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Reactive oxygen species (ROS), a class of reactive oxidants, play critical roles in signal transduction, cell metabolism, immune defense, and other physiological processes. Abnormally excessive levels of ROS can cause diseases and thus, investigations into the relevant biology and medicine are significant. The behavior of ROS in inflammation has been rarely elucidated. In this work, two ROS fluorescent probes, FS-ROS1 and FS-ROS2 have been designed and synthesized. FS-ROS1 responds rapidly (~1 min) to ClO– and gradually (~30 min) to H2O2 with an increase in fluorescence at ~656 nm and 640 nm of more than 100-fold in vitro. At a concentration of 10 μM, FS-ROS1 labels the L929 cell and Raw264.7 cell wells in 30 min with excellent biocompatibility and without washing. After labelling, FS-ROS1 exhibited a rational fluorescence increase upon the addition of 1, 10, 100, and 200 μM of H2O2. Based on these results, inflammatory cells, stimulated with 800 nM dexamethasone and polyIC, showed a higher increase in fluorescence than the control cells. These results suggest that H2O2 and ClO– might be important signaling molecules during inflammations.

A novel method for the challenging synthesis of unsymmetrically tetrasubstituted NH-pyrroles from chalcone derivatives is reported. The pyrrolo[1,2-a]pyrimidine derivatives that were synthesized from NH-pyrroles exhibit AIE and AIEE property.

Pyrroles are among the most important heterocycles in pharmaceuticals and agrochemicals. Construction of pyrrole scaffolds with different substituents and a free NH group, however, is challenging. Herein, a metal-free method for the synthesis of unsymmetrically tetrasubstituted NH-pyrroles using a consecutive chemoselective double cyanation is reported. The desired pyrroles were obtained with yields up to 99% and good functional group tolerance. Mechanistic studies identified a reaction mechanism that features a subtle sequence of first cyano-addition and migration, followed by cyano-addition and aromatization to afford the pyrrole skeleton. Pyrrolo[1,2

The straightforward strategy of building a chiral C-O bond directly on a general carbon radical center is challenging and stereocontrol of the reactions of open-chain hydrocarbon radicals remains a largely unsolved problem. Advance in this elementary step will spur the development of asymmetric radical C-O bond construction. Herein, we report a copper-catalyzed regioselective and enantioselective carboesterification of substituted dienes using alkyl diacyl peroxides as the source of both the carbon and oxygen substituents. The participation of external acids in this reaction substantially extends its applicability and leads to structurally diverse allylic ester products. This work represents the advance in the key elementary reaction of intermolecular enantioselective construction of C-O bond on open-chain hydrocarbon radicals and may lead to the discovery of other asymmetric radical reactions., Stereocontrol of C–O bond formation from a carbon-based radical is very difficult due to the rapid inversion of the carbon radical. Here the authors present a method to form chiral esters from conjugated dienes with copper and chiral PyBox ligands, likely proceeding via an allylic radical.

The first iron-catalyzed asymmetric azidation of benzylic peresters has been reported with trimethylsilyl azide (TMSN3) as the azido source. Hydrocarbon radicals that lack of strong interactions were capable to be enantioselectively azidated. The reaction features good functional group tolerance, high yields, and mild conditions. The chiral benzylic azides can further be used in click reaction, phosphoramidation, and reductive amination, which demonstrate the synthetic values of this reaction.

Deep Convolutional Neural Networks (CNNs) have long been the architecture of choice for computer vision tasks. Recently, Transformer-based architectures like Vision Transformer (ViT) have matched or even surpassed ResNets for image classification. However, details of the Transformer architecture -- such as the use of non-overlapping patches -- lead one to wonder whether these networks are as robust. In this paper, we perform an extensive study of a variety of different measures of robustness of ViT models and compare the findings to ResNet baselines. We investigate robustness to input perturbations as well as robustness to model perturbations. We find that when pre-trained with a sufficient amount of data, ViT models are at least as robust as the ResNet counterparts on a broad range of perturbations. We also find that Transformers are robust to the removal of almost any single layer, and that while activations from later layers are highly correlated with each other, they nevertheless play an important role in classification., Accepted for publication at ICCV 2021. Rewrote Section 5 and made other minor changes throughout

A general oxyalkylation of terminal alkynes enabled by iron catalysis has been developed. Primary and secondary alkyl iodides acted as the alkylating reagents and afforded a range of α-alkylated ketones under mild reaction conditions. Acetyl tert-butyl peroxide (TBPA) was used as the radical relay precursor, providing the initiated methyl radical to start the radical relay process. Preliminary mechanistic studies were conducted, and late-stage functionalizations of natural product derivatives were performed.

