Many bacteria can infect and persist inside their hosts for long periods of time. This can be due to immunosuppression of the host, immune evasion by the pathogen and/or ineffective killing by ...antibiotics. Bacteria can survive antibiotic treatment if they are resistant or tolerant to a drug. Persisters are a subpopulation of transiently antibiotic-tolerant bacterial cells that are often slow-growing or growth-arrested, and are able to resume growth after a lethal stress. The formation of persister cells establishes phenotypic heterogeneity within a bacterial population and has been hypothesized to be important for increasing the chances of successfully adapting to environmental change. The presence of persister cells can result in the recalcitrance and relapse of persistent bacterial infections, and it has been linked to an increase in the risk of the emergence of antibiotic resistance during treatment. If the mechanisms of the formation and regrowth of these antibiotic-tolerant cells were better understood, it could lead to the development of new approaches for the eradication of persistent bacterial infections. In this Review, we discuss recent developments in our understanding of bacterial persisters and their potential implications for the treatment of persistent infections.
Energy storage technologies are critical in addressing the global challenge of clean sustainable energy. Major advances in rechargeable batteries for portable electronics, electric vehicles and ...large-scale grid storage will depend on the discovery and exploitation of new high performance materials, which requires a greater fundamental understanding of their properties on the atomic and nanoscopic scales. This review describes some of the exciting progress being made in this area through use of computer simulation techniques, focusing primarily on positive electrode (cathode) materials for lithium-ion batteries, but also including a timely overview of the growing area of new cathode materials for sodium-ion batteries. In general, two main types of technique have been employed, namely electronic structure methods based on density functional theory, and atomistic potentials-based methods. A major theme of much computational work has been the significant synergy with experimental studies. The scope of contemporary work is highlighted by studies of a broad range of topical materials encompassing layered, spinel and polyanionic framework compounds such as LiCoO
2
, LiMn
2
O
4
and LiFePO
4
respectively. Fundamental features important to cathode performance are examined, including voltage trends, ion diffusion paths and dimensionalities, intrinsic defect chemistry, and surface properties of nanostructures.
Key advances in computational studies of lithium-ion battery materials, as well as recent highlights in the growing area of new materials for sodium-ion batteries.
Vascular smooth muscle cells (VSMCs) have long been associated with phenotypic modulation/plasticity or dedifferentiation. Innovative technologies in cell lineage tracing, single-cell RNA sequencing, ...and human genomics have been integrated to gain unprecedented insights into the molecular reprogramming of VSMCs to other cell phenotypes in experimental and clinical atherosclerosis. The current thinking is that an apparently small subset of contractile VSMCs undergoes a fate switch to transitional, multipotential cells that can adopt plaque-destabilizing (inflammation, ossification) or plaque-stabilizing (collagen matrix deposition) cell states. Several candidate mediators of such VSMC fate and state changes are coming to light with intriguing implications for understanding coronary artery disease risk and the development of new treatment modalities. Here, we briefly summarize some technical and conceptual advancements derived from 2 publications in
and another in
that, collectively, illuminate new research directions to further explore the role of VSMCs in atherosclerotic disease.
Inflammation contributes to many of the characteristics of plaques implicated in the pathogenesis of acute coronary syndromes. Moreover, inflammatory pathways not only regulate the properties of ...plaques that precipitate acute coronary syndromes but also modulate the clinical consequences of the thrombotic complications of atherosclerosis. This synthesis will provide an update on the fundamental mechanisms of inflammatory responses that govern acute coronary syndromes and also highlight the ongoing balance between proinflammatory mechanisms and endogenous pathways that can promote the resolution of inflammation. An appreciation of the countervailing mechanisms that modulate inflammation in relation to acute coronary syndromes enriches our fundamental understanding of the pathophysiology of this important manifestation of atherosclerosis. In addition, these insights provide glimpses into potential novel therapeutic interventions to forestall this ultimate complication of the disease.
Land surface models (LSMs) are a vital tool for understanding, projecting, and predicting the dynamics of the land surface and its role within the Earth system, under global change. Driven by the ...need to address a set of key questions, LSMs have grown in complexity from simplified representations of land surface biophysics to encompass a broad set of interrelated processes spanning the disciplines of biophysics, biogeochemistry, hydrology, ecosystem ecology, community ecology, human management, and societal impacts. This vast scope and complexity, while warranted by the problems LSMs are designed to solve, has led to enormous challenges in understanding and attributing differences between LSM predictions. Meanwhile, the wide range of spatial scales that govern land surface heterogeneity, and the broad spectrum of timescales in land surface dynamics, create challenges in tractably representing processes in LSMs. We identify three “grand challenges” in the development and use of LSMs, based around these issues: managing process complexity, representing land surface heterogeneity, and understanding parametric dynamics across the broad set of problems asked of LSMs in a changing world. In this review, we discuss progress that has been made, as well as promising directions forward, for each of these challenges.
