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Increased exposure to blue or visible light, fluctuations in oxygen tension, and the excessive accumulation of toxic retinoid byproducts places a tremendous amount of stress on the retina. Reduction of visual chromophore biosynthesis may be an effective method to reduce the impact of these stressors and preserve retinal integrity. A class of non-retinoid, small molecule compounds that target key proteins of the visual cycle have been developed. The first candidate in this class of compounds, referred to as visual cycle modulators, is emixustat hydrochloride (emixustat). Here, we describe the effects of emixustat, an inhibitor of the visual cycle isomerase (RPE65), on visual cycle function and preservation of retinal integrity in animal models. Emixustat potently inhibited isomerase activity in vitro (IC50 = 4.4 nM) and was found to reduce the production of visual chromophore (11-cis retinal) in wild-type mice following a single oral dose (ED50 = 0.18 mg/kg). Measure of drug effect on the retina by electroretinography revealed a dose-dependent slowing of rod photoreceptor recovery (ED50 = 0.21 mg/kg) that was consistent with the pattern of visual chromophore reduction. In albino mice, emixustat was shown to be effective in preventing photoreceptor cell death caused by intense light exposure. Pre-treatment with a single dose of emixustat (0.3 mg/kg) provided a ~50% protective effect against light-induced photoreceptor cell loss, while higher doses (1-3 mg/kg) were nearly 100% effective. In Abca4-/- mice, an animal model of excessive lipofuscin and retinoid toxin (A2E) accumulation, chronic (3 month) emixustat treatment markedly reduced lipofuscin autofluorescence and reduced A2E levels by ~60% (ED50 = 0.47 mg/kg). Finally, in the retinopathy of prematurity rodent model, treatment with emixustat during the period of ischemia and reperfusion injury produced a ~30% reduction in retinal neovascularization (ED50 = 0.46mg/kg). These data demonstrate the ability of emixustat to modulate visual cycle activity and reduce pathology associated with various biochemical and environmental stressors in animal models. Other attributes of emixustat, such as oral bioavailability and target specificity make it an attractive candidate for clinical development in the treatment of retinal disease.

The Energy Environment Experiential Learning (EEEL) project in Calgary Alberta Canada, responds to the necessity for modern, high caliber undergraduate learning environments. The facility, which opened September 2011, is studentcentric, providing opportunities for hands-on and experiential learning in both individual and collaborative settings. The five-story building provides instructional space for expanded programs in energy and environments, new laboratories for biology and chemistry, as well as space for the ISEEE (Institute for Sustainable Energy, Environment and Economy) Administrative Center. Here, McGinn features the Energy Environment Experiential Learning at the University of Calgary.

As the green building industry rapidly moves towards the mainstream of design, the challenge for firms not currently involved in designing green buildings is to adapt to maintain market share. McGinn discusses on setting fees for profitable green building projects. Among other things, a consultant with a demonstrated expertise in green design often will receive the commission based on the value brought to the team.

Thanks to [Tim Hunt] de Lisle for his piece on the road song (Drive- time Blues, August 26). Might I nominate another candidate? Van Morrison's song-poem Coney Island describes a childhood journey taken from East Belfast to the eponymous beach. The meaning of Coney Island and the journey to it is, in part, an internal one. The best road songs don't simply describe a route, they can change the nature of the journey, and the meaning of place itself. After all, before Route 66, Route 66 was, well, just, a road. Now, it's Route 66. Tim's favourite British road song appears to be A13 by Billy Bragg, but has he heard A13 by Jah Wobble, which was recorded in 1994? This track shows enormous warmth for this apparently quite grotty stretch of road. It is an almost Betjeman-like poem backed by some ominous, ambient noodling.

THE Omagh bombing was morally identical to the events of September 11, musician Sir Bob Geldof said yesterday, as he appealed for more money to help bring the suspected bombers to justice. Sir Bob was joined by First Minister David Trimble, former Northern Ireland Secretary Peter Mandelson and boxing hero Barry McGuigan in calling for funds to help the families of those killed mount a civil action against the alleged bombers. Mr Trimble echoed Sir Bob's comments, arguing that there was \"no moral distinction\" between Omagh and the terror attacks in America.

