Miracle-dz/UniFAR-FTUs huggingface dataset:
Highly Variable El Niño–Southern Oscillation Throughout the Holocene

ENSO Variability The El Niño–Southern Oscillation (ENSO) is the most energetic, quasiperiodic climate oscillation in the world—every few years warming large expanses of the surface equatorial Pacific Ocean surface and impacting temperatures and rainfall patterns across the globe. A pressing question, in the context of global warming, is whether ENSO might be affected by the rising atmospheric temperatures caused by anthropogenic greenhouse gas emissions. Climate models do not agree on the answer to this question, but one place to look for data about how global temperatures might influence ENSO is the record of past ENSO variability. Cobb et al. (p. 67) present a record of ENSO variability spanning the past 7000 years, in an attempt better to define its response to insolation forcing over this same period. The findings reveal high variability in ENSO behavior that has no clear dependence on insolation, which implies that a link to warming, if it exists, may be difficult to detect. Coral records show that the El Niño–Southern Oscillation may be less sensitive to past climate forcing than previously thought. The El Niño–Southern Oscillation (ENSO) drives large changes in global climate patterns from year to year, yet its sensitivity to continued anthropogenic greenhouse forcing is uncertain. We analyzed fossil coral reconstructions of ENSO spanning the past 7000 years from the Northern Line Islands, located in the center of action for ENSO. The corals document highly variable ENSO activity, with no evidence for a systematic trend in ENSO variance, which is contrary to some models that exhibit a response to insolation forcing over this same period. Twentieth-century ENSO variance is significantly higher than average fossil coral ENSO variance but is not unprecedented. Our results suggest that forced changes in ENSO, whether natural or anthropogenic, may be difficult to detect against a background of large internal variability.
Consensus algorithms and the decomposition-separation theorem

Convergence properties of time inhomogeneous Markov chain based discrete time linear consensus algorithms are analyzed. Provided that a so-called infinite jet flow property is satisfied by the underlying chains, necessary conditions for both consensus and multiple consensus are established. A recent extension by Sonin of the classical Kolmogorov-Doeblin decomposition-separation for homogeneous Markov chains to the non homogeneous case, is then employed to show that the obtained necessary conditions are also sufficient when the chain is of class P*, as defined by Touri and Nedič. It is also shown that Sonin's theorem leads to a rediscovery and generalization of most of the existing related consensus results in the literature.
Fluorescence Enhancement at Docking Sites of DNA-Directed Self-Assembled Nanoantennas

Building a Fluorescent Hotspot When two gold nanoparticles come close together, their overlapping plasmonic fields can create a region that acts as a nanoantenna that can enhance the fluorescent emission of a molecule. Acuna et al. (p. 506) used a surface-anchored DNA origami structure to assemble one or two gold nanoparticles next to a dye trapped within the structure. A > 100-fold enhancement in fluorescent emission was observed when the dye molecules were located in a 23-nm gap between two 100-nm gold nanoparticles. A DNA origami structure enhances the emission of a dye molecule by directing the proximate binding of gold nanoparticles. We introduce self-assembled nanoantennas to enhance the fluorescence intensity in a plasmonic hotspot of zeptoliter volume. The nanoantennas are prepared by attaching one or two gold nanoparticles (NPs) to DNA origami structures, which also incorporated docking sites for a single fluorescent dye next to one NP or in the gap between two NPs. We measured the dependence of the fluorescence enhancement on NP size and number and compare it to numerical simulations. A maximum of 117-fold fluorescence enhancement was obtained for a dye molecule positioned in the 23-nanometer gap between 100-nanometer gold NPs. Direct visualization of the binding and unbinding of short DNA strands, as well as the conformational dynamics of a DNA Holliday junction in the hotspot of the nanoantenna, show the compatibility with single-molecule assays.
Fibromyalgia in Maori and European New Zealanders

