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Beta‐decay half‐lives for the free neutron, for 6He and 8He, and for 8Li are calculated ab initio from geometrical thermodynamics arguments, independently of any quantum mechanics. Half‐lives for the decay of 8Be to two alphas and for the disintegration of the tetraneutron are also calculated. The calculated values are close to those experimentally observed. [ABSTRACT FROM AUTHOR]

Key content: Uterine artery embolisation can be used as a minimally invasive technique for the management of benign gynaecological conditions refractory to other medical treatments.The Royal College of Obstetricians and Gynaecologists (RCOG) and the Royal College of Radiologists (RCR) recommend the use of interventional radiology (IR) techniques for the prophylaxis and management of postpartum haemorrhage.Interventional radiologists can percutaneously drain post‐operative collections or tubo‐ovarian abscesses.Interventional radiology plays a role in the management of early pregnancy complications such as ectopic pregnancy and gestational trophoblastic disease.Interventional radiology can aid the care of patients with gynaecological malignancies. Learning objectives: To understand the various IR techniques applicable to obstetrics and gynaecologyTo understand the risk and benefit profiles of these techniquesTo understand when the techniques could be appropriate and how they compare to surgical alternatives Ethical issues: There are limited data regarding the use of some IR procedures owing to the ethical issues of using experimental techniques to treat pregnant women or women who wish to conceive.The availability of IR procedures is hospital specific so treatment is not available to all who may benefit. [ABSTRACT FROM AUTHOR]

The nuclear matter and charge radii of the helium isotopes (A=4,6,8) are calculated by quantitative geometrical thermodynamics (QGT) taking as input the symmetry of the alpha‐particle, the very weak binding (and hence halo nature) of the heavier helium isotopes, and a characteristic length scale given by the proton size. The results follow by considering each isotope in its ground state, with QGT representing each system as a maximum entropy configuration that conforms to the Holographic Principle. This allows key geometric parameters to be determined from the number of degrees of freedom available. QGT treats 6He as a 4He core plus a concentric neutron shell comprising a holomorphic pair of neutrons, and the 8He neutron halo is treated as a holomorphic pair of holomorphic pairs. Considering that the information content of each system allows a correlation angle of 2π/3 between the holomorphic entities to be inferred, then the charge radii of the three isotopes can be calculated from the displacement of the 4He core from the center of mass. The calculations for the charge and matter radii of 4,6,8He agree closely with observed values. Similar QGT calculation of the sizes of the self‐conjugate A=4n nuclei {4He,8Be,12C,16O,20Ne,24Mg,28Si,32S,36Ar,40Ca} also agree well with experiment. [ABSTRACT FROM AUTHOR]

This work proves that stability of C60 is a geometrical property of the thermodynamics of the system: a significant methodological advance since a detailed treatment of the energetics may be avoidable. This approach may be fruitful, not only for fullerenes but also for general problems of molecular stability and in other applications of conformational chemistry. For the non‐chiral C60, C384, and the weakly‐chiral C28, C76 and C380 (of these, C380 and C384 are classed as "unspirallable"), Schlegel projections are used to show that these fullerenes can all be represented by pairs of spirals counter‐propagating in anti‐parallel (C2) symmetry. For C60, the high symmetry is used to construct an analytical approximation for the spherical double‐spirals, shown mathematically to be Maximum Entropy (MaxEnt) using the formalism of Quantitative Geometrical Thermodynamics (QGT). Therefore C60 is necessarily stable. This MaxEnt stability criterion is general, depending only on the geometry and not the kinematics of the system. The sense and degree of chirality for C76 and C380 is also quantified using a Shannon entropy‐based fragmentation metric. [ABSTRACT FROM AUTHOR]

Objectives: In this paper we discuss the main ethical challenges related to the conduct of medicine quality surveys and make suggestions on how to address them.Method: Most evidence-based information regarding medicine quality derives from surveys. However, existing research ethical guidelines do not provide specific guidance for medicine quality surveys. Hence, those conducting surveys are often left wondering how to judge what counts as best practice. A list of the main ethical challenges in the design and conduct of surveys is presented.Results and Conclusions: It is vital that the design and conduct of medicine quality surveys uphold moral and ethical obligations and analyse the ethical implications and consequences of such work. These aspects include the impact on the local availability of and access to medicines; the confidentiality and privacy of the surveyors and the surveyed; questions as to whether outlet staff personnel should be told they are part of a survey; the need of ethical and regulatory approvals; and how the findings should be disseminated. Medicine quality surveys should ideally be conducted in partnership with the relevant national Medicine Regulatory Authorities. An international, but contextually sensitive, model of good ethical practice for such surveys is needed. [ABSTRACT FROM AUTHOR]

An enduring debate concerns how responsibility for patient safety should be distributed between organisational systems and individual professionals. Though rule-based, calculus-like approaches intended to support a 'just culture' have become popular, they perpetuate an asocial and atomised account. In this article, we use insights from practice theory - which sees organisational phenomena as accomplished in everyday actions, with individual agency and structural conditions as a mutually constitutive, dynamic duality - along with contributions from the political science and ethics literature as a starting point for analysis. Presenting ethnographic data from five hospitals, three in one high-income country and two in low-income countries, we offer an empirically informed, normative rethinking of the role of personal accountability, identifying the collective nature of the healthcare enterprise and the extent to which patient safety depends on contributions from many hands. We show that moral responsibility for actions and behaviours is an irreducible element of professional practice, but that individuals are not somehow 'outside' and separate from 'systems': they create, modify and are subject to the social forces that are an inescapable feature of any organisational system; each element acts on the other. Our work illustrates starkly the structuring effects of the broader institutional and socioeconomic context on opportunities to 'be good'. These findings imply that one of the key responsibilities of organisations and wider institutions in relation to patient safety is the fostering of the conditions of moral community. [ABSTRACT FROM AUTHOR]

