Construction of Vicinal Tertiary and All-Carbon Quaternary Stereocenters via Ir-Catalyzed Regio-, Diastereo-, and Enantioselective Allylic Alkylation and Applications in Sequential Pd Catalysis

Highly congested vicinal stereocenters comprised of tertiary and all-carbon quaternary centers were generated via Ir-catalyzed asymmetric allylic alkylation of β-ketoesters. These catalytic reactions proceed in excellent yields with a broad scope on either reaction partner and with outstanding regio-, diastereo-, and enantiocontrol. Implementation of a subsequent Pd-catalyzed alkylation affords dialkylated products with pinpoint stereochemical control of both chiral centers

The effect of Korean pine nut oil (PinnoThin™) on food intake, feeding behaviour and appetite: A double-blind placebo-controlled trial

Certain free fatty acids have been shown to have potent effects on food intake and self-reported changes in appetite; effects associated with increases in the release of endogenous cholecystokinin (CCK) and glucagon like peptide-1 (GLP-1). In the current study, the effects of a Korean pine nut oil product, PinnoThin™, at doses 2 g, 4 g and 6 g triglyceride (TG) and 2 g free fatty acid (FFA), on food intake and appetite were examined in a cross-over double-blind placebo-controlled randomised counter-balanced design in 42 overweight female volunteers. 2 g FFA PinnoThin™, given 30 minutes prior to an ad-libitum buffet test lunch, significantly reduced food intake (gram) by 9% (F(4,164) = 2.637, p = 0.036) compared to olive oil control. No significant effect of PinnoThin™ on macronutrient intake or ratings of appetite were observed. Given the recent data showing that the TG form of PinnoThin™ may also reduce appetite by increasing CCK release, the lack of any effect of the TG form found in this study could be attributed to the timing of the dosing regime. Collectively, these data suggest that PinnoThin™ may exert satiating effects consistent with its known action on CCK and GLP-1 release, and previously observed effects on self-reported appetite ratings

Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation

Pd-catalyzed enantioselective alkylation in conjunction with further synthetic elaboration enables the formal total syntheses of a number of “classic” natural product target molecules. This publication highlights recent methods for setting quaternary and tetrasubstituted tertiary carbon stereocenters to address the synthetic hurdles encountered over many decades across multiple compound classes spanning carbohydrate derivatives, terpenes, and alkaloids. These enantioselective methods will impact both academic and industrial settings, where the synthesis of stereogenic quaternary carbons is a continuing challenge

Persistent starspot signals on M dwarfs: multi-wavelength Doppler observations with the Habitable-zone Planet Finder and Keck/HIRES

Young, rapidly-rotating M dwarfs exhibit prominent starspots, which create quasiperiodic signals in their photometric and Doppler spectroscopic measurements. The periodic Doppler signals can mimic radial velocity (RV) changes expected from orbiting exoplanets. Exoplanets can be distinguished from activity-induced false positives by the chromaticity and long-term incoherence of starspot signals, but these qualities are poorly constrained for fully-convective M stars. Coherent photometric starspot signals on M dwarfs may persist for hundreds of rotations, and the wavelength dependence of starspot RV signals may not be consistent between stars due to differences in their magnetic fields and active regions. We obtained precise multi-wavelength RVs of four rapidly-rotating M dwarfs (AD Leo, G 227-22, GJ 1245B, GJ 3959) using the near-infrared (NIR) Habitable-zone Planet Finder, and the optical Keck/HIRES spectrometer. Our RVs are complemented by photometry from Kepler, TESS, and the Las Cumbres Observatory (LCO) network of telescopes. We found that all four stars exhibit large spot-induced Doppler signals at their rotation periods, and investigated the longevity and optical-to-NIR chromaticity for these signals. The phase curves remain coherent much longer than is typical for Sunlike stars. Their chromaticity varies, and one star (GJ 3959) exhibits optical and NIR RV modulation consistent in both phase and amplitude. In general, though, we find that the NIR amplitudes are lower than their optical counterparts. We conclude that starspot modulation for rapidly-rotating M stars frequently remains coherent for hundreds of stellar rotations, and gives rise to Doppler signals that, due to this coherence, may be mistaken for exoplanets.Comment: Accepted for publication in the Astrophysical Journa

