What are the limitations on the wider therapeutic use of phage?

Bacterial resistance to antibiotics poses a serious health threat. Since research into new antibiotics is not progressing at the same rate as the development of bacterial resistance, widespread calls for alternatives to antibiotics have been made. Phage therapy is an ideal alternative candidate to be investigated. However the success of phage therapy may be hampered by a lack of investment support from large pharmaceutical companies, due to their narrow spectrum of activity in antibiotics, very large costs associated with clinical trials of the variety of phages needed, and regulatory requirements remaining unclear. Intellectual property is difficult to secure for therapeutic phage products for a variety of reasons, and patenting procedures vary widely between the US and the EU. Consequently, companies are more likely to invest in phage products for decontamination or veterinary use, rather than clinical use in humans. Some still raise questions as to the safety of phage therapy overall, suggesting the possibility of cytotoxicity and immunogenicity, depending on the phage preparation and route. On the other hand, with patients dying because of infections untreatable with conventional antibiotics, the question arises as to whether it is ethical not to pursue phage therapy more diligently. A paradigm shift about how phage therapy is perceived is required, as well as more rigorous proof of efficacy in the form of clinical trials of existing medicinal phage products. Phage therapy potential may be fulfilled in the meantime by allowing individual preparations to be used on a named-patient basis, with extensive monitoring and multidisciplinary team input. The National Health Service and academia have a role in carrying out clinical phage research, which would be beneficial to public health, but not necessarily financially rewarding.

New insights into the compressibility and high-pressure stability of Ni(CN)2: a combined study of neutron diffraction, Raman spectroscopy, and inelastic neutron scattering

Nickel cyanide is a layered material showing markedly anisotropic behaviour. High-pressure neutron diffraction measurements show that at pressures up to 20.1 kbar, compressibility is much higher in the direction perpendicular to the layers, c, than in the plane of the strongly chemically bonded metal-cyanide sheets. Detailed examination of the behaviour of the tetragonal lattice parameters, a and c, as a function of pressure reveal regions in which large changes in slope occur, for example, in c(P) at 1 kbar. The experimental pressure dependence of the volume data is fitted to a bulk modulus, B0, of 1050 (20) kbar over the pressure range 0–1 kbar, and to 124 (2) kbar over the range 1–20.1 kbar. Raman spectroscopy measurements yield additional information on how the structure and bonding in the Ni(CN)2 layers change with pressure and show that a phase change occurs at about 1 kbar. The new high-pressure phase, (Phase PII), has ordered cyanide groups with sheets of D4h symmetry containing Ni(CN)4 and Ni(NC)4 groups. The Raman spectrum of phase PII closely resembles that of the related layered compound, Cu1/2Ni1/2(CN)2, which has previously been shown to contain ordered C≡N groups. The phase change, PI to PII, is also observed in inelastic neutron scattering studies which show significant changes occurring in the phonon spectra as the pressure is raised from 0.3 to 1.5 kbar. These changes reflect the large reduction in the interlayer spacing which occurs as Phase PI transforms to Phase PII and the consequent increase in difficulty for out-of-plane atomic motions. Unlike other cyanide materials e.g. Zn(CN)2 and Ag3Co(CN)6, which show an amorphization and/or a decomposition at much lower pressures (~100 kbar), Ni(CN)2 can be recovered after pressurising to 200 kbar, albeit in a more ordered form.

An assessment of the effects of climate change on horticulture

Horticulture may be defined as the intensive cultivation and harvesting of plants for financial, environmental and social profit. Evidence for the occurrence of climate change more generally and reasons why this process is happening with such rapidity are discussed. These changes are then considered in terms of the effects which might alter the options for worldwide intensive horticultural cultivation of plants and its interactions with other organisms. Potentially changing climates will have considerable impact upon horticultural processes and productivity across the globe . Climate change will alter the growth patterns and capabilities for flowering and fruiting of many perennial and annual horticultural plants. In some regions perennial fruit crops are likely to experience substantial difficulties because of altered seasonal conditions affecting dormancy, acclimation and subsequent flowering and fruiting. Elsewhere these crops may benefit from the effects of climate change as a result of reduced cold damage and increased length of the growing season. There will be considerable effects for aerial and edaphic microbes invertebrate and vertebrate animals which have benign and pathogenic interactions with horticultural plants. Microbial activity and as a consequence soil fertility may alter. New pests and pathogens may become prevalent and damaging in areas where the climate previously excluded their activity. Vital resources such as water and nutrients may become scarce in some regions reducing opportunities for growing horticultural crops. Wind and windiness are significant factors governing the success of horticultural plants and the scale of their impacts may change as climate alters. Damaging winds could limit crop growing in areas where previously it flourished. Forms of macro- and micro-landscaping will change as the spectrum of plants which can be cultivated alters and the availability of resources and their cost changes driven by scarcities brought about by climate change. The horticultural economy of India as it may be affected by climate change is described as an individual example in a detailed study.

Does modulation of the endocannabinoid system have potential therapeutic utility in cerebellar ataxia?

Cerebellar ataxias represent a spectrum of disorders which are, however, linked by common symptoms of motor incoordination and are typically associated with deficient in Purkinje cell firing activity and, often, degeneration. Cerebellar ataxias currently lack a curative agent. The endocannabinoid (eCB) system includes eCB compounds and their associated metabolic enzymes, together with cannabinoid receptors, predominantly the cannabinoid CB1 receptor (CB1R) in the cerebellum; activation of this system in the cerebellar cortex is associated with deficits in motor coordination characteristic of ataxia, effects which can be prevented by CB1R antagonists. Of further interest are various findings that CB1R deficits may also induce a progressive ataxic phenotype. Together these studies suggest that motor coordination is reliant on maintaining the correct balance in eCB system signalling. Recent work also demonstrates deficient cannabinoid signalling in the mouse ‘ducky2J’ model of ataxia. In light of these points, the potential mechanisms whereby cannabinoids may modulate the eCB system to ameliorate dysfunction associated with cerebellar ataxias are considered.

On the origins and timescales of geoeffective IMF

Southward Interplanetary Magnetic Field (IMF) in the Geocentric Solar Magnetospheric (GSM) reference frame is the key element that controls the level of space-weather disturbance in Earth’s magnetosphere, ionosphere and thermosphere. We discuss the relation of this geoeffective IMF component to the IMF in the Geocentric Solar Ecliptic (GSE) frame and, using the almost continuous interplanetary data for 1996-2015 (inclusive), we show that large geomagnetic storms are always associated with strong southward, out-of-ecliptic field in the GSE frame: dipole tilt effects, that cause the difference between the southward field in the GSM and GSE frames, generally make only a minor contribution to these strongest storms. The time-of-day/time-of-year response patterns of geomagnetic indices and the optimum solar wind coupling function are both influenced by the timescale of the index response. We also study the occurrence spectrum of large out-of-ecliptic field and show that for one-hour averages it is, surprisingly, almost identical in ICMEs (Interplanetary Coronal Mass Ejections), around CIRs/SIRs (Corotating and Stream Interaction Regions) and in the “quiet” solar wind (which is shown to be consistent with the effect of weak SIRs). However, differences emerge when the timescale over which the field remains southward is considered: for longer averaging timescales the spectrum is broader inside ICMEs, showing that these events generate longer intervals of strongly southward average IMF and consequently stronger geomagnetic storms. The behavior of out-of-ecliptic field with timescale is shown to be very similar to that of deviations from the predicted Parker spiral orientation, suggesting the two share common origins.