B Geometrical Thermodynamics b A new approach to physics, as described in article number 2100278, allows Mike Parker and co-workers to correctly calculate the sizes of the SP 4 sp He, SP 6 sp He, and SP 8 sp He nuclei ab initio from thermodynamics, with no quantum mechanics, inputting only the size of the proton. Halo Properties in Helium Nuclei from the Perspective of Geometrical Thermodynamics (Ann. The cover image illustrates the SP 8 sp He nucleus modelled as an alpha particle with its holomorphic 4-neutron halo. [Extracted from the article]

Eighteen years of field observations and five summer field experiments in a coastal California river suggest that hydrologic regimes influence algal blooms and the impacts of fish on algae, cyanobacteria, invertebrates, and small vertebrates. In this Mediterranean climate, rainy winters precede the biologically active summer low-flow season. Cladophora glomerata, the filamentous green alga that dominates primary producer biomass during summer, reaches peak biomass during late spring or early summer. Cladophora blooms are larger if floods during the preceding winter attained or exceeded "bankfull discharge" (sufficient to mobilize much of the river bed, estimated at 120 m3/s). In 9 out of 12 summers preceded by large bed-scouring floods, the average peak height of attached Cladophora turfs equaled or exceeded 50 cm. In five out of six years when flows remained below bankfull, Cladophora biomass peaked at lower levels. Flood effects on algae were partially mediated through impacts on consumers in food webs. In three experiments that followed scouring winter floods, juvenile steelhead (Oncorhynchus mykiss) and roach (Lavinia (Hesperoleucas) symmetricus) suppressed certain insects and young-of-the-year fish fry, affecting persistence or accrual of algae positively or negatively, depending on the predator-specific vulnerabilities of primary consumers capable of suppressing algae during a given year. During two post-flood years, these grazers were more vulnerable to small predators (odonates and fish fry, which stocked steelhead always suppressed) than to experimentally manipulated, larger fish, which had adverse effects on algae in those years. During one post-flood year, all enclosed grazers capable of suppressing algae were consumed by steelhead, which therefore had positive effects on algae. During drought years, when no bed-scouring winter flows occurred, large armored caddisflies (Dicosmoecus gilvipes) were more abundant during the subsequent summer. In drought-year experiments, stocked fish had little or no influence on algal standing crops, which increased only when Dicosmoecus were removed from enclosures. Flood scour, by suppressing invulnerable grazers, set the stage for fish mediated effects on algae in this river food web. Whether these effects were positive or negative depended on the predator-specific vulnerabilities of primary consumers that dominated during a given summer. [ABSTRACT FROM AUTHOR]

The cloned guinea-pig Y2 neuropeptide Y (NPY) receptors expressed in Chinese hamster ovary (CHO) cells, as well as the Y2 receptors natively expressed in rat forebrain, are distributed in two populations. A smaller population that is readily accessed by agonist peptides on the surface of intact cells constitutes less than 30% of Y2 receptors detected in particulates after cell homogenization. A much larger fraction of cell surface Y2 sites can be activated by sulfhydryl modifiers. A fast and large activation of these masked or cryptic sites could be obtained with membrane-permeating, vicinal cysteine-bridging arsenical phenylarsine oxide. A lower activation is effected by N -ethylmaleimide, an alkylator that slowly penetrates lipid bilayers. The restricted-access alkylator, 2-[(trimethylammonium)ethyl]methanethiosulfonate, was not effective in unmasking these sites. Some of the hidden cell surface Y2 sites could be activated by polyene filipin III through complexing of membrane cholesterol. The results are consistent with the presence of a large Y2 reserve in a compartment that can be accessed by alteration of sulfhydryl balance or fluidity of the cell membrane, and by␣treatments that affect the anchoring and aggregation of membrane proteins. [ABSTRACT FROM AUTHOR]

In this paper I analyse the ethical implications of the concept of ‘evidence-based patient choice’ in the light of criticism of the ‘individualism’ of patient-centred medicine. I argue that individualism in the sense used by the critics of patient centred medicine is not an inevitable consequence of an emphasis on patient choice and that a concern with the promotion of individual choices is not incompatible with ‘communitarian’ values. Indeed, I argue that any ethical approach to decision-making in health-care must be capable of taking seriously both the moral status of the individual (and of his or her choices) and the moral significance of the social dimensions of such choices. The best way to ensure respect for the principle of autonomy, I suggest, is to facilitate and encourage social interactions of a particular, deliberative, kind. This is also the best way to ensure that the broader public interest is taken into account in decision-making. [ABSTRACT FROM AUTHOR]

Anabaena flos-aquae (Lyngb.) Bréb. was grown in varying concentrations of nitrate. Specific growth rates, as estimated in batch culture, were constant and approached the maximum rate at all concentrations of NO[SUP-][SUB3] N tested between O and 400 μg/L. Steady-state biomass, as determined in semicontinuous culture, did not vary with NO[SUP-][SUB3] at slower dilution rates. However at a faster dilution rate, significantly less biomass occurred in intermediate concentrations. The results indicate that both growth rate and standing crop are maximized by either N[SUB2] fixation or NO[SUP-][SUB3] assimilation, but extracellular NO[SUP-][SUB3] reduces the rate of N[SUB2] fixation. Consequently, at very low NO[SUP-][SUB3] concentrations, growth is virtually maximized by N[SUB2] fixation. Consequently, at very low NO[SUP-][SUB3] concentrations, growth is virtually maximized by N[SUB2] fixation alone, and at high concentrations of NO[SUP-][SUB3], growth becomes a functions of NO[SUP-][SUB3] assimilation augmented by N[SUB2] fixation. In this case, full growth potential is realized only if hydraulic residence time is sufficiently long to compensate for the reduced rate of N[SUB2] fixation. Growth rate and standing crop are not diminished in response to the large amount of energy allocated to N[SUB2] fixation. Instead, other cellular processes are probably affected negatively during N[SUB2] fixation. [ABSTRACT FROM AUTHOR]