Aim: The objectives of this study were to determine: (i) the prevalence of fibromyalgia (FM) in Maori and European New Zealanders; and (ii) whether an association exists between hypermobility and FM. Methods: The 1990 American College of Rheumatology classification criteria were used to determine the prevalence of FM (both criteria), widespread pain (WP) only, and a tender point score (TPS) ≥ 11 only, in subjects aged 12 years and older. Beighton's method was used to determine hypermobility. Results: The prevalence of FM in Maori (1.1%) and European (1.5%) New Zealanders was similar (an overall prevalence of 1.3%); 1.7% Maori and 3.9% Europeans had WP only; and 1.7% Maori and 0.9% Europeans had a TPS of ≥ 11 only. In Maori, the prevalence of WP and a TPS ≥ 11 were the same and similar to the prevalence of FM. In Europeans, WP was 2.6-fold more common than FM. None of the subjects with FM, WP only or a TPS ≥ 11 only was hypermobile. Conclusion: The prevalence of FM was similar in Maori and European New Zealanders, and similar to most other population studies. In Maori, WP and a TPS ≥ 11 were equally specific for FM whereas in Europeans, WP was more sensitive but less specific for FM than a TPS ≥ 11. There was no association between hypermobility and FM.
Quantitative Phosphoproteomics Reveal mTORC1 Activates de Novo Pyrimidine Synthesis

Coordinating Metabolism Growth factors help to coordinate metabolism with growth in part by stimulating the activity of the protein kinase mTORC1 (mechanistic target of rapamycin complex 1). Ben-Sahra et al. (p. 1323, published online 21 February) and Robitaille et al. (p. 1320, published online 21 February) independently identified a key target of mTORC1—carbamolyl-phosphate synthase 2, or CAD, the rate-limiting enzyme for de novo synthesis of pyrimidines. Metabolomic profiling and phosphoproteomic analyses of normal cells and cells lacking signaling by mTORC1 converged on CAD as a key point at which growth-promoting signals also ramp up production of nucleic acids. In addition to its role in stimulating protein and lipid synthesis, the kinase mammalian target of rapamycin stimulates nucleotide biosynthesis. The Ser-Thr kinase mammalian target of rapamycin (mTOR) controls cell growth and metabolism by stimulating glycolysis and synthesis of proteins and lipids. To further understand the central role of mTOR in cell physiology, we used quantitative phosphoproteomics to identify substrates or downstream effectors of the two mTOR complexes. mTOR controlled the phosphorylation of 335 proteins, including CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase). CAD catalyzes the first three steps in de novo pyrimidine synthesis. mTORC1 indirectly phosphorylated CAD-S1859 through S6 kinase (S6K). CAD-S1859 phosphorylation promoted CAD oligomerization and thereby stimulated de novo synthesis of pyrimidines and progression through S phase of the cell cycle in mammalian cells. Thus, mTORC1 also stimulates the synthesis of nucleotides to control cell proliferation.
Kinematics and dynamics of a cable-like hyper-flexible manipulator

A Hyper-Flexible Manipulator (HFM, for short) is a kind of continuum robots with a simple mechanical structure like a cable, rope and string, which are useful tools utilized everywhere in various forms. In this paper, in order to achieve dexterous and useful manipulation by this type of robot, we discuss kinematics and dynamics of an HFM. We rigorously derive a spatial, nonlinear and continuum dynamics model with an underactuated mechanism using special kinematics based on curve geometry and theory of robot manipulation.
Platelet Factor 4 and Duffy Antigen Required for Platelet Killing of Plasmodium falciparum

Platelets Poison Parasites Activated platelets bound to malaria parasite–infected red blood cells were once thought to contribute to pathogenesis, but recently the platelets have been found to have a protective effect. McMorran et al. (p. 1348; see the Perspective by Engwerda and Good) extended this discovery to show that platelet activation releases intracellular granules containing a chemokine, PF4, which is internalized by Plasmodium falciparum–infected red cells. Subsequently, mature parasites within the cells die. The Duffy blood-group factor on red blood cells is known to act as a nonspecific receptor for chemokines, such as PF4, as well as a receptor for cell invasion by other species of malaria parasite. When the Duffy antigen was blocked by antibody treatment, platelets and PF4 were less able to kill the P. falciparum parasites within. Interaction of a platelet protein and a red cell protein enables platelets to attack malarial parasites inside red cells. Platelets restrict the growth of intraerythrocytic malaria parasites by binding to parasitized cells and killing the parasite within. Here, we show that the platelet molecule platelet factor 4 (PF4 or CXCL4) and the erythrocyte Duffy-antigen receptor (Fy) are necessary for platelet-mediated killing of Plasmodium falciparum parasites. PF4 is released by platelets on contact with parasitized red cells, and the protein directly kills intraerythrocytic parasites. This function for PF4 is critically dependent on Fy, which binds PF4. Genetic disruption of Fy expression inhibits binding of PF4 to parasitized cells and concomitantly prevents parasite killing by both human platelets and recombinant human PF4. The protective function afforded by platelets during a malarial infection may therefore be compromised in Duffy-negative individuals, who do not express Fy.
The Placental Mammal Ancestor and the Post–K-Pg Radiation of Placentals

