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.
Adult-to-adult living donor liver transplantation (A2ALDLT), outside of Asia, remains an important yet underutilized gift of life. For patients with end-stage liver disease, A2ALDLT is a proven ...transplantation option, with lower waiting list mortality and suffering, and equivalent or better allograft and patient survival than deceased-donor liver transplantation (DDLT). The risks to living donors and the benefit to their recipients have been carefully defined with long-term level 1 and 2 evidence-based study. An overview of the development and practice of living donor liver transplant (LDLT), including donor and recipient surgical allograft innovation, is provided. The issues of recipient selection, outcomes and morbidity, including disease-variable study and challenges past and present are presented in comparison with DDLT cohorts, and future insights are described. Central to practice is the careful and concise review of donor evaluation and selection and donor outcome, morbidity, quality of life and present and future strategies for donor advocacy and growth of the technique.
Rethinking drug design in the artificial intelligence era Schneider, Petra; Walters, W Patrick; Plowright, Alleyn T ...
Nature reviews. Drug discover/Nature reviews. Drug discovery,
05/2020, Letnik:
19, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Artificial intelligence (AI) tools are increasingly being applied in drug discovery. While some protagonists point to vast opportunities potentially offered by such tools, others remain sceptical, ...waiting for a clear impact to be shown in drug discovery projects. The reality is probably somewhere in-between these extremes, yet it is clear that AI is providing new challenges not only for the scientists involved but also for the biopharma industry and its established processes for discovering and developing new medicines. This article presents the views of a diverse group of international experts on the 'grand challenges' in small-molecule drug discovery with AI and the approaches to address them.
Cerebrovascular disease underpins vascular dementia (VaD), but structural and functional changes to the cerebral vasculature contribute to disease pathology and cognitive decline in Alzheimer's ...disease (AD). In this review, we discuss the contribution of cerebral amyloid angiopathy and non‐amyloid small vessel disease in AD, and the accompanying changes to the density, maintenance and remodelling of vessels (including alterations to the composition and function of the cerebrovascular basement membrane). We consider how abnormalities of the constituent cells of the neurovascular unit – particularly of endothelial cells and pericytes – and impairment of the blood‐brain barrier (BBB) impact on the pathogenesis of AD. We also discuss how changes to the cerebral vasculature are likely to impair Aβ clearance – both intra‐periarteriolar drainage (IPAD) and transport of Aβ peptides across the BBB, and how impaired neurovascular coupling and reduced blood flow in relation to metabolic demand increase amyloidogenic processing of APP and the production of Aβ. We review the vasoactive properties of Aβ peptides themselves, and the probable bi‐directional relationship between vascular dysfunction and Aβ accumulation in AD. Lastly, we discuss recent methodological advances in transcriptomics and imaging that have provided novel insights into vascular changes in AD, and recent advances in assessment of the retina that allow in vivo detection of vascular changes in the early stages of AD.
Structural and functional changes to blood vessels not only underpin disease pathogenesis in vascular dementia but are also major contributors to cognitive decline and disease progression in Alzheimer’s disease. We provide an updated review on the clinical and neuropathological vascular features (SVD, CAA) and underpinning functional changes to blood vessels in relation of disease pathology in Alzheimer’s disease. We also discuss recent methodological advances within the field that have provided novel insights into vascular changes in AD, including transcriptomics, imaging, and retinal assessment providing a window of opportunity for future clinical intervention.
The conception and animal modeling of hepatocyte transplantation along with a partial listing of human hepatocyte infusions over the last 13 years have been detailed in authoritative reviews. ...However, to adequately best represent the worldwide effort of moving from highly successful clinical solid liver transplants "back to" isolated hepatocyte therapy requires repeating important concepts with explanations of how or why not animal experimental data translate to human experience. This overview summarizes 78 human clinical hepatocyte transplant experiences authenticated by the authors. The human cell infusion experiences are categorized by liver disease treated (metabolic, chronic, and acute liver failure), and these are accompanied by seminal in vitro and in vivo experimental data.
ABSTRACT
We derive a generic spatial eigenvalue problem governing stars in hydrostatic equilibrium. Our approach generalizes the various Lane–Emden equations finding use over the past century, ...allowing for more general equations of state (EoS) while ensuring a stellar structure with finite size (without the need for artificial truncation of the radius). We show that the resulting stellar structure is encoded into two quantities: the eigenvalue, which determines the total size or mass of the star, and the density distribution, which encodes the internal structure. While our formalism recovers known results for polytrope and white dwarf EoS, we also study additional EoS, such as those incorporating excluded volumes or those calibrated through viral expansions. We obtain numerical values for the stellar structure under a variety of frameworks, comparing and contrasting stellar structure under different EoS. Interestingly, we show how different EoS can be calibrated to give solutions with the same stellar structure, highlighting the arbitrariness of a particular EoS for replicating observations. This leads us to comment on general properties EoS should obey to describe physically realistic stars. We also consider hydrostatic gas clouds immersed in larger regions having non-zero ambient density. We compare three analytical methods for finding solutions of these eigenvalue problems, including Taylor series solutions, the variational approximation, and the non-perturbative delta-expansion method. Although each method has benefits and drawbacks, we show that the delta-expansion method provides the most accuracy in replicating stellar structure.
Many bacterial infections are hard to treat and tend to relapse, possibly due to the presence of antibiotic-tolerant persisters. In vitro, persister cells appear to be dormant. After uptake of
...species by macrophages, nongrowing persisters also occur, but their physiological state is poorly understood. In this work, we show that
persisters arising during macrophage infection maintain a metabolically active state. Persisters reprogram macrophages by means of effectors secreted by the
pathogenicity island 2 type 3 secretion system. These effectors dampened proinflammatory innate immune responses and induced anti-inflammatory macrophage polarization. Such reprogramming allowed nongrowing
cells to survive for extended periods in their host. Persisters undermining host immune defenses might confer an advantage to the pathogen during relapse once antibiotic pressure is relieved.
This scientific commentary refers to ‘SARS-CoV-2 triggers pericyte-mediated cerebral capillary constriction’ by Hirunpattarasilp et al. (https://doi.org/10.1093/brain/awac272).
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