Fourth & Inches: Marking the Line of Athletes’ Free Speech (A Colin Kaepernick Inspired Discussion)

This note addresses the ongoing controversial stance that was ignited when Colin Kaepernick refused to stand for the playing of the national anthem in protest of what he deems are wrongdoings against African Americans and minorities in the United States. The scope of this note does not surround Kaepernick himself, but rather the professional NFL football player in general. Specifically, players are entitled to the full rights of free expression and free speech as human beings and public figures, up and until the line where that right is abused on the field or “on the job,” thereby threatening an increase of injury to the NFL, team owners, and the public interest. With anti-American sentiment growing and only 52% of Americans that are “extremely proud” of their country, it is time to start coming together and it is time to appropriately mark that line aforementioned. Professional football players should have a heightened threshold of professional responsibilities that coincide with their elevated status on the field when performing in uniform, and in their professional setting. Through exploring an athlete’s freedoms of speech and expression under the Constitution and the National Labor Relations Act while simultaneously navigating through the world of player contracts and working conditions under the NFL Collective Bargaining Agreement, this note will portray a potential solution to the growing issue at hand that when multiplied can devastate the mission of the NFL, and effectually change how our nation’s youth perceive this great country. Part II will lay the foundation of this analysis; by first giving the reader an inside look into the NFL’s corporate structure and the interrelations between the NFL League Office, NFL Executive Committee, and team owners. Then I will discuss the NFLPA, the power of unions, and the role of the NFLPA in collective bargaining for the interests of the NFL players. This section will also note the relevant sections of the current 2011 NFL CBA which governs the league. Part III will illustrate a successfully executed demonstration of free speech on the professional sports stage and then introduce the reader to the Kaepernick Stance and its continued effect on our society and popular culture during a major transition of government policy. Here, the facts surrounding the issue will be put on display in a time-line fashion along with notable reactions allowing for the reader to make an independent judgment call for or against the stance and manner at which it has been presented. Furthermore, insight into the impact of social media on political protesting will reveal why the Kaepernick Stance has grown so fast, so quick. Part IV will take the reader back in time and discuss the origins of the National Anthem as well as the right of free expression under the First and Fourteenth Amendment and its continued evolution in terms of its interpretation. Finally Part V will conclude this note with an argument and a proposed solution

Coupling Transcriptional State to Large-Scale Repeat Expansions in Yeast

SummaryExpansions of simple DNA repeats cause numerous hereditary disorders in humans. Replication, repair, and transcription are implicated in the expansion process, but their relative contributions are yet to be distinguished. To separate the roles of replication and transcription in the expansion of Friedreich’s ataxia (GAA)n repeats, we designed two yeast genetic systems that utilize a galactose-inducible GAL1 promoter but contain these repeats in either the transcribed or nontranscribed region of a selectable cassette. We found that large-scale repeat expansions can occur in the lack of transcription. Induction of transcription strongly elevated the rate of expansions in both systems, indicating that active transcriptional state rather than transcription through the repeat per se affects this process. Furthermore, replication defects increased the rate of repeat expansions irrespective of transcriptional state. We present a model in which transcriptional state, linked to the nucleosomal density of a region, acts as a modulator of large-scale repeat expansions

Population sequencing data reveal a compendium of mutational processes in human germline

Mechanistic processes underlying human germline mutations remain largely unknown.Variation in mutation rate and spectra along the genome is informative about the biological mechanisms. We statistically decompose this variation into separate processes using a blind source separation technique. The analysis of a large-scale whole genome sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. Seven of these processes lend themselves to a biological interpretation. One process is driven by bulky DNA lesions that resolve asymmetrically with respect to transcription and replication. Two processes independently track direction of replication fork and replication timing. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions. We also demonstrate that a recently discovered mutagenic process specific to oocytes can be localized solely from population sequencing data. This process is spread across all chromosomes and is highly asymmetric with respect to the direction of transcription, suggesting a major role of DNA damage

Selective disruption of Tcf7l2 in the pancreatic β cell impairs secretory function and lowers β cell mass

Type 2 diabetes (T2D) is characterized by β cell dysfunction and loss. Single nucleotide polymorphisms in the T-cell factor 7-like 2 (TCF7L2) gene, associated with T2D by genome-wide association studies, lead to impaired β cell function. While deletion of the homologous murine Tcf7l2 gene throughout the developing pancreas leads to impaired glucose tolerance, deletion in the β cell in adult mice reportedly has more modest effects. To inactivate Tcf7l2 highly selectively in β cells from the earliest expression of the Ins1 gene (∼E11.5) we have therefore used a Cre recombinase introduced at the Ins1 locus. Tcfl2fl/fl::Ins1Cre mice display impaired oral and intraperitoneal glucose tolerance by 8 and 16 weeks, respectively, and defective responses to the GLP-1 analogue liraglutide at 8 weeks. Tcfl2fl/fl::Ins1Cre islets displayed defective glucose- and GLP-1-stimulated insulin secretion and the expression of both the Ins2 (∼20%) and Glp1r (∼40%) genes were significantly reduced. Glucose- and GLP-1-induced intracellular free Ca2+ increases, and connectivity between individual β cells, were both lowered by Tcf7l2 deletion in islets from mice maintained on a high (60%) fat diet. Finally, analysis by optical projection tomography revealed ∼30% decrease in β cell mass in pancreata from Tcfl2fl/fl::Ins1Cre mice. These data demonstrate that Tcf7l2 plays a cell autonomous role in the control of β cell function and mass, serving as an important regulator of gene expression and islet cell coordination. The possible relevance of these findings for the action of TCF7L2 polymorphisms associated with Type 2 diabetes in man is discusse

A Defective mRNA Cleavage and Polyadenylation Complex Facilitates Expansions of Transcribed (GAA) n Repeats Associated with Friedreich’s Ataxia

Expansions of microsatellite repeats are responsible for numerous hereditary diseases in humans, including myotonic dystrophy and Friedreich's ataxia. Whereas the length of an expandable repeat is the main factor determining disease inheritance, recent data point to genomic trans modifiers that can impact the likelihood of expansions and disease progression. Detection of these modifiers may lead to understanding and treating repeat expansion diseases. Here, we describe a method for the rapid, genome-wide identification of trans modifiers for repeat expansion in a yeast experimental system. Using this method, we found that missense mutations in the endoribonuclease subunit (Ysh1) of the mRNA cleavage and polyadenylation complex dramatically increase the rate of (GAA) n repeat expansions but only when they are actively transcribed. These expansions correlate with slower transcription elongation caused by the ysh1 mutation. These results reveal an interplay between RNA processing and repeat-mediated genome instability, confirming the validity of our approach. Keywords: genome instability; repeat expansion; RNA polyadenylation; RNA processing; transcription-replication conflicts; Friedreich’s ataxia; DNA double-strand breaks; trans-modifiers of repeat expansions; genetic screen; whole-genome sequencin

Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses.

BACKGROUND World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). METHODS We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. RESULTS At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. CONCLUSIONS These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.)

Summary of changes in chromosome number in MD741 and MD704 isolates.

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Nanopore analysis of chromosome rearrangements in MD704-2h-1.

The I-DEL (coordinates 489–514 kb) on chromosome IV, evident by sequencing, has the same Ty-associated breakpoints as in MD741-5 (S9B Fig). The Ty elements that are at the breakpoints of the YJM789-derived homolog, but are absent in S288c are shown as a gap. (TIF)</p

Diagnosis of 5-FOA-resistant haploid isolates by PCR.

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