Isochrysis galbana is an important producer in the aquatic ecosystem because of its rich fucoxanthin content and fast growth. However, little is known about its evolutionary adaptation to live in a specific, complex and harsh environment. We report a high-quality genome sequence of I. galbana LG007, which has a 92.73 Mb genome size, a contig N50 of 6.99 Mb and 14,900 protein-coding genes. Phylogenomic inferences confirmed the monophyly of Haptophyta, showing I. galbana is a sister to E. huxleyi and C. tobinii. Evolutionary analysis revealed an estimated divergence of I. galbana from its close relative E. huxleyi ~133 million years ago, and I. galbana underwent one round of whole-genome duplication. Genes related to environmental adaptation and metabolic regulation in I. galbana were relatively conserved, but the basic transcriptional regulation toolkit for terrestrial plant development has been contracted or was not detected. The domain identification of one novel fucoxanthin biosynthesis gene that encodes diadinoxanthin-fucoxanthin hydroxylase (DFH) was investigated. Comparative genomic analysis revealed that I. galbana acquired several transcription factors specific to the control of pigment accumulation and production of LHCX2 to harvest blue-green light, which facilitates adaptation to the underwater environment. These findings provide new insights into the genomic characteristics of I. galbana and algae evolution for adaptation to blue-green light underwater.

The S-shaped hydrofoil is often used in the design of reversible machinery due to its centrally symmetrical camber line. The objective of this paper is to study the influence of cloud cavitation on the flow structure and the unsteady characteristics of lift and drag around an S-shaped hydrofoil via experimental tests and numerical simulations. In the experimental component, the tests were carried out in a cavitation tunnel and a high-speed camera was used to record the cavitation details around the S-shaped hydrofoil with different cavitation numbers. The experimental results show that sheet cavitation gradually transforms into cloud cavitation with a decrease in the inlet cavitation number, the maximum cavity length increases faster after the occurrence of cloud cavitation, and the shedding cycle time of cloud cavitation gradually increases with a decrease in the inlet cavitation number. In the numerical component, the numerical results are in good agreement with the experimental data. The numerical results show that the movement of the re-entrant jet is the main factor for the formation of the cloud cavitation around the S-shaped hydrofoil. The shedding cloud cavity induces the U-shaped vortex structure around the S-shaped hydrofoil, and it produces a higher vorticity distribution around the cavity. The periodic motion of cloud cavity causes the unsteady fluctuation of the lift–drag coefficient of the S-shaped hydrofoil, and because of the unique pressure distribution characteristics of the S-shaped hydrofoil, the lift and drag coefficient appeared as two peaks in one typical cycle of cloud cavitation.

DNA methylation abnormality is closely related to tumor occurrence and development. Chemical inhibitors targeting DNA methyltransferase (DNMTis) have been used in treating cancer. However, the impact of DNMTis on antitumor immunity has not been well elucidated. In this study, we show that zebularine (a demethylating agent) treatment of cancer cells led to increased levels of interferon response in a cyclic guanosine monophosphate-AMP (cGAMP) synthase (cGAS)- and stimulator of interferon genes (STING)-dependent manner. This treatment also specifically sensitized the cGAS-STING pathway in response to DNA stimulation. Incorporation of zebularine into genomic DNA caused demethylation and elevated expression of a group of genes, including STING. Without causing DNA damage, zebularine led to accumulation of DNA species in the cytoplasm of treated cells. In syngeneic tumor models, administration of zebularine alone reduced tumor burden and extended mice survival. This effect synergized with cGAMP and immune checkpoint blockade therapy. The efficacy of zebularine was abolished in nude mice and in cGAS(−/−) or STING(−/−) mice, indicating its dependency on host immunity. Analysis of tumor cells indicates upregulation of interferon-stimulated genes (ISGs) following zebularine administration. Zebularine promoted infiltration of CD8 T cells and natural killer (NK) cells into tumor and therefore suppressed tumor growth. This study unveils the role of zebularine in sensitizing the cGAS-STING pathway to promote anti-tumor immunity and provides the foundation for further therapeutic development.

This paper reports a new method for the generation of substituted 1,3-enynes, whose synthesis by other methods could be a challenge. The dehydrative decarboxylative cascade coupling reaction of propargyl alcohol with alkyl peroxides is enabled by an iron catalyst and alkylating reagents. Primary, secondary, and tertiary alkyl groups can be introduced into 1,3-enynes, affording various substituted 1,3-enynes in moderate to good yields. Mechanistic studies suggest the involvement of a radical-polar crossover pathway.

An environmentally benign, copper-catalyzed diazidation of a broad range of olefins, including vinylarenes, unactivated alkenes, allene, and dienes, under mild conditions with TMSN3 (trimethylazidosilane) as azido source, has been developed. This reaction can be carried out in organic solvent or in aqueous solution where water is the sole solvent. The functional group compatibility of this reaction is good, which is proved by late-stage functionalizations of complex substrates.

A highly regioselective and diastereoselective oxa-Diels-Alder reaction catalyzed by AlCl3 has been developed. This reaction is efficient and characterized by good functional group compatibility, F, Cl, CN, NO2, OMe and thiophenyl groups are tolerated. A Lewis acid catalyzed concerted cycloaddition mechanism is proposed based on the results.