The bacterial toxin colicin A binds spontaneously to the surfaces of negatively charged membranes. The surface-bound toxin must subsequently, however, become an acidic 'molten globule' before it can fully insert into the lipid bilayer. Clearly, electrostatic interactions must play a significant role in both events. The electrostatic field around the toxin in solution was calculated using the finite-difference Poisson-Boltzmann method of the Delphi programme and the known X-ray structure. A large positively charged surface was identified which could be involved in the binding of colicin to negatively charged membranes. The applicability of the result was tested by also calculating the fields around modelled structures of the closely related colicins B and N. Surprisingly, colicin N showed a similar charge distribution in spite of its isoelectric point of pI 10.20 (colicin A has pI 5.44). One reason for this is the strong conservation of certain negative charges in all colicins. There is a single highly conserved aspartate residue (Asp78) on the positively charged face which provides a small but discrete region of negative charge. This residue, Asp78, was replaced by asparagine in the mutant D78N. D78N binds faster to negatively charged vesicles but inserts only half as fast as the wild-type protein into the membrane core. This indicates that, first, the initial membrane binding has a significant electrostatic component and, second, that the isolated charge on Asp78 plays a role in the formation of the insertion intermediate. [ABSTRACT FROM AUTHOR]

Methanol dehydrogenase was purified from the obligate methanotroph, Methylosinus trichosporium OB3b, in two steps from disrupted biomass by aqueous two-phase partition and ion-exchange chromatography. Copartitioning of a cytochrome c was dependent upon the pH at which aqueous partition was carried out. The native enzyme has a Mr of 120 000, as determined by gel filtration chromatography, and consists of two identical subunits. The purified enzyme contained four electrophoretically distinct isoenzymes, with pI values of 6.3, 6.58, 6.63 and 6.88. The native enzyme has been crystallised in a form suitable for high-resolution X-ray crystallographic studies. The crystals diffract to better than 0.19 nm spacing and are relatively stable to irradiation with X-rays. The space group is P6122 (or P6522) with cell dimensions a = b = 10.21 am, c = 29.32 nm and the crystal probably contains a single monomer in the asymmetric unit. [ABSTRACT FROM AUTHOR]

This study investigated the physicochemical properties of sausages made from meat alternatives made from Maillard‐reacted beef bone hydrolysate and plant proteins (soy protein and wheat gluten) at different moisture contents (MC; S49%MC, S52%MC, S56%MC and S60%MC). S49%MC had the highest hardness and chewiness, observed with chunks of long fibres under SEM. The hardness and chewiness of sausages decreased as MC increased. S60%MC exhibited soft and mushy texture, and no fibre structure was observed. Sausages made from meat alternatives had higher protein oxidation as compared with reference sausage made from chicken breast (SCB), which could be due to longer storage period, as meat alternatives were extruded, frozen and stored before making into sausages. Sensory results showed that SCB obtained the highest scores for all attributes except for appearance, among all sausages. Overall results showed that further improvements can be made when using extruded meat alternatives to make sausages. [ABSTRACT FROM AUTHOR]

Summary: This study investigated the effects of moisture content (MC) on the physicochemical properties of extruded meat alternatives made from Maillard‐reacted beef bone hydrolysate and plant proteins. Samples were extruded at 170 °C (maximum barrel temperature), at 3.6 kg h−1 (liquid feed rate) and at 1.8, 2.2, 2.6 and 3.0 kg h−1 (dry feed rates) to obtain MC of 60%MC, 56%MC, 52%MC and 49%MC, respectively. Meat alternatives at 52%MC showed the greatest degree of texturisation. However, meat alternatives at 49%MC were the closest in terms of both textural and microstructural properties to reference sample, boiled chicken breast. Results from protein solubility suggested that a large amount of aggregated proteins were associated with hydrogen bonds, while disulphide bonds were the main contributor in the formation of fibrous structure in meat alternatives. Results showed that the change in MC as process parameter played an important role in the formation of fibrous structure in extruded meat alternatives. [ABSTRACT FROM AUTHOR]

The cholesterol‐dependent cytolysins (CDCs) are a major family of bacterial pore‐forming proteins secreted as virulence factors by Gram‐positive bacterial species. CDCs are produced as soluble, monomeric proteins that bind specifically to cholesterol‐rich membranes, where they oligomerize into ring‐shaped pores of more than 30 monomers. Understanding the details of the steps the toxin undergoes in converting from monomer to a membrane‐spanning pore is a continuing challenge. In this review we summarize what we know about CDCs and highlight the remaining outstanding questions that require answers to obtain a complete picture of how these toxins kill cells. [ABSTRACT FROM AUTHOR]

Bapineuzumab (AAB-001) and its derivative (AAB-003) are humanized versions of the anti-Aβ murine antibody 3D6 and are immunotherapy candidates in Alzheimer's disease. The common Fab fragment of these immunotherapies has been expressed, purified and crystallized in complex with β-amyloid peptides (residues 1-8 and 1-28). Diffraction data at high resolution were acquired from crystals of Fab-Aβ8 (2.0 Å) and Fab-Aβ28 (2.2 Å) complexes at the Australian Synchrotron. Both crystal forms belonged to the primitive orthorhombic space group P21221. [ABSTRACT FROM AUTHOR]

Objective: To test the hypothesis that steady-state drug delivery by continuous infusion is predictably affected by a second drug infusion in the same lumen. Background: Clinicians commonly administer two drugs by continuous infusion through one central venous catheter lumen (co-infusion). To limit fluid delivery, low flow rate carriers transport concentrated drug solutions; a method called microinfusion. How microinfusion delivery of one drug is affected by a second drug infusion has not been explored. Methods: Two water-soluble dyes, tartrazine and erioglaucine, infused at 3 ml·h−1, modeled drug delivery through a four stopcock linear manifold and catheter lumen. A pump drove a carrier fluid (10 ml·h−1). After tartrazine reached steady-state delivery, erioglaucine entered downstream or upstream of the tartrazine infusion. Quantitative spectrophotometry measured dye delivery. Results: Starting erioglaucine's infusion upstream of tartrazine's entry caused a transient tartrazine bolus (duration 10 min, peak drug delivery 20% higher than target levels). Starting erioglaucine's infusion downstream produced a similar amplitude, briefer, bolus. Stopping the erioglaucine infusion caused a transient reduction in tartrazine delivery. Measured delivery profiles were comparable to prediction models. Conclusions: We confirmed the hypothesis that delivery of one infused drug is transiently affected by starting or stopping a second drug infusion in the same line. The magnitude of the changes can be estimated quantitatively. The clinical impact depends on the drugs being co-infused and patient sensitivity, but could be clinically important; the findings have safety implications for infused medication delivery to critically ill or anesthetized children. We recommend minimizing infusion system dead volumes, connecting the most essential infusion(s) to the main fluid pathway as close as possible to the patient, and recognizing the potential for unintended alterations in delivery when multiple drugs co-infuse. [ABSTRACT FROM AUTHOR]

