Spectroscopic and Mechanistic Studies of Heterodimetallic Forms of Metallo-β-lactamase NDM-1

In an effort to characterize the roles of each metal ion in metallo-β-lactamase NDM-1, heterodimetallic analogues (CoCo-, ZnCo-, and CoCd-) of the enzyme were generated and characterized. UV–vis, 1H NMR, EPR, and EXAFS spectroscopies were used to confirm the fidelity of the metal substitutions, including the presence of a homogeneous, heterodimetallic cluster, with a single-atom bridge. This marks the first preparation of a metallo-β-lactamase selectively substituted with a paramagnetic metal ion, Co(II), either in the Zn1 (CoCd-NDM-1) or in the Zn2 site (ZnCo-NDM-1), as well as both (CoCo-NDM-1). We then used these metal-substituted forms of the enzyme to probe the reaction mechanism, using steady-state and stopped-flow kinetics, stopped-flow fluorescence, and rapid-freeze-quench EPR. Both metal sites show significant effects on the kinetic constants, and both paramagnetic variants (CoCd- and ZnCo-NDM-1) showed significant structural changes on reaction with substrate. These changes are discussed in terms of a minimal kinetic mechanism that incorporates all of the data

End of Green Sahara amplified mid- to late Holocene megadroughts in mainland Southeast Asia

Between 5 and 4 thousand years ago, crippling megadroughts led to the disruption of ancient civilizations across parts of Africa and Asia, yet the extent of these climate extremes in mainland Southeast Asia (MSEA) has never been defined. This is despite archeological evidence showing a shift in human settlement patterns across the region during this period. We report evidence from stalagmite climate records indicating a major decrease of monsoon rainfall in MSEA during the mid- to late Holocene, coincident with African monsoon failure during the end of the Green Sahara. Through a set of modeling experiments, we show that reduced vegetation and increased dust loads during the Green Sahara termination shifted the Walker circulation eastward and cooled the Indian Ocean, causing a reduction in monsoon rainfall in MSEA. Our results indicate that vegetation-dust climate feedbacks from Sahara drying may have been the catalyst for societal shifts in MSEA via ocean-atmospheric teleconnections

Crowdsourcing hypothesis tests: making transparent how design choices shape research results

To what extent are research results influenced by subjective decisions that scientists make as they design studies? Fifteen research teams independently designed studies to answer five original research questions related to moral judgments, negotiations, and implicit cognition. Participants from 2 separate large samples (total N > 15,000) were then randomly assigned to complete 1 version of each study. Effect sizes varied dramatically across different sets of materials designed to test the same hypothesis: Materials from different teams rendered statistically significant effects in opposite directions for 4 of 5 hypotheses, with the narrowest range in estimates being d = -0.37 to + 0.26. Meta-analysis and a Bayesian perspective on the results revealed overall support for 2 hypotheses and a lack of support for 3 hypotheses. Overall, practically none of the variability in effect sizes was attributable to the skill of the research team in designing materials, whereas considerable variability was attributable to the hypothesis being tested. In a forecasting survey, predictions of other scientists were significantly correlated with study results, both across and within hypotheses. Crowdsourced testing of research hypotheses helps reveal the true consistency of empirical support for a scientific claim.info:eu-repo/semantics/submittedVersio

Significant quantum effects in hydrogen activation

Dissociation of molecular hydrogen is an important step in a wide variety of chemical, biological, and physical processes. Due to the light mass of hydrogen, it is recognized that quantum effects are often important to its reactivity. However, understanding how quantum effects impact the reactivity of hydrogen is still in its infancy. Here, we examine this issue using a well-defined Pd/Cu(111) alloy that allows the activation of hydrogen and deuterium molecules to be examined at individual Pd atom surface sites over a wide range of temperatures. Experiments comparing the uptake of hydrogen and deuterium as a function of temperature reveal completely different behavior of the two species. The rate of hydrogen activation increases at lower sample temperature, whereas deuterium activation slows as the temperature is lowered. Density functional theory simulations in which quantum nuclear effects are accounted for reveal that tunneling through the dissociation barrier is prevalent for H2 up to ∼190 K and for D2 up to ∼140 K. Kinetic Monte Carlo simulations indicate that the effective barrier to H2 dissociation is so low that hydrogen uptake on the surface is limited merely by thermodynamics, whereas the D2 dissociation process is controlled by kinetics. These data illustrate the complexity and inherent quantum nature of this ubiquitous and seemingly simple chemical process. Examining these effects in other systems with a similar range of approaches may uncover temperature regimes where quantum effects can be harnessed, yielding greater control of bond-breaking processes at surfaces and uncovering useful chemistries such as selective bond activation or isotope separation