MicroRNAs are small non-coding RNAs acting as posttranscriptional repressors of gene expression. Identifying mRNA targets of a given miRNA remains an outstanding challenge in the field. We have developed a new experimental approach, TargetLink, that applied locked nucleic acid (LNA) as the affinity probe to enrich target genes of a specific microRNA in intact cells. TargetLink also consists a rigorous and systematic data analysis pipeline to identify target genes by comparing LNA-enriched sequences between experimental and control samples. Using miR-21 as a test microRNA, we identified 12 target genes of miR-21 in a human colorectal cancer cell by this approach. The majority of the identified targets interacted with miR-21 via imperfect seed pairing. Target validation confirmed that miR-21 repressed the expression of the identified targets. The cellular abundance of the identified miR-21 target transcripts varied over a wide range, with some targets expressed at a rather low level, confirming that both abundant and rare transcripts are susceptible to regulation by microRNAs, and that TargetLink is an efficient approach for identifying the target set of a specific microRNA in intact cells. C20orf111, one of the novel targets identified by TargetLink, was found to reside in the nuclear speckle and to be reliably repressed by miR-21 through the interaction at its coding sequence.

Re-examination of the Late Cretaceous Yangmeikeng tracksite, in the Zhutian Formation (Nanxiong Group) near Nanxiong, Guangdong Province, China, has led to the documentation of over 30 vertebrate tracks. The track assemblage is dominated by large and small ornithopod tracks. The larger ornithopod tracks have been assigned to Hadrosauropodus nanxiongensis and Hadrosauropodus isp. indet. The smaller ornithopod tracks are consistently incomplete, showing only three pes digit traces, without heel or manus impressions. For this reason the smaller tracks probably represent pes tracks penetrating from a higher layer, and therefore have not been assigned to any particular ichnotaxon. Previous photography at Yangmeikeng site confirms the presence of at least one small Wupus-like theropod track and a Pteraichnus-like pterosaur pes track. Large enigmatic didactyl tracks could be of deinonychosaurian affinity, but are more likely the poorly preserved prints of a tridactyl theropod trackmaker. The Nanxiong dinosaur tracks and skeleton records represent the most important and diverse ichnofauna from Upper Cretaceous strata of South China, and can be compared with the Shandong and Heilongjiang Late Cretaceous faunas. The composition of the ichnofauna, is significant because it reflects a diverse tetrapod community with hadrosaurs, avian theropods, non-avian theropods and pterosaurs, a co-occurrence not evident from the skeletal record of this region. From a global perspective this assemblage permits a unique insight into archosaur communities and interaction of animals in a typical Late Cretaceous lakeshore environment. Non-avian theropods may have been attracted by the other groups that were considered as a potential prey.

Proteasomes are highly abundant and conserved protease complexes that eliminate unwanted proteins in the cells. As a single-chain ATP-independent nuclear proteasome activator, proteasome activator 200 (PA200) associates with 20S core particle to form proteasome complex that catalyzes polyubiquitin-independent degradation of acetylated histones, thus playing a pivotal role in DNA repair and spermatogenesis. Here, we present cryo–electron microscopy (cryo-EM) structures of the human PA200-20S complex and PA200 at 2.72 Å and 3.75 Å, respectively. PA200 exhibits a dome-like architecture that caps 20S and uses its C-terminal YYA (Tyr-Tyr-Ala) to induce the α-ring rearrangements and partial opening of the 20S gate. Our structural data also indicate that PA200 has two openings formed by numerous positively charged residues that respectively bind (5,6)-bisdiphosphoinositol tetrakisphosphate (5,6[PP]2-InsP4) and inositol hexakisphosphate (InsP6) and are likely to be the gates that lead unfolded proteins through PA200 and into the 20S. Besides, our structural analysis of PA200 found that the bromodomain (BRD)-like (BRDL) domain of PA200 shows considerable sequence variation in comparison to other human BRDs, as it contains only 82 residues because of a short ZA loop, and cannot be classified into any of the eight typical human BRD families. Taken together, the results obtained from this study provide important insights into human PA200-induced 20S gate opening for substrate degradation and the opportunities to explore the mechanism for its recognition of H4 histone in acetylation-mediated proteasomal degradation., Proteasomes are highly abundant and conserved protease complexes that eliminate unwanted proteins in the cells. The cryo-EM structures of PA200 and the PA200-20S proteasome complex reveal two openings on PA200 which bind inositol phosphates as cofactors, and novel insights into PA200-induced gate-opening of 20S.