Plain Language Summary
Land surface models (LSMs) are the part of climate models that simulate processes happening at the Earth's surface. These include reflection of the sunlight, evaporation from ecosystems, and the amount of carbon from human emissions that the land takes up. LSMs also need to simulate how human management of the land surface changes the climate both directly (e.g., via the effect on evaporation) and in the long term (via changing the amount of carbon stored in wood and soil). Not surprisingly, trying to make a single mathematical representation of all of these different parts of the Earth system is difficult. Here we discuss themes that repeatedly affect all teams developing LSMs: how to manage the increasing number of complicated model components, how to represent the high degree of variability of the land surface, and how to predict how the properties of the surface (particularly those of plant communities) will change. These are large problems, with no obvious easy solutions. We hope to spark discussion and investment into their resolution, concomitant with the increasing importance of LSMs as our best tools for translating possible trajectories of climate change into impacts on humans, ecosystems, food and water supplies, and river systems.
Key Points
Land surface models have grown in complexity, and new methods of managing this complexity are required for scientific understanding
New methods are also needed to represent, classify, and benchmark models across the multidimensional heterogeneity of the land surface
A further challenge is to constrain model parameters in ways that are consistent with allowing long‐term ecological dynamics to occur
Atherosclerosis is a chronic inflammatory disease that arises from an imbalance in lipid metabolism and a maladaptive immune response driven by the accumulation of cholesterol-laden macrophages in ...the artery wall. Through the analysis of the progression and regression of atherosclerosis in animal models, there is a growing understanding that the balance of macrophages in the plaque is dynamic and that both macrophage numbers and the inflammatory phenotype influence plaque fate. In this Review, we summarize recently identified pro- and anti-inflammatory pathways that link lipid and inflammation biology with the retention of macrophages in plaques, as well as factors that have the potential to promote their egress from these sites.
Proton pump inhibitors (PPIs) are among the most commonly used medications in the world. Developed for the treatment and prevention of acid-mediated upper gastrointestinal conditions, these agents ...are being used increasingly for indications where their benefits are less certain. PPI overprescription imposes an economic cost and contributes to polypharmacy. In addition, PPI use has been increasingly linked to a number of adverse events (PPI-associated adverse events PAAEs). Therefore, de-prescribing of PPIs is an important strategy to lower pill burden while reducing real costs and theoretical risks. The purpose of this clinical update was to provide Best Practice Advice (BPA) statements about how to approach PPI de-prescribing in ambulatory patients.
Our guiding principle was that, although PPIs are generally safe, patients should not use any medication when there is not a reasonable expectation of benefit based on scientific evidence or prior treatment response. Prescribers are responsible for determining whether PPI use is absolutely or conditionally indicated and, when uncertainty exists, to incorporate patient perspectives into PPI decision making. We collaboratively outlined a high-level “process map” of the conceptual approach to de-prescribing PPIs in a clinical setting. We identified the following 3 key domains that required BPA guidance: documentation of PPI indication; identifying suitable candidates for consideration of de-prescribing; and optimizing successful de-prescribing. Co-authors drafted 1 or more potential BPAs, supported by literature review, for each domain. All co-authors reviewed, edited, and selected or rejected draft BPAs for inclusion in the final list submitted to the American Gastroenterological Association Governing Board. Because this was not a systematic review, we did not carry out a formal rating of the quality of evidence or strength of the presented considerations.
Best Practice Advice Statements
All patients taking a PPI should have a regular review of the ongoing indications for use and documentation of that indication. This review should be the responsibility of the patient’s primary care provider.
All patients without a definitive indication for chronic PPI should be considered for trial of de-prescribing.
Most patients with an indication for chronic PPI use who take twice-daily dosing should be considered for step down to once-daily PPI.
Patients with complicated gastroesophageal reflux disease, such as those with a history of severe erosive esophagitis, esophageal ulcer, or peptic stricture, should generally not be considered for PPI discontinuation.
Patients with known Barrett’s esophagus, eosinophilic esophagitis, or idiopathic pulmonary fibrosis should generally not be considered for a trial of de-prescribing.
PPI users should be assessed for upper gastrointestinal bleeding risk using an evidence-based strategy before de-prescribing.
Patients at high risk for upper gastrointestinal bleeding should not be considered for PPI de-prescribing.
Patients who discontinue long-term PPI therapy should be advised that they may develop transient upper gastrointestinal symptoms due to rebound acid hypersecretion.
When de-prescribing PPIs, either dose tapering or abrupt discontinuation can be considered.
The decision to discontinue PPIs should be based solely on the lack of an indication for PPI use, and not because of concern for PAAEs. The presence of a PAAE or a history of a PAAE in a current PPI user is not an independent indication for PPI withdrawal. Similarly, the presence of underlying risk factors for the development of an adverse event associated with PPI use should also not be an independent indication for PPI withdrawal.
The synthesis of a quantum computer remains an ongoing challenge in modern physics. Whereas decoherence stymies most approaches, topological quantum computation schemes evade decoherence at the ...hardware level by storing quantum information non-locally. Here we establish that a key operation--braiding of non-Abelian anyons--can be implemented using one-dimensional semiconducting wires. Such wires can be driven into a topological phase supporting long-sought particles known as Majorana fermions that can encode topological qubits. We show that in wire networks, Majorana fermions can be meaningfully braided by simply adjusting gate voltages, and that they exhibit non-Abelian statistics like vortices in a p+ip superconductor. We propose experimental set-ups that enable probing of the Majorana fusion rules and the efficient exchange of arbitrary numbers of Majorana fermions. This work should open a new direction in topological quantum computation that benefits from physical transparency and experimental feasibility. PUBLICATION ABSTRACT
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