Fatty-acid binding proteins (FABPs) are abundantly expressed proteins that bind a range of lipophilic molecules. They have been implicated in the import and intracellular distribution of their ligands and have been linked with metabolic and inflammatory responses in the cells in which they are expressed. Despite their high sequence identity, human intestinal FABP (hIFABP) and rat intestinal FABP (rIFABP) bind some ligands with different affinities. In order to address the structural basis of this differential binding, diffraction-quality crystals have been obtained of hIFABP and rIFABP in complex with the fluorescent fatty-acid analogue 11-(dansylamino)undecanoic acid. [ABSTRACT FROM AUTHOR]

A key selling point of pharmacogenetics is the genetic stratification of either patients or diseases in order to target the prescribing of medicine. The hope is that genetically ‘tailored’ medicines will replace the current ‘one-size-fits-all’ paradigm of drug development and usage. This paper is concerned with the relationship between difference and justice in the use of pharmacogenetics. This new technology, which facilitates the identification and use of difference, has, we shall argue, the potential to lead to injustice either by the inappropriate use of difference or through the inappropriate failure to use difference. We build on empirical data from a detailed study of the range of options for the development of pharmacogenetics to present a consideration of the ethical issues that surround patient and disease stratification. In it we explore the ways in which the use of pharmacogenetics may lead to the creation of new, genetically stratified, forms of difference and new forms of injustice based on these divisions. We also examine the ways in which existing forms of difference and social stratification may interact with the use of pharmacogenetics. In conclusion, we suggest how an understanding of these ethical issues could usefully inform future policy discussions. [ABSTRACT FROM AUTHOR]

Examines the cloned neuropeptide Y and pancreatic polypeptide Y[sub 4] receptors expressed in Chinese hamster ovary cells. Association of internalized receptors with endosome-like particulates; Effect of sucrose on the internalization of receptors; Restoration of Y[sub 1] and Y[sub 4] receptors after peptide pretreatment.

The length of a river food chain changed from year to year, shifting with the hydrologic regime. During drought years, grazers suppressed algae across a nutrient gradient, while predators were functionally unimportant. Following flood disturbance, predators suppressed grazers, releasing algae. These results suggest that hydrologic regime, rather than productivity, determines the functional length of this river food chain. Within years, algae and grazer biomass responded to an experimental productivity gradient in patterns predicted by simple trophic models that assume efficient energy transfer. Understanding differences among species within trophic levels, however, was crucial in delineating the controlling interactions. [ABSTRACT FROM AUTHOR]

This study aims to understand nutrition‐related roles, responsibilities and ethical issues of grandparents caring for their grandchildren in skip‐generation households in rural Cambodia. Over the past decade, Cambodia has experienced a rise in economic migration of working age populations. This has resulted in increasing numbers of 'skip‐generation' households, in which grandparents and grandchildren co‐reside without parents, reflecting potential household vulnerability. This qualitative study involved in‐depth interviews and focus group discussions with Cambodian grandparents who were primary caregivers to grandchildren for six months or longer. A total of 39 grandparents were recruited at two sites in north‐west Cambodia. Interviews and focus group discussions were conducted in Khmer and were recorded, transcribed and translated into English. Data were analysed using thematic analysis. Grandparents in this study looked after an average of three children, aged between two months and 18 years old. Overall, 40% were sole caregivers. Analysis showed that grandparents, particularly grandmothers, played a central role in their grandchildren's health and nutrition. Although grandchildren's health and nutrition were a major priority to grandparents, they reported facing significant challenges to safeguard their grandchildren's and their own nutritional needs. As a result, grandparents frequently faced difficult ethical trade‐offs and prioritised their grandchildren's health and nutrition over their own. This study highlights that in order to improve child nutrition, policies and interventions need to be designed in ways that support and enable grandparent caregivers to meet their grandchildren's health and nutritional needs without neglecting their own. [ABSTRACT FROM AUTHOR]

The CAMTA1‐associated phenotype was initially defined in patients with intragenic deletions and duplications who showed nonprogressive congenital ataxia, with or without intellectual disability. Here, we describe 10 individuals with CAMTA1 variants: nine previously unreported (likely) pathogenic variants comprising one missense, four frameshift and four nonsense variants, and one missense variant of unknown significance. Six patients were diagnosed following whole exome sequencing and four individuals with exome‐based targeted panel analysis. Most of them present with developmental delay, manifesting in speech and motor delay. Other frequent findings are hypotonia, cognitive impairment, cerebellar dysfunction, oculomotor abnormalities, and behavioral problems. Feeding problems occur more frequently than previously observed. In addition, we present a systematic review of 19 previously published individuals with causal variants, including copy number, truncating, and missense variants. We note a tendency of more severe cognitive impairment and recurrent dysmorphic features in individuals with a copy number variant. Pathogenic variants are predominantly observed in and near the N‐ and C‐ terminal functional domains. Clinical heterogeneity is observed, but 3′‐terminal variants seem to associate with less pronounced cerebellar dysfunction. [ABSTRACT FROM AUTHOR]

Expanding the phenotype of SETD5-related disorder and presenting a novel association with bone fragility Clinical screening and judicious use of imaging (e.g., lateral spine imaging with DXA) may enable early identification of bone fragility and ensure timely initiation of bone-targeted medication. There was no significant history of medication use impacting bone health or evidence of a connective tissue disorder in either patient. [Extracted from the article]