Fibulin-1 is required for morphogenesis of neural crest-derived structures

AbstractHere we report that mouse embryos homozygous for a gene trap insertion in the fibulin-1 (Fbln1) gene are deficient in Fbln1 and exhibit cardiac ventricular wall thinning and ventricular septal defects with double outlet right ventricle or overriding aorta. Fbln1 nulls also display anomalies of aortic arch arteries, hypoplasia of the thymus and thyroid, underdeveloped skull bones, malformations of cranial nerves and hemorrhagic blood vessels in the head and neck. The spectrum of malformations is consistent with Fbln1 influencing neural crest cell (NCC)-dependent development of these tissues. This is supported by evidence that Fbln1 expression is associated with streams of cranial NCCs migrating adjacent to rhombomeres 2–7 and that Fbln1-deficient embryos display patterning anomalies of NCCs forming cranial nerves IX and X, which derive from rhombomeres 6 and 7. Additionally, Fbln1-deficient embryos show increased apoptosis in areas populated by NCCs derived from rhombomeres 4, 6 and 7. Based on these findings, it is concluded that Fbln1 is required for the directed migration and survival of cranial NCCs contributing to the development of pharyngeal glands, craniofacial skeleton, cranial nerves, aortic arch arteries, cardiac outflow tract and cephalic blood vessels

Catastrophizing mediates the relationship between the personal belief in a just world and pain outcomes among chronic pain support group attendees

Health-related research suggests the belief in a just world can act as a personal resource that protects against the adverse effects of pain and illness. However, currently, little is known about how this belief, particularly in relation to one’s own life, might influence pain. Consistent with the suggestions of previous research, the present study undertook a secondary data analysis to investigate pain catastrophizing as a mediator of the relationship between the personal just world belief and chronic pain outcomes in a sample of chronic pain support group attendees. Partially supporting the hypotheses, catastrophizing was negatively correlated with the personal just world belief and mediated the relationship between this belief and pain and disability, but not distress. Suggestions for future research and intervention development are made

Across borders: External factors and prior behaviour influence North Pacific albatross associations with fishing vessels

Understanding encounters between marine predators and fisheries across national borders and outside national jurisdictions offers new perspectives on unwanted interactions to inform ocean management and predator conservation. Although seabird–fisheries overlap has been documented at many scales, remote identification of vessel encounters has lagged because vessel movement data often are lacking. Here, we reveal albatrosses–fisheries associations throughout the North Pacific Ocean. We identified commercial fishing operations using Global Fishing Watch data and algorithms to detect fishing vessels. We compiled GPS tracks of adult black-footed Phoebastria nigripes and Laysan Phoebastria immutabilis albatrosses, and juvenile short-tailed albatrosses Phoebastria albatrus. We quantified albatrosses-vessel encounters based on the assumed distance that birds perceive a vessel (≤30 km), and associations when birds approached vessels (≤3 km). For each event we quantified bird behaviour, environmental conditions and vessel characteristics and then applied Boosted Regression Tree models to identify drivers and the duration of these associations. In regions of greater fishing effort short-tailed and Laysan albatrosses associated with fishing vessels more frequently. However, fishing method (e.g. longline, trawl) and flag nation did not influence association prevalence nor the duration short-tailed albatrosses attended fishing vessels. Laysan albatrosses were more likely to approach longer vessels. Black-footed albatrosses were the most likely to approach vessels (61.9%), but limited vessel encounters (n = 21) prevented evaluation of meaningful explanatory models for this species of high bycatch concern. Temporal variables (time of day and month) and bird behavioural state helped explain when short-tailed albatrosses were in close proximity to a vessel, but environmental conditions were more important for explaining interaction duration. Laysan albatrosses were more likely to associate with vessels while searching and during the last 60% (by time) of their trips. Our results provide specific species–fisheries insight regarding contributing factors of high-risk associations that could lead to bycatch of albatrosses within national waters and on the high seas. Policy implications. Given the availability of Global Fishing Watch data, our analysis can be applied to other marine predators—if tracking data are available—to identify spatio-temporal patterns, vessel specific attributes and predator behaviours associated with fishing vessel associations, thus enabling predictive modelling and targeted mitigation measures

Identification of PADI2 as a potential breast cancer biomarker and therapeutic target.