Overcoming acculturation: physical education recruits' experiences of an alternative pedagogical approach to games teaching

© 2015 Association for Physical Education Background: Physical education teacher education (PETE) programmes have been identified as a critical platform to encourage the exploration of alternative teaching approaches by pre-service teachers. However, the socio-cultural constraint of acculturation or past physical education and sporting experiences results in the maintenance of the status quo of a teacher-driven, reproductive paradigm. Previous studies have reported successfully overcoming the powerful influence of acculturation, resulting in a change in PETE students' custodial teaching beliefs and receptiveness to alternative teaching approaches. However, to date, limited information has been reported about how PETE students' acculturation shaped their receptiveness to an alternative teaching approach. This is particularly the case for PETE recruits identified in the literature as most resistant to change. Purpose: To explore the features and experiences of an alternative games teaching approach that appealed to PETE recruits identified as most resistant to change, requiring a specific sample of PETE recruits with strong, custodial, traditional physical education teaching beliefs, and whom are high-achieving sporting products of this traditional culture. The alternative teaching approach explored in this study is the constraints-led approach (CLA), which is similar operationally to Teaching Games for Understanding, but distinguished by a neurobiological theoretical framework (nonlinear pedagogy) that informs learning design. Participants and setting: A purposive sample of 10 Australian PETE students was recruited for the study. All participants initially had strong, custodial, traditional physical education teaching beliefs, and were successful sporting products of this teaching approach. After experiencing the CLA as learners during a games unit, participants demonstrated receptiveness to the alternative pedagogy. Data collection and analysis: Semi-structured interviews and written reflections were sources of data collection. Each participant was interviewed separately, once prior to participation in the games unit to explore their positive physical education experiences, and then again after participation to explore the specific games unit learning experiences that influenced their receptiveness to the alternative pedagogy. Participants completed written reflections about their personal experiences after selected practical sessions. Data were qualitatively analysed using grounded theory. Findings: Thorough examination of the data resulted in establishment of two prominent themes related to the appeal of the CLA for the participants: (i) psychomotor (effective in developing skill) and (ii) inclusivity (included students of varying skill level). The efficacy of the CLA in skill development was clearly an important mediator of receptiveness for highly successful products of a traditional culture. This significant finding could be explained by three key factors: the acculturation of the participants, the motor learning theory underpinning the alternative pedagogy and the unit learning design and delivery. The inclusive nature of the CLA provided a solution to the problem of exclusion, which also made the approach attractive to participants. Conclusions: PETE educators could consider these findings when introducing an alternative pedagogy aimed at challenging PETE recruits' custodial, traditional teaching beliefs. To mediate receptiveness, it is important that the learning theory underpinning the alternative approach is operationalised in a research-informed pedagogical learning design that facilitates students' perceptions of the effectiveness of the approach through experiencing and or observing it working

The importance of interacting climate modes on Australia’s contribution to global carbon cycle extremes

The global carbon cycle is highly sensitive to climate-driven fluctuations of precipitation, especially in the Southern Hemisphere. This was clearly manifested by a 20% increase of the global terrestrial C sink in 2011 during the strongest sustained La Niña since 1917. However, inconsistencies exist between El Niño/La Niña (ENSO) cycles and precipitation in the historical record; for example, significant ENSO-precipitation correlations were present in only 31% of the last 100 years, and often absent in wet years. To resolve these inconsistencies, we used an advanced temporal scaling method for identifying interactions amongst three key climate modes (El Niño, the Indian Ocean dipole, and the southern annular mode). When these climate modes synchronised (1999-2012), drought and extreme precipitation were observed across Australia. The interaction amongst these climate modes, more than the effect of any single mode, was associated with large fluctuations in precipitation and productivity. The long-term exposure of vegetation to this arid environment has favoured a resilient flora capable of large fluctuations in photosynthetic productivity and explains why Australia was a major contributor not only to the 2011 global C sink anomaly but also to global reductions in photosynthetic C uptake during the previous decade of drought

“God is Hidden in the Earthly Kingdom:” The Lutheran Two-Kingdoms Theory as Foundation of Scandavanian Secularity

Martin Luther’s signature “two kingdoms” teaching of the sixteenth century was an early and innovative theory of secularization that lies at the heart of historical Scandinavian culture. Defying the organic medieval models of Western Christendom, Luther separated the heavenly and earthly kingdoms, the saint and the sinner, faith and reason, church and the state, Gospel and the Law, as well as the spiritual and secular uses of law, government and authority. Though God is separated from day-to-day life, Luther wrote, God is still hidden in the earthly kingdom” and can be seen through various “masks,” “mists,” and “mimes.” Though the visible church is separated from the state and other institutions, religion remains pervasive in the common callings of every person to be God’s prophet, priest and king in every vocation and location of life. Luther’s two kingdoms theory is a complicated and controversial part of this thinking, but it is worth re-exploring today as pluralistic Scandinavia faces strong new pressures of both sacralization and secularization and seeks to discern anew “the hidden sacraliity of the secular.