Two 1p36 contiguous gene deletion syndromes are known so far: the terminal 1p36 deletion syndrome and a 1p36 deletion syndrome with a critical region located more proximal at 1p36.23‐1p36.22. We present even more proximally located overlapping deletions from seven individuals, with the smallest region of overlap comprising 1 Mb at 1p36.13‐1p36.12 (chr1:19077793‐20081292 (GRCh37/hg19)) defining a new contiguous gene deletion syndrome. The characteristic features of this new syndrome are learning disability or mild intellectual disability, speech delay, behavioral abnormalities, and ptosis. The genes UBR4 and CAPZB are considered the most likely candidate genes for the features of this new syndrome. [ABSTRACT FROM AUTHOR]

Most structure‐based drug discovery methods utilize crystal structures of receptor proteins. Crystal engineering, on the other hand, utilizes the wealth of chemical information inherent in small‐molecule crystal structures in the Cambridge Structural Database (CSD). We show that the interaction surfaces and shapes of molecules in experimentally determined small‐molecule crystal structures can serve as effective tools in drug discovery. Our description of the shape and interaction propensities of molecules in their crystal structures can be used to screen them for specific binding compatibility with protein targets, as demonstrated through the high‐throughput profiling of around 138 000 small‐molecule structures in the CSD and a series of drug–protein crystal structures. Electron‐density‐based intermolecular boundary surfaces in small‐molecule crystal structures and in target‐protein pockets are utilized to identify potential ligand molecules from the CSD based on 3D shape and intermolecular interaction matching. [ABSTRACT FROM AUTHOR]

Most structure‐based drug discovery methods utilize crystal structures of receptor proteins. Crystal engineering, on the other hand, utilizes the wealth of chemical information inherent in small‐molecule crystal structures in the Cambridge Structural Database (CSD). We show that the interaction surfaces and shapes of molecules in experimentally determined small‐molecule crystal structures can serve as effective tools in drug discovery. Our description of the shape and interaction propensities of molecules in their crystal structures can be used to screen them for specific binding compatibility with protein targets, as demonstrated through the high‐throughput profiling of around 138 000 small‐molecule structures in the CSD and a series of drug–protein crystal structures. Electron‐density‐based intermolecular boundary surfaces in small‐molecule crystal structures and in target‐protein pockets are utilized to identify potential ligand molecules from the CSD based on 3D shape and intermolecular interaction matching. [ABSTRACT FROM AUTHOR]

Individual, small group, and program effectiveness can be evaluated quickly and painlessly using the binomial expansion. This powerful, but seldom used, nonparametic method is described and specific examples are used to illustrate its simplicity and elegance. An abbreviated table of probabilities is included.
Evaluation and accountability are frequently viewed as dark could looming over program development and individual staff appraisals. Every service provider faces challenges to prove that her of she has been effective in his or her job. But designing, conducting, and analyzing studies to evaluate services can be time consuming and complex, typically requiring changes in routines, identification and use of sophisticated measurement devices, and esoteric statistics long since forgotten, repressed, or joyously discarded. This is an unnecessary state of affairs because there are a number of simple procedures available. Perhaps because of their simplicity, these procedures have not received the attention they deserve. The subject of this article, the binomial expansion (BE), is one of these simple techniques. It requires only the identification of two numbers and a table of probabilities (see Table 1). [ABSTRACT FROM AUTHOR]

Patient and public involvement (PPI) has gained widespread support in health research and health policy circles, but there is little consensus on the precise meaning or justifications of PPI. We argue that an important step towards clarifying the meaning and justification for PPI is to split apart the familiar acronym and draw a distinction between patient and public involvement. Specifically, we argue that patient involvement should refer to the practice of involving individuals in health research or policy on the basis of their experience with a particular condition, while public involvement should refer to the practice of involving individuals in health policy or research based on their status as members of a relevant population. Analyzing cases from the UK, Australia, and the USA, we show how our proposed distinction can deliver much needed clarity to conversations on PPI, while guiding the development and evaluation of future PPI‐based policies. [ABSTRACT FROM AUTHOR]

In recent years, there has been an increase in the establishment of biobanks for genetic and genomic studies around the globe. One example of this is the Human Heredity and Health in Africa Initiative (H3Africa), which has established biobanks in the sub-region to facilitate future indigenous genomic studies. The concept of 'broad consent' has been proposed as a mechanism to enable potential research participants in biobanks to give permission for their samples to be used in future research studies. However, questions remain about the acceptability of this model of consent. Drawing on findings from empirical research about the role of trust in decision-making, we argue that an account of entrustment may be an appropriate way of addressing current challenges of seeking consent for biobank research in Africa. We propose a set of key points to consider that can support the proposed entrustment framework. [ABSTRACT FROM AUTHOR]

Studies of how birds mobilize nutrients to eggs have traditionally considered a continuum of possible allocation strategies ranging from income breeding (rely on food sources found on the breeding grounds) to capital breeding (rely on body reserves stored prior to the breeding season). For capital breeding, stored body reserves can be acquired either on or away from the breeding grounds, but it has been difficult to quantify the relative contribution of each, precluding identification of key habitats for acquiring nutrients for clutch formation. During 2006-2009, we explored the importance of spring-staging habitats versus breeding-area habitats for egg-lipid formation in female lesser scaup Aythya affinis using stable carbon (δ13C) isotope analyses. Although δ13C values for abdominal lipid reserves brought to the breeding grounds overlapped those of local amphipods, we were able to quantify the importance of local plant carbohydrates (seeds of emergent wetland plants) to the production of eggs. We compared the importance of local wetland seeds (overall δ13C: −29.1 ± 0.9‰ SD) to combined lipid stores and lipids from local amphipods (overall δ13C: −23.8 ± 2.2‰). Local seeds and stored body lipids contributed equally to egg lipid formation across years but we found evidence of annual variation in their relative importance. Wetland seeds contributed 39% (SE = 10%) to egg lipid production, and the importance of this source varied by year (90% CI = 47-75% in 2006, 13-42% in 2007, 29-65% in 2008, and 7-30% in 2009). In contrast to earlier studies that suggest lesser scaup predominantly employ a capital breeding strategy, our results suggest that in some years females may attain half of their energy for clutch formation from foods on the breeding grounds. [ABSTRACT FROM AUTHOR]