BACKGROUND: We have recently reported that the expression of peptidylarginine deiminase 2 (PADI2) is regulated by EGF in mammary cancer cells and appears to play a role in the proliferation of normal mammary epithelium; however, the role of PADI2 in the pathogenesis of human breast cancer has yet to be investigated. Thus, the goals of this study were to examine whether PADI2 plays a role in mammary tumor progression, and whether the inhibition of PADI activity has anti-tumor effects. METHODS: RNA-seq data from a collection of 57 breast cancer cell lines was queried for PADI2 levels, and correlations with known subtype and HER2/ERBB2 status were evaluated. To examine PADI2 expression levels during breast cancer progression, the cell lines from the MCF10AT model were used. The efficacy of the PADI inhibitor, Cl-amidine, was tested in vitro using MCF10DCIS cells grown in 2D-monolayers and 3D-spheroids, and in vivo using MCF10DCIS tumor xenografts. Treated MCF10DCIS cells were examined by flow-cytometry to determine the extent of apoptosis and by RT2 Profiler PCR Cell Cycle Array to detect alterations in cell cycle associated genes. RESULTS: We show by RNA-seq that PADI2 mRNA expression is highly correlated with HER2/ERBB2 (p = 2.2 x 106) in luminal breast cancer cell lines. Using the MCF10AT model of breast cancer progression, we then demonstrate that PADI2 expression increases during the transition of normal mammary epithelium to fully malignant breast carcinomas, with a strong peak of PADI2 expression and activity being observed in the MCF10DCIS cell line, which models human comedo-DCIS lesions. Next, we show that a PADI inhibitor, Cl-amidine, strongly suppresses the growth of MCF10DCIS monolayers and tumor spheroids in culture. We then carried out preclinical studies in nude (nu/nu) mice and found that Cl-amidine also suppressed the growth of xenografted MCF10DCIS tumors by more than 3-fold. Lastly, we performed cell cycle array analysis of Cl-amidine treated and control MCF10DCIS cells, and found that the PADI inhibitor strongly affects the expression of several cell cycle genes implicated in tumor progression, including p21, GADD45alpha, and Ki67. CONCLUSION: Together, these results suggest that PADI2 may function as an important new biomarker for HER2/ERBB2+ tumors and that Cl-amidine represents a new candidate for breast cancer therapy

Mechanisms Underlying Metabolic and Neural Defects in Zebrafish and Human Multiple Acyl-CoA Dehydrogenase Deficiency (MADD)

In humans, mutations in electron transfer flavoprotein (ETF) or electron transfer flavoprotein dehydrogenase (ETFDH) lead to MADD/glutaric aciduria type II, an autosomal recessively inherited disorder characterized by a broad spectrum of devastating neurological, systemic and metabolic symptoms. We show that a zebrafish mutant in ETFDH, xavier, and fibroblast cells from MADD patients demonstrate similar mitochondrial and metabolic abnormalities, including reduced oxidative phosphorylation, increased aerobic glycolysis, and upregulation of the PPARG-ERK pathway. This metabolic dysfunction is associated with aberrant neural proliferation in xav, in addition to other neural phenotypes and paralysis. Strikingly, a PPARG antagonist attenuates aberrant neural proliferation and alleviates paralysis in xav, while PPARG agonists increase neural proliferation in wild type embryos. These results show that mitochondrial dysfunction, leading to an increase in aerobic glycolysis, affects neurogenesis through the PPARG-ERK pathway, a potential target for therapeutic intervention