Biology subjects

Coles, A.

Publications and source records attributed to Coles, A..

4 recordsLinked to original sources

bioRxiv2022

More hot air: measuring the paradox of European ecology conferences

As scientists we cause an above average carbon footprint for work-related travel. International conferences are a common way for us to meet and discuss, and we do not address the environmental costs of these meetings. Knowing the costs might help us to reduce them. Here we estimated the carbon footprint of the last five physical conferences of the European Wildlife Disease Association (EWDA). We obtained the number of participants from each country for those conferences, and along with assumed travel options, commuting, accommodation, meals and printing, estimated the carbon emissions for each conference. The estimate ranged from 155 to 1205 tons CO2 per conference, or 0.7 to 2.4 tons per person. The outlying upper value was due to one joint global conference of the EWDA and the American mother association (WDA), which takes place every eight years. The geocentre was calculated for both the country of origin of the average conference attendants and for the society membership. The former was located in Luxembourg, and the latter near Dusseldorf, Germany, just approximately 170 km to the north. This represents the shortest total distance attendees would travel. Air transport to the conference country was the major source of CO2 emissions (87-97%), and the average distance flown per person increased from 1000 km (2010) to over 2000 km (2018), since later conferences were generally further from the geocentre. The biggest reduction in carbon emissions (up to 100 tons CO2) could therefore be achieved by decreasing air travel. This could be brought about by reducing the overall travel distance to the conference, i.e. a conference location near the membership geocentre, or - by a lesser amount - by encouraging travel to the conference by train or bus, i.e. conference location near good public travel hubs, and by promoting virtual attendance. Minor but yet substantial savings could be made elsewhere (2-6 tons CO2), including providing accommodation in greener hotels located closer to the conference venue and offering vegan/local food as the default option.

scientific communication and education↗

bioRxiv2022

Silencing of ApoE with Divalent siRNAs Drives Activation of Immune Clearance Pathways and Improves Amyloid Pathology in Mouse Models of Alzheimer's Disease

The most common genetic risk factor for late-onset Alzheimers disease (AD) is the APOE4 allele, with evidence for gain- and loss-of-function mechanisms. ApoE knockout in mice abrogates AD phenotypes but causes severe atherosclerosis due to the role of liver ApoE in cholesterol homeostasis. Previous attempts to inhibit brain-specific ApoE with anti-sense oligonucleotides only modestly reduced ApoE expression and had no effect on amyloid burden in adult AD mice. Here, we optimized a divalent small interfering RNA (di-siRNA) to selectively and potently silence ApoE in the brain. Silencing brain ApoE in AD mice significantly reduced amyloid plaque formation without affecting systemic cholesterol levels, confirming that brain and liver APOE pools are spatially and functionally distinct. Mechanistically, APOE appears to be a scaffold for beta-amyloid aggregation that limits clearance by microglia. Di-siRNAs from this study can be taken to pre-clinical and clinical trials to accelerate development of AD-modifying therapies and establish siRNA-based modulation of ApoE as a viable path towards therapeutic development.

neuroscience↗

bioRxiv2021

The MS remyelinating drug bexarotene (an RXR agonist) promotes induction of human Tregs and suppresses Th17 differentiation in vitro

The retinoid X receptor (RXR) agonist bexarotene has recently been shown to promote remyelination in individuals with multiple sclerosis. Murine studies demonstrated that RXR agonists can have anti-inflammatory effects by enhancing the ability of all-trans-retinoic acid (tRA), the primary active metabolite of vitamin A, to promote T regulatory cell (Treg) induction and reduce Th17 differentiation in vitro, following stimulation of naive CD4 cells in the presence of TGF-{beta}. Stimulating naive human CD4 T cells for 7 days, in the presence of either Treg or Th17 skewing cytokines {+/-} bexarotene (1 M), {+/-} other RXR agonists (9CisRA and NRX 194204), or {+/-} tRA (100 nM) shows that RXR agonists, including bexarotene, are capable of tipping the human Treg/Th17 axis in favour of Treg induction. Furthermore, this occurs independently of tRA and retinoic acid receptor (RAR) signalling. Tregs induced in the presence of bexarotene express many of the canonical markers of T cell regulation and are functionally suppressive in vitro. These findings support a potential immunomodulatory role for bexarotene and highlight the possible therapeutic application of RXR agonists in autoimmune disease, with bexarotenes pro-remyelinating effects making multiple sclerosis a particularly attractive disease target. Significance StatementThe pan-retinoid X receptor (RXR) agonist bexarotene has recently been shown to promote remyelination in patients with multiple sclerosis. Here we demonstrate that bexarotene, and other RXR agonists have immunomodulating effects, tipping the Th17/T regulatory cell (Treg) differentiation axis in favour of Treg development. These findings lend support to the idea of developing RXR agonists as treatments of autoimmune diseases, in particular multiple sclerosis.

immunology↗

bioRxiv2018

Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo

RNAi-based therapeutics show promising clinical data for treatment of liver-associated disorders. However, siRNA delivery into extra-hepatic tissues remains an obstacle, limiting the use of siRNA-based therapies. Here we report on a first example of chemical engineering of lipophilic conjugates to enable extra-hepatic delivery. We synthesized a panel of fifteen lipophilic siRNA and evaluated the impact of their chemical configuration on siRNA tissue distribution profile. Generally, lipophilic conjugates allow siRNA distribution to a wide range of tissues, where the degree of lipophilicity defines the ratio of liver/spleen to kidney distribution. In addition to primary clearance tissues, several conjugates achieve significant siRNA distribution to lung, heart, adrenal glands, fat, muscle. siRNA tissue accumulation leads to productive silencing, shown with two independent targets. siRNA concentrations necessary for productive silencing are tissue and conjugate dependent, varying significantly from 5 to 200 ng/mg. The collection of conjugated siRNA described here enables functional gene modulation in vivo in lung, muscle, fat, heart, adrenal glands opening these tissues for future therapeutic intervention.

biochemistry↗