Celastrol is one of most potent bioactive molecule isolated from the medicinal plant Tripterygium wilfordii (Thunder God Vine) and is well known for its potential therapeutic value against various chronic diseases including the autoimmune diseases, such as systemic lupus erythematosus and Aicardi-Goutieres syndrome, or other interferonopathies. However, the underlying mechanism of celastrol function remains unclear. Here we showed that celastrol caused inhibition of interferon regulatory factor 3 (IRF3) activation leading to the down-regulation of the interferon response triggered by cytosolic nucleic acids in vitro and in vivo. Moreover, celastrol treatment markedly ameliorates the autoimmune phenotypes including myocarditis, aberrant interferon response and autoantibody production, as well as the excessive T-cell activation in Trex1-/- autoimmune disease mouse model. Collectively, our results indicate that celastrol inhibits interferon response by targeting IRF3 activation and may be used as an effective treatment for interferon response-dependent autoimmune diseases.

Numerous mammalian cells contain abundant Zn(2+) in their secretory granules, yet available Zn(2+) sensors lack the desired specificity and sensitivity for imaging granular Zn(2+). We developed a fluorescent zinc granule indicator, ZIGIR, that possesses numerous desired properties for live cell imaging, including >100-fold fluorescence enhancement, membrane permeability, and selective enrichment to acidic granules. The combined advantages endow ZIGIR with superior sensitivity and specificity for imaging granular Zn(2+). ZIGIR enables separation of heterogenous β cells based on their insulin content and sorting of mouse islets into pure α cells and β cells. In human islets, ZIGIR facilitates sorting of endocrine cells into highly enriched α cells and β cells, reveals unexpectedly high Zn(2+) activity in the somatostatin granule of some δ cells, and uncovers variation in the glucagon content among human α cells. We expect broad applications of ZIGIR for studying Zn(2+) biology and Zn(2+)-rich secretory granules and for engineering β cells with high insulin content for treating diabetes.

RSSs (reactive sulfur species) and their metabolites, such as H2S, Sn2−, SO32−/HSO3−, S2O42− and S2O52− (Reactive Inorganic Sulfur Species, RISSs), play a crucial role in the cushion against oxidative stress and the other physiological events. The molecular mechanisms how they affect cellular signaling and other physiological events remain largely unknown. To address their physiological functions, the techniques that can track their levels should be invaluable. Herein, six coumarin hemicyanine scaffolds (CH-RISSs) were synthesized and their fast and strong responses upon H2S, Sn2−, SO32−, HSO3−, S2O42− and S2O52− (Reactive Inorganic Sulfur Species, RISSs) were clarified in the absorption (colorimetric) and fluorescence (ratiometric) spectra, which showed good stability in the physiological pH (7.4). Upon the analytes, the maxima absorption of CH-RISSs switched from ~580 nm to ~400 nm in the absorption spectra. The fluorescence of CH-RISSs depleted at 650–660 nm and increased at 480–505 nm upon the RISSs. Both of coumarin hemicyanine structures with C12 alkyl chain (CH-RISS-3 and CH-RISS-6) showed quick and robust ratiometric fluorescence switch in the living cell imaging. Access to the fluorescent probes for RISSs sets the stage for applying the developing technologies to probe reactive sulfur biology in living systems.

Theoretical predictions of light beam interactions with jet engine exhaust are of importance for optimization of various optical systems, including LIDARs, imagers and communication links operating in the vicinity of aircrafts and marine vessels. Here we extend the analysis previously carried out for coherent laser beams propagating in jet engine exhaust, to the broad class of Gaussian Schell-Model (GSM) beams, being capable of treating any degree of coherence in addition to size and radius of curvature. The analytical formulas for the spectral density (SD) and the spectral degree of coherence (DOC) of the GSM beam are obtained and analyzed on passage through a typical jet engine exhaust region. It is shown that for sources with high coherence, the transverse profiles of the SD and the DOC of the GSM beams gradually transition from initially circular to elliptical shape upon propagation at very short ranges. However, such transition is suppressed for sources with lower coherence and disappears in the incoherent source limit, implying that the GSM source with low source coherence is an excellent tool for mitigation of the jet engine exhaust-induced anisotropy of turbulence. The physical interpretation and the illustration are included.

Copper is an important element indispensable for human life and health. Many copper-determining probes have been created for exploring its functional behavior in various cell types but few of them contains both fluorescent and colorimetric characters. In the present study, we developed a set of copper probes by synthesizing several novel thiophene-based Schiff bases in order to make a suitable sensor for quantifying and imaging copper in living cells. We find that the ligand FS-1 has a splendid selectivity and affinity toward Cu2+ among the common divalent metal ions. Living cell imaging show that FS-1 has a robust and repetitive fluorescence response in the presence of Cu2+ only in the cytosolic space of Hepg2 cell and not in the other cells examined. These data suggest that we have developed a new copper probe that can be used as a Cu2+ fluorescent and colorimetric sensor for in vivo and in vitro copper studies.