Let There Be Mammals The timing of the evolution and radiation of placental mammals and their most recent common ancestor has long been debated, with many questions surrounding the relationships of groups that pre- and postdate the Cretaceous-Paleogene boundary (66 million years ago). While the fossil record suggests that placental mammals radiated after the Cretaceous, molecular clocks have consistently placed the ancestors of mammalian lineages earlier. O'Leary et al. (p. 662; see the Perspective by Yoder) examined the morphology of fossil and extant taxa and conclude that living placentals originated and radiated after the Cretaceous and reconstruct the phenotype of the ancestral placental mammal. Fossil and DNA phylogenies suggest that placental mammals diversified in the Cenozoic and reconstruct the ancestral form. [Also see Perspective by Yoder] To discover interordinal relationships of living and fossil placental mammals and the time of origin of placentals relative to the Cretaceous-Paleogene (K-Pg) boundary, we scored 4541 phenomic characters de novo for 86 fossil and living species. Combining these data with molecular sequences, we obtained a phylogenetic tree that, when calibrated with fossils, shows that crown clade Placentalia and placental orders originated after the K-Pg boundary. Many nodes discovered using molecular data are upheld, but phenomic signals overturn molecular signals to show Sundatheria (Dermoptera + Scandentia) as the sister taxon of Primates, a close link between Proboscidea (elephants) and Sirenia (sea cows), and the monophyly of echolocating Chiroptera (bats). Our tree suggests that Placentalia first split into Xenarthra and Epitheria; extinct New World species are the oldest members of Afrotheria.
Mononuclear cells infiltrating kidney allografts in the absence of rejection Effect of conversion from cyclosporin to azathioprine therapy

Abstract. Focal small mononuclear cell infiltrates were found in renal allograft biopsies of 13/14 transplant recipients with a stable function after long‐term cyclosporin A (CsA) therapy. Phenotypical analysis of the infiltrating cells using monoclonal antibodies showed a slight preponderance of T cells (56%8%), with only small percentages of B cells (5%2%), NK cells (2%1%), and monocytes (2%1%). Within the T‐cell population the median calculated CD4/CD8 ratio was 1:3. Thirty‐five percent of the infiltrating mononuclear cells remained unidentified with the monoclonal antibody panel used (silent cells). Three months after immunosuppressive therapy had been changed from CsA to azathioprine (AZA), the size of the infiltrates was significantly increased and there was a marked invasion of mononuclear cells between tubular epithelium despite a significant improvement in creatinine clearance (P < 0.01). The phenotypical composition of these infiltrates was dominated by T cells (84%3%), with a median CD4/CD8 ratio of 2:7 due to an increase in CD4+ cells and a decrease in CD8+ cells after conversion (P < 0.05). The percentages of B cells, NK cells, and monocytes showed no significant changes after conversion. During AZA therapy nearly all infiltrating mononuclear cells were stained with the monoclonals used, leaving no silent cells postconversion.
H5N1 Hybrid Viruses Bearing 2009/H1N1 Virus Genes Transmit in Guinea Pigs by Respiratory Droplet

