Although theory has demonstrated rather low levels of gene flow are sufficient to counteract opposing mutation, drift, and selection, widespread recognition of the evolutionary importance of gene ...flow has come slowly. The perceived role of gene flow as an evolutionary force has vacillated over the last century. In the last few decades, new methods and analyses have demonstrated that plant gene flow rates vary tremendously—from nil to very high—depending on the species and specific populations involved, and sometimes over time for individual populations. In many cases, the measured gene flow rates are evolutionarily significant at distances of hundreds and sometimes thousands of meters, occurring at levels sufficient to counteract drift, spread advantageous alleles, or thwart moderate levels of opposing local selection. Gene flow in plants is likely to often act as a cohesive force, uniting individual plant species into real evolutionary units. Also, gene flow can evolve under natural selection, decreasing or increasing. The fact of frequent, but variable, plant gene flow has important consequences for applied issues in which the presence or absence of gene flow might influence the outcome of a policy, regulatory, or management decision. Examples include the unintended spread of engineered genes, the evolution of invasiveness, and conservation. New data-rich genomic techniques allow closer scrutiny of the role of gene flow in plant evolution. Most plant evolutionists now recognize the importance of gene flow, and it is receiving increased recognition from other areas of plant biology as well.
Mangrove tidal wetland habitats are recognised as highly vulnerable to large and chronic oil spills. This review of current literature and public databases covers the last 6 decades, summarising ...global data on oil spill incidents affecting, or likely to have affected, mangrove habitat. Over this period, there have been at least 238 notable oil spills along mangrove shorelines worldwide. In total, at least 5.5milliontonnes of oil has been released into mangrove-lined, coastal waters, oiling possibly up to around 1.94millionha of mangrove habitat, and killing at least 126,000ha of mangrove vegetation since 1958. However, there were assessment limitations with incomplete and unavailable data, as well as unequal coverage across world regions. To redress the gaps described here in reporting on oil spill impacts on mangroves and their recovery worldwide, a number of recommendations and suggestions are made for refreshing and updating standard operational procedures for responders, managers and researchers alike.
Radiotherapy is under investigation for its ability to enhance responses to immunotherapy. However, the mechanisms by which radiation induces anti-tumour T cells remain unclear. We show that the DNA ...exonuclease Trex1 is induced by radiation doses above 12-18 Gy in different cancer cells, and attenuates their immunogenicity by degrading DNA that accumulates in the cytosol upon radiation. Cytosolic DNA stimulates secretion of interferon-β by cancer cells following activation of the DNA sensor cGAS and its downstream effector STING. Repeated irradiation at doses that do not induce Trex1 amplifies interferon-β production, resulting in recruitment and activation of Batf3-dependent dendritic cells. This effect is essential for priming of CD8
T cells that mediate systemic tumour rejection (abscopal effect) in the context of immune checkpoint blockade. Thus, Trex1 is an upstream regulator of radiation-driven anti-tumour immunity. Trex1 induction may guide the selection of radiation dose and fractionation in patients treated with immunotherapy.
The evolutionary significance of hybridization and subsequent introgression has long been appreciated, but evaluation of the genome-wide effects of these phenomena has only recently become possible. ...Crop-wild study systems represent ideal opportunities to examine evolution through hybridization. For example, maize and the conspecific wild teosinte Zea mays ssp. mexicana (hereafter, mexicana) are known to hybridize in the fields of highland Mexico. Despite widespread evidence of gene flow, maize and mexicana maintain distinct morphologies and have done so in sympatry for thousands of years. Neither the genomic extent nor the evolutionary importance of introgression between these taxa is understood. In this study we assessed patterns of genome-wide introgression based on 39,029 single nucleotide polymorphisms genotyped in 189 individuals from nine sympatric maize-mexicana populations and reference allopatric populations. While portions of the maize and mexicana genomes appeared resistant to introgression (notably near known cross-incompatibility and domestication loci), we detected widespread evidence for introgression in both directions of gene flow. Through further characterization of these genomic regions and preliminary growth chamber experiments, we found evidence suggestive of the incorporation of adaptive mexicana alleles into maize during its expansion to the highlands of central Mexico. In contrast, very little evidence was found for adaptive introgression from maize to mexicana. The methods we have applied here can be replicated widely, and such analyses have the potential to greatly inform our understanding of evolution through introgressive hybridization. Crop species, due to their exceptional genomic resources and frequent histories of spread into sympatry with relatives, should be particularly influential in these studies.
