The primary structural component of the bacterial cell wall is peptidoglycan, which is essential for viability and the synthesis of which is the target for crucial antibiotics
. Peptidoglycan is a ...single macromolecule made of glycan chains crosslinked by peptide side branches that surrounds the cell, acting as a constraint to internal turgor
. In Gram-positive bacteria, peptidoglycan is tens of nanometres thick, generally portrayed as a homogeneous structure that provides mechanical strength
. Here we applied atomic force microscopy
to interrogate the morphologically distinct Staphylococcus aureus and Bacillus subtilis species, using live cells and purified peptidoglycan. The mature surface of live cells is characterized by a landscape of large (up to 60 nm in diameter), deep (up to 23 nm) pores constituting a disordered gel of peptidoglycan. The inner peptidoglycan surface, consisting of more nascent material, is much denser, with glycan strand spacing typically less than 7 nm. The inner surface architecture is location dependent; the cylinder of B. subtilis has dense circumferential orientation, while in S. aureus and division septa for both species, peptidoglycan is dense but randomly oriented. Revealing the molecular architecture of the cell envelope frames our understanding of its mechanical properties and role as the environmental interface
, providing information complementary to traditional structural biology approaches.
The range of potential applications of compact laser-plasma ion sources motivates the development of new acceleration schemes to increase achievable ion energies and conversion efficiencies. Whilst ...the evolving nature of laser-plasma interactions can limit the effectiveness of individual acceleration mechanisms, it can also enable the development of hybrid schemes, allowing additional degrees of control on the properties of the resulting ion beam. Here we report on an experimental demonstration of efficient proton acceleration to energies exceeding 94 MeV via a hybrid scheme of radiation pressure-sheath acceleration in an ultrathin foil irradiated by a linearly polarised laser pulse. This occurs via a double-peaked electrostatic field structure, which, at an optimum foil thickness, is significantly enhanced by relativistic transparency and an associated jet of super-thermal electrons. The range of parameters over which this hybrid scenario occurs is discussed and implications for ion acceleration driven by next-generation, multi-petawatt laser facilities are explored.
Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of ...the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2
CD9
subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1
and PLVAP
endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFRα
collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis.
This manuscript reports the consensus statements regarding recurrent ovarian cancer (ROC), reached at the fifth Ovarian Cancer Consensus Conference (OCCC), which was held in Tokyo, Japan, in November ...2015. Three important questions were identified: (i) What are the subgroups for clinical trials in ROC? The historical definition of using platinum-free interval (PFI) to categorise patients as having platinum-sensitive/resistant disease was replaced by therapy-free interval (TFI). TFI can be broken down into TFIp (PFI), TFInp (non-PFI) and TFIb (biological agent-free interval). Additional criteria to consider include histology, BRCA mutation status, number/type of previous therapies, outcome of prior surgery and patient reported symptoms. (ii) What are the control arms for clinical trials in ROC? When platinum is considered the best option, the control arm should be a platinum-based therapy with or without an anti-angiogenic agent or a poly (ADP-ribose) polymerase (PARP) inhibitor. If platinum is not considered the best option, the control arm could include a non-platinum drug, either as single agent or in combination. (iii) What are the endpoints for clinical trials in ROC? Overall survival (OS) is the preferred endpoint for patient cohorts with an expected median OS < or = 12 months. Progression-free survival (PFS) is an alternative, and it is the preferred endpoint when the expected median OS is > 12 months. However, PFS alone should not be the only endpoint and must be supported by additional endpoints including pre-defined patient reported outcomes (PROs), time to second subsequent therapy (TSST), or time until definitive deterioration of quality of life (TUDD).
Electronic tags (both biotelemetry and biologging platforms) have informed conservation and resource management policy and practice by providing vital information on the spatial ecology of animals ...and their environments. However, the extent of the contribution of biological sensors (within electronic tags) that measure an animal's state (e.g., heart rate, body temperature, and details of locomotion and energetics) is less clear. A literature review revealed that, despite a growing number of commercially available state sensor tags and enormous application potential for such devices in animal biology, there are relatively few examples of their application to conservation. Existing applications fell under 4 main themes: quantifying disturbance (e.g., ecotourism, vehicular and aircraft traffic), examining the effects of environmental change (e.g., climate change), understanding the consequences of habitat use and selection, and estimating energy expenditure. We also identified several other ways in which sensor tags could benefit conservation, such as determining the potential efficacy of management interventions. With increasing sensor diversity of commercially available platforms, less invasive attachment techniques, smaller device sizes, and more researchers embracing such technology, we suggest that biological sensor tags be considered a part of the necessary toolbox for conservation. This approach can measure (in real time) the state of free‐ranging animals and thus provide managers with objective, timely, relevant, and accurate data to inform policy and decision making.
