An Orthogonal Test of the LL-functions Ratios Conjecture, II

Recently Conrey, Farmer, and Zirnbauer developed the L-functions Ratios conjecture, which gives a recipe that predicts a wealth of statistics, from moments to spacings between adjacent zeros and values of L-functions. The problem with this method is that several of its steps involve ignoring error terms of size comparable to the main term; amazingly, the errors seem to cancel and the resulting prediction is expected to be accurate up to square-root cancellation. We prove the accuracy of the Ratios Conjecture's prediction for the 1-level density of families of cuspidal newforms of constant sign (up to square-root agreement for support in (-1,1), and up to a power savings in (-2,2)), and discuss the arithmetic significance of the lower order terms. This is the most involved test of the Ratios Conjecture's predictions to date, as it is known that the error terms dropped in some of the steps do not cancel, but rather contribute a main term! Specifically, these are the non-diagonal terms in the Petersson formula, which lead to a Bessel-Kloosterman sum which contributes only when the support of the Fourier transform of the test function exceeds (-1, 1).Comment: 36 pages, first draf

Restocking Northern Bobwhites in East Texas: A Genetic Assessment

Habitat on a 610-ha study area in the Pineywoods Ecological Region of eastern Texas was enhanced for northern bobwhites ( Coli nus virginianus). In February and March 1990, 1991, and 1992, bobwhites from south Texas (C. v. texanus) and disjunct areas of east Texas (C. v. mexicanus) were captured, radio tagged, and relocated to the study area which had a small ( \u3c25 birds) resident population. Blood samples were collected from the birds relocated in 1991. Samples were also collected from birds in the resident population during 1991 and 1992; these birds were assumed to be offspring of the previous years\u27 resident and relocated bobwhites. Restriction site variation of mitochondrial DNA (mtDNA) revealed geographic subdivision between the subspecies but not between resident and east Texas relocated birds. The observed frequency differences of mtDNA haplotypes were used to assess the relative reproductive success of the 2 subspecies. Among the birds examined for mtDNA variation, offspring produced on the study area during 1990 and 1991 were genetically more similar to the east Texas subspecies than to the south Texas subspecies. These results suggest that efforts to restock northern bobwhite should involve either local birds or birds from the same subspecies. Management implications of these findings are discussed

Efficient Mutagenesis by Cas9 Protein-Mediated Oligonucleotide Insertion and Large-Scale Assessment of Single-Guide RNAs

The CRISPR/Cas9 system has been implemented in a variety of model organisms to mediate site-directed mutagenesis. A wide range of mutation rates has been reported, but at a limited number of genomic target sites. To uncover the rules that govern effective Cas9-mediated mutagenesis in zebrafish, we targeted over a hundred genomic loci for mutagenesis using a streamlined and cloning-free method. We generated mutations in 85% of target genes with mutation rates varying across several orders of magnitude, and identified sequence composition rules that influence mutagenesis. We increased rates of mutagenesis by implementing several novel approaches. The activities of poor or unsuccessful single-guide RNAs (sgRNAs) initiating with a 5′ adenine were improved by rescuing 5′ end homogeneity of the sgRNA. In some cases, direct injection of Cas9 protein/sgRNA complex further increased mutagenic activity. We also observed that low diversity of mutant alleles led to repeated failure to obtain frame-shift mutations. This limitation was overcome by knock-in of a stop codon cassette that ensured coding frame truncation. Our improved methods and detailed protocols make Cas9-mediated mutagenesis an attractive approach for labs of all sizes

Brief of Tribal Nations and Indian Organizations as Amici Curiae in Support of the Navajo Nation, U.S. Supreme Court Docket No. 21-1484

SUMMARY OF ARGUMENT: The Winters Doctrine recognizes and gives effect to the promises made by the United States in treaties, congressionally ratified agreements, and executive orders that Tribal Nations would retain permanent and viable homelands. These promises, made in exchange for the Tribal Nations’ cession of billions of acres of land, paved the way for the non-Indian settlement of the West. Although every tribal homeland is unique, invariably, each requires water to be livable. Applying the canons of construction this Court has developed as part of its federal Indian law jurisprudence, as well as the history and circumstances surrounding the creation of each individual reservation, the Winters Doctrine holds that the United States promised to provide water sufficient to fulfill the purposes for which the reservations were created. Concomitant with the promise to reserve water rights is the corresponding duty to protect and deliver on that promise and avoid rendering those rights meaningless through obstruction, depletion, or diversion to more junior users. In this way, the Winters Doctrine is a pathway for ensuring the United States fulfills its solemn obligations to Tribal Nations. The United States—through both Congress and the Executive—has repeatedly and expressly reaffirmed its understanding of these obligations. Petitioners here articulate no reason why the Lower Colorado River Basin should be treated differently. This Court should once again ensure the United States honors its obligations. In the 115 years since Winters v. United States, the Doctrine solidified into an integral part of the fabric that makes up Western water management. The Winters Doctrine forms the basis for extensive adjudication and settlement of claims by Tribal Nations to water rights. Today, millions of tribal and non-tribal citizens benefit from the certainty provided by the Winters Doctrine

