LINE-1 Evasion of Epigenetic Repression in Humans

Epigenetic silencing defends against LINE-1 (L1) retrotransposition in mammalian cells. However, the mechanisms that repress young L1 families and how L1 escapes to cause somatic genome mosaicism in the brain remain unclear. Here we report that a conserved Yin Yang 1 (YY1) transcription factor binding site mediates L1 promoter DNA methylation in pluripotent and differentiated cells. By analyzing 24 hippocampal neurons with three distinct single-cell genomic approaches, we characterized and validated a somatic L1 insertion bearing a 3' transduction. The source (donor) L1 for this insertion was slightly 5' truncated, lacked the YY1 binding site, and was highly mobile when tested in\ua0vitro. Locus-specific bisulfite sequencing revealed that the donor L1 and other young L1s with mutated YY1 binding sites were hypomethylated in embryonic stem cells, during neurodifferentiation, and in liver and brain tissue. These results explain how L1 can evade repression and retrotranspose in the human body

Waveform Modelling for the Laser Interferometer Space Antenna

LISA, the Laser Interferometer Space Antenna, will usher in a new era in gravitational-wave astronomy. As the first anticipated space-based gravitational-wave detector, it will expand our view to the millihertz gravitational-wave sky, where a spectacular variety of interesting new sources abound: from millions of ultra-compact binaries in our Galaxy, to mergers of massive black holes at cosmological distances; from the beginnings of inspirals that will venture into the ground-based detectors' view to the death spiral of compact objects into massive black holes, and many sources in between. Central to realising LISA's discovery potential are waveform models, the theoretical and phenomenological predictions of the pattern of gravitational waves that these sources emit. This white paper is presented on behalf of the Waveform Working Group for the LISA Consortium. It provides a review of the current state of waveform models for LISA sources, and describes the significant challenges that must yet be overcome.Comment: 239 pages, 11 figures, white paper from the LISA Consortium Waveform Working Group, invited for submission to Living Reviews in Relativity, updated with comments from communit

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

A real-world approach to Evidence-Based Medicine in general practice: a competency framework derived from a systematic review and Delphi process

Background Evidence-Based Medicine (EBM) skills have been included in general practice curricula and competency frameworks. However, GPs experience numerous barriers to developing and maintaining EBM skills, and some GPs feel the EBM movement misunderstands, and threatens their traditional role. We therefore need a new approach that acknowledges the constraints encountered in real-world general practice. The aim of this study was to synthesise from empirical research a real-world EBM competency framework for general practice, which could be applied in training, in the individual pursuit of continuing professional development, and in routine care. We sought to integrate evidence from the literature with evidence derived from the opinions of experts in the fields of general practice and EBM. Methods We synthesised two sets of themes describing the meaning of EBM in general practice. One set of themes was derived from a mixed-methods systematic review of the literature; the other set was derived from the further development of those themes using a Delphi process among a panel of EBM and general practice experts. From these two sets of themes we constructed a real-world EBM competency framework for general practice. Results A simple competency framework was constructed, that acknowledges the constraints of real-world general practice: (1) mindfulness - in one’s approach towards EBM itself, and to the influences on decision-making; (2) pragmatism – in one’s approach to finding and evaluating evidence; and (3) knowledge of the patient – as the most useful resource in effective communication of evidence. We present a clinical scenario to illustrate how a GP might demonstrate these competencies in their routine daily work. Conclusion We have proposed a real-world EBM competency framework for general practice, derived from empirical research, which acknowledges the constraints encountered in modern general practice. Further validation of these competencies is required, both as an educational resource and as a strategy for actual practice.</p