We recently used Virasoro symmetry considerations to propose an exact formula for a bulk proto-field $\phi$ in AdS$_3$. In this paper we study the propagator $\langle \phi \phi \rangle$. We show that many techniques from the study of conformal blocks can be generalized to compute it, including the semiclassical monodromy method and both forms of the Zamolodchikov recursion relations. When the results from recursion are expanded at large central charge, they match gravitational perturbation theory for a free scalar field coupled to gravity in our chosen gauge. We find that although the propagator is finite and well-defined at long distances, its perturbative expansion in $G_N = \frac{3}{2c}$ exhibits UV/IR mixing effects. If we nevertheless interpret $\langle \phi \phi \rangle$ as a probe of bulk locality, then when $G_N m_\phi \ll 1$ locality breaks down at the new short-distance scale $\sigma_* \sim \sqrt[4]{G_N R_{AdS}^3}$. For $\phi$ with very large bulk mass, or at small central charge, bulk locality fails at the AdS length scale. In all cases, locality `breakdown' manifests as singularities or branch cuts at spacelike separation arising from non-perturbative quantum gravitational effects., Comment: 42+17 pages, 7 figures

An environmentally benign, copper-catalyzed diazidation of a broad range of olefins, including vinylarenes, unactivated alkenes, allene, and dienes, under mild conditions with TMSN

The pancreatic islet beta cell plays an essential role in maintaining the normal blood glucose level by releasing insulin. Loss of functional beta cell mass leads to diabetes—a disease affecting ∼9% of the population worldwide. There has been great interest and intense effort in developing imaging probes for monitoring islet beta cells, and glucagon-like peptide-1 receptor (GLP-1R) has emerged as a valuable biomarker for targeting beta cells. However, efforts thus far in GLP-1R mediated beta cell labeling and imaging has largely, if not exclusively, focused on developing imaging probes for monitoring beta cell mass, and few studies have investigated imaging beta cell function (insulin release) through GLP-1R. We now report the design and synthesis of a bioconjugate, ZIMIR-Ex4(9-39), that consists of a fluorescent Zn(2+) sensor and a truncated exendin 4 peptide for imaging insulin/Zn(2+) release in islet beta cells. In vitro, the conjugate bound to Zn(2+) with high affinity and displayed a robust fluorescence enhancement upon Zn(2+) chelation. When added to beta cells at submicromolar concentration, ZIMIR-Ex4(9-39) rapidly labeled cell surface in minutes to report the dynamics of insulin/Zn(2+) release with high spatiotemporal resolution. Future explorations of this approach may lead to probes for tracking beta cell function using different imaging modalities.

Numerous mammalian cells contain Zn2+ in their secretory granules. During secretion, Zn2+ is coreleased with granular cargos into extracellular medium so Zn2+ serves as a convenient surrogate marker for tracking the dynamics of secretion. Fluorescent Zn2+ sensors that can be selectively targeted to cells of interest would be invaluable tools for imaging Zn2+ release in multicellular systems including tissues and live animals. Exploiting the HaloTag labeling technology and using an optimized linker, we have engineered a fluorescent Zn2+ indicator that displayed a 15-fold fluorescence enhancement upon Zn2+ binding while reacting efficiently with a HaloTag enzyme in a cellular environment. Two-color imaging of ZIMIR-HaloTag and a red-emitting calcium indicator in pancreatic islet beta cells demonstrated that photoactivation of a channelrhodopsin was able to induce exocytosis of Zn2+/insulin granules and revealed heterogeneity in secretory activity along the cell membrane that was uncoupled from cellular Ca2+ activity. This integrated photonic approach for imaging and controlling the release of large dense core granules provides exquisite cellular selectivity and should facilitate future studies of stimulus-secretion coupling and paracrine signaling in secretory cells.

One can obtain exact information about Virasoro conformal blocks by analytically continuing the correlators of degenerate operators. We argued in recent work that this technique can be used to explicitly resolve information loss problems in AdS$_3$/CFT$_2$. In this paper we use the technique to perform calculations in the small $1/c \propto G_N$ expansion: (1) we prove the all-orders resummation of logarithmic factors $\propto \frac{1}{c} \log z$ in the Lorentzian regime, demonstrating that $1/c$ corrections directly shift Lyapunov exponents associated with chaos, as claimed in prior work, (2) we perform another all-orders resummation in the limit of large $c$ with fixed $cz$, interpolating between the early onset of chaos and late time behavior, (3) we explicitly compute the Virasoro vacuum block to order $1/c^2$ and $1/c^3$, corresponding to $2$ and $3$ loop calculations in AdS$_3$, and (4) we derive the heavy-light vacuum blocks in theories with $\mathcal{N}=1,2$ superconformal symmetry., 34+20 pages, 2 figures

The numerical conformal bootstrap is used to study mixed correlators in $\mathcal{N}=1$ superconformal field theories (SCFTs) in $d=4$ spacetime dimensions. Systems of four-point functions involving scalar chiral and real operators are analyzed, including the case where the scalar real operator is the zero component of a global conserved current multiplet. New results on superconformal blocks as well as universal constraints on the space of 4D $\mathcal{N}=1$ SCFTs with chiral operators are presented. At the level of precision used, the conditions under which the putative "minimal" 4D $\mathcal{N}=1$ SCFT may be isolated into a disconnected allowed region remain elusive. Nevertheless, new features of the bounds are found that provide further evidence for the presence of a special solution to crossing symmetry corresponding to the "minimal" 4D $\mathcal{N}=1$ SCFT., Comment: 33 pages, 12 figures; v2: Some typos fixed

