Inhibitors of a Na⁺-pumping NADH-ubiquinone oxidoreductase play multiple roles to block enzyme function

The Na⁺-pumping NADH-ubiquinone (UQ) oxidoreductase (Na⁺-NQR) is present in the respiratory chain of many pathogenic bacteria and is thought to be a promising antibiotic target. Whereas many details of Na⁺-NQR structure and function are known, the mechanisms of action of potent inhibitors is not well-understood; elucidating the mechanisms would not only advance drug design strategies but might also provide insights on a terminal electron transfer from riboflavin to UQ. To this end, we performed photoaffinity labeling experiments using photoreactive derivatives of two known inhibitors, aurachin and korormicin, on isolated Vibrio cholerae Na⁺-NQR. The inhibitors labeled the cytoplasmic surface domain of the NqrB subunit including a protruding N-terminal stretch, which may be critical to regulate the UQ reaction in the adjacent NqrA subunit. The labeling was blocked by short-chain UQs such as ubiquinone-2. The photolabile group (2-aryl-5-carboxytetrazole (ACT)) of these inhibitors reacts with nucleophilic amino acids, so we tested mutations of nucleophilic residues in the labeled region of NqrB, such as Asp49 and Asp52 (to Ala), and observed moderate decreases in labeling yields, suggesting that these residues are involved in the interaction with ACT. We conclude that the inhibitors interfere with the UQ reaction in two ways: the first is blocking structural rearrangements at the cytoplasmic interface between NqrA and NqrB, and the second is the direct obstruction of UQ binding at this interfacial area. Unusual competitive behavior between the photoreactive inhibitors and various competitors corroborates our previous proposition that there may be two inhibitor binding sites in Na⁺-NQR

LitMiner: integration of library services within a bio-informatics application

BACKGROUND: This paper examines how the adoption of a subject-specific library service has changed the way in which its users interact with a digital library. The LitMiner text-analysis application was developed to enable biologists to explore gene relationships in the published literature. The application features a suite of interfaces that enable users to search PubMed as well as local databases, to view document abstracts, to filter terms, to select gene name aliases, and to visualize the co-occurrences of genes in the literature. At each of these stages, LitMiner offers the functionality of a digital library. Documents that are accessible online are identified by an icon. Users can also order documents from their institution's library collection from within the application. In so doing, LitMiner aims to integrate digital library services into the research process of its users. METHODS: Case study RESULTS: This integration of digital library services into the research process of biologists results in increased access to the published literature. CONCLUSION: In order to make better use of their collections, digital libraries should customize their services to suit the research needs of their patrons

Safety and efficacy of alternative alglucosidase alfa regimens in Pompe disease

AbstractEmerging phenotypes in long-term survivors with Pompe disease on standard enzyme replacement therapy (ERT) (alglucosidase alfa 20 mg/kg/2 weeks) can include patients with worsening motor function. Whether higher doses of ERT improve skeletal function in these patients has not been systematically studied. This exploratory, randomized, open-label, 52-week study examined the safety and efficacy of 2 ERT regimens of alglucosidase alfa (20 mg/kg/week or 40 mg/kg/2 weeks) in 13 patients with Pompe disease and clinical decline or a lack of improvement on standard ERT: late-onset (n = 4), infantile-onset (n = 9). Cross-reactive immunologic material assay-negative patients were excluded. Eleven of 13 patients completed the study. Trends for improvement were seen in total gross motor function, but not mobility; however, 6 (late-onset, 2; infantile-onset, 4) of 11 patients (55%) who met the entry criteria of motor decline (late-onset, 4; infantile-onset, 7) showed improvement in motor and/or mobility skills. No between-regimen differences in efficacy emerged. Two case studies highlight the benefits of increased ERT dose in patients with Pompe disease experiencing clinical decline. Both alternative regimens were generally well tolerated. This study was limited by the small sample size, which is not uncommon for small clinical studies of rare diseases. Additionally, the study did not include direct assessment of muscle pathology, which may have identified potential causes of decreased response to ERT. Results were inconclusive but suggest that increased ERT dose may be beneficial in some patients with Pompe disease experiencing motor decline. Controlled studies are needed to clarify the benefits and risks of this strategy

Population Health Solutions for Assessing Cognitive Impairment in Geriatric Patients.

In December 2017, the National Academy of Neuropsychology convened an interorganizational Summit on Population Health Solutions for Assessing Cognitive Impairment in Geriatric Patients in Denver, Colorado. The Summit brought together representatives of a broad range of stakeholders invested in the care of older adults to focus on the topic of cognitive health and aging. Summit participants specifically examined questions of who should be screened for cognitive impairment and how they should be screened in medical settings. This is important in the context of an acute illness given that the presence of cognitive impairment can have significant implications for care and for the management of concomitant diseases as well as pose a major risk factor for dementia. Participants arrived at general principles to guide future screening approaches in medical populations and identified knowledge gaps to direct future research. Key learning points of the summit included: recognizing the importance of educating patients and healthcare providers about the value of assessing current and baseline cognition;emphasizing that any screening tool must be appropriately normalized and validated in the population in which it is used to obtain accurate information, including considerations of language, cultural factors, and education; andrecognizing the great potential, with appropriate caveats, of electronic health records to augment cognitive screening and tracking of changes in cognitive health over time

