
Seeded-mediated growth of ternary Ag–In–S and quaternary Ag–In–Zn–S nanocrystals from binary Ag2S seeds and the composition-tunable optical properties
Authors: Zeng Bin , Chen Fei , Liu Zhenyang , Guan Zhongyuan , Li Xu , Teng Feng , Tang Aiwei
Published: January 2019

Ternary AgInS2 and quaternary Ag–In–Zn–S nanocrystals, which could be partially exchanged with either In3+ or Zn2+ ions, were synthesized by using a seeded-mediated growth method.
Face changing companion of the redback millisecond pulsar PSR J1048+2339
Authors: Yap Y. X. , Li K. L. , Kong A. K. H. , Takata J. , Lee J. , Hui C. Y.
Published: January 2019

We present optical observations of the redback millisecond pulsar PSR J1048+2339, which is a 4.66 ms radio pulsar in a compact binary with an orbital period of six hours. We obtained high-quality light curves of PSR J1048+2339 with the Lulin 1 m Telescope. The system shows two distinct six-hour orbital modulations, in which an ellipsoidal modulation changes into a sinusoidal-like profile in less than 14 days. In addition to the change, the brightness of the companion increased by one magnitude, suggesting that the latter type of modulation is caused by the pulsar wind heating of the companion and that the heating became dominant in the system. While the changes are not unexpected, such a timescale is the shortest among similar systems. We performed modeling analysis to extract the properties of the system. We obtained a derived pulsar mass of 2.1 M⊙ and a companion star mass of 0.4 M⊙ for the system. The irradiation power increased by a factor of 6 during which the pulsar wind heating dominates. We also report on the two archival Chandra X-ray observations and discuss several possibilities that might cause the varying heating on the companion.
Quantum corral herds surface electrons into a fractal lattice
Authors: Miller Johanna L.
Published: January 2019

The method, based on scanning tunneling microscopy, lets researchers explore quantum mechanics in geometries not found in nature.
Dandelion seeds are optimized for wind-based travel
Authors: Middleton Christine
Published: January 2019

A newly observed type of vortex stabilizes the flight of plumed seeds.
Iranian scientists persevere under renewed sanctions
Authors: Feder Toni
Published: January 2019

The greatest impact on science and society comes from the devaluation of currency.
When condensed-matter physics became king
Authors: Martin Joseph D.
Published: January 2019

The story of how solid-state physics emerged in the postwar period and was eventually rebranded as condensed-matter physics illuminates some major shifts in the late-20th-century physics community.
Artificial gauge fields with ultracold atoms
Authors: Galitski Victor , Juzeliūnas Gediminas , Spielman Ian B.
Published: January 2019

Suitable combinations of laser beams can make neutral atoms behave like electrons in a magnetic field.
Protecting planets beyond Earth
Authors: Mogul Rakesh
Published: January 2019

Part of exploring other worlds is to prevent harmful organisms from hitching a ride from or to our planet.
Designing combinatorial exchanges for the reallocation of resource rights
Authors: Bichler Martin , Fux Vladimir , Goeree Jacob K.
Published: January 2019

Significance

Overfishing is a prime environmental concern. Catch share systems have been shown to be effective tools to combat overfishing. But flawed initial allocations and the subsequent need for reallocation of catch shares often create challenging policy problems. Market-based solutions have attracted interest but the complex institutional and political constraints necessitate market forms to avoid undesirable outcomes. The combinatorial exchange we designed and implemented is a market design for the reallocation of catch shares. The design was adopted because it addressed stakeholders’ key requirements: fair pricing, avoiding fragmented share portfolios, and mitigating distortions from the introduction of catch shares via cost-effective and market-based subsidies.
Patched1–ArhGAP36–PKA–Inversin axis determines the ciliary translocation of Smoothened for Sonic Hedgehog pathway activation
Authors: Zhang Boyan , Zhuang Tenghan , Lin Qiaoyu , Yang Biying , Xu Xiaowei , Xin Guangwei , Zhu Shicong , Wang Gang , Yu Bin , Zhang Tingting , Jiang Qing , Zhang Chuanmao
Published: January 2019

Significance

The ciliary membrane-localized transmembrane Hedgehog receptor Patched1 suppresses the ciliary translocation of the transmembrane oncoprotein Smoothened and consequently Hedgehog pathway activation, but the mechanism underlying this process remains largely unknown. Here, we show that the Patched1–ArhGAP36–PKA–Inversin–Smoothened axis determines this process. We uncover that the ciliary translocation of Smoothened depends on its interaction with phosphorylated ciliary Inversin, which is sequentially achieved by the removal of centrosomal ArhGAP36 with ciliary Patched1 and the accumulation of centrosomal PKA during Hedgehog pathway activation. Our findings reveal how the Hedgehog pathway is spontaneously activated in tumor cells carrying loss-of-function mutations of Patched1 or oncogenic mutations of Smoothened.
Neoproterozoic glacial origin of the Great Unconformity
Authors: Keller C. Brenhin , Husson Jon M. , Mitchell Ross N. , Bottke William F. , Gernon Thomas M. , Boehnke Patrick , Bell Elizabeth A. , Swanson-Hysell Nicholas L. , Peters Shanan E.
Published: January 2019

