Anthracycline-based chemotherapy can result in the development of a cumulative and progressively developing cardiomyopathy. Doxorubicin is one of the most highly prescribed anthracyclines in the ...United States due to its broad spectrum of therapeutic efficacy. Interference with different mitochondrial processes is chief among the molecular and cellular determinants of doxorubicin cardiotoxicity, contributing to the development of cardiomyopathy. The present review provides the basis for the involvement of mitochondrial toxicity in the different functional hallmarks of anthracycline toxicity. Our objective is to understand the molecular determinants of a progressive deterioration of functional integrity of mitochondria that establishes a historic record of past drug treatments (mitochondrial memory) and renders the cancer patient susceptible to subsequent regimens of drug therapy. We focus on the involvement of doxorubicin-induced mitochondrial oxidative stress, disruption of mitochondrial oxidative phosphorylation, and permeability transition, contributing to altered metabolic and redox circuits in cardiac cells, ultimately culminating in disturbances of autophagy/mitophagy fluxes and increased apoptosis. We also suggest some possible pharmacological and nonpharmacological interventions that can reduce mitochondrial damage. Understanding the key role of mitochondria in doxorubicin-induced cardiomyopathy is essential to reduce the barriers that so dramatically limit the clinical success of this essential anticancer chemotherapy.
Training a deep convolutional neural network (CNN) from scratch is difficult because it requires a large amount of labeled training data and a great deal of expertise to ensure proper convergence. A ...promising alternative is to fine-tune a CNN that has been pre-trained using, for instance, a large set of labeled natural images. However, the substantial differences between natural and medical images may advise against such knowledge transfer. In this paper, we seek to answer the following central question in the context of medical image analysis: Can the use of pre-trained deep CNNs with sufficient fine-tuning eliminate the need for training a deep CNN from scratch? To address this question, we considered four distinct medical imaging applications in three specialties (radiology, cardiology, and gastroenterology) involving classification, detection, and segmentation from three different imaging modalities, and investigated how the performance of deep CNNs trained from scratch compared with the pre-trained CNNs fine-tuned in a layer-wise manner. Our experiments consistently demonstrated that 1) the use of a pre-trained CNN with adequate fine-tuning outperformed or, in the worst case, performed as well as a CNN trained from scratch; 2) fine-tuned CNNs were more robust to the size of training sets than CNNs trained from scratch; 3) neither shallow tuning nor deep tuning was the optimal choice for a particular application; and 4) our layer-wise fine-tuning scheme could offer a practical way to reach the best performance for the application at hand based on the amount of available data.
Liquid formulations of vaccines are subject to instabilities that result from degradation processes that proceed via a variety of physical and chemical pathways. In dried formulations, such as those ...prepared by lyophilization or spray drying, many of these degradation pathways may be avoided or inhibited. Thus, the stability of vaccine formulations can be enhanced significantly in the absence of bulk water. Potential advantages of dry vaccine formulations include extended shelf lives and less stringent cold-chain storage requirements, both of which offer possibilities of reduced vaccine wastage and facilitated distribution to resource-poor areas. Lyophilization and spray drying represent the most common methods of stabilizing vaccines through drying. This article reviews several lyophilized and spray dried vaccines that address a diverse set of pathogens, as well as some of the assays used to quantify their stability. Recent dry vaccine trends include needle-free delivery of dry powder via non-parenteral routes of administration and the incorporation of advanced vaccine adjuvants into formulations, which further contribute to the goal of increasing vaccine distribution to resource-poor areas. Challenges associated with development of these newer technologies are also discussed.
The ocean‐atmosphere system is typically envisioned to have gone through a unidirectional oxygenation with significant oxygen increases in the earliest (ca. 635 Ma), middle (ca. 580 Ma), or late (ca. ...560 Ma) Ediacaran Period. However, temporally discontinuous geochemical data and the patchy metazoan fossil record have been inadequate to chart the details of Ediacaran ocean oxygenation, raising fundamental debates about the timing of ocean oxygenation, its purported unidirectional rise, and its causal relationship, if any, with the evolution of early animal life. To better understand the Ediacaran ocean redox evolution, we have conducted a multi‐proxy paleoredox study of a relatively continuous, deep‐water section in South China that was paleogeographically connected with the open ocean. Iron speciation and pyrite morphology indicate locally euxinic (anoxic and sulfidic) environments throughout the Ediacaran in this section. In the same rocks, redox sensitive element enrichments and sulfur isotope data provide evidence for multiple oceanic oxygenation events (OOEs) in a predominantly anoxic global Ediacaran–early Cambrian ocean. This dynamic redox landscape contrasts with a recent view of a redox‐static Ediacaran ocean without significant change in oxygen content. The duration of the Ediacaran OOEs may be comparable to those of the oceanic anoxic events (OAEs) in otherwise well‐oxygenated Phanerozoic oceans. Anoxic events caused mass extinctions followed by fast recovery in biologically diversified Phanerozoic oceans. In contrast, oxygenation events in otherwise ecologically monotonous anoxic Ediacaran–early Cambrian oceans may have stimulated biotic innovations followed by prolonged evolutionary stasis.