Influencing Influenza Currently, there is anxiety that the avian H5N1 influenza virus will reassort with the highly transmissible and epidemic H1N1 subtype to trigger a virulent human pandemic. Y. Zhang et al. (p. 1459, published online 2 May) used reverse genetics to make all possible reassortants between a virulent bird H5N1 with genes from a human pandemic H1N1. Virulence was tested in mice and transmissibility was tested between guinea pigs, which have both avian- and human-like airway influenza virus receptors. To assess what is happening to the receptor-ligand interactions as a result of these mutations, W. Zhang et al. (p. 1463, published online 2 May) probed the structure of both wild-type and mutant hemagglutinin of H5 in complex with analogs of the avian and human receptor types. Certain mutations in the receptor-binding site changed binding affinity. Some reassortants between H5N1 and H1N1 influenza viruses are transmissible by respiratory droplet among mammals. In the past, avian influenza viruses have crossed species barriers to trigger human pandemics by reassorting with mammal-infective viruses in intermediate livestock hosts. H5N1 viruses are able to infect pigs, and some of them have affinity for the mammalian type α-2,6-linked sialic acid airway receptor. Using reverse genetics, we systematically created 127 reassortant viruses between a duck isolate of H5N1, specifically retaining its hemagglutinin (HA) gene throughout, and a highly transmissible, human-infective H1N1 virus. We tested the virulence of the reassortants in mice as a correlate for virulence in humans and tested transmissibility in guinea pigs, which have both avian and mammalian types of airway receptor. Transmission studies showed that the H1N1 virus genes encoding acidic polymerase and nonstructural protein made the H5N1 virus transmissible by respiratory droplet between guinea pigs without killing them. Further experiments implicated other H1N1 genes in the enhancement of mammal-to-mammal transmission, including those that encode nucleoprotein, neuraminidase, and matrix, as well as mutations in H5 HA that improve affinity for humanlike airway receptors. Hence, avian H5N1 subtype viruses do have the potential to acquire mammalian transmissibility by reassortment in current agricultural scenarios.
Aggravating Genetic Interactions Allow a Solution to Redundancy in a Bacterial Pathogen

Resolving Redundancy Many intracellular bacterial pathogens, like Salmonella, Legionella, and Chlamydia, make their homes within a host cell vacuole. Although we have cataloged many of the effector proteins secreted by these bacteria and their individual effects on host cell pathways, it is often not clear how the effectors work in concert to optimize bacterial growth. O'Connor et al. (p. 1440) tackled this complexity problem in Legionella pneumophila. This pathogen has an exceptionally long list of apparently redundant effector proteins to its name and, indeed, initial screening produced a library of 678 Legionella genes important for intracellular growth. Using bacterial mutagenesis to manipulate effector proteins and RNA interference in host cells to inhibit specific cellular membrane-trafficking pathways allowed systematic prediction by cluster analysis of sets of bacterial proteins with common targets required for intracellular growth. Insertional mutagenesis and depletion dissects the interplay between intracellular Legionella pneumophila and its host. Interactions between hosts and pathogens are complex, so understanding the events that govern these interactions requires the analysis of molecular mechanisms operating in both organisms. Many pathogens use multiple strategies to target a single event in the disease process, confounding the identification of the important determinants of virulence. We developed a genetic screening strategy called insertional mutagenesis and depletion (iMAD) that combines bacterial mutagenesis and RNA interference, to systematically dissect the interplay between a pathogen and its host. We used this technique to resolve the network of proteins secreted by the bacterium Legionella pneumophila to promote intracellular growth, a critical determinant of pathogenicity of this organism. This strategy is broadly applicable, allowing the dissection of any interface between two organisms involving numerous interactions.
Human Tau in an Ultradian Light-Dark Cycle

Multiple experimental approaches have been used to assess the free-running period, or “tau,” of humans. One approach has been to study circadian rhythms in free-running blind humans. For example, Sack et al. (1992) measured the plasma melatonin rhythm in 11 free-running blind people and reported an average tau of 24.55 h.
Right-Sizing Stem-Rust Research

