Acetazolamide-based fungal chitinase inhibitors

Chitin is an essential structural component of the fungal cell wall. Chitinases are thought to be important for fungal cell wall remodelling, and inhibition of these enzymes has been proposed as a potential strategy for development of novel anti-fungals. The fungal pathogen Aspergillus fumigatus possesses two distinct multi-gene chitinase families. Here we explore acetazolamide as a chemical scaffold for the inhibition of an A. fumigatus ‘plant-type’ chitinase. A co-crystal structure of AfChiA1 with acetazolamide was used to guide synthesis and screening of acetazolamide analogues that yielded SAR in agreement with these structural data. Although acetazolamide and its analogues are weak inhibitors of the enzyme, they have a high ligand efficiency and as such are interesting leads for future inhibitor development

Gemini and Lowell observations of 67P/Churyumov−Gerasimenko during the <i>Rosetta</i> mission

We present observations of comet 67P/Churyumov−Gerasimenko acquired in support of the Rosetta mission. We obtained usable data on 68 nights from 2014 September until 2016 May, with data acquired regularly whenever the comet was observable. We collected an extensive set of near-IR J, H and Ks data throughout the apparition plus visible-light images in g', r', i' and z' when the comet was fainter. We also obtained broad-band R and narrow-band CN filter observations when the comet was brightest using telescopes at Lowell Observatory. The appearance was dominated by a central condensation and the tail until 2015 June. From 2015 August onwards, there were clear asymmetries in the coma, which enhancements revealed to be due to the presence of up to three features (i.e. jets). The features were similar in all broad-band filters; CN images did not show these features but were instead broadly enhanced in the southeastern hemisphere. Modelling using the parameters from Vincent et al. replicated the dust morphology reasonably well, indicating that the pole orientation and locations of active areas have been relatively unchanged over at least the last three apparitions. The dust production, as measured by A(0°)fρ peaked ∼30 d after perihelion and was consistent with predictions from previous apparitions. A(0°)fρ as a function of heliocentric distance was well fitted by a power law with slope −4.2 from 35 to 120 d post-perihelion. We detected photometric evidence of apparent outbursts on 2015 August 22 and 2015 September 19, although neither was discernible morphologically in this data set

Microarray gene expression profiling of osteoarthritic bone suggests altered bone remodelling, WNT and transforming growth factor-β/bone morphogenic protein signalling

Osteoarthritis (OA) is characterized by alterations to subchondral bone as well as articular cartilage. Changes to bone in OA have also been identified at sites distal to the affected joint, which include increased bone volume fraction and reduced bone mineralization. Altered bone remodelling has been proposed to underlie these bone changes in OA. To investigate the molecular basis for these changes, we performed microarray gene expression profiling of bone obtained at autopsy from individuals with no evidence of joint disease (control) and from individuals undergoing joint replacement surgery for either degenerative hip OA, or fractured neck of femur (osteoporosis [OP]). The OP sample set was included because an inverse association, with respect to bone density, has been observed between OA and the low bone density disease OP. Compugen human 19K-oligo microarray slides were used to compare the gene expression profiles of OA, control and OP bone samples. Four sets of samples were analyzed, comprising 10 OA-control female, 10 OA-control male, 10 OA-OP female and 9 OP-control female sample pairs. Print tip Lowess normalization and Bayesian statistical analyses were carried out using linear models for microarray analysis, which identified 150 differentially expressed genes in OA bone with t scores above 4. Twenty-five of these genes were then confirmed to be differentially expressed (P < 0.01) by real-time PCR analysis. A substantial number of the top-ranking differentially expressed genes identified in OA bone are known to play roles in osteoblasts, osteocytes and osteoclasts. Many of these genes are targets of either the WNT (wingless MMTV integration) signalling pathway (TWIST1, IBSP, S100A4, MMP25, RUNX2 and CD14) or the transforming growth factor (TGF)-β/bone morphogenic protein (BMP) signalling pathway (ADAMTS4, ADM, MEPE, GADD45B, COL4A1 and FST). Other differentially expressed genes included WNT (WNT5B, NHERF1, CTNNB1 and PTEN) and TGF-β/BMP (TGFB1, SMAD3, BMP5 and INHBA) signalling pathway component or modulating genes. In addition a subset of genes involved in osteoclast function (GSN, PTK9, VCAM1, ITGB2, ANXA2, GRN, PDE4A and FOXP1) was identified as being differentially expressed in OA bone between females and males. Altered expression of these sets of genes suggests altered bone remodelling and may in part explain the sex disparity observed in OA