We analytically solve the conformal bootstrap equations in the Regge limit for large N conformal field theories. For theories with a parametrically large gap, the amplitude is dominated by spin-2 exchanges and we show how the crossing equations naturally lead to the construction of AdS exchange Witten diagrams. We also show how this is encoded in the anomalous dimensions of double-trace operators of large spin and large twist. We use the chaos bound to prove that the anomalous dimensions are negative. Extending these results to correlators containing two scalars and two conserved currents, we show how to reproduce the CEMZ constraint that the three-point function between two currents and one stress tensor only contains the structure given by Einstein-Maxwell theory in AdS, up to small corrections. Finally, we consider the case where operators of unbounded spin contribute to the Regge amplitude, whose net effect is captured by summing the leading Regge trajectory. We compute the resulting anomalous dimensions and corrections to OPE coefficients in the crossed channel and use the chaos bound to show that both are negative., Comment: 40 pages, 1 figure; V2: Small corrections and clarifications

Inference of colour patterning in extinct dinosaurs has been based on the relationship between the morphology of melanin-containing organelles (melanosomes) and colour in extant bird feathers. When this relationship evolved relative to the origin of feathers and other novel integumentary structures, such as hair and filamentous body covering in extinct archosaurs, has not been evaluated. Here we sample melanosomes from the integument of 181 extant amniote taxa and 13 lizard, turtle, dinosaur and pterosaur fossils from the Upper-Jurassic and Lower-Cretaceous of China. We find that in the lineage leading to birds, the observed increase in the diversity of melanosome morphologies appears abruptly, near the origin of pinnate feathers in maniraptoran dinosaurs. Similarly, mammals show an increased diversity of melanosome form compared to all ectothermic amniotes. In these two clades, mammals and maniraptoran dinosaurs including birds, melanosome form and colour are linked and colour reconstruction may be possible. By contrast, melanosomes in lizard, turtle and crocodilian skin, as well as the archosaurian filamentous body coverings (dinosaur 'protofeathers' and pterosaur 'pycnofibres'), show a limited diversity of form that is uncorrelated with colour in extant taxa. These patterns may be explained by convergent changes in the key melanocortin system of mammals and birds, which is known to affect pleiotropically both melanin-based colouration and energetic processes such as metabolic rate in vertebrates, and may therefore support a significant physiological shift in maniraptoran dinosaurs.

Background: The beneficial properties of tea polyphenols have been extensively studied; however, less attention has been paid to their effects, especially anti-inflammatory effect during exhaustive exercise. Objective: The present study assessed the potential protective effects of tea polyphenols against the fatigue, inflammation and tissue injury caused by an exhaustive exercise bout in rats. Design: Twenty-four healthy male rats were divided into three groups. Group C was a sedentary control group, Groups E+TP and Group E performed a single exhaustive swimming test; all groups had normal diets, but Group E+TP was supplemented with tea polyphenols. All rats were immediately euthanized after exhaustive exercise, and biochemical and inflammatory parameters, including lactic acid (LA), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), lactic dehydrogenase (LDH), and creatine kinase (CK) activity levels, were measured. Reverse transcription (RT) and Real-Time PCR was employed to evaluate the mRNA expression of IL-1β in the liver. Results: The results showed a decrease in serum LA levels (22%, p

In this paper, we prove that the "conformal collider bounds" originally proposed by Hofman and Maldacena hold for any unitary parity-preserving conformal field theory (CFT) with a unique stress tensor in spacetime dimensions larger than 2. In particular this implies that the ratio of central charges for a unitary 4d CFT lies in the interval $\frac{31}{18} \geq \frac{a}{c} \geq \frac{1}{3}$. For superconformal theories this is further reduced to $\frac{3}{2} \geq \frac{a}{c} \geq \frac{1}{2}$. The proof relies only on CFT first principles - in particular, bootstrap methods - and thus constitutes the first complete field theory proof of these bounds. We further elaborate on similar bounds for non-conserved currents and relate them to results obtained recently from deep inelastic scattering., 25 pages, 2 figures

We analytically study the lightcone limit of the conformal bootstrap equations for 4-point functions containing global symmetry currents and the stress tensor in 3d CFTs. We show that the contribution of the stress tensor to the anomalous dimensions of large spin double-twist states is negative if and only if the conformal collider physics bounds are satisfied. In the context of AdS/CFT these results indicate a relation between the attractiveness of AdS gravity and positivity of the CFT energy flux. We also study the contribution of non-Abelian conserved currents to the anomalous dimensions of double-twist operators, corresponding to the gauge binding energy of 2-particle states in AdS. We show that the representation of the double-twist state determines the sign of the gauge binding energy if and only if the coefficient appearing in the current 3-point function satisfies a similar bound, which is equivalent to an upper bound on the charge flux asymmetry of the CFT., Comment: 56 pages, 1 table

