The Role of the Free Fatty Acid Receptor 4 (FFAR4)/GPR120 in Adipocyte Lipolysis

Metabolites are intermediates or end products of metabolism. They are also building blocks for a variety of metabolic pathways and often function as intracellular and extracellular signalling molecules. Several G protein-coupled receptors (GPCRs) have the capacity to sense metabolites to control hormone secretion, or to regulate the metabolic activity of certain cell types. In metabolic diseases, such as diabetes and obesity, metabolites are dysregulated. Therefore, further understanding the mechanisms behind metabolite sensing GPCR signalling could help to identify novel therapeutic targets. Within this study, using bioluminescence resonance energy transfer (BRET) and other imaging-based approaches, I present evidence that the free fatty acid receptor 4 (FFAR4), a GPCR for long chain fatty acids (LCFA), is localised in close proximity to the lipid droplet membrane in adipocytes, where it can act as an intracrine negative-feedback regulator of lipolysis by inhibiting cyclic adenosine monophosphate (cAMP) production in response to the local concentration of intracellular FFAs. This intracrine signalling phenomenon is anticipated to assist the FFAR4 in its control of adipocyte metabolism

Gas Metallicities in the Extended Disks of NGC 1512 and NGC 3621. Chemical Signatures of Metal Mixing or Enriched Gas Accretion?

(Abridged) We have obtained spectra of 135 HII regions located in the inner and extended disks of the spiral galaxies NGC 1512 and NGC 3621, spanning the range of galactocentric distances 0.2-2 x R25 (from 2-3 kpc to 18-25 kpc). We find that the excitation properties of nebulae in the outer (R>R25) disks are similar to those of the inner disks, but on average younger HII regions tend to be selected in the bright inner disks. Reddening by dust is not negligible in the outer disks, and subject to significant large-scale spatial variations. For both galaxies the radial abundance gradient flattens to a constant value outside of the isophotal radius. The outer disk O/H abundance ratio is highly homogeneous, with a scatter of only ~0.06 dex. Based on the excitation and chemical (N/O ratio) analysis we find no compelling evidence for variations in the upper initial mass function of the ionizing clusters of extended disks. The O/H abundance in the outer disks of the target galaxies corresponds to 35% of the solar value (or higher, depending on the metallicity diagnostic). This conflicts with the notion that metallicities in extended disks of spiral galaxies are necessarily low. The observed metal enrichment cannot be produced with the current level of star formation. We discuss the possibility that metal transport mechanisms from the inner disks lead to metal pollution of the outer disks. Gas accretion from the intergalactic medium, enriched by outflows, offers an alternative solution.Comment: Accepted for publication in the Astrophysical Journa

Metal-enriched halo gas across galaxy overdensities over the last 10 billion years

We present a study of metal-enriched halo gas traced by Mg II and C IV absorption at z 1. It is clear from our results that environmental processes have a significant impact on the distribution of metals around galaxies and need to be fully accounted for when analysing correlations between gaseous haloes and galaxy properties

ADRA1A-Gα_q signalling potentiates adipocyte thermogenesis through CKB and TNAP

Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis(1). Aside from cAMP signalling downstream of β-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated α(1)-adrenergic receptor (AR) and β(3)-AR signalling induces the expression of thermogenic genes of the futile creatine cycle(2,3), and that early B cell factors, oestrogen-related receptors and PGC1α are required for this response in vivo. NA triggers physical and functional coupling between the α(1)-AR subtype (ADRA1A) and Gα(q) to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase B and tissue-non-specific alkaline phosphatase. Combined Gα(q) and Gα(s) signalling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and creatine kinase B is required for this effect. Thus, the ADRA1A–Gα(q)–futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis

Typing myalgic encephalomyelitis by infection at onset: A DecodeME study [version 4; peer review: 2 approved]

Background: People with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) experience core symptoms of post-exertional malaise, unrefreshing sleep, and cognitive impairment. Despite numbering 0.2-0.4% of the population, no laboratory test is available for their diagnosis, no effective therapy exists for their treatment, and no scientific breakthrough regarding pathogenesis has been made. It remains unknown, despite decades of small-scale studies, whether individuals experience different types of ME/CFS separated by onset-type, sex or age. Methods: DecodeME is a large population-based study of ME/CFS that recruited 17,074 participants in the first 3 months following full launch. Detailed questionnaire responses from UK-based participants who all reported being diagnosed with ME/CFS by a health professional provided an unparalleled opportunity to investigate, using logistic regression, whether ME/CFS severity or onset type is significantly associated with sex, age, illness duration, comorbid conditions or symptoms. Results: The well-established sex-bias among ME/CFS patients is evident in the initial DecodeME cohort: 83.5% of participants were females. What was not known previously was that females tend to have more comorbidities than males. Moreover, being female, being older and being over 10 years from ME/CFS onset are significantly associated with greater severity.  Five different ME/CFS onset types were examined in the self-reported data: those with ME/CFS onset (i) after glandular fever (infectious mononucleosis); (ii) after COVID-19 infection; (iii) after other infections; (iv) without an infection at onset; and, (v) where the occurrence of an infection at or preceding onset is not known. Among other findings, ME/CFS onset with unknown infection status was significantly associated with active fibromyalgia. Conclusions: DecodeME participants differ in symptoms, comorbid conditions and/or illness severity when stratified by their sex-at-birth and/or infection around the time of ME/CFS onset