Decode-and-forward relaying has been shown to be a viable transmission protocol for wireless networks incorporating distributed spatial diversity. Practical systems may employ relay channels that ...experience statistically different signal fading. The performance of decode-and-forward relaying in channels with dissimilar fading parameters is investigated. In particular, a closed-form expression for the outage probability of a system with an arbitrary number of relays is derived
Since 1969, racial and ethnic preferences have existed throughout the American medical academy. The primary purpose has been to increase the number of blacks and Hispanics within the physician ...workforce as they were deemed to be "underrepresented in medicine." To this day, the goal continues to be population parity or proportional representation. These affirmative action programs were traditionally voluntary, created and implemented at the state or institutional level, limited to the premedical and medical school stages, and intended to be temporary. Despite these efforts, numerical targets for underrepresented minorities set by the Association of American Medical Colleges have consistently fallen short. Failures have largely been attributable to the limited qualified applicant pool and legal challenges to the use of race and ethnicity in admissions to institutions of higher education. In response, programs under the appellation of diversity, inclusion, and equity have recently been created to increase the number of blacks and Hispanics as medical school students, internal medicine trainees, cardiovascular disease trainees, and cardiovascular disease faculty. These new diversity programs are mandatory, created and implemented at the national level, imposed throughout all stages of academic medicine and cardiology, and intended to be permanent. The purpose of this white paper is to provide an overview of policies that have been created to impact the racial and ethnic composition of the cardiology workforce, to consider the evolution of racial and ethnic preferences in legal and medical spheres, to critically assess current paradigms, and to consider potential solutions to anticipated challenges.
Increased synthesis of Apolipoprotein A-I (ApoA-I) and HDL is believed to provide a new approach to treating atherosclerosis through the stimulation of reverse cholesterol transport. RVX-208 ...increases the production of ApoA-I in hepatocytes in vitro, and in vivo in monkeys and humans, which results in increased HDL-C, but the molecular target was not previously reported. Using binding assays and X-ray crystallography, we now show that RVX-208 selectively binds to bromodomains of the BET (Bromodomain and Extra Terminal) family, competing for a site bound by the endogenous ligand, acetylated lysine, and that this accounts for its pharmacological activity. siRNA experiments further suggest that induction of ApoA-I mRNA is mediated by BET family member BRD4. These data indicate that RVX-208 increases ApoA-I production through an epigenetic mechanism and suggests that BET inhibition may be a promising new approach to the treatment of atherosclerosis.
Abstract
Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell ...senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of “one-two punch” cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.
Clinical development of bromodomain and extra‐terminal (BET) protein inhibitors differs from the traditional course of drug development. These drugs are simultaneously being evaluated for treating a ...wide spectrum of human diseases due to their novel mechanism of action. BET proteins are epigenetic “readers,” which play a primary role in transcription. Here, we briefly describe the BET family of proteins, of which BRD4 has been studied most extensively. We discuss BRD4 activity at latent enhancers as an example of BET protein function. We examine BRD4 redistribution and enhancer reprogramming in embryonic development, cancer, cardiovascular, autoimmune, and metabolic diseases, presenting hallmark studies that highlight BET proteins as attractive targets for therapeutic intervention. We review the currently available approaches to targeting BET proteins, methods of selectively targeting individual bromodomains, and review studies that compare the effects of selective BET inhibition to those of pan‐BET inhibition. Lastly, we examine the current clinical landscape of BET inhibitor development.
Immune checkpoint inhibitors are effective in cancer treatment. A pre-existing immune response demonstrated by significant pretreatment tumor lymphocytic infiltration is a pre-requisite for response. ...Within such infiltrated tumors, referred as "hot", immune checkpoint inhibitors rescue anti-tumor T cells activity. In contrast, "cold" tumors lack lymphocytic infiltration and are refractory to immunotherapy. Preclinical data show that radiotherapy sensitizes refractory tumors to immune checkpoint inhibitors by recruiting anti-tumor T cells. Despite the growing number of clinical studies testing radiation's ability to enhance immunotherapy, clinical evidence that it converts cold tumors into responsive ones remains elusive. Here we review evidence that radiotherapy is not only an occasional enhancer of immunotherapy's effects but a "game changer", and propose a blueprint to test this.
PDF
