Nobel Laureates of the University of California

Two entangled 2D square covalent organic frameworks (COFs) have been synthesized from 4,4',4″,4‴-(9,9'-spirobi[fluorene]-2,2',7,7'-tetrayl)-tetrabenzaldehhyde (SFTB) and p-phenylenediamine (PPA) and benzidine (BZD) to form COF-38, [(SFTB)(PPA)₂]_imine, and its isoreticular form COF-39, [(SFTB)(BZD)₂]_imine. We also report the single-crystal electron diffraction structure of COF-39 and find that it is composed of mutually entangled 2D square nets (sql). These COFs represent the first examples of entangled 2D COF structures, which, as we illustrate, were made possible by our strategy of using the distorted tetrahedral SFTB building unit. SFTB overcomes the propensity of 2D COFs to stack through π-π stacking and allows entanglements to form. This work significantly adds to the design principles of COFs.

Unimolecular decomposition pathways are challenging to address in transition-metal catalysis and have previously not been suppressed via incorporation into a solid support. Two robust metal-organic frameworks (IRMOF-10 and bio-MOF-100) are used for the architectural stabilization of a structurally well-defined gold(III) catalyst. The inherent rigidity of these materials is utilized to preclude a unimolecular decomposition pathway - reductive elimination. Through this architectural stabilization strategy, decomposition of the incorporated gold(III) catalyst in the metal-organic frameworks is not observed; in contrast, the homogeneous analogue is prone to decomposition in solution. Stabilization of the catalyst in these metal-organic frameworks precludes leaching and enables recyclability, which is crucial for productive heterogeneous catalysis.

We present a strategy whereby selective formation of imine covalent organic frameworks (COFs) based on linking of triangles and squares into the fjh topology was achieved by the conformational design of the building units. 1,3,5-Trimethyl-2,4,6-tris(4-formylphenyl)benzene (TTFB, triangle) and 1,1,2,2-tetrakis(4-aminophenyl)ethene (ETTA, square) were reticulated into [(TTFB)₄(ETTA)₃]_imine, termed COF-790, which was fully characterized by spectroscopic, microscopic, and X-ray diffraction techniques. COF-790 exhibits permanent porosity and a Brunauer-Emmett-Teller (BET) surface area of 2650 m² g^-1. Key to the formation of this COF in crystalline form is the pre-designed conformation of the triangle and the square units to give dihedral angles in the range of 75-90°, without which the reaction results in the formation of amorphous product. We demonstrate the versatility of our strategy by also reporting the synthesis and characterization of two isoreticular forms of COF-790, COF-791 and COF-792, based on other square building units.

Coral snake's potent toxin identifiedThe bite of the Texas coral snake, although not fatal, causes excruciating and long-lasting pain. The toxin involved has now been characterized. The purified active component (MitTx) results from an unusual combination of two housekeeping enzymes, the dimerization of which produces a potent and selective activator of the acid-sensing ion channel ASIC1. Activation of ASIC1 recruits primary afferent nociceptors that detect thermal and inflammatory pain. The identification of MitTx, and the unexpected involvement of ASIC1 channels in nociception, open new routes for the study of these ion channels in particular, and pain research in general.

Transient receptor potential (TRP) ion channels are sophisticated signaling machines that detect a wide variety of environmental and physiological signals. Every cell in the body expresses one or more members of the extended TRP channel family, which consists of over 30 subtypes, each likely possessing distinct pharmacological, biophysical, and/or structural attributes. While the function of some TRP subtypes remains enigmatic, those involved in sensory signaling are perhaps best characterized and have served as models for understanding how these excitatory ion channels serve as polymodal signal integrators. With the recent resolution revolution in cryo-electron microscopy, these and other TRP channel subtypes are now yielding their secrets to detailed atomic analysis, which is beginning to reveal structural underpinnings of stimulus detection and gating, ion permeation, and allosteric mechanisms governing signal integration. These insights are providing a framework for designing and evaluating modality-specific pharmacological agents for treating sensory and other TRP channel-associated disorders.