The Great Unconformity, a profound gap in Earth’s stratigraphic record often evident below the base of the Cambrian system, has remained among the most enigmatic field observations in Earth science for over a century. While long associated directly or indirectly with the occurrence of the earliest complex animal fossils, a conclusive explanation for the formation and global extent of the Great Unconformity has remained elusive. Here we show that the Great Unconformity is associated with a set of large global oxygen and hafnium isotope excursions in magmatic zircon that suggest a late Neoproterozoic crustal erosion and sediment subduction event of unprecedented scale. These excursions, the Great Unconformity, preservational irregularities in the terrestrial bolide impact record, and the first-order pattern of Phanerozoic sedimentation can together be explained by spatially heterogeneous Neoproterozoic glacial erosion totaling a global average of 3–5 vertical kilometers, along with the subsequent thermal and isostatic consequences of this erosion for global continental freeboard.
Photoswitching FRET to monitor protein–protein interactions
Authors: Rainey Kristin H. , Patterson George H.
Published: January 2019

FRET is a powerful approach to study the interactions of fluorescent molecules, and numerous methods have been developed to measure FRET in cells. Here, we present a method based on a donor molecule’s photoswitching properties, which are slower in the presence vs. the absence of an acceptor. The technique, photoswitching FRET (psFRET), is similar to an established but underutilized method called photobleaching FRET (pbFRET), with the major difference being that the molecules are switched “off” rather than photobleached. The psFRET technique has some of the FRET imaging advantages normally attributed to fluorescence lifetime imaging microscopy (FLIM), such as monitoring only donor fluorescence. However, it can be performed on a conventional widefield microscope, requires less illumination light to photoswitch off than photobleaching, and can be photoswitched “on” again to repeat the experiment. We present data testing the validity of the psFRET approach to quantify FRET in cells and demonstrate its use in imaging protein–protein interactions and fluorescent protein-based biosensors.
Exploiting regulatory heterogeneity to systematically identify enhancers with high accuracy
Authors: Arbel Hamutal , Basu Sumanta , Fisher William W. , Hammonds Ann S. , Wan Kenneth H. , Park Soo , Weiszmann Richard , Booth Benjamin W. , Keranen Soile V. , Henriquez Clara , Shams Solari Omid , Bickel Peter J. , Biggin Mark D. , Celniker Susan E. , Brown James B.
Published: January 2019

Significance

We demonstrate a high-accuracy method for predicting enhancers genome-wide with >85% precision as validated by transgenic reporter assays in
Drosophila
embryos. This accuracy in a metazoan system enables us to predict with high confidence 1,640 enhancers genome-wide that participate in body segmentation during early development. The predicted enhancers are demarcated by heterogeneous collections of epigenetic marks; many strong enhancers are free from classic indicators of activity, including H3K27ac, but are bound by key transcription factors.
Nutrition, the visceral immune system, and the evolutionary origins of pathogenic obesity
Authors: West-Eberhard Mary Jane
Published: January 2019

The global obesity epidemic is the subject of an immense, diversely specialized research effort. An evolutionary analysis reveals connections among disparate findings, starting with two well-documented facts: Obesity-associated illnesses (e.g., type-2 diabetes and cardiovascular disease), are especially common in: (
i
) adults with abdominal obesity, especially enlargement of visceral adipose tissue (VAT), a tissue with important immune functions; and (
ii
) individuals with poor fetal nutrition whose nutritional input increases later in life. I hypothesize that selection favored the evolution of increased lifelong investment in VAT in individuals likely to suffer lifelong malnutrition because of its importance in fighting intraabdominal infections. Then, when increased nutrition violates the adaptive fetal prediction of lifelong nutritional deficit, preferential VAT investment could contribute to abdominal obesity and chronic inflammatory disease. VAT prioritization may help explain several patterns of nutrition-related disease: the paradoxical increase of chronic disease with increased food availability in recently urbanized and migrant populations; correlations between poor fetal nutrition, improved childhood (catch-up) growth, and adult metabolic syndrome; and survival differences between children with marasmus and kwashiorkor malnutrition. Fats and sugars can aggravate chronic inflammation via effects on intestinal bacteria regulating gut permeability to visceral pathogens. The extremes in a nutrition-sensitive trade-off between visceral (immune-function) vs. subcutaneous (body shape) adiposity may have been favored by selection in highly stratified premedicine societies. Altered adipose allocation in populations with long histories of social stratification and malnutrition may be the result of genetic accommodation of developmental responses to poor maternal/fetal conditions, increasing their vulnerability to inflammatory disease.
The genomic basis of Red Queen dynamics during rapid reciprocal host–pathogen coevolution
Authors: Papkou Andrei , Guzella Thiago , Yang Wentao , Koepper Svenja , Pees Barbara , Schalkowski Rebecca , Barg Mike-Christoph , Rosenstiel Philip C. , Teotónio Henrique , Schulenburg Hinrich
Published: January 2019

