A [4Fe-4S]-Fe(CO)(CN)-L-cysteine intermediate is the first organometallic precursor in [FeFe] hydrogenase H-cluster bioassembly.

Biosynthesis of the [FeFe] hydrogenase active site (the 'H-cluster') requires the interplay of multiple proteins and small molecules. Among them, the radical S-adenosylmethionine enzyme HydG, a tyrosine lyase, has been proposed to generate a complex that contains an Fe(CO)2(CN) moiety that is eventually incorporated into the H-cluster. Here we describe the characterization of an intermediate in the HydG reaction: a [4Fe-4S][(Cys)Fe(CO)(CN)] species, 'Complex A', in which a CO, a CN- and a cysteine (Cys) molecule bind to the unique 'dangler' Fe site of the auxiliary [5Fe-4S] cluster of HydG. The identification of this intermediate-the first organometallic precursor to the H-cluster-validates the previously hypothesized HydG reaction cycle and provides a basis for elucidating the biosynthetic origin of other moieties of the H-cluster

"That never would have occurred to me": a qualitative study of medical students' views of a cultural competence curriculum

BACKGROUND: The evidence is mixed regarding the efficacy of cultural competence curricula in developing learners' knowledge, attitudes and skills. More research is needed to better understand both the strengths and shortcomings of existing curricula from the perspective of learners in order to improve training. METHODS: We conducted three focus groups with medical students in their first year of clinical training to assess their perceptions of the cultural competence curriculum at a public university school of medicine. RESULTS: Students evaluated the informal curriculum as a more important source of learning about cultural competence than the formal curriculum. In terms of bias in both self and others, the cultural competence curriculum increased awareness, but was less effective in teaching specific interventional skills. Students also noted that the cultural competence curriculum did not always sufficiently help them find a balance between group-specific knowledge and respect for individual differences. Despite some concerns as to whether political correctness characterized the cultural competence curriculum, it was also seen as a way to rehumanize the medical education experience. CONCLUSION: Future research needs to pay attention to issues such as perceived relevance, stereotyping, and political correctness in developing cross-cultural training programs

Should a colon cancer screening decision aid include the option of no testing? A comparative trial of two decision aids

<p>Abstract</p> <p>Background</p> <p>An important question in the development of decision aids about colon cancer (CRC) screening is whether to include an explicit discussion of the option of not being screened. We examined the effect of including or not including an explicit discussion of the option of deciding not to be screened in a CRC screening decision aid on subjective measures of decision aid content; interest in screening; and knowledge.</p> <p>Methods</p> <p>Adults ages 50–85 were assigned to view one of two versions of the decision aid. The two versions differed only in the inclusion of video segments of two men, one of whom decided against being screened. Participants completed questionnaires before and after viewing the decision aid to compare subjective measures of content, screening interest and intent, and knowledge between groups. Likert response categories (5-point) were used for subjective measures of content (eg. clarity, balance in favor/against screening, and overall rating), and screening interest. Knowledge was measured with a three item index and individual questions. Higher scores indicated favorable responses for subjective measures, greater interest, and better knowledge. For the subjective balance, lower numbers were associated with the impression of the decision aid favoring CRC screening.</p> <p>Results</p> <p>57 viewed the "with" version which included the two segments and 49 viewed the "without" version. After viewing, participants found the "without" version to have better subjective clarity about benefits of screening ("with" 3.4, "without" 4.1, <it>p </it>< 0.01), and to have greater clarity about downsides of screening ("with" 3.2, "without" 3.6, <it>p </it>= 0.03). The "with" version was considered to be less strongly balanced in favor of screening. ("with" 1.8, "without" 1.6, <it>p </it>= 0.05); but the "without" version received a better overall rating ("with" 3.5, "without" 3.8, <it>p </it>= 0.03). Groups did not differ in screening interest after viewing a decision aid or knowledge.</p> <p>Conclusion</p> <p>A decision aid with the explicit discussion of the option of deciding not to be screened appears to increase the impression that the program was not as strongly in favor of screening, but decreases the impression of clarity and resulted in a lower overall rating. We did not observe clinically important or statistically significant differences in interest in screening or knowledge.</p