Environmentalism, pre-environmentalism, and public policy

In the last decade, thousands of new grassroots groups have formed to oppose environmental pollution on the basis that it endangers their health. These groups have revitalized the environmental movement and enlarged its membership well beyond the middle class. Scientists, however, have been unable to corroborate these groups' claims that exposure to pollutants has caused their diseases. For policy analysts this situation appears to pose a choice between democracy and science. It needn't. Instead of evaluating the grassroots groups from the perspective of science, it is possible to evaluate science from the perspective of environmentalism. This paper argues that environmental epidemiology reflects ‘pre-environmentalist’ assumptions about nature and that new ideas about nature advanced by the environmental movement could change the way scientists collect and interpret data.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45449/1/11077_2005_Article_BF01006494.pd

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Second-order gravitational self-force in a highly regular gauge

Gravitational-wave emission from extreme-mass-ratio inspirals (EMRIs) is expected to be a key source for the Laser Interferometer Space Antenna (LISA), a future space-based gravitational-wave detector. In this thesis, we detail an approach to model these systems through a perturbative method known as gravitational self-force theory. Accurate EMRI science requires us to go to second order in perturbation theory, which introduces a number of obstacles. One major problem that we focus on ameliorating in this thesis is the strong divergence encountered on the worldline of the small object. This divergence creates a severe computational cost in numerical simulations and hinders the rapid calculations that are required for waveform generation for LISA. However, building on previous work by Pound [Phys. Rev. D 95, 104056 (2017)], we develop a class of "highly regular" gauges with a weaker singularity structure. We calculate all orders of the metric perturbations required for numerical implementation and generate fully covariant and generic coordinate-expansion expressions for the metric perturbations in this class of gauges. Not only will the weaker divergences enable quicker numerical calculations, they also allow us to rigorously derive a pointlike second-order stress-energy tensor for the small object. We demonstrate that the form of this second-order stress-energy tensor is valid in any smoothly related gauge and, using a specific distributional definition, also valid in a widely used gauge in self-force calculations, the Lorenz gauge. This stress-energy tensor can then be used as part of the source when solving for the full, physical fields at second order and we outline how this can be done through the introduction of a counter term that cancels the most singular part of the second-order source in the Lorenz gauge. Finally, we present the calculation of the gauge vector required to transform from the Lorenz gauge to the highly regular gauge and provide it in mode-decomposed form for the case of quasicircular orbits in Schwarzschild spacetime. While this work is motivated by EMRIs, much of the work in this thesis is valid for a small object in any vacuum background spacetime with an external lengthscale much larger than the size of the small object

Second-order gravitational self-force in a highly regular gauge: covariant and coordinate punctures

Gravitational self-force theory is the primary way of modelling extreme-mass-ratio inspirals (EMRIs). One difficulty that appears in second-order self-force calculations is the strong divergence at the worldline of the small object, which causes both numerical and analytical issues. Previous work [Phys. Rev. D 95, 104056 (2017); ibid. 103, 124016 (2021)] demonstrated that this could be alleviated within a class of highly regular gauges and presented the metric perturbations in these gauges in a local coordinate form. We build on this previous work by deriving expressions for the highly regular gauge metric perturbations in both fully covariant form and as a generic coordinate expansion. With the metric perturbations in covariant or generic coordinate form, they can easily be expressed in any convenient coordinate system. These results can then be used as input into a puncture scheme in order to solve the field equations describing an EMRI

Low-energy Lorentz violation from high-energy modified dispersion in inertial and circular motion

We consider an Unruh-DeWitt detector in inertial and circular motion in Minkowski spacetime of arbitrary dimension, coupled to a quantized scalar field with the Lorentz-violating dispersion relation ω=|k|f(|k|/M†), where M↠is the Lorentz-breaking scale. Assuming that f dips below unity somewhere, we show that an inertial detector experiences large low-energy Lorentz violations in all spacetime dimensions greater than two, generalizing previous results in four dimensions. For a detector in circular motion, we show that a similar low-energy Lorentz violation occurs in three spacetime dimensions, and we lay the analytic groundwork for examining circular motion in all dimensions greater than three, generalizing previous work by Stargen, Kajuri and Sriramkumar in four dimensions. The circular motion results may be relevant for the prospects of observing the circular motion Unruh effect in analogue laboratory systems.</p