Interleukin-3 (IL-3) is a member of the beta common family of cytokines that regulate multiple functions of myeloid cells. The IL-3 receptor-specific alpha subunit (IL3Rα) is overexpressed on stem cells/progenitor cells of patients with acute myeloid leukaemia, where elevated receptor expression correlates clinically with a reduced patient survival rate. The monoclonal antibody (MAb) CSL362 is a humanized MAb derived from the murine MAb 7G3, originally identified for its ability to specifically recognize the human IL-3 receptor and for blocking the signalling of IL-3 in myeloid and endothelial cells. In order to elucidate the molecular mechanism of CSL362 antagonism, a preliminary structure of human IL3Rα in complex with the MAb CSL362 has been determined. [ABSTRACT FROM AUTHOR]

Both of the TNF superfamily ligands, TNF and LTα, can bind and signal through TNFR1 and TNFR2, yet mice mutant for each have different phenotypes. Part of this difference is because LTα but not TNF can activate Herpes Virus Entry Mediator and also heterotrimerise with LTβ to activate LTβR, which is consistent with the similar phenotypes of the LTα and LTβR deficient mice. However, it has also been reported that the LTα3 homotrimer signals differently than TNF through TNFR1, and has unique roles in initiation and exacerbation of some inflammatory diseases. Our modeling of the TNF/ TNFR1 interface compared to the LTα3/ TNFR1 structure revealed some differences that could affect signalling by the two ligands. To determine whether there were any functional differences in the ability of TNF and LTα3 to induce TNFR1-dependent apoptosis or necroptosis, and if there were different requirements for c IAPs and Sharpin to transmit the TNFR1 signal, we compared the ability of cells to respond to TNF and LTα3. Contrary to our hypothesis, we were unable to discover differences in signalling by TNFR1 in response to TNF and LTα3. Our results imply that the reasons for the conservation of LTα are most likely due either to differential regulation, the ability to signal through Herpes Virus Entry Mediator or the ability of LTα to form heterotrimers with LTβ. Structured digital abstract LT alpha physically interacts with RIPK1 and cIAP1 by tandem affinity purification (View interaction), TNF and TNF bind by blue native page (View interaction), LT alpha and LT alpha bind by blue native page (View interaction), TNF physically interacts with cIAP1 and RIPK1 by tandem affinity purification (View interaction) [ABSTRACT FROM AUTHOR]

Community Engagement ( CE) has been presented by bio-ethicists and scientists as a straightforward and unequivocal good which can minimize the risks of exploitation and ensure a fair distribution of research benefits in developing countries. By means of ethnographic fieldwork undertaken in Kenya between 2007 and 2009 we explored how CE is understood and enacted in paediatric vaccine trials conducted by the Kenyan Medical Research Institute and the US Centers for Disease Control ( KEMRI/ CDC). In this paper we focus on the role of paid volunteers who act as an interface between villagers KEMRI/ CDC. Village Reporters' ( VRs) position of being both with the community and with KEMRI/ CDC is advantageous for the conduct of trials. However it is also problematic in terms of exercising trust, balancing allegiances and representing community views. VRs role is shaped by ambiguities related to their employment status and their dual accountability to researchers and their villages. VRs are understandably careful to stress their commitment to self-less community service since it augments their respectability at community level and opens up opportunities for financial gain and self-development. Simultaneously VRs association with KEMRI/ CDC and proximity to trial participants requires them to negotiate implicit and explicit expectations for material and medical assistance in a cultural setting in which much importance is placed on sharing and mutuality. To ensure continuity of productive interactions between VRs, and similar community intermediaries, and researchers, open discussion is needed about the problematic aspects of relational ethics, issues concerning undue influence, power relations and negotiating expectations. [ABSTRACT FROM AUTHOR]

Granulocyte-macrophage colony-stimulating factor ( GM- CSF), interleukin-3 ( IL-3), and IL-5 are members of a discrete family of cytokines that regulates the growth, differentiation, migration and effector function activities of many hematopoietic cells and immunocytes. These cytokines are involved in normal responses to infectious agents, bridging innate and adaptive immunity. However, in certain cases, the overexpression of these cytokines or their receptors can lead to excessive or aberrant initiation of signaling resulting in pathological conditions, with chronic inflammatory diseases and myeloid leukemias the most notable examples. Recent crystal structures of the GM- CSF receptor ternary complex and the IL-5 binary complex have revealed new paradigms of cytokine receptor activation. Together with a wealth of associated structure-function studies, they have significantly enhanced our understanding of how these receptors recognize cytokines and initiate signals across cell membranes. Importantly, these structures provide opportunities for structure-based approaches for the discovery of novel and disease-specific therapeutics. In addition, recent biochemical evidence has suggested that the GM- CSF/ IL-3/ IL-5 receptor family is capable of interacting productively with other membrane proteins at the cell surface. Such interactions may afford additional or unique biological activities and might be harnessed for selective modulation of the function of these receptors in disease. [ABSTRACT FROM AUTHOR]

Two structurally distinct peptides, angiotensin IV and LVV-haemorphin 7, both competitive high-affinity inhibitors of insulin-regulated aminopeptidase (IRAP), were found to enhance aversion-associated and spatial memory in normal rats and to improve performance in a number of memory tasks in rat deficits models. These findings provide compelling support for the development of specific, high-affinity inhibitors of the enzyme as new cognitive enhancing agents. Different classes of IRAP inhibitors have been developed including peptidomimetics and small molecular weight compounds identified through in silico screening with a homology model of the catalytic domain of IRAP. The proof of principal that inhibition of IRAP activity results in facilitation of memory has been obtained by the demonstration that the small-molecule IRAP inhibitors also exhibit memory-enhancing properties. [ABSTRACT FROM AUTHOR]