Red Queen dynamics, involving coevolutionary interactions between species, are ubiquitous, shaping the evolution of diverse biological systems. To date, information on the underlying selection dynamics and the involved genome regions is mainly available for bacteria–phage systems or only one of the antagonists of a eukaryotic host–pathogen interaction. We add to our understanding of these important coevolutionary interactions using an experimental host–pathogen model, which includes the nematode
Caenorhabditis elegans
and its pathogen
Bacillus thuringiensis
. We combined experimental evolution with time-shift experiments, in which a focal host or pathogen is tested against a coevolved antagonist from the past, present, or future, followed by genomic analysis. We show that (
i
) coevolution occurs rapidly within few generations, (
ii
) temporal coadaptation at the phenotypic level is found in parallel across replicate populations, consistent with antagonistic frequency-dependent selection, (
iii
) genomic changes in the pathogen match the phenotypic pattern and include copy number variations of a toxin-encoding plasmid, and (
iv
) host genomic changes do not match the phenotypic pattern and likely involve selective responses at more than one locus. By exploring the dynamics of coevolution at the phenotypic and genomic level for both host and pathogen simultaneously, our findings demonstrate a more complex model of the Red Queen, consisting of distinct selective processes acting on the two antagonists during rapid and reciprocal coadaptation.
Secondary magnetite in ancient zircon precludes analysis of a Hadean geodynamo
Authors: Tang Fengzai , Taylor Richard J. M. , Einsle Josh F. , Borlina Cauê S. , Fu Roger R. , Weiss Benjamin P. , Williams Helen M. , Williams Wyn , Nagy Lesleis , Midgley Paul A. , Lima Eduardo A. , Bell Elizabeth A. , Harrison T. Mark , Alexander Ellen W. , Harrison Richard J.
Published: January 2019

Significance

The Earth’s geodynamo is critical in protecting our atmosphere, and thus plays an important role in the habitability of our planet. As such, the Earth’s magnetic field has likely played a crucial role in the emergence of life around 4 billion years ago during the Hadean–Archean Eons. However, we know little about the behavior of the geodynamo during this critical period. Recent efforts have focused on the magnetic signals harbored by Jack Hills zircon crystals, the oldest terrestrial material. Here we show the magnetic carriers in such grains. Our results demonstrate that although ancient zircon grains may contain ideal magnetic recorders, they do not record the magnetic field strength at the time of zircon growth.
Early patterns of skill acquisition and immigrants’ specialization in STEM careers
Authors: Rangel Marcos A. , Shi Ying
Published: January 2019

Significance

Do net returns to early investments in skill acquisition explain patterns of occupational specialization among immigrants? We design an empirical analysis of nationally representative data to show that age at immigration and mother tongue influence course-taking patterns in high school and college major choice. Immigrant children with greater relative endowments in nonlanguage skills specialize in math and science course credits over English and are more likely to pursue science-, technology-, engineering-, and math-intensive subjects in college. This reveals the early influence of comparative advantage over immigrant career choices and economic assimilation in the United States.
Anthropogenic drivers of 2013–2017 trends in summer surface ozone in China
Authors: Li Ke , Jacob Daniel J. , Liao Hong , Shen Lu , Zhang Qiang , Bates Kelvin H.
Published: January 2019

Significance

Drastic air pollution control in China since 2013 has achieved sharp decreases in fine particulate matter (PM
2.5
), but ozone pollution has not improved. After removing the effect of meteorological variability, we find that surface ozone has increased in megacity clusters of China, notably Beijing and Shanghai. The increasing trend cannot be simply explained by changes in anthropogenic precursor [NO
x
and volatile organic compound (VOC)] emissions, particularly in North China Plain (NCP). The most important cause of the increasing ozone in NCP appears to be the decrease in PM
2.5
, slowing down the sink of hydroperoxy radicals and thus speeding up ozone production. Decreasing ozone in the future will require a combination of NO
x
and VOC emission controls to overcome the effect of decreasing PM
2.5
.
Global-scale dispersal and connectivity in mangroves
Authors: Van der Stocken Tom , Carroll Dustin , Menemenlis Dimitris , Simard Marc , Koedam Nico
Published: January 2019

Significance

Mangroves are of considerable ecological and socioeconomical importance; however, substantial areal losses have been recorded in many regions, driven primarily by anthropogenic disturbances and sea level rise. Oceanic dispersal of mangrove propagules provides a key mechanism for shifting distributions in response to environmental change. Here we provide a model framework for describing global dispersal and connectivity in mangroves. We identify important dispersal routes, barriers, and stepping-stones and quantify the influence of minimum and maximum floating periods on simulated connectivity patterns. Our study provides a baseline to improve our understanding of observed mangrove species distributions and, in combination with climate data, the expected range shifts under climate change.
Thermal disequilibration of ions and electrons by collisionless plasma turbulence
Authors: Kawazura Yohei , Barnes Michael , Schekochihin Alexander A.
Published: January 2019

