Preservation of Garnet Growth Zoning and the Duration of Prograde Metamorphism

Chemically zoned garnet growth and coeval modification of this zoning through diffusion are calculated during prograde metamorphic heating to temperatures of up to 850°C. This permits quantification of how the preservation or elimination of zoning profiles in garnet crystals of a given size is sensitive to the specific burial and heating (P-T) path followed, and the integrated duration spent at high temperature (dT/dt). Slow major element diffusion in garnet at T 30 Myr at amphibolite-grade conditions, but small-scale (tens of micrometres) zoning features will be lost early in the prograde stage unless this is ‘rapid' (5 Myr for rocks reaching c. 600°C). Calculations indicate that preservation of unmodified growth compositions in even relatively large (up to 3 mm diameter) pelitic garnet crystals requires prograde and exhumational events to be <10 Myr for rocks reaching c. 600°C. This timescale can be 5 Myr for garnet in rocks reaching 650°C or hotter. It is likely, therefore, that most natural prograde-zoned crystals record compositions already partially re-equilibrated between the time of crystal growth and of reaching maximum temperature. However, a large T-t window exists within which crystals begin to lose their growth compositions but retain evidence of crystal-scale zoning trends that may still be useful for thermobarometry purposes. The upper limit of this window for 500 μm diameter crystals can be as much as several tens of millions of years of heating to c. 700°C. Absolute re-equilibration timescales can be significantly different for garnet growing in different rock compositions, with examples of a granodiorite and a pelite give

Regioselective and stoichiometrically controlled conjugation of photodynamic sensitizers to a HER2 targeting antibody fragment

The rapidly increasing interest in the synthesis of antibody–drug conjugates as powerful targeted anticancer agents demonstrates the growing appreciation of the power of antibodies and antibody fragments as highly selective targeting moieties. This targeting ability is of particular interest in the area of photodynamic therapy, as the applicability of current clinical photosensitizers is limited by their relatively poor accumulation in target tissue in comparison to healthy tissue. Although synthesis of porphyrin–antibody conjugates has been previously demonstrated, existing work in this area has been hindered by the limitations of conventional antibody conjugation methods. This work describes the attachment of azide-functionalized, water-soluble porphyrins to a tratuzumab Fab fragment via a novel conjugation methodology. This method allows for the synthesis of a homogeneous product without the loss of structural stability associated with conventional methods of disulfide modification. Biological evaluation of the synthesized conjugates demonstrates excellent selectivity for a HER2 positive cell line over the control, with no dark toxicity observed in either case

Inositol 1,3,4,5,6-pentakisphosphate 2-kinase is a distant IPK member with a singular inositide binding site for axial 2-OH recognition

Inositol phosphates (InsPs) are signaling molecules with multiple roles in cells. In particular Graphic (InsP6) is involved in mRNA export and editing or chromatin remodeling among other events. InsP6 accumulates as mixed salts (phytate) in storage tissues of plants and plays a key role in their physiology. Human diets that are exclusively grain-based provide an excess of InsP6 that, through chelation of metal ions, may have a detrimental effect on human health. Ins(1,3,4,5,6)P5 2-kinase (InsP5 2-kinase or Ipk1) catalyses the synthesis of InsP6 from InsP5 and ATP, and is the only enzyme that transfers a phosphate group to the axial 2-OH of the myo-inositide. We present the first structure for an InsP5 2-kinase in complex with both substrates and products. This enzyme presents a singular structural region for inositide binding that encompasses almost half of the protein. The key residues in substrate binding are identified, with Asp368 being responsible for recognition of the axial 2-OH. This study sheds light on the unique molecular mechanism for the synthesis of the precursor of inositol pyrophosphates

San Francisco Bar Pilot Fatigue Study

The purpose of this study was to evaluate the extent of fatigue among San Francisco Bar Pilots (Maritime Pilots) and its potential impact on safety, and to make recommendations concerning how the risk of fatigue could be managed. Information was gathered via a literature review, observations of Bar Pilots at work, surveys, a task analysis, and an analysis of dispatch records.The work of San Francisco Bar Pilots involves an unusual mix of activities and job demands. Their work calls for situational awareness, reasoning, communication, and perceptual abilities comparable to those required by airline pilots and air traffic controllers. Errors can have severe consequences for public safety and the environment, as well as significant financial costs. Fatigue is increasingly recognized as a hazard that must be managed by the transportation industry. The reduced sleep quality and quantity experienced by personnel who work at night, in conjunction with human circadian rhythms can lead to an operationally significant level of cognitive impairment. The cognitive impact of fatigue includes functions that are critical to safe maritime piloting, such as vigilance, judgment, reaction time and communication. The surveys distributed to Bar Pilots did not uncover evidence of widespread fatigue. The survey results also suggested that fatigue was not a major concern of Bar Pilots. Bar Pilots had overall low scores on the subjective fatigue measures used in the survey, and generally assessed the safety risk due to fatigue as low. Compared to air traffic controllers, Bar Pilots gave significantly lower ratings on questions concerning the prevalence and impact of fatigue. The application of fatigue modeling software to Bar Pilot dispatch records identified that in most cases, pilot's cognitive effectiveness was predicted to be acceptable during their duty periods. However, these results could not be verified with objective data.The study identified a number of fatigue issues that deserve attention. These include Bar Pilot work periods that frequently infringe on the circadian low, consecutive work periods without a significant break, consecutive periods of night work, unpredictable work schedules, start time variability, the potential for sleep inertia, and the number of pilots on the board at any given time