BACKGROUND: Shrinkage of the donor pool coupled with an increasing demand for blood presents a major challenge to maintaining an adequate blood supply. Consequently it has become even more important to reduce inappropriate blood use, including decisions about when and how much blood to prescribe. This study aimed to ascertain the levels of inappropriate practice and factors associated with it. STUDY DESIGN AND METHODS: The medical records of a randomly selected sample of hospital patients in Northern Ireland who received a red blood cell transfusion during 2005 (n = 1474) were reviewed, and inappropriate transfusion and overtransfusion criteria were applied. Logistic regression models were used to identify factors associated with inappropriate practice and overtransfusion. RESULTS: In this study 23% of transfusions were considered inappropriate, occurring most commonly where the lowest hemoglobin (Hb) threshold for transfusion applied. Younger patients, those undergoing surgery, and those with lower comorbidity and higher Hb values were most likely to have an inappropriate transfusion. Among patients appropriately transfused, 19% were overtransfused. Females and those of lower weight (<65 kg) were most likely to be overtransfused. CONCLUSION: While the choice of criteria used to judge decisions will influence the absolute level of inappropriate or overtransfusion reported, our findings suggest that a significant minority of clinicians are either unaware of or are reluctant to accept lower transfusion thresholds. To improve further improve transfusion practice we suggest that barriers to the implementation of recommended transfusion thresholds should be examined and guidance on an appropriate posttransfusion Hb level developed. [ABSTRACT FROM AUTHOR]

The article discusses an attempt to eliminate the covalent binding of the diuretic drug ethacrynic acid (EA) to reactive Cys-47 by producing a double mutant C47S/Y108V using site directed mutagenesis. The results showed that the double mutant does not substantially alter the unfolding mechanism of pi class glutathione S-transferase (GST P1-1) in either the absence or presence of ligand. It also confirms that the Cys-101 residue is a target site for reaction with ligands if Cys-47 is absent.

The C-terminal Src kinase (Csk) and Csk-homologous kinase (CHK) are endogenous inhibitors of the proto-oncogenic Src family of protein tyrosine kinases (SFKs). Phosphotyrosyl peptide binding to their Src-homology 2 (SH2) domains activates Csk and CHK, enhancing their ability to suppress SFK signalling; however, the detailed mechanistic basis of this activation event is unclear. The CHK SH2 was expressed in Escherichia coli and the purified protein was characterized as monomeric by synchrotron small-angle X-ray scattering in-line with size-exclusion chromatography. The CHK SH2 crystallized in 0.2 M sodium bromide, 0.1 M bis-Tris propane pH 6.5 and 20% polyethylene glycol 3350 and the best crystals diffracted to ∼1.6 Å resolution. The crystals belonged to space group P2, with unit-cell parameters a = 25.8, b = 34.6, c = 63.2 Å, β = 99.4°. [ABSTRACT FROM AUTHOR]

Abstract: Glutathione transferase reaches 0.5–0.8mM concentration in the cell so it works in vivo under the unusual conditions of, [S]≪[E]. As glutathione transferase lowers the pK a of glutathione (GSH) bound to the active site, it increases the cytosolic concentration of deprotonated GSH about five times and speeds its conjugation with toxic compounds that are non-typical substrates of this enzyme. This acceleration becomes more efficient in case of GSH depletion and/or cell acidification. Interestingly, the enzymatic conjugation of GSH to these toxic compounds does not require the assumption of a substrate–enzyme complex; it can be explained by a simple bimolecular collision between enzyme and substrate. Even with typical substrates, the astonishing concentration of glutathione transferase present in hepatocytes, causes an unusual “inverted” kinetics whereby the classical trends of v versus E and v versus S are reversed. [ABSTRACT FROM AUTHOR]

Dihydrodipicolinate synthase (DHDPS) is an oligomeric enzyme that catalyzes the first committed step of the lysine-biosynthesis pathway in plants and bacteria, which yields essential building blocks for cell-wall and protein synthesis. DHDPS is therefore of interest to drug-discovery research as well as to studies that probe the importance of quaternary structure to protein function, stability and dynamics. Accordingly, DHDPS from the psychrophilic (cold-dwelling) organism Shewanella benthica ( Sb-DHDPS) was cloned, expressed, purified and crystallized. The best crystals of Sb-DHDPS were grown in 200 m M ammonium sulfate, 100 m M bis-tris pH 5.0-6.0, 23-26%( w/ v) PEG 3350, 0.02%( w/ v) sodium azide and diffracted to beyond 2.5 Å resolution. Processing of diffraction data to 2.5 Å resolution resulted in a unit cell with space group P212121 and dimensions a = 73.1, b = 84.0, c = 143.7 Å. These studies of the first DHDPS enzyme to be characterized from a bacterial psychrophile will provide insight into the molecular evolution of enzyme structure and dynamics. [ABSTRACT FROM AUTHOR]

Cytokines are secreted soluble peptides that precisely regulate multiple cellular functions. Amongst these the GM-CSF/IL-3/IL-5 family of cytokines controls whether hematopoietic cells will survive or apoptose, proliferate, differentiate, migrate, or perform effector functions such as phagocytosis or reactive oxygen species release. Their potent and pleiotropic activities are mediated through binding to high affinity membrane receptors at surprisingly low numbers per cell. Receptor binding triggers a cascade of intracellular signaling events, including reversible phosphorylation of receptor subunits and associated signaling molecules, leading to multiple biological responses, with the prevention of apoptosis or “cell survival” being a key cellular function that underpins all others. Many chronic inflammatory diseases and a number of haematological malignancies are driven by deregulated GM-CSF, IL-3, or IL-5 cytokine receptor signaling, highlighting their importance in disease. A major step in understanding how these cytokine receptors function is to elucidate their three dimensional structure and to relate this to the many signaling pathways emanating from their receptors. We have recently solved the structure of the human GM-CSF receptor complexed to GM-CSF which revealed distinct forms of receptor assembly: a hexamer that comprises two molecules each of GM-CSF, GM-CSF receptor alpha chain and GM-CSF receptor beta chain; and an unexpected dodecamer in which two hexameric complexes associate through a novel site 4. This latter form is necessary to bring JAK2 molecules sufficiently close together to enable full receptor activation. In this review we focus on the most recent insights in cytokine receptor signaling, and in receptor assembly. The stage is now set to link distinct forms of cytokine receptor assembled structures to specific forms of cytokine receptor signaling and function. Armed with this knowledge it may be possible to map distinct cytokine receptor signaling pathways from the cell surface to the cell nucleus which may themselves become new therapeutic targets. © 2010 IUBMB IUBMB Life, 62(7): 509–518, 2010 [ABSTRACT FROM AUTHOR]