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Navigating the chemical space of amide activation to drug discovery

This presentation will describe my scientific journey from graduate school to industry. My doctoral research at UCLA focused on the development of nickel-catalyzed reactions of amides. In particular, the Suzuki-Miyaura coupling, esterification, and transamidation of amide substrates will be described. These studies demonstrate that amides, despite classically being considered inert substrates, can be harnessed as synthons for use in the construction of C-heteroatom and C-C bonds via non-precious metal catalysis. After an abbreviated tenure in a post-doctoral position, I made the exciting decision to transition to a start-up drug discovery company where I am now a medicinal chemist working in small mol. drug discovery

Navigating the chemical space of amide activation to drug discovery

This presentation will describe my scientific journey from graduate school to industry. My doctoral research at UCLA focused on the development of nickel-catalyzed reactions of amides. In particular, the Suzuki-Miyaura coupling, esterification, and transamidation of amide substrates will be described. These studies demonstrate that amides, despite classically being considered inert substrates, can be harnessed as synthons for use in the construction of C-heteroatom and C-C bonds via non-precious metal catalysis. After an abbreviated tenure in a post-doctoral position, I made the exciting decision to transition to a start-up drug discovery company where I am now a medicinal chemist working in small mol. drug discovery

Total Synthesis of N-Methylwelwitindolinone B Isothiocyanate and Nickel-Catalyzed Reactions of Amide Derivatives

This dissertation describes our efforts toward the total synthesis of N-methyl welwitindolinone B isothioscyanate, as well as the development of reactions involving the nickel-catalyzed activation of amide C–N bonds. The welwitindolinones have been long-standing targets in total synthesis for over two decades due to their complex structures and interesting biological profiles. This dissertation describes the completed total synthesis of a particularly challenging family member, N-methylwelwitindolinone B isothiocyanate. Moreover, several nickel-catalyzed transformations of amides are described each showcasing the unique reactivity of this non-precious metal and highlighting the utility of amides, once considered inert substrates, as useful synthons in organic synthesis.Chapter one describes our enantiospecific total synthesis of N-methylwelwitindolinone B isothiocyanate. Our approach to the natural product features an aryne cyclization to construct the bicyclo[4.3.1]decane core of the molecule, as well as a C–H nitrene insertion reaction to introduce the bridgehead nitrogen substituent. The key step involving a regio- and diastereoselective chlorinative oxabicycle opening is detailed, which enables the first total synthesis of N-methylwelwitindolinone B isothiocyanate.Chapters two and three describe the development of nickel-catalyzed esterification reactions of amides. Chapter two showcases the first nickel-catalyzed activation of amides in an esterification of benzamides. This study suggests that amides could serve to be useful synthetic building blocks in a variety of cross-coupling reactions. Chapter three builds upon the previous study to expand the scope to include the activation of amides derived from aliphatic carboxylic acids. Chapters four and five describe the development of nickel-catalyzed C–N bond-forming reactions of amides. More specifically, chapters four and five outline the transamidation reaction of aromatic and aliphatic amides, respectively. These methodologies utilize a two-step approach to enable the transamidation of secondary amides. These two methods address the long-standing challenge of secondary amide transamidation.Chapter six describes the development of a nickel-catalyzed C–C bond-forming reaction of amides. The first nickel-catalyzed Suzuki–Miyaura coupling of aromatic amides is disclosed and provides a new and mild method for ketone synthesis. This study demonstrates that amides can now be utilized as synthons for use in C–C bond forming reactions through cleavage of the amide C–N bond

Comparing Design Thinking Traits between National Samples of Civil Engineering and Architecture Students

International audienceCivil engineers and architects are both trained in design thinking, but they approach the process of design from differing perspectives largely due to the divergence in their educational curriculums. With an interest in the effect of differing educational perspectives on design thinking outcomes, comparisons were made between the self-identified design thinking abilities of students in their final year of undergraduate civil engineering or architecture programs. Perceived design thinking ability was evaluated through a survey that was distributed to students enrolled in 4-year institutions across the United States. An analysis of variance (ANOVA) test was used to compare responses between the civil engineering (n=356) and architecture (n=335) student samples. There is a significant difference in perceived design thinking ability between the groups. Architecture students score higher than civil engineering students on all design thinking traits. Based on these results, the civil engineering curriculum may benefit from the incorporation of pedagogy that emphasizes design thinking, like studio-based learning