Significance

Large-scale astrophysical processes inject energy into turbulent motions and electromagnetic fields, which carry this energy to small scales and eventually thermalize it. How this energy is partitioned between ions and electrons is important both in plasma physics and in astrophysics. Here we determine this energy partition via gyrokinetic turbulence simulations and provide a simple prescription for the ion-to-electron heating ratio. We find that turbulence promotes disequilibration of the species: When magnetic energy density is greater than the thermal energy density, electrons are preferentially heated, whereas when it is smaller, ions are. This is a relatively rare example of nature promoting an ever more out-of-equilibrium state in an environment where particle collisions are not frequent enough to equalize the temperatures of the species.
Allele frequency dynamics in a pedigreed natural population
Authors: Chen Nancy , Juric Ivan , Cosgrove Elissa J. , Bowman Reed , Fitzpatrick John W. , Schoech Stephan J. , Clark Andrew G. , Coop Graham
Published: January 2019

A central goal of population genetics is to understand how genetic drift, natural selection, and gene flow shape allele frequencies through time. However, the actual processes underlying these changes—variation in individual survival, reproductive success, and movement—are often difficult to quantify. Fully understanding these processes requires the population pedigree, the set of relationships among all individuals in the population through time. Here, we use extensive pedigree and genomic information from a long-studied natural population of Florida Scrub-Jays (
Aphelocoma coerulescens
) to directly characterize the relative roles of different evolutionary processes in shaping patterns of genetic variation through time. We performed gene dropping simulations to estimate individual genetic contributions to the population and model drift on the known pedigree. We found that observed allele frequency changes are generally well predicted by accounting for the different genetic contributions of founders. Our results show that the genetic contribution of recent immigrants is substantial, with some large allele frequency shifts that otherwise may have been attributed to selection actually due to gene flow. We identified a few SNPs under directional short-term selection after appropriately accounting for gene flow. Using models that account for changes in population size, we partitioned the proportion of variance in allele frequency change through time. Observed allele frequency changes are primarily due to variation in survival and reproductive success, with gene flow making a smaller contribution. This study provides one of the most complete descriptions of short-term evolutionary change in allele frequencies in a natural population to date.
Analysis of research intensity on infectious disease by disease burden reveals which infectious diseases are neglected by researchers
Authors: Furuse Yuki
Published: January 2019

Significance

Threats from emerging and reemerging infectious diseases have increased globally. However, neglected tropical diseases, such as Chagas disease and schistosomiasis, are believed to attract low attention. We investigated which infectious diseases have been neglected by researchers and which have received attention through an analysis of disease burden and research activity. We found, for example, that influenza and HIV/AIDS have attracted high research attention in relation to their disease burden, while paratyphoid fever has attracted low attention considering the disease burden. Interestingly, not all so-called neglected tropical diseases were subject to low research intensity. Further discussion must occur with regard to the appropriate allocation of resources for research into infectious diseases.
ParST is a widespread toxin–antitoxin module that targets nucleotide metabolism
Authors: Piscotta Frank J. , Jeffrey Philip D. , Link A. James
Published: January 2019

Toxin–antitoxin (TA) systems interfere with essential cellular processes and are implicated in bacterial lifestyle adaptations such as persistence and the biofilm formation. Here, we present structural, biochemical, and functional data on an uncharacterized TA system, the COG5654–COG5642 pair. Bioinformatic analysis showed that this TA pair is found in 2,942 of the 16,286 distinct bacterial species in the RefSeq database. We solved a structure of the toxin bound to a fragment of the antitoxin to 1.50 Å. This structure suggested that the toxin is a mono-ADP-ribosyltransferase (mART). The toxin specifically modifies phosphoribosyl pyrophosphate synthetase (Prs), an essential enzyme in nucleotide biosynthesis conserved in all organisms. We propose renaming the toxin ParT for Prs ADP-ribosylating toxin and ParS for the cognate antitoxin. ParT is a unique example of an intracellular protein mART in bacteria and is the smallest known mART. This work demonstrates that TA systems can induce bacteriostasis through interference with nucleotide biosynthesis.
Rigidification of the
Escherichia coli
cytoplasm by the human antimicrobial peptide LL-37 revealed by superresolution fluorescence microscopy
Authors: Zhu Yanyu , Mohapatra Sonisilpa , Weisshaar James C.
Published: January 2019

Significance

Natural antimicrobial peptides (AMPs) that exhibit broad-spectrum antibacterial activity are often highly positively charged. Fluorescence microscopy shows that after permeabilization of
Escherichia coli
membranes by the cationic AMP LL-37 a massive influx of peptide freezes the diffusive motion of the chromosomal DNA and a subset of ribosomes. Both are highly negatively charged. Cells cannot recover growth. We suggest that LL-37 forms noncovalent, electrostatic linkages between DNA strands and among polyribosomes, rigidifying the entire cytoplasm. While the preponderance of polyanionic biopolymers in the cytoplasm facilitates diffusion in normal growth, this same characteristic renders the bacterium highly susceptible to attack by polycationic AMPs. The results help explain why bacteria develop resistance to AMPs very slowly and may inform the design of new antibacterial agents.
Ca
2+
-activated Cl
−
current ensures robust and reliable signal amplification in vertebrate olfactory receptor neurons
Authors: Reisert Johannes , Reingruber Jürgen
Published: January 2019