A methodology that combines alchemical free energy calculations (FEP) with machine learning (ML) has been developed to compute accurate absolute hydration free energies. The hybrid FEP/ML methodology ...was trained on a subset of the FreeSolv database and retrospectively shown to outperform most submissions from the SAMPL4 competition. Compared to pure machine-learning approaches, FEP/ML yields more precise estimates of free energies of hydration and requires a fraction of the training set size to outperform standalone FEP calculations. The ML-derived correction terms are further shown to be transferable to a range of related FEP simulation protocols. The approach may be used to inexpensively improve the accuracy of FEP calculations and to flag molecules which will benefit the most from bespoke force field parametrization efforts.
Sleep disorders are common in the general population and even more so in clinical practice, yet are relatively poorly understood by doctors and other health care practitioners. These British ...Association for Psychopharmacology guidelines are designed to address this problem by providing an accessible up-to-date and evidence-based outline of the major issues, especially those relating to reliable diagnosis and appropriate treatment. A consensus meeting was held in London in May 2009. Those invited to attend included BAP members, representative clinicians with a strong interest in sleep disorders and recognized experts and advocates in the field, including a representative from mainland Europe and the USA. Presenters were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomized controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aimed to reach consensus where the evidence and/or clinical experience was considered adequate or otherwise to flag the area as a direction for future research. A draft of the proceedings was then circulated to all participants for comment. Key subsequent publications were added by the writer and speakers at draft stage. All comments were incorporated as far as possible in the final document, which represents the views of all participants although the authors take final responsibility for the document.
Purpose - The purpose of this paper is to advance supply chain network theory by applying theoretical and empirical developments in complex network literature to the context of supply chains as ...complex adaptive systems. The authors synthesize these advancements to gain an understanding of the network properties underlying efficient supply chains. To develop a suitable theory of supply chain networks, the authors look to mirror the properties of complex network models with real-world supply chains.Design methodology approach - The authors review complex network literature drawn from multiple disciplines in top scientific journals. From this interdisciplinary review a series of propositions are developed around supply chain complexity and adaptive phenomena.Findings - This paper proposes that the structure of efficient supply chains follows a "scale-free" network. This proposal emerges from arguments that the key properties of efficient supply chains are a short characteristic path length, a high clustering coefficient and a power law connectivity distribution.Research limitations implications - The authors' discussion centres on applying advances found in recent complex network literature. Hence, the need is noted to empirically validate the series of propositions developed in this paper in a supply chain context.Practical implications - If efficient supply chains resemble a scale-free network, then managers can derive a number of implications. For example, supply chain resilience is derived by the presence of hub firms. To reduce the vulnerability of supply chains to cascading failures, it is recognized that managers could build in redundancy, undertake a multi-sourcing strategy or intermediation between hub firms.Originality value - This paper advances supply chain network theory. It offers a novel understanding of supply chains as complex adaptive systems and, in particular, that efficient and resilient supply chain systems resemble a scale-free network. In addition, it provides a series of propositions that allow modelling and empirical research to proceed.
Summary Background WHO estimates that about 170 000 deaths by suicide occur in India every year, but few epidemiological studies of suicide have been done in the country. We aimed to quantify suicide ...mortality in India in 2010. Methods The Registrar General of India implemented a nationally representative mortality survey to determine the cause of deaths occurring between 2001 and 2003 in 1·1 million homes in 6671 small areas chosen randomly from all parts of India. As part of this survey, fieldworkers obtained information about cause of death and risk factors for suicide from close associates or relatives of the deceased individual. Two of 140 trained physicians were randomly allocated (stratified only by their ability to read the local language in which each survey was done) to independently and anonymously assign a cause to each death on the basis of electronic field reports. We then applied the age-specific and sex-specific proportion of suicide deaths in this survey to the 2010 UN estimates of absolute numbers of deaths in India to estimate the number of suicide deaths in India in 2010. Findings About 3% of the surveyed deaths (2684 of 95 335) in individuals aged 15 years or older were due to suicide, corresponding to about 187 000 suicide deaths in India in 2010 at these ages (115 000 men and 72 000 women; age-standardised rates per 100 000 people aged 15 years or older of 26·3 for men and 17·5 for women). For suicide deaths at ages 15 years or older, 40% of suicide deaths in men (45 100 of 114 800) and 56% of suicide deaths in women (40 500 of 72 100) occurred at ages 15–29 years. A 15-year-old individual in India had a cumulative risk of about 1·3% of dying before the age of 80 years by suicide; men had a higher risk (1·7%) than did women (1·0%), with especially high risks in south India (3·5% in men and 1·8% in women). About half of suicide deaths were due to poisoning (mainly ingestions of pesticides). Interpretation Suicide death rates in India are among the highest in the world. A large proportion of adult suicide deaths occur between the ages of 15 years and 29 years, especially in women. Public health interventions such as restrictions in access to pesticides might prevent many suicide deaths in India. Funding US National Institutes of Health.
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