Ruthenium-Catalyzed Mono-Selective C–H Methylation and d₃-Methylation of Arenes

[Image: see text] Site-selective installation of C–Me bonds remains a powerful and sought-after tool to alter the chemical and pharmacological properties of a molecule. Direct C–H functionalization provides an attractive means of achieving this transformation. Such protocols, however, typically utilize harsh conditions and hazardous methylating agents with poor applicability toward late-stage functionalization. Furthermore, highly monoselective methylation protocols remain scarce. Herein, we report an efficient monoselective, directed ortho-methylation of arenes using N,N,N-trimethylanilinium salts as noncarcinogenic, bench-stable methylating agents. We extend this protocol to d(3)-methylation in addition to the late-stage functionalization of pharmaceutically active compounds. Detailed kinetic studies indicate the rate-limiting in situ formation of MeI is integral to the observed reactivity

Macrophage-derived insulin-like growth factor-1 is a key neurotrophic and nerve-sensitizing factor in pain associated with endometriosis

Endometriosis is a common incurable inflammatory disorder that is associated with debilitating pelvic pain in women. Macrophages are central to the pathophysiology of endometriosis: they dictate the growth and vascularization of endometriosis lesions and more recently have been shown to promote lesion innervation. The aim of this study was to determine the mechanistic role of macrophages in producing pain associated with endometriosis. Herein, we show that macrophage depletion in a mouse model of endometriosis can reverse abnormal changes in pain behavior. We identified that disease-modified macrophages exhibit increased expression of IGF-1 in an in vitro model of endometriosis-associated macrophages and confirmed expression by lesion-resident macrophages in mice and women. Concentrations of IGF-1 were elevated in peritoneal fluid from women with endometriosis and positively correlate with their pain scores. Mechanistically, we demonstrate that macrophage-derived IGF-1 promotes sprouting neurogenesis and nerve sensitization in vitro. Finally, we show that the Igf-1 receptor inhibitor linsitinib reverses the pain behavior observed in mice with endometriosis. Our data support a role for macrophage-derived IGF-1 as a key neurotrophic and sensitizing factor in endometriosis, and we propose that therapies that modify macrophage phenotype may be attractive therapeutic options for the treatment of women with endometriosis-associated pain.—Forster, R., Sarginson, A., Velichkova, A., Hogg, C., Dorning, A., Horne, A. W., Saunders, P. T. K., Greaves, E. Macrophage-derived insulin-like growth factor-1 is a key neurotrophic and nerve-sensitizing factor in pain associated with endometriosis

Bioluminescent imaging in induced mouse models of endometriosis reveals differences in four model variations

Our understanding of the etiology and pathophysiology of endometriosis remains limited. Disease modelling in the field is problematic as many versions of induced mouse models of endometriosis exist. We integrated bioluminescent imaging of ‘lesions’ generated using luciferase-expressing donor mice. We compared longitudinal bioluminescence and histology of lesions, sensory behavior of mice with induced endometriosis and the impact of the GnRH antagonist Cetrorelix on lesion regression and sensory behavior. Four models of endometriosis were tested. We found that the nature of the donor uterine material was a key determinant of how chronic the lesions were as well as their cellular composition. The severity of pain-like behavior also varied across models. Whilst Cetrorelix significantly reduced lesion bioluminescence in all models, it had varying impacts on pain-like behavior. Collectively, our results demonstrate key differences in the progression of the ‘disease’ across different mouse models of endometriosis. We propose that validation and testing in multiple models, each of which may be representative of the different subtypes / heterogeneity observed in women should become a standard approach to discovery science in the field of endometriosis

Resveratrol, Acetyl-Resveratrol, and Polydatin Exhibit Antigrowth Activity against 3D Cell Aggregates of the SKOV-3 and OVCAR-8 Ovarian Cancer Cell Lines

Resveratrol has aroused significant scientific interest as it has been claimed that it exhibits a spectrum of health benefits. These include effects as an anti-inflammatory and an antitumour compound. The purpose of this study was to investigate and compare any potential antigrowth effects of resveratrol and two of its derivatives, acetyl-resveratrol and polydatin, on 3D cell aggregates of the EGFR/Her-2 positive and negative ovarian cancer cell lines SKOV-3 and OVCAR-8, respectively. Results showed that resveratrol and acetyl-resveratrol reduced cell growth in the SKOV-3 and OVCAR-8 in a dose-dependant manner. The growth reduction was mediated by the induction of apoptosis via the cleavage of poly(ADP-ribose) polymerase (PARP-1). At lower concentrations, 5 and 10 µM, resveratrol, acetyl-resveratrol, and polydatin were less effective than higher concentrations, 50 and 100 µM. In SKOV-3 line, at higher concentrations, resveratrol and polydatin significantly reduced the phosphorylation of Her-2 and EGFR and the expression of Erk. Acetyl-resveratrol, on the other hand, did not change the activation of Her-2 and EGFR. Resveratrol, acetyl-resveratrol, and polydatin suppressed the secretion of VEGF in a dose-dependant fashion. In the OVCAR-8 cell line, resveratrol and acetyl-resveratrol at 5 and 10 µM increased the activation of Erk. Above these concentrations they decreased activation. Polydatin did not produce this effect. This study demonstrates that resveratrol and its derivatives may inhibit growth of 3D cell aggregates of ovarian cancer cell lines via different signalling molecules. Resveratrol and its derivatives, therefore, warrant further in vivo evaluation to assess their potential clinical utility