Significance

The cilia of olfactory receptor neurons, embedded in the nasal mucus, are tiny organelles that detect and transduce inhaled odorants into electrical currents. We addressed the long-standing question of why the olfactory transduction pathway relies on the activation of a depolarizing

Cl

−

current as the main amplification step, contrary to an otherwise more common

Na

+

current. Our results show that a

Cl

−

as opposed to a

Na

+

current provides several major advantages: It renders the odorant response robust against mucosal ion concentration changes, it keeps the intracellular

Na

+

concentration low to ensure

Ca

2
+

clearance, and it prevents an increase in the ciliary osmotic pressure. As a result, olfaction functions faithfully even in an unstable nasal environment with fluctuating ion concentrations.
Novel genetic code and record-setting AT-richness in the highly reduced plastid genome of the holoparasitic plant
Balanophora
Authors: Su Huei-Jiun , Barkman Todd J. , Hao Weilong , Jones Samuel S. , Naumann Julia , Skippington Elizabeth , Wafula Eric K. , Hu Jer-Ming , Palmer Jeffrey D. , dePamphilis Claude W.
Published: January 2019

Plastid genomes (plastomes) vary enormously in size and gene content among the many lineages of nonphotosynthetic plants, but key lineages remain unexplored. We therefore investigated plastome sequence and expression in the holoparasitic and morphologically bizarre Balanophoraceae. The two
Balanophora
plastomes examined are remarkable, exhibiting features rarely if ever seen before in plastomes or in any other genomes. At 15.5 kb in size and with only 19 genes, they are among the most reduced plastomes known. They have no tRNA genes for protein synthesis, a trait found in only three other plastid lineages, and thus
Balanophora
plastids must import all tRNAs needed for translation.
Balanophora
plastomes are exceptionally compact, with numerous overlapping genes, highly reduced spacers, loss of all
cis
-spliced introns, and shrunken protein genes. With A+T contents of 87.8% and 88.4%, the
Balanophora
genomes are the most AT-rich genomes known save for a single mitochondrial genome that is merely bloated with AT-rich spacer DNA. Most plastid protein genes in
Balanophora
consist of ≥90% AT, with several between 95% and 98% AT, resulting in the most biased codon usage in any genome described to date. A potential consequence of its radical compositional evolution is the novel genetic code used by
Balanophora
plastids, in which TAG has been reassigned from stop to tryptophan. Despite its many exceptional properties, the
Balanophora
plastome must be functional because all examined genes are transcribed, its only intron is correctly
trans
-spliced, and its protein genes, although highly divergent, are evolving under various degrees of selective constraint.
Role of domain interactions in the aggregation of full-length immunoglobulin light chains
Authors: Rennella Enrico , Morgan Gareth J. , Kelly Jeffery W. , Kay Lewis E.
Published: January 2019

Significance

The misfolding and/or aggregation of proteins can give rise to amyloid diseases, including immunoglobulin light-chain (LC) amyloidosis, leading to large proteinaceous deposits in organs throughout the body. A third of patients die within a year of diagnosis. The LC structure–proteotoxicity relationships and how protein aggregation causes degeneration are not understood. Using solution NMR we characterized the strengths of interactions between different domains in the dimeric 2-domain immunoglobulin LC structure to dissect their relative importance in protecting against aggregation. The constant domain (C
L
) is particularly important in conferring protection, as are the stabilities of the individual domains. Our studies establish a threshold of stability, below which aggregation occurs rapidly, suggesting that stabilizing the C
L
–C
L
domain interface could prevent aggregation.
Herpes simplex virus 1 ICP8 mutant lacking annealing activity is deficient for viral DNA replication
Authors: Weerasooriya Savithri , DiScipio Katherine A. , Darwish Anthar S. , Bai Ping , Weller Sandra K.
Published: January 2019

Significance

Herpes simplex virus (HSV) is a ubiquitous human pathogen. The mechanism of HSV DNA replication is poorly understood. ICP8, the multifunctional HSV single-strand DNA binding protein (SSB), is essential for viral growth and DNA replication. ICP8 is also capable of efficiently annealing complementary ssDNA and has been classified as a single-strand annealing protein (SSAP); however, the role of annealing during infection is still unclear. In this paper, we characterize a mutant of ICP8 that retains many of its functions as a replicative SSB but lacks annealing activity. We show that ICP8 annealing activity is essential for viral DNA replication. These findings support our hypothesis that HSV-1 uses recombination-dependent mechanisms to replicate its DNA.
Unregulated antigen-presenting cell activation by T cells breaks self tolerance
Authors: Yi Jaeu , Jung Jisun , Hong Sung-Wook , Lee Jun Young , Han Daehee , Kim Kwang Soon , Sprent Jonathan , Surh Charles D.
Published: January 2019