When integral membrane proteins are visualized in detergents or other artificial systems, an important layer of information is lost regarding lipid interactions and their effects on protein structure. This is especially relevant to proteins for which lipid

In the version of this Article initially published, there were errors in the author affiliations, Fig. 3, main text and Acknowledgements section.

Applications of adenine base editors (ABEs) have been constrained by the limited compatibility of the deoxyadenosine deaminase component with Cas homologs other than SpCas9. We evolved the deaminase component of ABE7.10 using phage-assisted non-continuous and continuous evolution (PANCE and PACE), which resulted in ABE8e. ABE8e contains eight additional mutations that increase activity (kapp) 590-fold compared with that of ABE7.10. ABE8e offers substantially improved editing efficiencies when paired with a variety of Cas9 or Cas12 homologs. ABE8e is more processive than ABE7.10, which could benefit screening, disruption of regulatory regions and multiplex base editing applications. A modest increase in Cas9-dependent and -independent DNA off-target editing, and in transcriptome-wide RNA off-target editing can be ameliorated by the introduction of an additional mutation in the TadA-8e domain. Finally, we show that ABE8e can efficiently install natural mutations that upregulate fetal hemoglobin expression in the BCL11A enhancer or in the the HBG promoter in human cells, targets that were poorly edited with ABE7.10. ABE8e augments the effectiveness and applicability of adenine base editing.

CRISPR-Cas systems provide adaptive immunity in bacteria and archaea, beginning with integration of foreign sequences into the host CRISPR genomic locus and followed by transcription and maturation of CRISPR RNAs (crRNAs). In some CRISPR systems, a reverse transcriptase (RT) fusion to the Cas1 integrase and Cas6 maturase creates a single protein that enables concerted sequence integration and crRNA production. To elucidate how the RT-integrase organizes distinct enzymatic activities, we present the cryo-EM structure of a Cas6-RT-Cas1—Cas2 CRISPR integrase complex. The structure reveals a heterohexamer in which the RT directly contacts the integrase and maturase domains, suggesting functional coordination between all three active sites. Together with biochemical experiments, our data support a model of sequential enzymatic activities that enable CRISPR sequence acquisition from RNA and DNA substrates. These findings highlight an expanded capacity of some CRISPR systems to acquire diverse sequences that direct CRISPR-mediated interference.

Owing to its extremely high luminosity and long duration, supernova (SN) 2006gy radiated more energy in visual light than any other known SN. Two hypotheses to explain its high luminosity at early times - that it was powered by shock interaction with circumstellar material (CSM) as implied by its Type IIn spectrum, or that it was fueled by radioactive decay from a large mass of 56Ni synthesized in a pair-instability SN-predicted different late-time properties. Here we present observations of SN 2006gy obtained more than a year after discovery. We were unable to detect it at visual wavelengths, but clear near-infrared (IR) K′ and H-band detections show that it is still at least as luminous as the peak of a normal Type II SN. We also present spectra giving an upper limit to the late-time Ha luminosity of ≲S10 39 erg s-1. Based on the weak late-time Ha, X-ray, and radio emission, combined with the difficulty of explaining the shift to IR wavelengths, we can rule out ongoing CSM interaction as the primary late-time power source of SN 2006gy. Instead, we propose that the evolution of SN 2006gy is consistent with one of two possible scenarios: (1)apairinstability SN plus modest CSM interaction, where the radioactive decay luminosity shifts to the IR because of dust formation; or (2) an IR echo, where radiation emitted during peak luminosity heats a pre-existing dust shell at radii near 1 light year, requiring the progenitor star to have ejected another shell of ∼10 M ⊙ about 1500 yr before the SN. © 2008. The American Astronomical Society. All rights reserved.

Motion of short-period stars orbiting the supermassive black hole in our Galactic Center has been monitored for more than 20 years. These observations are currently offering a new way to test the gravitational theory in an unexplored regime: in a strong gravitational field, around a supermassive black hole. In this proceeding, we present three results: (i) a constraint on a hypothetical fifth force obtained by using 19 years of observations of the two best measured short-period stars S0-2 and S0-38; (ii) an upper limit on the secular advance of the argument of the periastron for the star S0-2; (iii) a sensitivity analysis showing that the relativistic redshift of S0-2 will be measured after its closest approach to the black hole in 2018.