Reliability and Concurrent Validity of Global Physical Activity Questionnaire (GPAQ): A Systematic Review

This study aimed to systematically review previous studies on the reliability and concurrent validity of the Global Physical Activity Questionnaire (GPAQ). A systematic literature search was conducted (n = 26) using the online EBSCOHost databases, PubMed, Web of Science, and Google Scholar up to September 2019. A previously developed coding sheet was used to collect the data. The Modified Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies was employed to assess risk of bias and study quality. It was found that GPAQ was primarily revalidated in adult populations in Asian and European countries. The sample size ranged from 43 to 2657 with a wide age range (i.e., 15–79 years old). Di erent populations yielded inconsistent results concerning the reliability and validity of the GPAQ. Short term (i.e., one- to two-week interval) and long-term (i.e., two- to three-month apart) test–retest reliability was good to very good. The concurrent validity using accelerometers, pedometers, and physical activity (PA) log was poor to fair. The GPAQ data and accelerometer/pedometer/PA log data were not compared using the same measurements in some validation studies. Studies with more rigorous research designs are needed before any conclusions concerning the concurrent validity of GPAQ can be reached

AI as a Medical Device for Ophthalmic Imaging in Europe, Australia, and the United States:Protocol for a Systematic Scoping Review of Regulated Devices

BACKGROUND: Artificial intelligence as a medical device (AIaMD) has the potential to transform many aspects of ophthalmic care, such as improving accuracy and speed of diagnosis, addressing capacity issues in high-volume areas such as screening, and detecting novel biomarkers of systemic disease in the eye (oculomics). In order to ensure that such tools are safe for the target population and achieve their intended purpose, it is important that these AIaMD have adequate clinical evaluation to support any regulatory decision. Currently, the evidential requirements for regulatory approval are less clear for AIaMD compared to more established interventions such as drugs or medical devices. There is therefore value in understanding the level of evidence that underpins AIaMD currently on the market, as a step toward identifying what the best practices might be in this area. In this systematic scoping review, we will focus on AIaMD that contributes to clinical decision-making (relating to screening, diagnosis, prognosis, and treatment) in the context of ophthalmic imaging.OBJECTIVE: This study aims to identify regulator-approved AIaMD for ophthalmic imaging in Europe, Australia, and the United States; report the characteristics of these devices and their regulatory approvals; and report the available evidence underpinning these AIaMD.METHODS: The Food and Drug Administration (United States), the Australian Register of Therapeutic Goods (Australia), the Medicines and Healthcare products Regulatory Agency (United Kingdom), and the European Database on Medical Devices (European Union) regulatory databases will be searched for ophthalmic imaging AIaMD through a snowballing approach. PubMed and clinical trial registries will be systematically searched, and manufacturers will be directly contacted for studies investigating the effectiveness of eligible AIaMD. Preliminary regulatory database searches, evidence searches, screening, data extraction, and methodological quality assessment will be undertaken by 2 independent review authors and arbitrated by a third at each stage of the process.RESULTS: Preliminary searches were conducted in February 2023. Data extraction, data synthesis, and assessment of methodological quality commenced in October 2023. The review is on track to be completed and submitted for peer review by April 2024.CONCLUSIONS: This systematic review will provide greater clarity on ophthalmic imaging AIaMD that have achieved regulatory approval as well as the evidence that underpins them. This should help adopters understand the range of tools available and whether they can be safely incorporated into their clinical workflow, and it should also support developers in navigating regulatory approval more efficiently.INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52602.</p

Understanding the faint red galaxy population using large-scale clustering measurements from SDSS DR7

We use data from the SDSS to investigate the evolution of the large-scale galaxy bias as a function of luminosity for red galaxies. We carefully consider correlation functions of galaxies selected from both photometric and spectroscopic data, and cross-correlations between them, to obtain multiple measurements of the large-scale bias. We find, for our most robust analyses, a strong increase in bias with luminosity for the most luminous galaxies, an intermediate regime where bias does not evolve strongly over a range of two magnitudes in galaxy luminosity, and no evidence for an upturn in bias for fainter red galaxies. Previous work has found an increase in bias to low luminosities that has been widely interpreted as being caused by a strong preference for red dwarf galaxies to be satellites in the most massive halos. We can recover such an upturn in bias to faint luminosities if we push our measurements to small scales, and include galaxy clustering measurements along the line-of-sight, where we expect non-linear effects to be the strongest. The results that we expect to be most robust suggest that the low luminosity population of red galaxies is not dominated by satellite galaxies occupying the most massive haloes.Comment: Matches version accepted by MNRA