Is increased support needed for wheat disease research to avert crop losses from current and future strains? Stem rust caused by Puccinia graminis f. sp. tritici is a potentially devastating fungal disease that can kill wheat plants and small grain cereals but more typically reduces foliage, root growth, and grain yields [e.g., (1, 2)]. After years of success in keeping the disease at bay, new virulent races (collectively referred to as “Ug99”) have emerged, with the potential to infect much of the world's wheat (3). Despite, or because of, the success of past research, these programs saw an eventual rundown in support (4). We estimate global wheat losses over the past 50 years absent investments in research to limit impacts of stem rust and discuss how this can inform decisions about “right-sizing” research investments.
Effects of prd Circadian Clock Mutations on FRQ-Less Rhythms in Neurospora

Rhythmic conidiation (spore formation) in Neurospora crassa provides a model system for investigating the molecular mechanisms of circadian rhythmicity. A feedback loop involving the frq, wc-1, and wc-2 gene products (FRQ/ WCC) is an important component of the mechanism; however, rhythmic conidiation can still be observed when these gene products are absent. The nature of the oscillator(s) that drives this FRQ-less rhythmicity (FLO) is an important question in Neurospora circadian biology. We have looked for interactions between FRQ/WCC and FLO by assaying the effects on FRQ-less rhythms of mutations known to affect the period in the presence of FRQ. We assayed 4 prd mutations (prd-1, prd-2, prd-3, and prd-4) under 2 conditions in frqnull strains: long-period free-running rhythms in chol-1 strains grown without choline, and heat-entrainable rhythms in choline-sufficient conditions. We found effects of all 4 mutations on both types of FRQ-less rhythms. The greatest effects were seen with prd-1 and prd-2, which abolished free-running rhythms in the chol-1; frq10 backgrounds and significantly affected entrained peak timing under heat-entrainment conditions in frq 10 backgrounds. The prd-3 and prd-4 mutations had more subtle effects on period and stability of free-running rhythms in the chol-1; frq10 backgrounds and had little effect on peak timing under heat-entrainment conditions in frq10 backgrounds. These results, along with previously published evidence for effects of prd mutations on other FRQ-less rhythms, suggest that either there are common components shared between the FRQ/WCC oscillator and several FRQ-less oscillators or that there is a single oscillator driving all conidiation rhythms. We favor a model of the Neurospora circadian system in which a single FRQ-less oscillator drives conidiation and interacts with the FRQ/WCC feedback loop; the output or amplitude of the FRQ-less oscillator can be affected by many gene products and metabolic conditions that reveal FRQ-less rhythmicity. We propose that prd-1 and prd-2 are good candidates for components of the FRQ-less oscillator and that prd-3 and prd-4 act on the system mainly through effects on FRQ/WCC.
Cyclic GMP-AMP Is an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA

DNA Sensing Is a (c)GAS DNA is normally localized to the nucleus, and so its cytoplasmic localization sends off alarm bells to the immune system because it indicates that a virus may have entered. But how does the immune system actually detect the DNA (see the Perspective by O'Neill)? Sun et al. (p. 786, published online 20 December) identify cyclic GMP-AMP (cGAMP) cyclase (cGAS), which can bind to cytoplasmic DNA directly and catalyze the production of cGAMP. cGAMP then acts as a second messenger to activate downstream signaling events that trigger antiviral immunity. Wu et al. (p. 826, published online 20 December) show that cGAMP, produced in response to cytoplasmic DNA, binds to and activates the signaling adaptor protein STING. Cyclic guanosine monophosphate–adenosine monophosphate acts as a second messenger that turns on antiviral immunity in response to cytoplasmic DNA. [Also see Perspective by O'Neill] Cytosolic DNA induces type I interferons and other cytokines that are important for antimicrobial defense but can also result in autoimmunity. This DNA signaling pathway requires the adaptor protein STING and the transcription factor IRF3, but the mechanism of DNA sensing is unclear. We found that mammalian cytosolic extracts synthesized cyclic guanosine monophosphate–adenosine monophosphate (cyclic GMP-AMP, or cGAMP) in vitro from adenosine triphosphate and guanosine triphosphate in the presence of DNA but not RNA. DNA transfection or DNA virus infection of mammalian cells also triggered cGAMP production. cGAMP bound to STING, leading to the activation of IRF3 and induction of interferon-β. Thus, cGAMP functions as an endogenous second messenger in metazoans and triggers interferon production in response to cytosolic DNA.