We rely on plants and fungi for most aspects of our lives. Yet plants and fungi are under threat, and we risk losing species before we know their identity, roles, and potential uses. Knowing names, distributions and threats are first steps towards effective conservation action. Accessible products like field guides and online resources engage society, harnessing collective support for conservation. Here we review current knowledge of the plants and fungi of the UK and UK Overseas Territories, highlighting gaps to help direct future research efforts towards conserving these vital elements of biodiversity. Societal Impact Statement We rely on plants and fungi for most aspects of our lives. Yet plants and fungi are under threat, and we risk losing species before we know their identity, roles, and potential uses. Knowing names, distributions, and threats are first steps toward effective conservation action. Accessible products like field guides and online resources engage society, harnessing collective support for conservation. Here, we review current knowledge of the plants and fungi of the UK and UK Overseas Territories, highlighting gaps to help direct future research efforts toward conserving these vital elements of biodiversity. Summary This review summarizes current knowledge of the status and threats to the plants and fungi of Great Britain and the UK Overseas Territories (UKOTs). Although the body of knowledge is considerable, the distribution of information varies substantially, and we highlight knowledge gaps. The UK vascular flora is the most well studied and we have a relatively clear picture of its 9,001 native and alien taxa. We have seedbanked 72% of the native and archaeophyte angiosperm taxa and 78% of threatened taxa. Knowledge of the UKOTs flora varies across territories and we report a UKOTs flora comprising 4,093 native and alien taxa. We have conserved 56% of the native flora and 51% of the threatened vascular plants in Kew's Millennium Seed Bank, UK. We need a better understanding of the conservation status of plants in the wild, and progress toward completion or updating national red lists varies. Site‐based protection of key plant assemblages is outlined, and progress in identifying Important Plant Areas analyzed. Knowledge of the non‐vascular flora, especially seaweeds remains patchy, particularly in many UKOTs. The biggest gaps overall are in fungi, particularly non‐lichenized fungi. Considerable investment is needed to fill these knowledge gaps and instigate effective conservation strategies.

What's interesting isn't that [Rich] Gannon threw five interceptions, including three in the final seven minutes of an easy Packers' victory. Rather, it was the feisty attitude Gannon revealed after his horrid performance that stayed with him and helped prolong his career. \"If we're 1-14 going into the 16th week, I'm going to play hard and I'm going to work,\" Gannon said that day. \"(Don) Majkowski threw five interceptions a couple weeks ago; that (expletive) is going to happen. It had nothing to do with my preparation or ability. I'm never going to quit.\" It was Gannon's work ethic, savvy and sense of teamwork that sold coach Jon Gruden on the idea of signing Gannon for $16 million over four years on the first day of the unrestricted free-agent signing period. Gruden didn't feel rifle-armed loner Jeff George fit his West Coast offense.

Importance:  This three-part study characterizes the widespread implementation of telehealth during the first year of the COVID-19 pandemic, giving us insight into the role of telehealth as we enter a stage of “new normal” healthcare delivery in the U.S. Objective: The COVID-19 Telehealth Impact Study was designed to describe the natural experiment of telehealth adoption during the pandemic.  Using a large claims data stream and surveys of providers and patients, we studied telehealth in all 50 states to inform healthcare leaders.  Design, Setting, Participants: In March 2020, the MITRE Corporation and Mayo Clinic founded the COVID-19 Healthcare Coalition (C19HCC), to respond to the pandemic. We report trends using a dataset of over 2 billion healthcare claims covering over 50% of private insurance activity in the U.S. (January 2019-December 2020), along with key elements from our provider survey (July-August 2020) and patient survey (November 2020 - February 2021). Main Outcomes and Measures: There was rapid and widespread adoption of telehealth in Spring 2020 with over 12 million telehealth claims in April 2020, accounting for 49.4% of total health care claims. Providers and patients expressed high levels of satisfaction with telehealth. 75% of providers indicated that telehealth enabled them to provide quality care.  84% of patients agreed that quality of their telehealth visit was good. Results: Peak levels of telehealth use varied widely among states ranging from 74.9% in Massachusetts to 25.4% in Mississippi.  Every clinical discipline saw a steep rise with the largest claims volume in behavioral health. Provision of care by out-of-state provider was common at 6.5% (October-December 2020). Providers reported multiple modalities of telehealth care delivery.  74% of patients indicated they will use telehealth services in the future. Conclusions and Relevance: Innovation shown by providers and patients during this period of rapid telehealth expansion constitutes a great natural experiment in care delivery with evidence supporting widespread clinical adoption and satisfaction on the part of both patients and clinicians. The authors encourage continued broad access to telehealth over the next 12 months to allow telehealth best practices to emerge, creating a more effective and resilient system of care delivery.

Considerable offseason farmland lays fallow because there are few crops that can profitably fit between primary crops. To remedy, we employed CRISPR genome editing to the freeze-tolerant, rapid cycling wild Brassica, Thlaspi arvense L. (field pennycress). High-yielding domesticated pennycress varieties were created having seed compositions comparable to “double low” canola (low erucic acid and glucosinolate). Seed glucosinolate content was reduced 75 % by combining mutations in R2R3-MYB (MYB28) and bHLH MYC (MYC3) transcription factors. Pennycress weediness was greatly reduced by knockout of the bHLH transcription factor TRANSPARENT TESTA8 (TT8), lowering seed dormancy and seed coat protections thereby mitigating pennycress re-emergence in fields. Domesticated pennycress offers farmers a profitable, low-carbon-intensity intermediate crop that confers ecosystem benefits while producing grain for renewable fuels and enhanced food security.