Statistical analyses and quality of individual participant data network meta-analyses were suboptimal: a cross-sectional study

Background Network meta-analyses using individual participant data (IPD-NMAs) have been increasingly used to compare the effects of multiple interventions. Although there have been many studies on statistical methods for IPD-NMAs, it is unclear whether there are statistical defects in published IPD-NMAs and whether the reporting of statistical analyses has improved. This study aimed to investigate statistical methods used and assess the reporting and methodological quality of IPD-NMAs. Methods We searched four bibliographic databases to identify published IPD-NMAs. The methodological quality was assessed using AMSTAR-2 and reporting quality assessed based on PRISMA-IPD and PRISMA-NMA. We performed stratified analyses and correlation analyses to explore the factors that might affect quality. Results We identified 21 IPD-NMAs. Only 23.8% of the included IPD-NMAs reported statistical techniques used for missing participant data, 42.9% assessed the consistency, and none assessed the transitivity. None of the included IPD-NMAs reported sources of funding for trials included, only 9.5% stated pre-registration of protocols, and 28.6% assessed the risk of bias in individual studies. For reporting quality, compliance rates were lower than 50.0% for more than half of the items. Less than 15.0% of the IPD-NMAs reported data integrity, presented the network geometry, or clarified risk of bias across studies. IPD-NMAs with statistical or epidemiological authors often better assessed the inconsistency (P = 0.017). IPD-NMAs with a priori protocol were associated with higher reporting quality in terms of search (P = 0.046), data collection process (P = 0.031), and syntheses of results (P = 0.006). Conclusions The reporting of statistical methods and compliance rates of methodological and reporting items of IPD-NMAs were suboptimal. Authors of future IPD-NMAs should address the identified flaws and strictly adhere to methodological and reporting guidelines

Cobalamin in inflammation III — glutathionylcobalamin and methylcobalamin/adenosylcobalamin coenzymes: the sword in the stone? How cobalamin may directly regulate the nitric oxide synthases

Several mysteries surround the structure and function of the nitric oxide synthases (NOS). The NOS oxygenase domain structure is unusually open with a large area of solvent that could accommodate an unidentified ligand. The exact mechanism of the two-step five-electron monoxygenation of arginine to NG-hydroxy-L-arginine, thence to citrulline and nitric oxide (NO), is not clear, particularly as arginine/NG-hydroxy-L-arginine is bound at a great distance to the supposed catalytic heme Fe [III], as the anti-stereoisomer. The Return of the Scarlet Pimpernel Paper proposed that cobalamin is a primary indirect regulator of the NOS. An additional direct regulatory effect of the ‘base-off’ dimethylbenzimidazole of glutathionylcobalamin (GSCbl), which may act as a sixth ligand to the heme iron, promote Co-oriented, BH4/BH3 radical catalysed oxidation of L-arginine to NO, and possibly regulate the rate of inducible NOS/NO production by the NOS dimers, is further advanced. The absence of homology between the NOS and methionine synthase/methylmalonyl CoA mutase may enable GSCbl to regulate both sets of enzymes simultaneously by completely separate mechanisms. Thus, cobalamin may exert central control over both pro-and anti-inflammatory systems

A model of management academics' intentions to influence values

Business schools face increased criticism for failing in the teaching of management studies to nurture their students’ values. Assuming that individual academics play an important role in shaping the value-related influence of business schools, I model management academics’ intentions to influence values. The suggested model encompasses academics’ economic and social values as internal variables, as well as perceived support for attempting to influence values and academic tenure as social and structural variables. A test with empirical data from 1,254 management academics worldwide reveals that perceived external support is most relevant for explaining intentions. Moreover, academics’ social values, but not their economic ones, contribute to an explanation of their intentions to influence values. The results reveal how important it is for academics to believe that their colleagues, higher education institutions, and other stakeholders support their value-related behavioral intentions