Abstract: HIV integrase (IN) is an essential enzyme in HIV replication and an important target for drug design. IN has been shown to interact with a number of cellular and viral proteins during the integration process. Disruption of these important interactions could provide a mechanism for allosteric inhibition of IN. We present the highest resolution crystal structure of the IN core domain to date. We also present a crystal structure of the IN core domain in complex with sucrose which is bound at the dimer interface in a region that has previously been reported to bind integrase inhibitors. Structured summary: MINT-7713125: IN (uniprotkb:P04585) and IN (uniprotkb:P04585) bind (MI:0407) by X-ray crystallography (MI:0114) [Copyright &y& Elsevier]

Dihydrodipicolinate reductase (DHDPR; EC 1.3.1.26) catalyzes the nucleotide (NADH/NADPH) dependent second step of the lysine-biosynthesis pathway in bacteria and plants. Here, the cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of DHDPR from methicillin-resistant Staphylococcus aureus (MRSA-DHDPR) are presented. The enzyme was crystallized in a number of forms, predominantly with ammonium sulfate as a precipitant, with the best crystal form diffracting to beyond 3.65 Å resolution. Crystal structures of the apo form as well as of cofactor (NADPH) bound and inhibitor (2,6-pyridinedicarboxylate) bound forms of MRSA-DHDPR will provide insight into the structure and function of this essential enzyme and valid drug target. [ABSTRACT FROM AUTHOR]

Dihydrodipicolinate synthase (DHDPS; EC 4.2.1.52) catalyzes the rate-limiting step in the ( S)-lysine biosynthesis pathway of bacteria and plants. Here, the cloning of the DHDPS gene from a clinical isolate of Streptococcus pneumoniae (OXC141 strain) and the strategy used to express, purify and crystallize the recombinant enzyme are described. Diffracting crystals were grown in high-molecular-weight PEG precipitants using the hanging-drop vapour-diffusion method. The best crystal, from which data were collected, diffracted to beyond 2.0 Å resolution. Initially, the crystals were thought to belong to space group P42212, with unit-cell parameters a = 105.5, b = 105.5, c = 62.4 Å. However, the R factors remained high following initial processing of the data. It was subsequently shown that the data set was twinned and it was thus reprocessed in space group P2, resulting in a significant reduction in the R factors. Determination of the structure will provide insight into the design of novel antimicrobial agents targeting this important enzyme from S. pneumoniae. [ABSTRACT FROM AUTHOR]

Social and cognitive characteristics of adults with intellectual disabilities (ID) place them at risk for inappropriate inclusion in or exclusion from research participation. As we grapple with how to include adults with ID in research in order to secure their right to contribute to scientific advancements and be positioned to derive benefit from ensuing knowledge, it is critical to consider scientific gatekeepers' perspectives on risks of and protections for including adults with ID in research. We surveyed 199 Institutional Review Board members and intellectual disability researchers in the United States to identify their perceptions of specific risks and necessary protections in (hypothetical) research studies. The research studies varied as to whether they included adults with ID in the research sample and the level of harm to which research participants were exposed. Results suggest that identification of psychological, social, and legal risks and necessary protections varied by the disability status of the sample, the level of risk, and the role of the person reviewing the study. For example, participants identified more psychological, information control, legal, and social risks in higher harm research studies. Participants reported a need for more protections in high-harm studies as well as studies that included adults with ID. In some instances the nature of identified risks and protections and respondents' characterization of these risks and necessary protections suggested concerns related specifically to adults with ID. Implications for practice, policy, and future research related to access to research participation are discussed. [ABSTRACT FROM AUTHOR]

Dihydrodipicolinate synthase (DHDPS) catalyses the first committed step in the lysine-biosynthesis pathway in bacteria, plants and some fungi. In this study, the expression of DHDPS from Bacillus anthracis ( Ba-DHDPS) and the purification of the recombinant enzyme in the absence and presence of the substrate pyruvate are described. It is shown that DHDPS from B. anthracis purified in the presence of pyruvate yields greater amounts of recombinant enzyme with more than 20-fold greater specific activity compared with the enzyme purified in the absence of substrate. It was therefore sought to crystallize Ba-DHDPS in the presence of the substrate. Pyruvate was soaked into crystals of Ba-DHDPS prepared in 0.2 M sodium fluoride, 20%( w/ v) PEG 3350 and 0.1 M bis-tris propane pH 8.0. Preliminary X-ray diffraction data of the recombinant enzyme soaked with pyruvate at a resolution of 2.15 Å are presented. The pending crystal structure of the pyruvate-bound form of Ba-DHDPS will provide insight into the function and stability of this essential bacterial enzyme. [ABSTRACT FROM AUTHOR]

Approximately one-quarter of people over the age of 65 are estimated to suffer some form of cognitive impairment, underscoring the need for effective cognitive-enhancing agents. Insulin-regulated aminopeptidase (IRAP) is potentially an innovative target for the development of cognitive enhancers, as its peptide inhibitors exhibit memory-enhancing effects in both normal and memory-impaired rodents. Using a homology model of the catalytic domain of IRAP and virtual screening, we have identified a class of nonpeptide, small-molecule inhibitors of IRAP. Structure-based computational development of an initial "hit" resulted in the identification of two divergent families of compounds. Subsequent medicinal chemistry performed on the highest affinity compound produced inhibitors with nanomolar affinities (Ki 20-700 nM) for IRAP. In vivo efficacy of one of these inhibitors was demonstrated in rats with an acute dose (1 nmol in 1 p.l) administered into the lateral ventricles, improving performance in both spatial working and recognition memory paradigms. We have identified a family of specific IRAP inhibitors that is biologically active which will be useful both in understanding the physiological role of IRAP and potentially in the development of clinically useful cognitive enhancers. Notably, this study also provides unequivocal proof of principal that inhibition of IRAP results in memory enhancement. [ABSTRACT FROM AUTHOR]