Pharmacist-led management of chronic pain in primary care:results from a randomised controlled exploratory trial

To compare the effectiveness of pharmacist medication review, with or without pharmacist prescribing, with standard care, for patients with chronic pain

MIT SchMUSE: Class-Based Remote Delegation in a Capricious Distributed Environment

MIT SchMUSE (pronounced "shmooz") is a concurrent, distributed, delegation-based object-oriented interactive environment with persistent storage. It is designed to run in a "capricious" network environment, where servers can migrate from site to site and can regularly become unavailable. Our design introduces a new form of unique identifiers called "globally unique tickets" that provide globally unique time/space stamps for objects and classes without being location specific. Object location is achieved by a distributed hierarchical lazy lookup mechanism that we call "realm resolution." We also introduce a novel mechanism called "message deferral" for enhanced reliability in the face of remote delegation. We conclude with a comparison to related work and a projection of future work on MIT SchMUSE

Implementing a design thinking approach to de-risk the digitalisation of manufacturing SMEs

Industry 4.0 (I4.0) has proposed a significant shift in the way companies approach manufacturing. However, this new paradigm is not without faults. The integration of processes and equipment (‘digitalisation’) can be prohibitively expensive or too technically complex for small-to-medium enterprises (SMEs) with limited resources and technical expertise. Another barrier to digitalisation lies in the ambiguity of not knowing what precise practices to adopt to improve productivity. Although these challenges have been identified in the literature, there is still little evidence on how to tackle them. Thus, we explore how design thinking can help overcome these challenges, given that it has been used in many organisations and disciplines to deal with complex and ambiguous problems. We do so by investigating the research question ‘How can designers and design thinking processes assist manufacturing SMEs’ digitalisation?’ We address this research question by presenting a case study of a university–industry collaboration where the authors utilised a design-thinking process to select and implement technologies to capture, process and analyse data for an Australian medical device manufacturer. By reflecting on the case study, we identified the user-centeredness of design thinking as crucial in selecting technologies for implementation that prioritised usability and brought value to all stakeholders. Furthermore, iterative prototyping was critical to scale up the required expertise and deliver a successful sustainable solution without investing vast resources. Our work suggests that designers and design thinking have the potential to help de-risk digitalisation. Finally, we suggest a framework that may assist in guiding other SMEs approaching digitalisation and provide a starting point for further design thinking research in this area

Cryptic marine barriers to gene flow in a vulnerable coastal species, the dugong (Dugong dugon)

Despite the lack of obvious physical barriers and their ability to travel significant distances, many marine mammals exhibit substantial population structuring over relatively short geographical distances. The dugong (Dugong dugon), the only extant representative of family Dugongidae, is listed as Vulnerable to Extinction globally. We investigated the genetic population structure of dugongs in the shallow coastal waters along >2,000 km of the eastern Queensland coast, including the Great Barrier Reef region. Microsatellite genotypes for 22 loci in 293 dugongs, SNP genotypes based on 10,690 loci in 43 dugongs, and 410 bp mitochondrial control-region sequences from 639 dugongs were analyzed. Clustering analysis techniques consistently identified an abrupt genetic break in the Whitsunday Islands region (20.3°S), which interrupts an overall pattern of isolation-by-distance. Geographic distance was relatively more important than sea-surface temperature and seagrass distribution in explaining pairwise microsatellite genetic distances. The cause of reduced dispersal across this region is unknown but might relate to an unusual tidal and current mix, termed the “sticky-water” effect, and/or a break in the geographical distribution of off-shore seagrass meadows. The genetic structure suggests distinct breeding units north and south of the Whitsunday Islands region for consideration in further developing management plans for Queensland dugongs

Full-text information retrieval: Further analysis and clarification

In 1985, an article by Blair and Maron described a detailed evaluation of the effectiveness of an operational full text retrieval system used to support the defense of a large corporate lawsuit. The following year Salton published an article which called into question the conclusions of the 1985 study. The following article briefly reviews the initial study, replies to the objections raised by the second article, and clarifies several confusions and misunderstandings about the 1985 study.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28883/1/0000719.pd