Aspects of black hole thermodynamics and information loss can be derived as a consequence of Virasoro symmetry. To bolster the connection between Virasoro conformal blocks and AdS$_3$ quantum gravity, we study sl$(2)$ Chern-Simons Wilson line networks and revisit the idea that they compute a variety of CFT$_2$ observables, including Virasoro OPE blocks, exactly. We verify this in the semiclassical large central charge limit and to low orders in a perturbative $1/c$ expansion. Wilson lines connecting the boundary to points in the bulk play a natural role in bulk reconstruction. Because quantum gravity in AdS$_3$ is rigidly fixed by Virasoro symmetry, we argue that sl$(2)$ Wilson lines provide building blocks for background independent bulk reconstruction. In particular, we show explicitly that they automatically compute the uniformizing coordinates appropriate to any background state., Comment: V3- Added some references V2- Significantly Expanded Appendix on Regulation; 32+21 pages

Current methods of monitoring insulin secretion lack the required spatial and temporal resolution to adequately map the dynamics of exocytosis of native insulin granules in intact cell populations in three dimensions. Exploiting the fact that insulin granules contain a high level of Zn 2+ , and that Zn 2+ is coreleased with insulin during secretion, we have developed a fluorescent, cell surface-targeted zinc indicator for monitoring induced exocytotic release (ZIMIR). ZIMIR displayed a robust fluorescence enhancement on Zn 2+ chelation and bound Zn 2+ with high selectivity against Ca 2+ and Mg 2+ . When added to cultured β cells or intact pancreatic islets at low micromolar concentrations, ZIMIR labeled cells rapidly, noninvasively, and stably, and it reliably reported changes in Zn 2+ concentration near the sites of granule fusion with high sensitivity that correlated well with membrane capacitance measurement. Fluorescence imaging of ZIMIR-labeled β cells followed the dynamics of exocytotic activity at subcellular resolution, even when using simple epifluorescence microscopy, and located the chief sites of insulin release to intercellular junctions. Moreover, ZIMIR imaging of intact rat islets revealed that Zn 2+ /insulin release occurred largely in small groups of adjacent β cells, with each forming a “secretory unit.” Concurrent imaging of ZIMIR and Fura-2 showed that the amplitude of cytosolic Ca 2+ elevation did not necessarily correlate with insulin secretion activity, suggesting that events downstream of Ca 2+ signaling underlie the cell-cell heterogeneity in insulin release. In addition to studying stimulation-secretion coupling in cells with Zn 2+ -containing granules, ZIMIR may find applications in β-cell engineering and screening for molecules regulating insulin secretion on high-throughput platforms.

Convenient procedure for coupling of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose and 4-nitroimidazole was provided to obtain β-anomer as major product. A novel category of nucleoside analogues with an imidazole base moiety bearing amino-acid residue was designed and synthesized to develop selective and effective antiviral agents. They were evaluated for the anti-HBV activity.

Novel bis(oxazoline) ligands derived from camphoric acid were prepared and applied to Cu-catalyzed asymmetric cyclopropanation of styrene or 1,1-diphenylethylene with diazoacetate. Good ee values (up to 81%) were obtained for 1,1-diphenylethylene; however, the enantioselectivities for styrene were poor. The chirality of the oxazolyl group dominated the configuration of the products. The rigid structure and the chiral centers in the camphor backbone of the ligands proved to be not helpful in increasing enantioselectivity.

A convenient procedure for coupling 1,2,3,5‐tetra‐O‐acetyl‐β‐D‐ribofuranose and 4‐nitroimidazole was developed to obtain β‐anomer as the major product. A novel category of nucleoside analogues with the introduction of natural L‐amino acids to the base moiety were designed and synthesized to develop selective and effective antiviral agents.

From easily available camphoric acid, endo‐2‐hydroxyepicamphor 1 and endo‐3‐hydroxycamphor 2 have been prepared as a mixture which can be further separated to pure forms. This method offers a convenient synthesis of 1 and 2.

