Hydrogenases display a wide range of catalytic rates and biases in reversible hydrogen gas oxidation catalysis. The interactions of the iron–sulfur-containing catalytic site with the local protein ...environment are thought to contribute to differences in catalytic reactivity, but this has not been demonstrated. The microbe Clostridium pasteurianum produces three FeFe-hydrogenases that differ in “catalytic bias” by exerting a disproportionate rate acceleration in one direction or the other that spans a remarkable 6 orders of magnitude. The combination of high-resolution structural work, biochemical analyses, and computational modeling indicates that protein secondary interactions directly influence the relative stabilization/destabilization of different oxidation states of the active site metal cluster. This selective stabilization or destabilization of oxidation states can preferentially promote hydrogen oxidation or proton reduction and represents a simple yet elegant model by which a protein catalytic site can confer catalytic bias.
Online interaction is now a regular part of daily life for a demographically diverse population of hundreds of millions of people worldwide. These interactions generate fine-grained time-stamped ...records of human behavior and social interaction at the level of individual events, yet are global in scale, allowing researchers to address fundamental questions about social identity, status, conflict, cooperation, collective action, and diffusion, both by using observational data and by conducting in vivo field experiments. This unprecedented opportunity comes with a number of methodological challenges, including generalizing observations to the offline world, protecting individual privacy, and solving the logistical challenges posed by "big data" and web-based experiments. We review current advances in online social research and critically assess the theoretical and methodological opportunities and limitations.
Metal ion cofactors afford proteins virtually unlimited catalytic potential, enable electron transfer reactions and have a great impact on protein stability. Consequently, metalloproteins have key ...roles in most biological processes, including respiration (iron and copper), photosynthesis (manganese) and drug metabolism (iron). Yet, predicting from genome sequence the numbers and types of metal an organism assimilates from its environment or uses in its metalloproteome is currently impossible because metal coordination sites are diverse and poorly recognized. We present here a robust, metal-based approach to determine all metals an organism assimilates and identify its metalloproteins on a genome-wide scale. This shifts the focus from classical protein-based purification to metal-based identification and purification by liquid chromatography, high-throughput tandem mass spectrometry (HT-MS/MS) and inductively coupled plasma mass spectrometry (ICP-MS) to characterize cytoplasmic metalloproteins from an exemplary microorganism (Pyrococcus furiosus). Of 343 metal peaks in chromatography fractions, 158 did not match any predicted metalloprotein. Unassigned peaks included metals known to be used (cobalt, iron, nickel, tungsten and zinc; 83 peaks) plus metals the organism was not thought to assimilate (lead, manganese, molybdenum, uranium and vanadium; 75 peaks). Purification of eight of 158 unexpected metal peaks yielded four novel nickel- and molybdenum-containing proteins, whereas four purified proteins contained sub-stoichiometric amounts of misincorporated lead and uranium. Analyses of two additional microorganisms (Escherichia coli and Sulfolobus solfataricus) revealed species-specific assimilation of yet more unexpected metals. Metalloproteomes are therefore much more extensive and diverse than previously recognized, and promise to provide key insights for cell biology, microbial growth and toxicity mechanisms.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In 2012, the US Preventive Services Task Force (USPSTF) discouraged prostate-specific antigen (PSA) -based prostate cancer screening. Previous USPSTF recommendations did not appreciably alter ...prostate cancer screening. Therefore, we designed a trend analysis to determine the population-based impact of the 2012 recommendation.
The nationally representative National Health Interview Survey was used to estimate the proportion of men age 40 years and older who saw a physician and were screened for prostate cancer in 2013. An externally validated 9-year mortality index was used to analyze screening rates based on remaining life expectancy. Screening rates from 2005, 2010, and 2013 were compared using logistic regression.
PSA-based screening did not significantly change from 2010 to 2013 among 40- to 49-year-old men (from 12.5% to 11.2%; P = .4). Screening rates significantly declined in men age 50 to 59 years (from 33.2% to 24.8%; P < .01), age 60 to 74 years (from 51.2% to 43.6%; P < .01), and age 75 years or older (from 43.9% to 37.1%; P = .03). A large percentage of men were screened for prostate cancer despite a high risk (> 52%) of 9-year mortality, including approximately one third of men older than age 75 years. Approximately 1.4 million men age 65 years or older with a high risk (> 52%) of 9-year mortality were screened in 2013.
Prostate cancer screening significantly declined among men older than age 50 years after the 2012 USPSTF guideline discouraging PSA-based screening. A significant proportion of men continue to be screened despite a high risk of 9-year mortality, including one third of men age 75 years and older.
We identified individual-level diurnal and seasonal mood rhythms in cultures across the globe, using data from millions of public Twitter messages. We found that individuals awaken in a good mood ...that deteriorates as the day progresses—which is consistent with the effects of sleep and circadian rhythm—and that seasonal change in baseline positive affect varies with change in daylength. People are happier on weekends, but the morning peak in positive affect is delayed by 2 hours, which suggests that people awaken later on weekends.