Making sense of theory construction: Metaphor and disciplined imagination

This article draws upon Karl Weick’s insights into the nature of theorizing, and extends and refines his conception of theory construction as ‘disciplined imagination’. An essential ingredient in Weick’s ‘disciplined imagination’ involves his assertion that thought trials and theoretical representations typically involve a transfer from one epistemic sphere to another through the creative use of metaphor. The article follows up on this point and draws out how metaphor works, how processes of metaphorical imagination partake in theory construction, and how insightful metaphors and the theoretical representations that result from them can be selected. The paper also includes a discussion of metaphors-in-use (organizational improvisation as jazz and organizational behavior as collective mind) which Weick proposed in his own writings. The whole purpose of this exercise is to theoretically augment and ground the concept of ‘disciplined imagination’, and in particular to refine the nature of thought trials and selection within it. In doing so, we also aim to provide pointers for the use of metaphorical imagination in the process of theory construction

Diverse sediment microbiota shape methane emission temperature sensitivity in Arctic lakes

Northern post-glacial lakes are significant, increasing sources of atmospheric carbon through ebullition (bubbling) of microbially-produced methane (CH4) from sediments. Ebullitive CH4 flux correlates strongly with temperature, reflecting that solar radiation drives emissions. However, here we show that the slope of the temperature-CH4 flux relationship differs spatially across two post-glacial lakes in Sweden. We compared these CH4 emission patterns with sediment microbial (metagenomic and amplicon), isotopic, and geochemical data. The temperature-associated increase in CH4 emissions was greater in lake middles—where methanogens were more abundant—than edges, and sediment communities were distinct between edges and middles. Microbial abundances, including those of CH4-cycling microorganisms and syntrophs, were predictive of porewater CH4 concentrations. Results suggest that deeper lake regions, which currently emit less CH4 than shallower edges, could add substantially to CH4 emissions in a warmer Arctic and that CH4 emission predictions may be improved by accounting for spatial variations in sediment microbiota

Science and Technology Issues in the 115th Congress

Science and technology (S&T) have a pervasive influence over a wide range of issues confronting the nation. Public and private research and development spur scientific and technological advancement. Such advances can drive economic growth, help address national priorities, and improve health and quality of life. The constantly changing nature and ubiquity of science and technology frequently create public policy issues of congressional interest. The federal government supports scientific and technological advancement directly by funding and performing research and development and indirectly by creating and maintaining policies that encourage private sector efforts. Additionally, the federal government establishes and enforces regulatory frameworks governing many aspects of S&T activities. This report briefly outlines an array of science and technology policy issues that may come before the 115th Congress. Given the rapid pace of S&T advancement and its importance in many diverse public policy issues, S&T-related issues not discussed in this report may come before the 115th Congress. The selected issues are grouped into 9 categories: - Overarching S&T Policy Issues, - Agriculture, - Biomedical Research and Development, - Defense, - Energy, - Environment and Natural Resources, - Homeland Security, - Information Technology, - Physical and Material Sciences, and - Space. Each of these categories includes concise analysis of multiple policy issues. The material presented in this report should be viewed as illustrative rather than comprehensive. Each section identifies CRS reports, when available, and the appropriate CRS experts to contact for further information and analysis

The carbon-rich type Ic supernova 2016adj in the iconic dust lane of Centaurus A: signatures of interaction with circumstellar hydrogen?

We present a comprehensive data set of supernova (SN) 2016adj located within the central dust lane of Centaurus A. SN 2016adj is significantly reddened and after correcting the peak apparent $B$-band magnitude ($m_B = 17.48\pm0.05$) for Milky Way reddening and our inferred host-galaxy reddening parameters (i.e., $R_{V}^{host} = 5.7\pm0.7$ and $A_{V}^{host} = 6.3\pm0.2$), we estimate it reached a peak absolute magnitude of $M_B \sim -18$. Detailed inspection of the optical/NIR spectroscopic time-series reveals a carbon-rich SN Ic and not a SN Ib/IIb as previously suggested in the literature. The NIR spectra shows prevalent carbon-monoxide formation occurring already by +41 days past $B$-band maximum, which is $\approx 11$ days earlier than previously reported in the literature for this object. Interestingly around two months past maximum, the NIR spectrum of SN~2016adj begins to exhibit H features, with a +97~d medium resolution spectrum revealing both Paschen and Bracket lines with absorption minima of $\sim 2000$ km/s, full-width-half-maximum emission velocities of $\sim 1000$ km/s, and emission line ratios consistent with a dense emission region. We speculate these attributes are due to circumstellar interaction (CSI) between the rapidly expanding SN ejecta and a H-rich shell of material formed during the pre-SN phase. A bolometric light curve is constructed and a semi-analytical model fit suggests the supernova synthesized 0.5 solar masses of $^{56}$Ni and ejected 4.2 solar masses of material, though these values should be approached with caution given the large uncertainties associated with the adopted reddening parameters, possible CSI contamination, and known light echo emission. Finally, inspection of Hubble Space Telescope archival data yielded no progenitor detection.Comment: Submitted to A&A, comments are welcom