Abstract In the last decade we have witnessed a dramatic increase in the proportion and absolute number of bacterial pathogens resistant to multiple antibacterial agents. Multidrug-resistant bacteria ...are currently considered as an emergent global disease and a major public health problem. The B-Debate meeting brought together renowned experts representing the main stakeholders (i.e. policy makers, public health authorities, regulatory agencies, pharmaceutical companies and the scientific community at large) to review the global threat of antibiotic resistance and come up with a coordinated set of strategies to fight antimicrobial resistance in a multifaceted approach. We summarize the views of the B-Debate participants regarding the current situation of antimicrobial resistance in animals and the food chain, within the community and the healthcare setting as well as the role of the environment and the development of novel diagnostic and therapeutic strategies, providing expert recommendations to tackle the global threat of antimicrobial resistance.
The paucity of licensed monoclonal antibodies (mAbs) in the infectious diseases arena strongly contrasts with the ready availability of these therapeutics for use in other conditions.
This narrative ...review aims to assess the potential of monoclonal antibody-based interventions for infectious diseases.
A review of the literature via the Medline database was performed and complemented by published official documents on licensed anti-infective mAbs. In addition, ongoing trials were identified through a search of the clinical trial registration platform ClinicalTrials.gov.
We identified the few infections for which mAbs have been added to the therapeutic armamentarium and stressed their potential in representing a readily available protection tool against biothreats and newly emerging and reemerging infectious agents. In reviewing the historical context and main features of mAbs, we assert a potentially wider applicability and cite relevant examples of ongoing therapeutic developments. Factors hindering successful introduction of mAbs on a larger scale are outlined and thoughts are offered on how to possibly address some of these limitations.
mAbs may represent important tools in treating or preventing infections occurring with reasonably sufficient prevalence to justify demand and for which existing alternatives are not deemed fully adequate. Future initiatives need to address the prohibitive costs encountered in the development process. The feasibility of more large-scale administration of alternative modalities merits further exploration. In order to ensure optimal prospect of regulatory success, an early dialogue with competent authorities is encouraged.
Worldwide, the hepatitis B virus (HBV) and the hepatitis C virus (HCV) cause, respectively, 600 000 and 350 000 deaths each year. Viral hepatitis is the leading cause of cirrhosis and liver cancer, ...which in turn ranks as the third cause of cancer death worldwide. Within the WHO European region, approximately 14 million people are chronically infected with HBV, and nine million people are chronically infected with HCV. Lack of reliable epidemiological data on HBV and HCV is one of the biggest hurdles to advancing policy. Risk groups such as migrants and injecting drug users (IDU) tend to be under‐represented in existing prevalence studies; thus, targeted surveillance is urgently needed to correctly estimate the burden of HBV and HCV. The most effective means of prevention against HBV is vaccination, and most European Union (EU) countries have universal vaccination programmes. For both HBV and HCV, screening of individuals who present a high risk of contracting the virus is critical given the asymptomatic, and thereby silent, nature of disease. Screening of migrants and IDUs has been shown to be effective and potentially cost‐effective. There have been significant advances in the treatment of HCV and HBV in recent years, but health care professionals remain poorly aware of treatment options. Greater professional training is needed on the management of hepatitis including the treatment of liver cancer to encourage adherence to guidelines and offer patients the best possible outcomes. Viral hepatitis knows no borders. EU Member States, guided by the EU, need to work in a concerted manner to implement lasting, effective policies and programmes and make tackling viral hepatitis a public health priority.