Patterns of daily human activity are controlled by an intrinsic circadian clock that promotes ∼24 hr rhythms in many behavioral and physiological processes. This system is altered in delayed sleep ...phase disorder (DSPD), a common form of insomnia in which sleep episodes are shifted to later times misaligned with the societal norm. Here, we report a hereditary form of DSPD associated with a dominant coding variation in the core circadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadian activator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. The allele has a frequency of up to 0.6%, and reverse phenotyping of unrelated families corroborates late and/or fragmented sleep patterns in carriers, suggesting that it affects sleep behavior in a sizeable portion of the human population.
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•A human subject with DSPD with a variation in CRY1 has altered circadian rhythms•Proband kindred and unrelated carrier families display aberrant sleep patterns•The allele alters circadian molecular rhythms•The genetic variation enhances CRY1 function as a transcriptional inhibitor
A variation in the human circadian clock gene CRY1 is associated with a familial form of delayed sleep phase disorder, providing genetic underpinnings for “night owls.”
Instruction in English is a priority around the globe, but instructional methodologies have not always kept pace with the changing needs of students. To explore the benefits of the flipped classroom ...model for learners of English as a Foreign Language, the researchers used flipped learning and Wen's Output-driven/Input-enabled model to design a holistic oral training course that included extensive online written and verbal communication for the learning of a wide range of English idioms. The participants were 48 sophomore English majors in two required English oral training classes. A within-subjects research design exposed all participants to learning English idioms by flipped learning, using the LINE smartphone app, and by conventional instruction. A mixed research method was employed, using multiple sources of data collection, including pre- and post-tests on idioms, two questionnaires ("Perception of Flipped Learning Experience" and "Technology Acceptance Model"), the teachers' in-class observations, and semi-structured focus-group interviews. The results revealed that the theory-based flipped instruction using online written and oral interaction not only enhanced the participants' motivation, making them more active in using idioms in class, but also significantly improved their idiomatic knowledge, indicating that the flipped learning was successful in achieving the instructional goals of the class. The authors present insights into the impact of theory-based flipped learning on motivation and idiomatic acquisition; student impressions of the online platform used, LINE; and offer recommendations for practice.
Through engagement with a range of recent publications, this article offers a mini-ethnography of wonder discourses in the anthropology of ontology, leading to a rethink of the concept of religion. ...It has sometimes been suggested that science and religion are antithetical orientations to the experience of wonder: whereas science seeks to banish wonder by replacing it with knowledge, religion remains open to wonder in the face of the unknowable. With this criterion of difference in view, this article identifies certain trends in the anthropology of ontology that appear to enjoin and pursue open-ended wonder in ways that might be read as constituting anthropology as religious science. This coincidence of supposed opposites recommends, I conclude, a relational account of religion. A partir d'une lecture de plusieurs publications récentes, le présent article présente une mini-ethnographie des discours sur l'émerveillement dans l'anthropologie de l'ontologie qui conduit à repenser le concept de religion. On a parfois suggéré que la science et la religion étaient des approches antithétiques de l'expérience de l'émerveillement : alors que la science cherche à bannir l'émerveillement en le remplaçant par le savoir, la religion reste ouverte à l'émerveillement face à l'inconnaissable. Compte tenu de cette différence, l'article identifie certaines tendances dans l'anthropologie de l'ontologie qui semblent susciter et rechercher un émerveillement en forme de questionnement ouvert, d'une manière qui pourrait, selon son interprétation, instituer l'anthropologie comme une science religieuse. En conclusion, cette coïncidence de contraires supposés milite pour que soit fait un compte-rendu de la religion sous un angle relationnel.
Next-generation DNA sequencing promises to revolutionize clinical medicine and basic research. However, while this technology has the capacity to generate hundreds of billions of nucleotides of DNA ...sequence in a single experiment, the error rate of ∼1% results in hundreds of millions of sequencing mistakes. These scattered errors can be tolerated in some applications but become extremely problematic when “deep sequencing” genetically heterogeneous mixtures, such as tumors or mixed microbial populations. To overcome limitations in sequencing accuracy, we have developed a method termed Duplex Sequencing. This approach greatly reduces errors by independently tagging and sequencing each of the two strands of a DNA duplex. As the two strands are complementary, true mutations are found at the same position in both strands. In contrast, PCR or sequencing errors result in mutations in only one strand and can thus be discounted as technical error. We determine that Duplex Sequencing has a theoretical background error rate of less than one artifactual mutation per billion nucleotides sequenced. In addition, we establish that detection of mutations present in only one of the two strands of duplex DNA can be used to identify sites of DNA damage. We apply the method to directly assess the frequency and pattern of random mutations in mitochondrial DNA from human cells.
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