T cells proliferate vigorously following acute depletion of CD4+Foxp3+T regulatory cells [natural Tregs (nTregs)] and also when naive T cells are transferred to syngeneic, nTreg-deficientRag1−/−hosts. Here, using mice raised in an antigen-free (AF) environment, we show that proliferation in these two situations is directed to self ligands rather than food or commensal antigens. In both situations, the absence of nTregs elevates B7 expression on host dendritic cells (DCs) and enables a small subset of naive CD4 T cells with high self affinity to respond overtly to host DCs: bidirectional T/DC interaction ensues, leading to progressive DC activation and reciprocal strong proliferation of T cells accompanied by peripheral Treg (pTreg) formation. Likewise, high-affinity CD4 T cells proliferate vigorously and form pTregs when cultured with autologous DCs in vitro in the absence of nTregs: this anti-self response is MHCII/peptide dependent and elicited by the raised level of B7 on cultured DCs. The data support a model in which self tolerance is imposed via modulation of CD28 signaling and explains the pathological effects of superagonistic CD28 antibodies.
Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response
Authors: Park Donglim Esther , Cheng Jingwei , Berrios Christian , Montero Joan , Cortés-Cros Marta , Ferretti Stéphane , Arora Reety , Tillgren Michelle L. , Gokhale Prafulla C. , DeCaprio James A.
Published: January 2019

Significance

Merkel cell carcinoma (MCC) is an aggressive skin cancer. While virus-negative [Merkel cell polyomavirus (MCV)] MCC contains inactivating mutations in RB and p53, MCV-positive MCC usually contains wild-type RB and p53. We demonstrate that MCV large T antigen binding to RB results in p53 activation, while MCV small T antigen reduces p53 activation by increasing levels of MDM2 and CK1

α

, an activator of MDM4. Targeted degradation of CK1

α

by lenalidomide or a specific MDM4 inhibitor acts synergistically with MDM2 inhibitors to activate p53 and induce apoptosis. Our work uncovers the mechanism behind MCV control of p53 in MCC and demonstrates the utility of targeting MDM2 and MDM4 combinatorially in p53 wild-type tumors.
Mcm10 has potent strand-annealing activity and limits translocase-mediated fork regression
Authors: Mayle Ryan , Langston Lance , Molloy Kelly R. , Zhang Dan , Chait Brian T. , O’Donnell Michael E.
Published: January 2019

Significance

Fork regression is a way of circumventing or dealing with DNA lesions and is important to genome integrity. Fork regression is performed by double-strand DNA ATPases that initially cause newly synthesized strands to unpair from the parental strands, followed by pairing of the new strands and reversal of the fork. This study shows that Mcm10, an essential replication factor, efficiently anneals complementary strands and also inhibits fork regression by SMARCAL1. Moreover, the study localizes the Mcm10 DNA-binding domain to the N-terminal domains of the replicative CMG helicase at the forked nexus. Thus, forks that are unimpeded would contain Mcm10 at a strategic position where its DNA-binding and/or annealing function may block fork regression enzymes and thereby protect active forks from becoming reversed.
A nostalgic look back 40 years after the discovery of receptor-mediated endocytosis
Authors: Schmid Sandra L.
Published: January 2019

The concept of receptor-mediated endocytosis was proposed 40 years ago in a seminal review by Joseph Goldstein, Michael Brown, and Richard Anderson. Not only their hypothesis but also the lessons learned that guided their discovery have stood the test of time. I recount some of these herein, while also looking back nostalgically at a forgotten era of scientific communication.
Transthoracic clamp versus endoaortic balloon occlusion in minimally invasive mitral valve surgery: a systematic review and meta-analysis
Authors: Rival Paul Martin , Moore Theresa H M , McAleenan Alexandra , Hamilton Hamish , Du Toit Zachary , Akowuah Enoch , Angelini Gianni D , Vohra Hunaid A
Published: January 2019