We develop a systematic and general approach to study the effective Higgs Lagrangian in a supersymmetric framework in which the Higgs fields in the visible sector couple weakly to another sector. The extra sector may be strongly coupled in general. It is assumed to be superconformal in the ultraviolet, but develop a mass-gap with supersymmetry breaking in the infrared. The main technique used in our approach is that of the operator product expansion (OPE). By using OPE methods we are able to compute the parameters in the Higgs Lagrangian to quadratic order and make general statements that are applicable to many classes of models. Not only does this approach allow us to understand the traditional problems plaguing simple models from a different perspective, it also reveals new possibilities for solutions of these problems. The methods and results of our work should be useful in constructing a viable and natural model of physics beyond the Standard Model., 34 pages. v3: Fixed a typo in eq. (3.33) and a mistake in eq. (3.34)

Single nucleotide polymorphisms (SNPs) within the ADCY5 gene, encoding adenylate cyclase 5, are associated with elevated fasting glucose and increased type 2 diabetes (T2D) risk. Despite this, the mechanisms underlying the effects of these polymorphic variants at the level of pancreatic β-cells remain unclear. Here, we show firstly that ADCY5 mRNA expression in islets is lowered by the possession of risk alleles at rs11708067. Next, we demonstrate that ADCY5 is indispensable for coupling glucose, but not GLP-1, to insulin secretion in human islets. Assessed by in situ imaging of recombinant probes, ADCY5 silencing impaired glucose-induced cAMP increases and blocked glucose metabolism toward ATP at concentrations of the sugar >8 mmol/L. However, calcium transient generation and functional connectivity between individual human β-cells were sharply inhibited at all glucose concentrations tested, implying additional, metabolism-independent roles for ADCY5. In contrast, calcium rises were unaffected in ADCY5-depleted islets exposed to GLP-1. Alterations in β-cell ADCY5 expression and impaired glucose signaling thus provide a likely route through which ADCY5 gene polymorphisms influence fasting glucose levels and T2D risk, while exerting more minor effects on incretin action. © 2014 by the American Diabetes Association.

Based upon the new data of spore-pollen, plant and bivalve fossils, the coal-bearing strata in the Liupanshan Basin, Ningxia Hui Autonomous Region, Northwest China, which were formerly assigned to the Middle Jurassic Yan’an Formation, are divided into two parts in the present study. The major part is assigned to the Upper Triassic and the overlying part remains in the Jurassic. The new division is of significance to the oil-gas exploration of the basin and the interpretation of the sedimentary and tectonic history and the geographic environment of Liupanshan area during the early Mesozoic.

Numerous secretory cells use the regulated secretory pathway to release signaling molecules. Regulated secretion is an essential component of the intercellular communication network of a multicellular organism and serves diverse functions in neurobiology, endocrinology, and many other aspects of animal physiology. Probes that can monitor a specific exocytotic event with high temporal and spatial resolution would be invaluable tools for studying the molecular and cellular mechanisms underlying stimulus-secretion coupling, and for characterizing secretion defects that are found in different human diseases. This review summarizes different strategies and recent progress in developing fluorescent sensors for imaging regulated cell secretion.

Pancreatic β cells respond to increases in glucose concentration with enhanced metabolism, the closure of ATP-sensitive K+ channels and electrical spiking. The latter results in oscillatory Ca2+ influx through voltage-gated Ca2+ channels and the activation of insulin release. The relationship between changes in cytosolic and mitochondrial free calcium concentration ([Ca2+]cyt and [Ca2+]mit, respectively) during these cycles is poorly understood. Importantly, the activation of Ca2+-sensitive intramitochondrial dehydrogenases, occurring alongside the stimulation of ATP consumption required for Ca2+ pumping and other processes, may exert complex effects on cytosolic ATP/ADP ratios and hence insulin secretion. To explore the relationship between these parameters in single primary β cells, we have deployed cytosolic (Fura red, Indo1) or green fluorescent protein-based recombinant-targeted (Pericam, 2mt8RP for mitochondria; D4ER for the ER) probes for Ca2+ and cytosolic ATP/ADP (Perceval) alongside patch-clamp electrophysiology. We demonstrate that: (1) blockade of mitochondrial Ca2+ uptake by shRNA-mediated silencing of the uniporter MCU attenuates glucose- and essentially blocks tolbutamide-stimulated, insulin secretion; (2) during electrical stimulation, mitochondria decode cytosolic Ca2+ oscillation frequency as stable increases in [Ca2+]mit and cytosolic ATP/ADP; (3) mitochondrial Ca2+ uptake rates remained constant between individual spikes, arguing against activity-dependent regulation (“plasticity”) and (4) the relationship between [Ca2+]cyt and [Ca2+]mit is essentially unaffected by changes in endoplasmic reticulum Ca2+ ([Ca2+]ER). Our findings thus highlight new aspects of Ca2+ signalling in β cells of relevance to the actions of both glucose and sulphonylureas. Electronic supplementary material The online version of this article (doi:10.1007/s00424-012-1177-9) contains supplementary material, which is available to authorized users.

We extend the superembedding formalism for 4D N=1 superconformal field theory (SCFT) to the case of fields in arbitrary representations of the superconformal group SU(2,2|1). As applications we obtain manifestly superconformally covariant expressions for two- and three-point functions involving conserved currents, e.g. the supercurrent multiplet or global symmetry current superfields. The embedding space results are presented in a compact form by employing an index-free formalism. Our expressions are consistent with the literature, but the manifestly covariant forms of correlators presented here are new., Comment: 26 pages