Marine Ecoregion and Deepwater Horizon Oil Spill Affect Recruitment and Population Structure of a Salt Marsh Snail

Marine species with planktonic larvae often have high spatial and temporal variation in recruitment that leads to subsequent variation in the ecology of benthic adults. Using a combination of published and unpublished data, we compared the population structure of the salt marsh snail, Littoraria irrorata, between the South Atlantic Bight and the Gulf Coast of the United States to infer geographic differences in recruitment and to test the hypothesis that the Deepwater Horizon oil spill led to widespread recruitment failure of L. irrorata in Louisiana in 2010. Size-frequency distributions in both ecoregions were bimodal, with troughs in the distributions consistent with a transition from sub-adults to adults at ~13 mm in shell length as reported in the literature; however, adult snails reached larger sizes in the Gulf Coast. The ratio of sub-adults to adults was 1.5–2 times greater in the South Atlantic Bight than the Gulf Coast, consistent with higher recruitment rates in the South Atlantic Bight. Higher recruitment rates in the South Atlantic Bight could contribute to higher snail densities and reduced adult growth in this region. The ratio of sub-adults to adults in Louisiana was lower in 2011 than in previous years, and began to recover in 2012–2014, consistent with widespread recruitment failure in 2010, when large expanses of spilled oil were present in coastal waters. Our results reveal an important difference in the ecology of a key salt marsh invertebrate between the two ecoregions, and also suggest that the Deepwater Horizon oil spill may have caused widespread recruitment failure in this species and perhaps others with similar planktonic larval stages

A unitary test of the Ratios Conjecture

The Ratios Conjecture of Conrey, Farmer and Zirnbauer predicts the answers to numerous questions in number theory, ranging from n-level densities and correlations to mollifiers to moments and vanishing at the central point. The conjecture gives a recipe to generate these answers, which are believed to be correct up to square-root cancelation. These predictions have been verified, for suitably restricted test functions, for the 1-level density of orthogonal and symplectic families of L-functions. In this paper we verify the conjecture's predictions for the unitary family of all Dirichlet $L$-functions with prime conductor; we show square-root agreement between prediction and number theory if the support of the Fourier transform of the test function is in (-1,1), and for support up to (-2,2) we show agreement up to a power savings in the family's cardinality.Comment: Version 2: 24 pages, provided additional details, fixed some small mistakes and expanded the exposition in place

Genome sequencing of the extinct Eurasian wild aurochs, Bos primigenius, illuminates the phylogeography and evolution of cattle

Background Domestication of the now-extinct wild aurochs, Bos primigenius, gave rise to the two major domestic extant cattle taxa, B. taurus and B. indicus. While previous genetic studies have shed some light on the evolutionary relationships between European aurochs and modern cattle, important questions remain unanswered, including the phylogenetic status of aurochs, whether gene flow from aurochs into early domestic populations occurred, and which genomic regions were subject to selection processes during and after domestication. Here, we address these questions using whole-genome sequencing data generated from an approximately 6,750-year-old British aurochs bone and genome sequence data from 81 additional cattle plus genome-wide single nucleotide polymorphism data from a diverse panel of 1,225 modern animals. Results Phylogenomic analyses place the aurochs as a distinct outgroup to the domestic B. taurus lineage, supporting the predominant Near Eastern origin of European cattle. Conversely, traditional British and Irish breeds share more genetic variants with this aurochs specimen than other European populations, supporting localized gene flow from aurochs into the ancestors of modern British and Irish cattle, perhaps through purposeful restocking by early herders in Britain. Finally, the functions of genes showing evidence for positive selection in B. taurus are enriched for neurobiology, growth, metabolism and immunobiology, suggesting that these biological processes have been important in the domestication of cattle. Conclusions This work provides important new information regarding the origins and functional evolution of modern cattle, revealing that the interface between early European domestic populations and wild aurochs was significantly more complex than previously thought

Comparative analysis of the domestic cat genome reveals genetic signatures underlying feline biology and domestication

Little is known about the genetic changes that distinguish domestic cat populations from their wild progenitors. Here we describe a high-quality domestic cat reference genome assembly and comparative inferences made with other cat breeds, wildcats, and other mammals. Based upon these comparisons, we identified positively selected genes enriched for genes involved in lipid metabolism that underpin adaptations to a hypercarnivorous diet. We also found positive selection signals within genes underlying sensory processes, especially those affecting vision and hearing in the carnivore lineage. We observed an evolutionary tradeoff between functional olfactory and vomeronasal receptor gene repertoires in the cat and dog genomes, with an expansion of the feline chemosensory system for detecting pheromones at the expense of odorant detection. Genomic regions harboring signatures of natural selection that distinguish domestic cats from their wild congeners are enriched in neural crest-related genes associated with behavior and reward in mouse models, as predicted by the domestication syndrome hypothesis. Our description of a previously unidentified allele for the gloving pigmentation pattern found in the Birman breed supports the hypothesis that cat breeds experienced strong selection on specific mutations drawn from random bred populations. Collectively, these findings provide insight into how the process of domestication altered the ancestral wildcat genome and build a resource for future disease mapping and phylogenomic studies across all members of the Felidae

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707