This systematic review and meta-analysis aims to determine outcomes following aortic occlusion with the transthoracic clamp (TTC) versus endoaortic balloon occlusion (EABO) in patients undergoing minimally invasive mitral valve surgery. A subgroup analysis compares TTC to EABO with femoral cannulation separately from EABO with aortic cannulation. We searched Medline and Embase up to December 2018. Two people independently and in duplicate screened title and abstracts, full-text reports, extracted data and assessed the risk of bias using the Cochrane risk-of-bias tool for non-randomized studies. We identified 1564 reports from which 11 observational studies with 4181 participants met the inclusion criteria. We found no evidence of difference in the risk of postoperative death or cerebrovascular accident (CVA) between the 2 techniques. Evidence for a reduction in aortic dissection with TTC was found: 4 of 1590 for the TTC group vs 19 of 2492 for the EABO group [risk ratio 0.33, 95% confidence interval (CI) 0.12–0.93; P = 0.04]. There was no difference in aortic cross-clamp (AoX) time between TTC and EABO [mean difference (MD) −5.17 min, 95% CI −12.40 to 2.06; P = 0.16]. TTC was associated with a shorter AoX time compared to EABO with femoral cannulation (MD −9.26 min, 95% CI −17.00 to −1.52; P = 0.02). EABO with aortic cannulation was associated with a shorter AoX time compared to TTC (MD 7.77 min, 95% CI 3.29–12.26; P < 0.001). There was no difference in cardiopulmonary bypass (CPB) time between TTC and EABO with aortic cannulation (MD −4.98 min, 95% CI −14.41 to 4.45; P = 0.3). TTC was associated with a shorter CPB time compared to EABO with femoral cannulation (MD −10.08 min, 95% CI −19.93 to −0.22; P = 0.05). Despite a higher risk of aortic dissection with EABO, the rates of survival and cerebrovascular accident across the 2 techniques are similar in minimally invasive mitral valve surgery.
A Scoping Review of Literature on Sex and Gender Differences Among Dementia Spousal Caregivers
Authors: Arbel Ifah , Bingham Kathleen S , Dawson Deirdre R
Published: January 2019

Background and Objectives

Sex and gender differences among dementia spousal caregivers have been investigated, but never systematically reviewed or synthesized. A synthesis of findings can help facilitate specificity in practice and in health policy development. As a first step towards such a synthesis, this scoping review reports the available evidence, identifies research gaps, and suggests possible directions for future research.

Research Design and Methods

A scoping review methodology was used to identify articles, and to chart and analyze data. Systematic searches for published, empirical studies, with an explicit goal or hypothesis related to sex or gender differences were conducted in seven databases.

Results

Sixty-one studies met inclusion criteria. Most (n = 45) were quantitative, cross-sectional studies. Caregivers included in the studies were generally 61–70 years old, Caucasian, middle-class, and highly educated. The most extensively investigated differences are: depression, burden, objective physical health, and informal supports.

Discussion and Implications

This scoping review is the first to summarize and critique the research on sex and gender differences that are specific to dementia spousal caregivers. The review can be used by researchers to make decisions regarding future systematic reviews and primary studies. To further strengthen the evidence base, future studies may benefit from including more caregivers of ethnic minorities, using more qualitative, longitudinal, or experimental designs, and focusing on variables needed to inform caregiving models and theories. Overall, this scoping review contributes to furthering gender-sensitive practices and policies that are better tailored to the specific needs of this population.
Regulation of GDSL Lipase Gene Expression by the MPK3/MPK6 Cascade and Its Downstream WRKY Transcription Factors in Arabidopsis Immunity
Authors: Han Xiaofei , Li Sen , Zhang Miao , Yang Liuyi , Liu Yidong , Xu Juan , Zhang Shuqun
Published: January 2019

Mitogen-activated protein kinase (MAPK) cascades serve as unified signaling modules in plant development and defense response. Previous reports demonstrated an essential role of Arabidopsis GLIP1, a member of the GDSL-like-motif lipase family, in both local and systemic resistance. GLIP1 expression is highly induced by pathogen attack. However, the one or more signaling pathways involved are unknown. Here, we report that two pathogen-responsive MAPKs, MPK3 and MPK6, are implicated in regulating gene expression of GLIP1 as well as GLIP3 and GLIP4. After gain-of-function activation, MPK3 and MPK6 can strongly induce the expression of GLIP1, GLIP3, and GLIP4. Both GLIP1 and GLIP3 contribute to the plant resistance to Botrytis cinerea. WRKY33, a MPK3/MPK6 substrate, is essential for the MPK3/MPK6-dependent GLIP1 induction. In addition, WRKY2 and WRKY34, two close homologs of WRKY33, have a minor effect in MPK3/MPK6-regulated GLIP1 expression in B. cinerea–infected plants. Chromatin immunoprecipitation-quantitative polymerase chain reaction analysis demonstrated that the GLIP1 gene is a direct target of WRKY33. In addition, we demonstrated that MPK3/MPK6-induced GLIP1 expression is independent of ethylene and jasmonic acid, two important hormones in plant defense. Our results provide insights into the regulation of the GLIP family at the transcriptional level in plant immunity.
A network-based integrated framework for predicting virus-host interactions
Authors: Wang Weili , Ren Jie , Tang Kujin , Dart Emily , Ignacio-Espinoza Julio Cesar , Fuhrman Jed A. , Braun Jonathan , Sun Fengzhu , Ahlgren Nathan A.
Published: January 2019