The prognosis for malignant glioma, the most common brain tumor, is still poor, underscoring the need to develop novel treatment strategies. Because glioma cells commonly exhibit genomic alterations ...involving genes that regulate cell-cycle control, there is a strong rationale for examining the potential efficacy of strategies to counteract this process. In this study, we examined the antiproliferative effects of the cyclin-dependent kinase inhibitor dinaciclib in malignant human glioma cell lines, with intact, deleted, or mutated p53 or phosphatase and tensin homolog on chromosome 10; intact or deleted or p14ARF or wild-type or amplified epidermal growth factor receptor. Dinaciclib inhibited cell proliferation and induced cell-cycle arrest at the G2/M checkpoint, independent of p53 mutational status. In a standard 72-hour 3-4,5-dimethylthiazol- 2yl-5-3-carboxymethoxyphenyl-2-4-sulfophenyl-2H, tetrazolium (MTS) assay, at clinically relevant concentrations, dose-dependent antiproliferative effects were observed, but cell death was not induced. Moreover, the combination of conventional chemotherapeutic agents and various growth-signaling inhibitors with dinaciclib did not yield synergistic cytotoxicity. In contrast, combination of the Bcl-2/Bcl-xL inhibitors ABT-263 (4-4-2-(4-chlorophenyl)-5,5-dimethylcyclohexen-1-ylmethylpiperazin-1-yl-N-4-(2R)-4-morpholin-4-yl-1-phenylsulfanylbutan-2-ylamino-3-(trifluoromethylsulfonyl)phenylsulfonylbenzamide) or ABT-737 (4-4-2-(4-chlorophenyl)phenylmethylpiperazin-1-yl-N-4-(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-ylamino-3-nitrophenylsulfonylbenzamide) with dinaciclib potentiated the apoptotic response induced by each single drug. The synergistic killing by ABT-737 with dinaciclib led to cell death accompanied by the hallmarks of apoptosis, including an early loss of the mitochondrial transmembrane potential; the release of cytochrome c, smac/DIABLO, and apoptosis-inducing factor; phosphatidylserine exposure on the plasma membrane surface and activation of caspases and poly ADP-ribose polymerase. Mechanistic studies revealed that dinaciclib promoted proteasomal degradation of Mcl-1. These observations may have important clinical implications for the design of experimental treatment protocols for malignant human glioma.
Leaf mass per area (LMA, g m(-2)) is an essential trait for modeling canopy function due to its strong association with photosynthesis, respiration and leaf nitrogen. Leaf mass per area, which is ...influenced by both leaf thickness and density (LMA = thickness × density), generally increases from the bottom to the top of tree canopies, yet the mechanisms behind this universal pattern are not yet resolved. For decades, the light environment was assumed to be the most influential driver of within-canopy variation in LMA, yet recent evidence has shown hydrostatic gradients to be more important in upper canopy positions, especially in tall evergreen trees in temperate and tropical forests. The aim of this study was to disentangle the importance of various environmental drivers on vertical LMA gradients in a mature sugar maple (Acer saccharum Marshall) forest. We compared LMA, leaf density and leaf thickness relationships with height, light and predawn leaf water potential (ΨPre) within a closed and an exposed canopy to assess leaf morphological traits at similar heights but different light conditions. Contrary to our expectations and recent findings in the literature, we found strong evidence that light was the primary driver of vertical gradients in leaf morphology. At similar heights (13-23 m), LMA was greater within the exposed canopy than the closed canopy, and light had a stronger influence over LMA compared with ΨPre. Light also had a stronger influence over both leaf thickness and density compared with ΨPre; however, the increase in LMA within both canopy types was primarily due to increasing leaf thickness with increasing light availability. This study provides strong evidence that canopy structure and crown exposure, in addition to height, should be considered as a parameter for determining vertical patterns in LMA and modeling canopy function.
Antimicrobial resistance is recognised as a growing problem that seriously threatens public health and requires prompt action. Concerns have therefore been raised about the potential harmful effects ...of making antibiotics available without prescription. Because of the very serious concerns regarding further spread of resistance, the over-the-counter (OTC) availability of antibiotics was analysed here. Topical and systemic OTC antibiotics and their indications were determined across 26 European Union (EU) countries and Norway by means of a European survey. We identified a total of 48 OTC products containing 20 different single antibiotics and three antibiotic combinations as active substances, used mainly as topical preparations in short treatment courses. Given the relevance of these medicines and the increasing risk of antimicrobial resistance, it is important to limit the availability of OTC antibiotics and to monitor their use.
Leaf maintenance respiration (Rleaf,m) is a major but poorly understood component of the terrestrial carbon cycle (C). Earth systems models (ESMs) use simple sub‐models relating Rleaf,m to leaf ...traits, applied at canopy scale. Rleaf,m models vary depending on which leaf N traits they incorporate (e.g., mass or area based) and the form of relationship (linear or nonlinear). To simulate vegetation responses to global change, some ESMs include ecological optimization to identify canopy structures that maximize net C accumulation. However, the implications for optimization of using alternate leaf‐scale empirical Rleaf,m models are undetermined. Here we combine alternate well‐known empirical models of Rleaf,m with a process model of canopy photosynthesis. We quantify how net canopy exports of C vary with leaf area index (LAI) and total canopy N (TCN). Using data from tropical and arctic canopies, we show that estimates of canopy Rleaf,m vary widely among the three models. Using an optimization framework, we show that the LAI and TCN values maximizing C export depends strongly on the Rleaf,m model used. No single model could match observed arctic and tropical LAI‐TCN patterns with predictions of optimal LAI‐TCN. We recommend caution in using leaf‐scale empirical models for components of ESMs at canopy‐scale. Rleaf,m models may produce reasonable results for a specified LAI, but, due to their varied representations of Rleaf,mfoliar N sensitivity, are associated with different and potentially unrealistic optimization dynamics at canopy scale. We recommend ESMs to be evaluated using response surfaces of canopy C export in LAI‐TCN space to understand and mitigate these risks.