Aim: Species distribution models (SDMs) have been used to address a wide range of theoretical and applied questions in the terrestrial realm, but marine-based applications remain relatively scarce. ...In this review, we consider how conceptual and practical issues associated with terrestrial SDMs apply to a range of marine organisms and highlight the challenges relevant to improving marine SDMs. Location: We include studies from both marine and terrestrial systems that encompass many geographic locations around the globe. Methods: We first performed a literature search and analysis of marine and terrestrial SDMs in ISI Web of Science to assess trends and applications. Using knowledge from terrestrial applications, we critically evaluate the application of SDMs in marine systems in the context of ecological factors (dispersal, species interactions, aggregation and ontogenetic shifts) and practical considerations (data quality, alternative modelling approaches and model validation) that facilitate or create difficulties for model application. Results: The relative importance of ecological factors to be considered when applying SDMs varies among terrestrial and marine organisms. Correctly incorporating dispersal is frequently considered an important issue for terrestrial models, but because there is greater potential for dispersal in the ocean, it is often less of a concern in marine SDMs. By contrast, ontogenetic shifts and feeding have received little attention in terrestrial SDM applications, but these factors are important to many marine SDMs. Opportunities also exist for applying more advanced SDM approaches in the marine realm, including mechanistic ecophysiological models, where water balance and heat transfer equations are simpler for some marine organisms relative to their terrestrial counterparts. Main conclusions: SDMs have generally been under-utilized in the marine realm relative to terrestrial applications. Correlative SDM methods should be tested on a range of marine organisms, and we suggest further development of methods that address ontogenetic shifts and feeding interactions. We anticipate developments in, and cross-fertilization between, coupled correlative and process-based SDMs, mechanistic eco-physiological SDMs, and spatial population dynamic models for climate change and species invasion applications in particular. Comparisons of the outputs of different model types will provide insight that is useful for improved spatial management of marine species.
Mitochondrial toxicity is rapidly gaining the interest of researchers and practitioners as a prominent liability in drug discovery and development, accounting for a growing proportion of preclinical ...drug attrition and post-market withdrawals or black box warnings by the U.S. FDA. To date, the focus of registries of drugs that elicit mitochondrial toxicity has been largely restricted to those that either inhibit the mitochondrial electron transport chain (ETC) or uncouple mitochondrial oxidative phosphorylation. Less appreciated are the toxicities that are secondary to the drug affecting either the molecular regulation, assembly or incorporation of the ETC into the inner mitochondrial membrane or those that limit substrate availability. The current article describes the complexities of molecular events and biochemical pathways required to sustain mitochondrial fidelity and substrate homeostasis with examples of drugs that interfere which the various pathways. The principal objective of this review is to shed light on the broader scope of drug-induced mitochondrial toxicities and how these secondary targets may account for a large portion of drug failures.
•Dementia involves the chronic and progressive deterioration of cognitive functions.•Alzheimer’s disease is the most common form of dementia.•Abnormally hyperphosphorylated tau (p-tau) is implicated ...in the pathogenesis of AD.•Abrogating p-tau aggregation may lead to the reduction of neurofibrillary tangles (NFTs).
Alzheimer’s disease (AD) is the most common form of dementia, characterized by intracellular neurofibrillary tangles (NFTs) and extracellular β-amyloid (βA) plaques. No disease-modifying therapy is currently available to prevent the progression of, or cure, the disease. Misfolded hyperphosphorylated tau (p-tau) is considered a pivotal point in the pathogenesis of AD and other tauopathies. Compelling evidence suggests that it is a key driver of the accumulation of NFTs and can be directly correlated with the extent of dementia in patients with AD. Therefore, inhibiting tau hyperphosphorylation-induced aggregation could be a viable strategy to discover and develop therapeutics for patients with AD.
PDF