Metagenomic sequencing has greatly enhanced the discovery of viral genomic sequences; however it remains challenging to identify the host(s) of these new viruses. We developed VirHostMatcher-Net, a flexible, network-based, Markov random field framework for predicting virus-host interactions using multiple, integrated features: CRISPR sequences, sequence homology, and alignment-free similarity measures (and WIsH). Evaluation of this method on a benchmark set of 1,075 known viruses-host pairs yielded host prediction accuracy of 62% and 85% at the genus and phylum levels, representing 12-27% and 10-18% improvement respectively over previous single-feature prediction approaches. We applied our host-prediction tool to three metagenomic virus datasets: human gut crAss-like phages, marine viruses, and viruses recovered from globally-distributed, diverse habitats. Host predictions were frequently consistent with those of previous studies, but more importantly, this new tool made many more confident predictions than previous tools, up to 6-fold more (n>60,000), greatly expanding the diversity of known virus-host interactions.
Whole-genome sequencing of rare disease patients in a national healthcare system
Authors: Ouwehand Willem H ,   on behalf of the NIHR BioResource and the 100,000 Genomes Project
Published: January 2019

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and mediating genes for more than half such disorders remain to be discovered. We implemented whole-genome sequencing (WGS) in a national healthcare system to streamline diagnosis and to discover unknown aetiological variants, in the coding and non-coding regions of the genome. In a pilot study for the 100,000 Genomes Project, we generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 patients with detailed phenotypic data. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed aetiological. Using WGS of UK Biobank1, we showed that rare alleles can explain the presence of some individuals in the tails of a quantitative red blood cell (RBC) trait. Finally, we reported 4 novel non-coding variants which cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.
FinDonor 10 000 study: A cohort to identify iron depletion and factors affecting it in Finnish blood donors
Authors: Partanen Jukka , Niittymäki Pia , Nikiforow Nina , Palokangas Elina , Lobier Muriel , Larjo Antti , Mattila Pirkko , Castrén Johanna , Arvas Mikko
Published: January 2019

Background and Objectives

There is increasing evidence that frequent blood donation depletes the iron stores of some blood donors. The FinDonor 10 000 study was set up to study iron status and factors affecting iron stores in Finnish blood donors. In Finland, iron supplementation for at-risk groups has been in place since the 1980’s.

Material and Methods

2584 blood donors (N= 8003 samples) were recruited into the study alongside the standard donation at three donation sites in the capital region of Finland between 5/2015 and 12/2017. All participants were asked to fill out a questionnaire about their health and lifestyle. Blood samples were collected from the sample pouch of whole blood collection set, kept in cool temperature and processed centrally. Whole blood count, CRP, ferritin and sTFR were measured from the samples and DNA was isolated for GWAS studies.

Results

Participant demographics, albeit in general similar to the general blood donor population in Finland, indicated some bias toward older and more frequent donors. Participation in the study increased median donation frequency of the donors. Analysis of the effect of time lag from the sampling to the analysis and the time of day when sample was drawn revealed small but significant time-dependent changes.

Conclusion

The FinDonor cohort now provides us with tools to identify potential donor groups at increased risk of iron deficiency as factors explaining this risk. The increase in donation frequency during the study suggests that scientific projects can be used to increase the commitment of blood donors.
Detection of circulating extracellular mRNAs by modified small RNA-sequencing analysis
Authors: Akat Kemal M. , Lee Youngmin A. , Hurley Arlene , Morozov Pavel , Max Klaas E.A. , Brown Miguel , Bogardus Kimberly , Sopeyin Anuoluwapo , Hildner Kai , Diacovo Thomas , Neurath Markus F. , Borggrefe Martin , Tuschl Thomas
Published: January 2019

Extracellular mRNAs (ex-mRNAs) potentially supersede extracellular miRNAs (ex-miRNAs) and other RNA classes as biomarkers. Here, we present a comprehensive extracellular RNA (exRNA) study in human blood circulation based on conventional small RNA-sequencing (sRNA-seq) and sRNA-seq after T4 polynucleotide kinase (PNK) end-treatment of total exRNA isolated from serum and platelet-poor EDTA, ACD, and heparin plasma. Applying strict criteria for read mapping and annotation, we found that compared to conventional sRNA-seq PNK-treatment increased the detection of informative ex-mRNAs reads up to 50-fold. Based on captured ex-mRNAs from healthy individuals, we concluded that the exRNA pool is dominated by hematopoietic cells and platelets, with additional contribution from the liver. About 60% of the 15- to 42-nt long reads originated from the coding sequences, in a pattern reminiscent of ribosome-profiling studies for high abundance transcripts. Blood sample type had a considerable influence on the exRNA profile. The number of detected distinct ex-mRNA transcripts ranged from on average ~350 to 1100 in the different plasma types. In serum, additional transcripts from neutrophils and hematopoietic cells increased this number to ~2300. For EDTA and ACD, in particular, we found evidence of destabilization of mRNA and non-coding RNA ribonucleoprotein complexes. In a proof-of-concept study, we compared patients with acute coronary syndrome (ACS) to healthy controls. The improved tissue resolution of ex-mRNAs after PNK-treatment enabled us to detect a neutrophil-signature in ACS that escaped detection in an ex-miRNA analysis. Thus, ex-mRNAs provide superior resolution for the study of exRNA changes in vivo and ex vivo. They can be readily studied by sRNA-seq after T4 PNK end-treatment.