We summarize work on the central parsec of the Galactic center based on imaging and spectroscopic observations at the Keck and Gemini telescopes. These observations include stellar positions in two dimension and the velocity in three dimensions. Spectroscopic observations also enables measurements of the physical properties of individual stars, such as the spectral type and in some cases the effective temperature, metallicity, and surface gravity. These observations show a complex stellar population with a young (4-6 Myr) compact star cluster in the central 0.5 pc embedded in in an older and much more massive nuclear star cluster. Surprisingly, the old late-type giants do not show a cusp profile as long been expected from theoretical work. The majority of the stars have higher than solar metallicity, with only about 6% of the stars having [M/Fe] < -0.5, which is consistent with an origin from the MW disk.

We report on the measurement of the lateral distribution of the junction current of an electrical biased p-n GaN diode by electron emission microscopy using a low-energy electron microscope. The vacuum level at the surface of the diode was lowered by deposition of cesium to achieve negative electron affinity, allowing overflow electrons at the surface of the biased diodes to be emitted and their spatial distribution imaged. The results were compared to the literature, and a good match with analytical solutions by Joyce and Wemple [J. Appl. Phys. 41, 3818 (1970)] was obtained.

Large coat protein complex II (COPII)-coated vesicles serve to convey the large cargo procollagen I (PC1) from the endoplasmic reticulum (ER). The link between large cargo in the lumen of the ER and modulation of the COPII machinery remains unresolved. TANGO1 is required for PC secretion and interacts with PC and COPII on opposite sides of the ER membrane, but evidence suggests that TANGO1 is retained in the ER, and not included in normal size (<100 nm) COPII vesicles. Here we show that TANGO1 is exported out of the ER in large COPII-coated PC1 carriers, and retrieved back to the ER by the retrograde coat, COPI, mediated by the C-terminal RDEL retrieval sequence of HSP47. TANGO1 is known to target the COPII initiation factor SEC12 to ER exit sites through an interacting protein, cTAGE5. SEC12 is important for the growth of COPII vesicles, but it is not sorted into small budded vesicles. We found both cTAGE5 and SEC12 were exported with TANGO1 in large COPII carriers. In contrast to its exclusion from small transport vesicles, SEC12 was particularly enriched around ER membranes and large COPII carriers that contained PC1. We constructed a split GFP system to recapitulate the targeting of SEC12 to PC1 via the luminal domain of TANGO1. The minimal targeting system enriched SEC12 around PC1 and generated large PC1 carriers. We conclude that TANGO1, cTAGE5, and SEC12 are copacked with PC1 into COPII carriers to increase the size of COPII, thus ensuring the capture of large cargo.

Protein and membrane trafficking pathways are critical for cell and tissue homeostasis. Traditional genetic and biochemical approaches have shed light on basic principles underlying these processes. However, the list of factors required for secretory pathway function remains incomplete, and mechanisms involved in their adaptation poorly understood. Here, we present a powerful strategy based on a pooled genome-wide CRISPRi screen that allowed the identification of new factors involved in protein transport. Two newly identified factors, TTC17 and CCDC157, localized along the secretory pathway and were found to interact with resident proteins of ER-Golgi membranes. In addition, we uncovered that upon TTC17 knockdown, the polarized organization of Golgi cisternae was altered, creating glycosylation defects, and that CCDC157 is an important factor for the fusion of transport carriers to Golgi membranes. In conclusion, our work identified and characterized new actors in the mechanisms of protein transport and secretion and opens stimulating perspectives for the use of our platform in physiological and pathological contexts.