Inhibition of HIV-1 Replication by Isoxazolidine and Isoxazole Sulfonamides

Targeting host factors is a complementary strategy for the development of new antiviral drugs. We screened a library of isoxazolidine and isoxazole sulfonamides and found four compounds that inhibited HIV-1 infection in human CD4+ lymphocytic T cells with no toxicity at IC90 concentrations. Structure-activity relationship showed that benzyl sulfonamides and a halo-substituted aromatic ring on the heterocycle scaffold were critical for antiretroviral activity. The size and position of the incorporated halogen had a marked effect on the antiretroviral activity. The sulfonamide derivatives had no significant effect on HIV-1 entry, reverse transcription and integration but impaired a step necessary for activation of viral gene expression. This step was Tat-independent, strongly suggesting that the target is a cell factor. A virus partially resistant to the least potent compounds could be selected but could not be propagated in the long term, consistent with the possibility that HIV-1 may be less likely to develop resistance against drugs targeting some host factors. Here, we provide evidence that novel synthetic methods can be applied to develop small molecules with antiretroviral activity that target host factors important for HIV-1 replication

Analytical Pluralism in Qualitative Research: A Meta-Study

Recent interest in analytical pluralism – the application of more than one qualitative analytical method to a single data set – has demonstrated its potential to produce multiple, complex and varied understandings of phenomena. However tensions remain regarding the commensurability of findings produced from diverse theoretical frameworks, the practical application of multiple methods of analysis and the capacity of pluralism to contribute to knowledge in psychology. This study addresses these issues, through a critical interpretation of existing qualitative studies that utilised analytical pluralism. Using a meta-study design, we examined the use of theory, application of methods and production of findings in studies that had adopted qualitative analytical pluralism. Following comprehensive database searches, 10 articles were included in the analysis. Epistemological and ontological considerations, the influence of decisions made in the practical application of pluralism and approaches to interpreting findings produced from multiple analyses are discussed, and implications for future research are considered

Potential new fluoroquinolone treatments for suspected bacterial keratitis.

Topical fluoroquinolones (FQs) are an established treatment for suspected microbial keratitis. An increased FQ resistance in some classes of bacterial pathogens is a concern. Some recently developed FQs have an extended spectrum of activity, making them a suitable alternative for topical ophthalmic use. For example, the new generation FQs, avarofloxacin, delafloxacin, finafloxacin, lascufloxacin, nadifloxacin, levonadifloxacin, nemonoxacin and zabofloxacin have good activity against the common ophthalmic pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumoniae and several of the Enterobacteriaceae However, because there are no published ophthalmic break-point concentrations, the susceptibility of an isolated micro-organism to a topical FQ is extrapolated from systemic break-point data and wild type susceptibility. The purpose of this review is to compare the pharmacokinetics and pharmacodynamics of the FQs licensed for topical ophthalmic use with the same parameters for new generation FQs. We performed a literature review of the FQs approved for topical treatment and the new generation FQs licensed to treat systemic infections. We then compared the minimum inhibitory concentrations (MIC) of bacterial isolates and the published concentrations that FQs achieved in the cornea and aqueous. We also considered the potential suitability of new generation FQs for topical use based on their medicinal properties. Notably, we found significant variation in the reported corneal and aqueous FQ concentrations so that reliance on the reported mean concentration may not be appropriate, and the first quartile concentration may be more clinically relevant. The provision of the MIC for the microorganism together with the achieved lower (first) quartile concentration of a FQ in the cornea could inform management decisions such as whether to continue with the prescribed antimicrobial, increase the frequency of application, use a combination of antimicrobials or change treatment

Homogeneous antibody fragment conjugation by disulfide bridging introduces 'spinostics'

A major obstacle to the efficient production of antibody conjugates for therapy and diagnosis is the non-ideal performance of commonly used chemical methods for the attachment of effector-molecules to the antibody of interest. Here we demonstrate that this limitation can be simply addressed using 3,4-substituted maleimides to bridge and thus functionalize disulfide bonds to generate homogeneous antibody conjugates. This one-step conjugation reaction is fast, site-specific, quantitative and generates products with full binding activity, good plasma stability and the desired functional properties. Furthermore, the rigid nature of this modification by disulfide bridging enables the successful detection of antigen with a spin labeled antibody fragment by continuous-wave electron paramagnetic resonance (cw-EPR), which we report here for the first time. Antigen detection is concentration dependent, observable in human blood and allows the discrimination of fragments with different binding affinity. We envisage broad potential for antibody based in-solution diagnostic methods by EPR or 'spinostics'

Adjusting to Retirement from Sport: Narratives of Former Competitive Rhythmic Gymnasts

This study used narrative inquiry to understand the retirement experiences of rhythmic gymnasts. Eight female former competitive gymnasts (M age = 24.5, SD = 8.33) each participated in four life-history interviews. Following dialogical narrative analysis, three narrative typologies were outlined: Entangled Narrative, Going Forward Narrative, and Making Sense Narrative. The entangled narrative shows an individual with a monological athletic identity, who is unable to develop a new identity following her retirement to the detriment of her well-being, and wishes to return to being a gymnast. The going-forward narrative describes those former gymnasts who were able to develop multiple identities during their gymnastics career, and are now flourishing in their life post-retirement. The making-sense narrative is an emergent narrative, which transcends the previous two narratives. Findings expand narrative research by providing new narrative resources to understand the experience of retirement from gymnastics. These narrative resources might assist gymnasts to expand their narrative repertoire by raising awareness of different narratives available in their culture