Dont Mess with Texas: Getting the Lone Star State to Net-Zero by 2050

The world is decarbonizing. Many countries, companies, and financial institutions have committed to cutting their emissions. Decarbonization commitments have been issued by: 136 countries including Canada, China, and the UK, at least 16 U.S. states including New York, Louisiana, and Virginia, and a third of the largest 2,000 publicly traded companies in the world, including Apple, Amazon, and Walmart, and numerous Texas companies like ExxonMobil, American and Southwest Airlines, Baker Hughes, and AT&T.1–9 These decarbonizing countries, states, cities, and companies are Texas's energy customers. If Texas ignores the challenge to decarbonize its economy, it may eventually face the more difficult challenge of selling carbon-intensive products to customers around the world who do not want them. We are already seeing this scenario beginning to play out with France canceling a liquified natural gas deal from Texas gas producers and both U.S. and international automakers announcing shifts to electric vehicles. Proactive net-zero emissions strategies might allow Texas to maintain energy leadership and grow the economy within a rapidly decarbonizing global marketplace.Thankfully, Texas is uniquely positioned to lead the world in the transition to a carbon-neutral energy economy. With the second highest Gross State Product in the US, the Texas economy is on par with countries like Canada, Italy, or Brazil. Thus, Texas's decisions have global implications. Texas also has an abundant resource of low-carbon energy sources to harness and a world-class workforce with technical capabilities to implement solutions at a large-scale quickly and safely. Texas has a promising opportunity to lead the world towards a better energy system in a way that provides significant economic benefits to the state by leveraging our renewable resources, energy industry expertise, and strong manufacturing and export markets for clean electricity, fuels, and products. The world is moving, with or without Texas, but it is likely to move faster--and Texas will be more prosperous--if Texans lead the way.There are many ways to fully decarbonize the Texas economy across all sectors by 2050. In this analysis, we present a Business as Usual (BAU) scenario and four possible pathways to Texas achieving state-wide net-zero emissions by 2050. Figure ES-1 provides a visual comparison of scenario conditions

Deliver Me From Food Waste: Model Framework for Comparing the Energy Use of Meal-Kit Delivery and Groceries

This work shares a model that was developed to compare the energy requirements of meal-kit delivery systems to conventional grocery shopping. Meal-kit services can reduce food waste because the kits pre-portion ingredients for each recipe, thereby saving energy. However, the supply chain and packaging requirements of meal-kit delivery are different than those for grocery stores, potentially offsetting any energetic benefits of reduced food waste. If meal-kit delivery replaces some trips to the grocery store, then transportation-related savings might be significant. The tradeoffs of these competing effects are non-obvious, so mass and energy balances were used to assess embedded energy in both pathways. The model was illustrated under representative operating conditions for a consumer in Austin, Texas using Monte Carlo simulation. Both per-meal and per-week, a meal-kit delivery service meal is more energy intensive than procuring the same meal from conventional grocery stores primarily due to single-use packaging. Consumer transportation to the grocery store was also found to be particularly energy intensive. These results suggest that the energetic requirements of meal-kit delivery services could be reduced such that they are less than conventional grocery shopping if reusable or low-impact packaging is used, and if the delivery services are able to reduce the number of weekly trips to the grocery store

Clonal fitness inferred from time-series modelling of single-cell cancer genomes

Progress in defining genomic fitness landscapes in cancer, especially those defined by copy number alterations (CNAs), has been impeded by lack of time-series single-cell sampling of polyclonal populations and temporal statistical models1-7. Here we generated 42,000 genomes from multi-year time-series single-cell whole-genome sequencing of breast epithelium and primary triple-negative breast cancer (TNBC) patient-derived xenografts (PDXs), revealing the nature of CNA-defined clonal fitness dynamics induced by TP53 mutation and cisplatin chemotherapy. Using a new Wright-Fisher population genetics model8,9 to infer clonal fitness, we found that TP53 mutation alters the fitness landscape, reproducibly distributing fitness over a larger number of clones associated with distinct CNAs. Furthermore, in TNBC PDX models with mutated TP53, inferred fitness coefficients from CNA-based genotypes accurately forecast experimentally enforced clonal competition dynamics. Drug treatment in three long-term serially passaged TNBC PDXs resulted in cisplatin-resistant clones emerging from low-fitness phylogenetic lineages in the untreated setting. Conversely, high-fitness clones from treatment-naive controls were eradicated, signalling an inversion of the fitness landscape. Finally, upon release of drug, selection pressure dynamics were reversed, indicating a fitness cost of treatment resistance. Together, our findings define clonal fitness linked to both CNA and therapeutic resistance in polyclonal tumours

\u3ci\u3eDrosophila\u3c/i\u3e Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics

The value of open-source clinical science in pandemic response: lessons from ISARIC

International audienc