Antimicrobial graft copolymer gels

In view of the growing worldwide rise in microbial resistance, there is considerable interest in designing new antimicrobial copolymers. The aim of the current study was to investigate the relationship between antimicrobial activity and copolymer composition/ architecture to gain a better understanding of their mechanism of action. Specifically, the antibacterial activity of several copolymers based on 2- (methacryloyloxy)ethyl phosphorylcholine [MPC] and 2-hydroxypropyl methacrylate (HPMA) toward Staphylococcus aureus was examined. Both block and graft copolymers were synthesized using either atom transfer radical polymerization or reversible addition−fragmentation chain transfer polymerization and characterized via 1H NMR, gel permeation chromatography, rheology, and surface tensiometry. Antimicrobial activity was assessed using a range of well-known assays, including direct contact, live/dead staining, and the release of lactate dehydrogenase (LDH), while transmission electron microscopy was used to study the morphology of the bacteria before and after the addition of various copolymers. As expected, PMPC homopolymer was biocompatible but possessed no discernible antimicrobial activity. PMPC-based graft copolymers comprising PHPMA side chains (i.e. PMPC-g-PHPMA) significantly reduced both bacterial growth and viability. In contrast, a PMPC−PHPMA diblock copolymer comprising a PMPC stabilizer block and a hydrophobic core-forming PHPMA block did not exhibit any antimicrobial activity, although it did form a biocompatible worm gel. Surface tensiometry studies and LDH release assays suggest that the PMPC-g-PHPMA graft copolymer exhibits surfactantlike activity. Thus, the observed antimicrobial activity is likely to be the result of the weakly hydrophobic PHPMA chains penetrating (and hence rupturing) the bacterial membrane

Whole-pattern profile fitting of powder diffraction data collected in parallel-beam flat-plate asymmetric reflection geometry

Abstract: A simple, physically based model that allows the whole-pattern profile fitting of diffraction data collected in parallel-beam flat-plate asymmetric reflection geometry is presented. In this arrangement, there is a fixed angle between the incident beam and the sample, resulting in a fixed-length beam footprint. The use of a wide-angle detector for the simultaneous detection of the data precludes the use of any diffracted beam optics. Therefore, the observed peak widths are a function of the length of the beam footprint on the sample. The model uses up to three refinable parameters, depending on the intensity profile of the beam, to calculate the effect of diffraction angle on the width of all diffracted peaks. The use of this model reduces the total number of parameters required to fit the observed peak widths and shapes, hence leading to increased stability in the profile analysis. Implementations of the model are provided for both fundamental parameters and empirical approaches

Characterisation and expression of SPLUNC2, the human orthologue of rodent parotid secretory protein

We recently described the Palate Lung Nasal Clone (PLUNC) family of proteins as an extended group of proteins expressed in the upper airways, nose and mouth. Little is known about these proteins, but they are secreted into the airway and nasal lining fluids and saliva where, due to their structural similarity with lipopolysaccharide-binding protein and bactericidal/permeability-increasing protein, they may play a role in the innate immune defence. We now describe the generation and characterisation of novel affinity-purified antibodies to SPLUNC2, and use them to determine the expression of this, the major salivary gland PLUNC. Western blotting showed that the antibodies identified a number of distinct protein bands in saliva, whilst immunohistochemical analysis demonstrated protein expression in serous cells of the major salivary glands and in the ductal lumens as well as in cells of minor mucosal glands. Antibodies directed against distinct epitopes of the protein yielded different staining patterns in both minor and major salivary glands. Using RT-PCR of tissues from the oral cavity, coupled with EST analysis, we showed that the gene undergoes alternative splicing using two 5' non-coding exons, suggesting that the gene is regulated by alternative promoters. Comprehensive RACE analysis using salivary gland RNA as template failed to identify any additional exons. Analysis of saliva showed that SPLUNC2 is subject to N-glycosylation. Thus, our study shows that multiple SPLUNC2 isoforms are found in the oral cavity and suggest that these proteins may be differentially regulated in distinct tissues where they may function in the innate immune response

Paediatric patient safety and the need for aviation black box thinking to learn from and prevent medication errors

Since the publication of To Err Is Human: Building a Safer Health System in 1999, there has been much research conducted into the epidemiology, nature and causes of medication errors in children, from prescribing and supply to administration. It is reassuring to see growing evidence of improving medication safety in children; however, based on media reports, it can be seen that serious and fatal medication errors still occur. This critical opinion article examines the problem of medication errors in children and provides recommendations for research, training of healthcare professionals and a culture shift towards dealing with medication errors. There are three factors that we need to consider to unravel what is missing and why fatal medication errors still occur. (1) Who is involved and affected by the medication error? (2) What factors hinder staff and organisations from learning from mistakes? Does the fear of litigation and criminal charges deter healthcare professionals from voluntarily reporting medication errors? (3) What are the educational needs required to prevent medication errors? It is important to educate future healthcare professionals about medication errors and human factors to prevent these from happening. Further research is required to apply aviation’s ‘black box’ principles in healthcare to record and learn from near misses and errors to prevent future events. There is an urgent need for the black box investigations to be published and made public for the benefit of other organisations that may have similar potential risks for adverse events. International sharing of investigations and learning is also needed