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Human pluripotent stem cell-derived cardiomyocytes (CMs) are a promising tool for cardiac cell therapy. Although transplantation of induced pluripotent stem cell (iPSC)-derived CMs have been reported in several animal models, the treatment effect was limited, probably due to poor optimization of the injected cells. To optimize graft cells for cardiac reconstruction, we compared the engraftment efficiency of intramyocardially-injected undifferentiated-iPSCs, day4 mesodermal cells and day8, day20 and day30 purified iPSC-CMs after initial differentiation by tracing the engraftment ratio (ER) using in vivo bioluminescence imaging. This analysis revealed the ER of day20 CMs was significantly higher compared to other cells. Transplantation of day20 CMs into the infarcted hearts of immunodeficient mice showed good engraftment and echocardiography showed significant functional improvement by cell therapy. Moreover, the imaging signal and ratio of Ki67-positive CMs at 3 months post injection indicated engrafted CMs proliferated in the host heart. Although this graft growth reached a plateau at 3 months, histological analysis confirmed progressive maturation from 3 to 6 months. These results suggested that day20 CMs had very high engraftment, proliferation and therapeutic potential in host mouse hearts. They also demonstrate this model can be used to track the fate of transplanted cells over a long time.

NANOG (from Irish mythology Tír na nÓg) transcription factor plays a central role in maintaining pluripotency, cooperating with OCT4 (also known as POU5F1 or OCT3/4), SOX2, and other pluripotency factors. Although the physiological roles of the NANOG protein have been extensively explored, biochemical and biophysical properties in relation to its structural analysis are poorly understood. Here we determined the crystal structure of the human NANOG homeodomain (hNANOG HD) bound to an OCT4 promoter DNA, which revealed amino acid residues involved in DNA recognition that are likely to be functionally important. We generated a series of hNANOG HD alanine substitution mutants based on the protein-DNA interaction and evolutionary conservation and determined their biological activities. Some mutant proteins were less stable, resulting in loss or decreased affinity for DNA binding. Overexpression of the orthologous mouse NANOG (mNANOG) mutants failed to maintain self-renewal of mouse embryonic stem cells without leukemia inhibitory factor. These results suggest that these residues are critical for NANOG transcriptional activity. Interestingly, one mutant, hNANOG L122A, conversely enhanced protein stability and DNA-binding affinity. The mNANOG L122A, when overexpressed in mouse embryonic stem cells, maintained their expression of self-renewal markers even when retinoic acid was added to forcibly drive differentiation. When overexpressed in epiblast stem cells or human induced pluripotent stem cells, the L122A mutants enhanced reprogramming into ground-state pluripotency. These findings demonstrate that structural and biophysical information on key transcriptional factors provides insights into the manipulation of stem cell behaviors and a framework for rational protein engineering.

We present the discovery and measurements of a gravitationally lensed supernova (SN) behind the galaxy cluster MOO J1014+0038. Based on multi-band Hubble Space Telescope and Very Large Telescope (VLT) photometry of the supernova, and VLT spectroscopy of the host galaxy, we find a 97.5% probability that this SN is a SN Ia, and a 2.5% chance of a CC SN. Our typing algorithm combines the shape and color of the light curve with the expected rates of each SN type in the host galaxy. With a redshift of 2.2216, this is the highest redshift SN Ia discovered with a spectroscopic host-galaxy redshift. A further distinguishing feature is that the lensing cluster, at redshift 1.23, is the most distant to date to have an amplified SN. The SN lies in the middle of the color and light-curve shape distributions found at lower redshift, disfavoring strong evolution to z = 2.22. We estimate an amplification due to gravitational lensing of (1.10 ± 0.23 mag)—compatible with the value estimated from the weak-lensing-derived mass and the mass–concentration relation from ΛCDM simulations—making it the most amplified SN Ia discovered behind a galaxy cluster.

We present a novel technique for fitting restframe I-band light curves on a data set of 42 type Ia supernovae (SNe Ia). Using the result of the fit, we construct a Hubble diagram with 26 SNe from the subset at . Adding two SNe at yields results consistent with a flat Λ-dominated “concordance universe” () = (0.25, 0.75). For one of these, SN 2000fr, new near infrared data are presented. The high redshift supernova NIR data are also used to test for systematic effects in the use of SNe Ia as distance estimators. A flat, , universe where the faintness of supernovae at is due to grey dust homogeneously distributed in the intergalactic medium is disfavoured based on the high-z Hubble diagram using this small data-set. However, the uncertainties are large and no firm conclusion may be drawn. We explore the possibility of setting limits on intergalactic dust based on and colour measurements, and conclude that about 20 well measured SNe are needed to give statistically significant results. We also show that the high redshift restframe I-band data points are better fit by light curve templates that show a prominent second peak, suggesting that they are not intrinsically underluminous.