Online Continual Learning on Sequences

Online continual learning (OCL) refers to the ability of a system to learn over time from a continuous stream of data without having to revisit previously encountered training samples. Learning continually in a single data pass is crucial for agents and robots operating in changing environments and required to acquire, fine-tune, and transfer increasingly complex representations from non-i.i.d. input distributions. Machine learning models that address OCL must alleviate \textit{catastrophic forgetting} in which hidden representations are disrupted or completely overwritten when learning from streams of novel input. In this chapter, we summarize and discuss recent deep learning models that address OCL on sequential input through the use (and combination) of synaptic regularization, structural plasticity, and experience replay. Different implementations of replay have been proposed that alleviate catastrophic forgetting in connectionists architectures via the re-occurrence of (latent representations of) input sequences and that functionally resemble mechanisms of hippocampal replay in the mammalian brain. Empirical evidence shows that architectures endowed with experience replay typically outperform architectures without in (online) incremental learning tasks.Comment: L. Oneto et al. (eds.), Recent Trends in Learning From Data, Studies in Computational Intelligence 89

An essential function for the ATR-Activation-Domain (AAD) of TopBP1 in mouse development and cellular senescence

ATR activation is dependent on temporal and spatial interactions with partner proteins. In the budding yeast model, three proteins – Dpb11TopBP1, Ddc1Rad9 and Dna2 - all interact with and activate Mec1ATR. Each contains an ATR activation domain (ADD) that interacts directly with the Mec1ATR:Ddc2ATRIP complex. Any of the Dpb11TopBP1, Ddc1Rad9 or Dna2 ADDs is sufficient to activate Mec1ATR in vitro. All three can also independently activate Mec1ATR in vivo: the checkpoint is lost only when all three AADs are absent. In metazoans, only TopBP1 has been identified as a direct ATR activator. Depletion-replacement approaches suggest the TopBP1-AAD is both sufficient and necessary for ATR activation. The physiological function of the TopBP1 AAD is, however, unknown. We created a knock-in point mutation (W1147R) that ablates mouse TopBP1-AAD function. TopBP1-W1147R is early embryonic lethal. To analyse TopBP1-W1147R cellular function in vivo, we silenced the wild type TopBP1 allele in heterozygous MEFs. AAD inactivation impaired cell proliferation, promoted premature senescence and compromised Chk1 signalling following UV irradiation. We also show enforced TopBP1 dimerization promotes ATR-dependent Chk1 phosphorylation. Our data suggest that, unlike the yeast models, the TopBP1-AAD is the major activator of ATR, sustaining cell proliferation and embryonic development

Off-Label Biologic Regimens in Psoriasis: A Systematic Review of Efficacy and Safety of Dose Escalation, Reduction, and Interrupted Biologic Therapy

Objectives: While off-label dosing of biologic treatments may be necessary in selected psoriasis patients, no systematic review exists to date that synthesizes the efficacy and safety of these off-label dosing regimens. The aim of this systematic review is to evaluate efficacy and safety of off-label dosing regimens (dose escalation, dose reduction, and interrupted treatment) with etanercept, adalimumab, infliximab, ustekinumab, and alefacept for psoriasis treatment

The impact of xerostomia on oral-health-related quality of life among younger adults

BACKGROUND: Recent research has suggested that chronic dry mouth affects the day-to-day lives of older people living in institutions. The condition has usually been considered to be a feature of old age, but recent work by our team produced the somewhat surprising finding that 10% of people in their early thirties are affected. This raises the issue of whether dry mouth is a trivial condition or a more substantial threat to quality of life among younger people. The objective of this study was to examine the association between xerostomia and oral-health-related quality of life among young adults while controlling for clinical oral health status and other potential confounding factors. METHODS: Cross-sectional analysis of data from a longstanding prospective observational study of a Dunedin (New Zealand) birth cohort: clinical dental examinations and questionnaires were used at age 32. The main measures were xerostomia (the subjective feeling of dry mouth, measured with a single question) and oral-health-related quality of life (OHRQoL) measured using the short-form Oral Health Impact Profile (OHIP-14). RESULTS: Of the 923 participants (48.9% female), one in ten were categorised as 'xerostomic', with no apparent gender difference. There was a strong association between xerostomia and OHRQoL (across all OHIP-14 domains) which persisted after multivariate analysis to control for clinical characteristics, gender, smoking status and personality characteristics (negative emotionality and positive emotionality). CONCLUSION: Xerostomia is not a trivial condition; it appears to have marked and consistent effects on sufferers' day-to-day lives

On opportunistic software reuse

The availability of open source assets for almost all imaginable domains has led the software industry toopportunistic design-an approach in which people develop new software systems in an ad hoc fashion by reusing and combining components that were not designed to be used together. In this paper we investigate this emerging approach. We demonstrate the approach with an industrial example in whichNode.jsmodules and various subsystems are used in an opportunistic way. Furthermore, to study opportunistic reuse as a phenomenon, we present the results of three contextual interviews and a survey with reuse practitioners to understand to what extent opportunistic reuse offers improvements over traditional systematic reuse approaches.Peer reviewe