A Cross-Correlation Analysis of Mg II Absorption Line Systems and Luminous Red Galaxies from the SDSS DR5

We analyze the cross-correlation of 2,705 unambiguously intervening Mg II (2796,2803A) quasar absorption line systems with 1,495,604 luminous red galaxies (LRGs) from the Fifth Data Release of the Sloan Digital Sky Survey within the redshift range 0.36<=z<=0.8. We confirm with high precision a previously reported weak anti-correlation of equivalent width and dark matter halo mass, measuring the average masses to be log M_h(M_[solar]h^-1)=11.29 [+0.36,-0.62] and log M_h(M_[solar]h^-1)=12.70 [+0.53,-1.16] for systems with W[2796A]>=1.4A and 0.8A<=W[2796A]<1.4A, respectively. Additionally, we investigate the significance of a number of potential sources of bias inherent in absorber-LRG cross-correlation measurements, including absorber velocity distributions and the weak lensing of background quasars, which we determine is capable of producing a 20-30% bias in angular cross-correlation measurements on scales less than 2'. We measure the Mg II - LRG cross-correlation for 719 absorption systems with v<60,000 km s^-1 in the quasar rest frame and find that these associated absorbers typically reside in dark matter haloes that are ~10-100 times more massive than those hosting unambiguously intervening Mg II absorbers. Furthermore, we find evidence for evolution of the redshift number density, dN/dz, with 2-sigma significance for the strongest (W>2.0A) absorbers in the DR5 sample. This width-dependent dN/dz evolution does not significantly affect the recovered equivalent width-halo mass anti-correlation and adds to existing evidence that the strongest Mg II absorption systems are correlated with an evolving population of field galaxies at z<0.8, while the non-evolving dN/dz of the weakest absorbers more closely resembles that of the LRG population.Comment: 21 pages, 19 figures; Published in Astrophysical Journa

The Morphology of Galaxies in the Baryon Oscillation Spectroscopic Survey

We study the morphology of luminous and massive galaxies at 0.3<z<0.7 targeted in the Baryon Oscillation Spectroscopic Survey (BOSS) using publicly available Hubble Space Telescope imaging from COSMOS. Our sample (240 objects) provides a unique opportunity to check the visual morphology of these galaxies which were targeted based solely on stellar population modelling. We find that the majority (74+/-6%) possess an early-type morphology (elliptical or S0), while the remainder have a late-type morphology. This is as expected from the goals of the BOSS target selection which aimed to predominantly select slowly evolving galaxies, for use as cosmological probes, while still obtaining a fair fraction of actively star forming galaxies for galaxy evolution studies. We show that a colour cut of (g-i)>2.35 selects a sub-sample of BOSS galaxies with 90% early-type morphology - more comparable to the earlier Luminous Red Galaxy (LRG) samples of SDSS-I/II. The remaining 10% of galaxies above this cut have a late-type morphology and may be analogous to the "passive spirals" found at lower redshift. We find that 23+/-4% of the early-type galaxies are unresolved multiple systems in the SDSS imaging. We estimate that at least 50% of these are real associations (not projection effects) and may represent a significant "dry merger" fraction. We study the SDSS pipeline sizes of BOSS galaxies which we find to be systematically larger (by 40%) than those measured from HST images, and provide a statistical correction for the difference. These details of the BOSS galaxies will help users of the data fine-tune their selection criteria, dependent on their science applications. For example, the main goal of BOSS is to measure the cosmic distance scale and expansion rate of the Universe to percent-level precision - a point where systematic effects due to the details of target selection may become important.Comment: 18 pages, 11 figures; v2 as accepted by MNRA

The Eighth Data Release of the Sloan Digital Sky Survey: First Data from SDSS-III

The Sloan Digital Sky Survey (SDSS) started a new phase in August 2008, with new instrumentation and new surveys focused on Galactic structure and chemical evolution, measurements of the baryon oscillation feature in the clustering of galaxies and the quasar Ly alpha forest, and a radial velocity search for planets around ~8000 stars. This paper describes the first data release of SDSS-III (and the eighth counting from the beginning of the SDSS). The release includes five-band imaging of roughly 5200 deg^2 in the Southern Galactic Cap, bringing the total footprint of the SDSS imaging to 14,555 deg^2, or over a third of the Celestial Sphere. All the imaging data have been reprocessed with an improved sky-subtraction algorithm and a final, self-consistent photometric recalibration and flat-field determination. This release also includes all data from the second phase of the Sloan Extension for Galactic Understanding and Evolution (SEGUE-2), consisting of spectroscopy of approximately 118,000 stars at both high and low Galactic latitudes. All the more than half a million stellar spectra obtained with the SDSS spectrograph have been reprocessed through an improved stellar parameters pipeline, which has better determination of metallicity for high metallicity stars.Comment: Astrophysical Journal Supplements, in press (minor updates from submitted version