Results from the CLIC Test Facility

In order to study the principle of the Compact Linear Collider (CLIC) based on the Two Beam Acceleration (TBA) scheme at high frequency, a CLIC Test Facility (CTF) has been set-up at CERN. After four years of successful running, the experimental programme is now fully completed and all its objectives reached, particularly the generation of a high intensity drive beam with short bunches by a photo-injector, the production of 30 GHz RF power and the acceleration of a probe beam by 30 GHz structures. A summary of the CTF results and their impact on linear collider design is given. This covers 30 GHz high power testing, study of intense, short single bunches; as well as RF-Gun, photocathode and beam diagnostic developments. A second phase of the test facility (CTF2) is presently being installed to demonstrate the feasibility of the TBA scheme by constructing a fully engineered, 10 m long, test section very similar to the CLIC drive and main linacs, producing up to 480 MW of peak RF power at 30 GHz and accelerating the beam up to 320 MeV. The present status of CTF2 is reported

Climate challenges, vulnerabilities, and food security

This paper identifies rare climate challenges in the long-term history of seven areas, three in the subpolar North Atlantic Islands and four in the arid-to-semiarid deserts of the US Southwest. For each case, the vulnerability to food shortage before the climate challenge is quantified based on eight variables encompassing both environmental and social domains. These data are used to evaluate the relationship between the “weight” of vulnerability before a climate challenge and the nature of social change and food security following a challenge. The outcome of this work is directly applicable to debates about disaster management policy

Antipredatory Function of Head Shape for Vipers and Their Mimics

Most research into the adaptive significance of warning signals has focused on the colouration and patterns of prey animals. However, behaviour, odour and body shape can also have signal functions and thereby reduce predators' willingness to attack defended prey. European vipers all have a distinctive triangular head shape; and they are all venomous. Several non-venomous snakes, including the subfamily Natricinae, commonly flatten their heads (also known as head triangulation) when disturbed. The adaptive significance of this potential behavioural mimicry has never been investigated

‘It Takes Two Hands to Clap’: How Gaddi Shepherds in the Indian Himalayas Negotiate Access to Grazing

This article examines the effects of state intervention on the workings of informal institutions that coordinate the communal use and management of natural resources. Specifically it focuses on the case of the nomadic Gaddi shepherds and official attempts to regulate their access to grazing pastures in the Indian Himalayas. It is often predicted that the increased presence of the modern state critically undermines locally appropriate and community-based resource management arrangements. Drawing on the work of Pauline Peters and Francis Cleaver, I identify key instances of socially embedded ‘common’ management institutions and explain the evolution of these arrangements through dynamic interactions between individuals, communities and the agents of the state. Through describing the ‘living space’ of Gaddi shepherds across the annual cycle of nomadic migration with their flocks I explore the ways in which they have been able to creatively reinterpret external interventions, and suggest how contemporary arrangements for accessing pasture at different moments of the annual cycle involve complex combinations of the formal and the informal, the ‘traditional’ and the ‘modern’

The Tissue-Specific Rep8/UBXD6 Tethers p97 to the Endoplasmic Reticulum Membrane for Degradation of Misfolded Proteins

The protein known as p97 or VCP in mammals and Cdc48 in yeast is a versatile ATPase complex involved in several biological functions including membrane fusion, protein folding, and activation of membrane-bound transcription factors. In addition, p97 plays a central role in degradation of misfolded secretory proteins via the ER-associated degradation pathway. This functional diversity of p97 depends on its association with various cofactors, and to further our understanding of p97 function it is important that these cofactors are identified and analyzed. Here, we isolate and characterize the human protein named Rep8 or Ubxd6 as a new cofactor of p97. Mouse Rep8 is highly tissue-specific and abundant in gonads. In testes, Rep8 is expressed in post-meiotic round spermatids, whereas in ovaries Rep8 is expressed in granulosa cells. Rep8 associates directly with p97 via its UBX domain. We show that Rep8 is a transmembrane protein that localizes to the ER membrane with its UBX domain facing the cytoplasm. Knock-down of Rep8 expression in human cells leads to a decreased association of p97 with the ER membrane and concomitantly a retarded degradation of misfolded ER-derived proteasome substrates. Thus, Rep8 tethers p97 to the ER membrane for efficient ER-associated degradation