We present a weak-lensing study of SPT-CL J2040-4451 and IDCS J1426+3508 at z = 1.48 and 1.75, respectively. The two clusters were observed in our "See Change" program, a Hubble Space Telescope survey of 12 massive high-redshift clusters aimed at high-z supernova measurements and weak-lensing estimation of accurate cluster masses. We detect weak but significant galaxy shape distortions using infrared images from the Wide Field Camera 3 (WFC3), which has not yet been used for weak-lensing studies. Both clusters appear to possess relaxed morphology in projected mass distribution, and their mass centroids agree nicely with those defined by both the galaxy luminosity and X-ray emission. Using a Navarro-Frenk-White profile, for which we assume that the mass is tightly correlated with the concentration parameter, we determine the masses of SPT-CL J2040-4451 and IDCS J1426 + 3508 to be M200 = 8.6+1.7-1.4 × 1014 Moand 2.2+1.1-0.7 × 1014Mo, respectively. The weak-lensing mass of SPT-CL J2040-4451 shows that the cluster is clearly a rare object. Adopting the central value, the expected abundance of such a massive cluster at z ≳1.48 is only ∼ 0.07 in the parent 2500 sq. deg. survey. However, it is yet premature to claim that the presence of this cluster creates a serious tension with the current ΛCDM paradigm unless that tension will remain in future studies after marginalizing over many sources of uncertainties such as the accuracy of the mass function and the mass-concentration relation at the high-mass end. The mass of IDCS J1426+3508 is in excellent agreement with our previous Advanced Camera for Surveys-based weak-lensing result, while the much higher source density from our WFC3 imaging data makes the current statistical uncertainty ∼40% smaller.

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Accelerated cell aging, indexed in peripheral leukocytes by telomere shortness and in peripheral blood mononuclear cells (PBMCs) by telomerase activity, has been reported in several studies of major depressive disorder (MDD). However, the relevance of these peripheral measures for brain indices that are presumably more directly related to MDD pathophysiology is unknown. In this study, we explored the relationship between PBMC telomerase activity and leukocyte telomere length and magnetic resonance imaging-estimated hippocampal volume in un-medicated depressed individuals and healthy controls. We predicted that, to the extent peripheral and central telomerase activity are directly related, PBMC telomerase activity would be positively correlated with hippocampal volume, perhaps due to hippocampal telomerase-associated neurogenesis, neuroprotection or neurotrophic facilitation, and that this effect would be clearer in individuals with increased PBMC telomerase activity, as previously reported in un-medicated MDD. We did not have specific hypotheses regarding the relationship between leukocyte telomere length and hippocampal volume, due to conflicting reports in the published literature. We found, in 25 un-medicated MDD subjects, that PBMC telomerase activity was significantly positively correlated with hippocampal volume; this relationship was not observed in 18 healthy controls. Leukocyte telomere length was not significantly related to hippocampal volume in either group (19 unmedicated MDD subjects and 17 healthy controls). Although the nature of the relationship between peripheral telomerase activity and telomere length and the hippocampus is unclear, these preliminary data are consistent with the possibility that PBMC telomerase activity indexes, and may provide a novel window into, hippocampal neuroprotection and/or neurogenesis in MDD.