Plain Language Summary
While we have good understanding of plant photosynthesis, its links to climate and leaf nitrogen and process models to estimate photosynthesis; the same is not true for respiration. Measurements of leaf respiration are used to calibrate simple respiration models, which are applied at canopy‐scale. Here we investigate the risks associated with using various alternate simple respiration models in the context of viewing plant canopies as economic structures that must produce more carbon through photosynthesis than they use in respiration and tissue construction. We model the carbon economy of canopies with measured properties (leaf coverage and nitrogen) in arctic and in the tropical ecosystems, comparing the results using three different respiration models. First, we note the respiration estimates vary greatly among the models, so the models are not consistent. Second, we show that the optimal canopy properties (those most economically successful) also depend strongly on the respiration model used. This means that the choice of respiration model will have significant effects on the predictions of canopy response, and therefore C cycling, under global change. Our research highlights the need for more robust, process modeling of respiration.
Key Points
Estimates of annual canopy maintenance respiration, a globally important C flux, vary widely among models calibrated from leaf trait data
Using an optimization framework, we show that the canopy properties maximizing C export depend strongly on the respiration model used
Leaf‐scale empirical models should be applied cautiously at the canopy‐scale, particularly in Earth system models with canopy optimization.
To gain understanding about invasive species physiology and also potential water conservation strategies, we investigated tree-level water use following a woody invasive removal experiment in Hawaii. ...Invasives had much higher water use rates than the native tree species, and stand level water use decreased by ∼50% after invasive removal.
While the supply of freshwater is expected to decline in many regions in the coming decades, invasive plant species, often ‘high water spenders’, are greatly expanding their ranges worldwide. In this study, we quantified the ecohydrological differences between native and invasive trees and also the effects of woody invasive removal on plot-level water use in a heavily invaded mono-dominant lowland wet tropical forest on the Island of Hawaii. We measured transpiration rates of co-occurring native and invasive tree species with and without woody invasive removal treatments. Twenty native Metrosideros polymorpha and 10 trees each of three invasive species, Cecropia obtusifolia, Macaranga mappa and Melastoma septemnervium, were instrumented with heat-dissipation sap-flux probes in four 100 m2 plots (two invaded, two removal) for 10 months. In the invaded plots, where both natives and invasives were present, Metrosideros had the lowest sap-flow rates per unit sapwood, but the highest sap-flow rates per whole tree, owing to its larger mean diameter than the invasive trees. Stand-level water use within the removal plots was half that of the invaded plots, even though the removal of invasives caused a small but significant increase in compensatory water use by the remaining native trees. By investigating the effects of invasive species on ecohydrology and comparing native vs. invasive physiological traits, we not only gain understanding about the functioning of invasive species, but we also highlight potential water-conservation strategies for heavily invaded mono-dominant tropical forests worldwide. Native-dominated forests free of invasive species can be conservative in overall water use, providing a strong rationale for the control of invasive species and preservation of native-dominated stands.
The mechanisms that have evolved to maintain genome stability during cell cycle progression are challenged when a somatic cell nucleus is placed in a meiotic environment such as the ooplasm. ...Chromosomal spindle aberrations ensue in the majority of reconstructed oocytes within 2 h of transplantation, but it is not known if they recover or persist with the onset of embryonic divisions. We analyzed the chromosomal spindles and the karyotype of cumulus cell-derived mouse clones through the initial and hence most critical mitoses. Cloned embryos start out with less aneuploidy than fertilized embryos but surpass them after ES cell derivation, as measured by frequencies of chromosome trisomies and structural rearrangements. Despite the limited proportion of cloned mouse embryos that reach late gestation, a phenotypic mutation lacking a karyotypic mark was found in a newborn mouse cloned in 2002 and has been inherited since by its offspring. These data concur with a prevalent epigenetic, rather than genetic, basis for cloned embryo failure, but they also warn against the temptation to think that all conditions of clones are epigenetic and recover during gametogenesis. The cloning procedure is defenseless (no matter how technically refined) towards pre-existing or induced subchromosomal mutations that are below the experimental detection limit of the cytogenetic assay.
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