Telomere length, a reliable predictor of disease pathogenesis, can be affected by genetics, chronic stress and health behaviors. Cross-sectionally, highly stressed postmenopausal women have shorter telomeres, but only if they are inactive. However, no studies have prospectively examined telomere length change over a short period, and if rate of attrition is affected by naturalistic factors such as stress and engagement in healthy behaviors, including diet, exercise, and sleep. Here we followed healthy women over 1 year to test if major stressors that occurred over the year predicted telomere shortening, and whether engaging in healthy behaviors during this period mitigates this effect. In 239 postmenopausal, non-smoking, disease-free women, accumulation of major life stressors across a 1-year period predicted telomere attrition over the same period—for every major life stressor that occurred during the year, there was a significantly greater decline in telomere length over the year of 35 bp (P<0.05). Yet, these effects were moderated by health behaviors (interaction B=0.19, P=0.04). Women who maintained relatively higher levels of health behaviors (1 s.d. above the mean) appeared to be protected when exposed to stress. This finding has implications for understanding malleability of telomere length, as well as expectations for possible intervention effects. This is the first study to identify predictors of telomere length change over the short period of a year.

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

The time is right for biologists to post their research findings onto preprint servers A preprint is a complete scientific manuscript (often one also being submitted to a peer-reviewed journal) that is uploaded by the authors to a public server without formal review. After a brief inspection to ensure that the work is scientific in nature, the posted scientific manuscript can be viewed without charge on the Web. Thus, preprint servers facilitate the direct and open delivery of new knowledge and concepts to the worldwide scientific community before traditional validation through peer review ( 1 , 2 ). Although the preprint server arXiv.org has been essential for physics, mathematics, and computer sciences for over two decades, preprints are currently used minimally in biology.

Synthesizing, localizing, and stabilizing new protein copies at synapses are crucial factors in maintaining the synaptic changes required for storing long-term memories. PKMζ recently emerged as a molecule putatively responsible for maintaining encoded memories over time because its presence correlates with late LTP and because its inhibition disrupts LTP in vitro and long-term memory storage in vivo. Here we investigated PKMζ stability in rat neurons to better understand its role during information encoding and storage. We used TimeSTAMP reporters to track the synthesis and degradation of PKMζ as well as a related atypical PKC, PKCλ. These reporters revealed that both PKMζ and PKCλ were upregulated after chemical LTP induction; however, these new PKMζ copies exhibited more rapid turnover than basally produced PKMζ, particularly in dendritic spines. In contrast to PKMζ, new PKCλ copies exhibited elevated stability. Stable information storage over long periods of time is more challenging the shorter the metabolic lifetime of the candidate molecules.

In the P388D1 macrophage-like cell line, phospholipase A2 activity and prostaglandin production are stimulated by platelet-activating factor (PAF) and bacterial lipopolysaccharide (LPS). We have investigated the role of Ins(1,4,5)P3 and Ca2+ in signal transduction of PAF-induced prostaglandin E2 (PGE2) formation in these cells. The role of Ca2+ in the activation mechanism was studied by fluorescence imaging of intracellular Ca2+ in individual adherent cells and by determining the PGE2 production in the same population of cells. This new approach enabled us to correlate directly events on the single-cell level with a physiologically relevant response of the cell population. Priming the cells with LPS was required for PAF to stimulate PGE2 formation, yet LPS affected neither the intracellular free Ca2+ concentration ([Ca2+]i) nor the PAF-induced rise in [Ca2+]i. In addition, basal and PAF-stimulated Ins(1,4,5)P3 levels were not affected by LPS priming. However, the Ca2+ transient, the release of Ins(1,4,5)P3 and the formation of PGE2 induced by PAF were inhibited in cells pretreated with pertussis toxin. Buffering the [Ca2+]i with intracellular BAPTA [bis-(o-aminophenoxy)ethane-NNN'N'-tetra-acetic acid] blocked the PAF-stimulated rise in [Ca2+]i and PGE2 formation. Removal of extracellular Ca2+ during PAF stimulation prevented the influx of Ca2+, but did not affect the initial [Ca2+]i transient, nor did it inhibit PGE2 formation. Under the same conditions, ionomycin stimulated an identical [Ca2+]i transient, but, in contrast with PAF stimulation, no PGE2 formation was observed. PGE2 production could be rescued by prompt subsequent addition of PAF, which caused no further [Ca2+]i change on its own. These results show that the transient initial rise in [Ca2+]i, produced either by PAF via the formation of Ins(1,4,5)P3 or directly by ionomycin, is necessary, but not sufficient for the formation of PGE2 in LPS-primed P388D1 cells. Furthermore, we have demonstrated for the first time that PAF triggers a second signal that is not mediated by a change in [Ca2+]i. However, both signals are required to induce PGE2 formation.

We combine a novel boronate trap for F(-) with a near-infrared fluorophore into a single molecule. Attachment to targeting ligands enables localization by positron emission tomography (PET) and near-infrared fluorescence (NIRF). Our first application of this generic tag is to label Lymphoseek (tilmanocept), an agent designed for receptor-specific sentinel lymph node (SLN) mapping. The new conjugate incorporates (18)F(-) in a single, aqueous step, targets mouse SLN rapidly (1 h) with reduced distal lymph node accumulation, permits PET or scintigraphic imaging of SLN, and enables NIRF-guided excision and histological verification even after (18)F decay. This embodiment is superior to current SLN mapping agents such as nontargeted [(99m)Tc]sulfur colloids and Isosulfan Blue, as well as the phase III targeted ligand [(99m)Tc]SPECT Lymphoseek counterpart, species that are visible by SPECT or visible absorbance separately. Facile incorporation of (18)F into a NIRF probe should promote many synergistic PET and NIRF combinations.

Tungsten NAr^R alkylidene complexes have been prepared that contain the electron-withdrawing Ar^R groups 2,4,6-X₃C₆H₂ (Ar^X3, X = Cl, Br), 2,6-Cl₂-4-CF₃C₆H₂ (Ar^Cl2CF3), and 3,5-(CF₃)₂C₆H₃ (Ar^(CF3)2). Reported complexes include W(NAr^R)₂Cl₂(dme) (dme = 1,2-dimethoxyethane), W(NAr^R)₂(CH₂CMe₃)₂, W(NAr^R)(CHCMe₃)(OTf)₂(dme), and W(NAr^R)(CHCMe₃)(ODBMP)₂ (DBMP = 4-Me-2,6-(CHPh₂)C₆H₂). The W(NAr^R)(CHCMe₃)(ODBMP)₂ complexes were explored as initiators for the polymerization of 2,3-dicarbomethoxynorbornadiene (DCMNBD).

Nitriles are found in many bioactive compounds, and are among the most versatile functional groups in organic chemistry. Despite many notable recent advances, however, there are no approaches that may be used for the preparation of di- or tri-substituted alkenyl nitriles. Related approaches that are broad in scope and can deliver the desired products in high stereoisomeric purity are especially scarce. Here, we describe the development of several efficient catalytic cross-metathesis strategies, which provide direct access to a considerable range of Z- or E-di-substituted cyano-substituted alkenes or their corresponding tri-substituted variants. Depending on the reaction type, a molybdenum-based monoaryloxide pyrrolide or chloride (MAC) complex may be the optimal choice. The utility of the approach, enhanced by an easy to apply protocol for utilization of substrates bearing an alcohol or a carboxylic acid moiety, is highlighted in the context of applications to the synthesis of biologically active compounds.

Cis,syndiotacticA-alt-B copolymers, where A and B are two enantiomerically pure trans-2,3-disubstituted-5,6-norbornenes with "opposite" chiralities, can be prepared with stereogenic-at-metal initiators of the type M(NR)(CHR')(OR")(pyrrolide). Formation of a high percentage of alternating AB copolymer linkages relies on an inversion of chirality at the metal with each propagating step and a relatively fast formation of an AB sequence as a consequence of a preferred diastereomeric relationship between the chirality at the metal and the chirality of the monomer. This approach to formation of an alternating AB copolymer contrasts dramatically with the principle of forming AB copolymers from achiral monomers and catalysts.

Over the U.S. business cycle, fluctuations in residential investment are well known to systematically lead GDP. These dynamics are documented here to be specific to the U.S. and Canada. In other developed economies residential investment is broadly coincident with GDP. Nonresidential investment has the opposite dynamics, being coincident with or lagging GDP. These observations are in sharp contrast with the properties of nearly all business cycle models with disaggregated investment. Including mortgages and interest rate dynamics aligns the theory more closely with U.S. observations. Longer time to build in housing construction makes residential investment coincident with output.