Refactorings of Design Defects using Relational Concept Analysis

Software engineers often need to identify and correct design defects, ıe} recurring design problems that hinder development and maintenance\ud by making programs harder to comprehend and--or evolve. While detection\ud of design defects is an actively researched area, their correction---mainly\ud a manual and time-consuming activity --- is yet to be extensively\ud investigated for automation. In this paper, we propose an automated\ud approach for suggesting defect-correcting refactorings using relational\ud concept analysis (RCA). The added value of RCA consists in exploiting\ud the links between formal objects which abound in a software re-engineering\ud context. We validated our approach on instances of the <span class='textit'></span>Blob\ud design defect taken from four different open-source programs

Performance analysis of packet layer FEC codes and interleaving in FSO channels

The combination of forward-error-correction (FEC) and interleaving can be used to improve free-space optical (FSO) communication systems. Recent research has optimized the codeword length and interleaving depth under the assumption of a fixed buffering size, however, how the buffering size influences the system performance remains unsolved. This paper models the system performance as a function of buffering size and FEC recovery threshold, which allows system designers to determine optimum parameters in consideration of the overhead. The modelling is based on statistics of temporal features of correct data reception and burst error length through the measurement of the channel good time and outage time. The experimental results show good coherence with the theoretical values. This method can also be applied in other channels if a Continuous-Time-Markov-Chain (CTMC) model of the channel can be derive

Core Alzheimer’s disease cerebrospinal fluid biomarker assays are not affected by aspiration or gravity drip extraction methods

Background CSF biomarkers are well-established for routine clinical use, yet a paucity of comparative assessment exists regarding CSF extraction methods during lumbar puncture. Here, we compare in detail biomarker profiles in CSF extracted using either gravity drip or aspiration. Methods Biomarkers for β-amyloidopathy (Aβ1–42, Aβ1–40), tauopathy (total tau), or synapse pathology (BACE1, Neurogranin Trunc-p75, α-synuclein) were assessed between gravity or aspiration extraction methods in a sub-population of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study (cognitively normal, N = 36; mild cognitive impairment, N = 8; Alzheimer’s disease, N = 6). Results High biomarker concordance between extraction methods was seen (concordance correlation > 0.85). Passing Bablock regression defined low beta coefficients indicating high scalability. Conclusions Levels of these commonly assessed CSF biomarkers are not influenced by extraction method. Results of this study should be incorporated into new consensus guidelines for CSF collection, storage, and analysis of biomarkers

Engineering Pathways in Central Carbon Metabolism Help to Increase Glycan Production and Improve N-Type Glycosylation of Recombinant Proteins in E. coli.

Escherichia coli strains have been modified in a variety of ways to enhance the production of different recombinant proteins, targeting membrane protein expression, proteins with disulphide bonds, and more recently, proteins which require N-linked glycosylation. The addition of glycans to proteins remains a relatively inefficient process and here we aimed to combine genetic modifications within central carbon metabolic pathways in order to increase glycan precursor pools, prior to transfer onto polypeptide backbones. Using a lectin screen that detects cell surface representation of glycans, together with Western blot analyses using an O-antigen ligase mutant strain, the enhanced uptake and phosphorylation of sugars (ptsA) from the media combined with conservation of carbon through the glyoxylate shunt (icl) improved glycosylation efficiency of a bacterial protein AcrA by 69% and over 100% in an engineered human protein IFN-α2b. Unexpectedly, overexpression of a gene involved in the production of DXP from pyruvate (dxs), which was previously seen to have a positive impact on glycosylation, was detrimental to process efficiency and the possible reasons for this are discussed

Convexity in partial cubes: the hull number

We prove that the combinatorial optimization problem of determining the hull number of a partial cube is NP-complete. This makes partial cubes the minimal graph class for which NP-completeness of this problem is known and improves some earlier results in the literature. On the other hand we provide a polynomial-time algorithm to determine the hull number of planar partial cube quadrangulations. Instances of the hull number problem for partial cubes described include poset dimension and hitting sets for interiors of curves in the plane. To obtain the above results, we investigate convexity in partial cubes and characterize these graphs in terms of their lattice of convex subgraphs, improving a theorem of Handa. Furthermore we provide a topological representation theorem for planar partial cubes, generalizing a result of Fukuda and Handa about rank three oriented matroids.Comment: 19 pages, 4 figure

Plasma Aβ42/40 ratio, p‐tau181, GFAP, and NfL across the Alzheimer's disease continuum: A cross‐sectional and longitudinal study in the AIBL cohort

Introduction Plasma amyloid beta (Aβ)1-42/Aβ1-40 ratio, phosphorylated-tau181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) are putative blood biomarkers for Alzheimer's disease (AD). However, head-to-head cross-sectional and longitudinal comparisons of the aforementioned biomarkers across the AD continuum are lacking. Methods Plasma Aβ1-42, Aβ1-40, p-tau181, GFAP, and NfL were measured utilizing the Single Molecule Array (Simoa) platform and compared cross-sectionally across the AD continuum, wherein Aβ-PET (positron emission tomography)–negative cognitively unimpaired (CU Aβ−, n = 81) and mild cognitive impairment (MCI Aβ−, n = 26) participants were compared with Aβ-PET–positive participants across the AD continuum (CU Aβ+, n = 39; MCI Aβ+, n = 33; AD Aβ+, n = 46) from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) cohort. Longitudinal plasma biomarker changes were also assessed in MCI (n = 27) and AD (n = 29) participants compared with CU (n = 120) participants. In addition, associations between baseline plasma biomarker levels and prospective cognitive decline and Aβ-PET load were assessed over a 7 to 10-year duration. Results Lower plasma Aβ1-42/Aβ1-40 ratio and elevated p-tau181 and GFAP were observed in CU Aβ+, MCI Aβ+, and AD Aβ+, whereas elevated plasma NfL was observed in MCI Aβ+ and AD Aβ+, compared with CU Aβ− and MCI Aβ−. Among the aforementioned plasma biomarkers, for models with and without AD risk factors (age, sex, and apolipoprotein E (APOE) ε4 carrier status), p-tau181 performed equivalent to or better than other biomarkers in predicting a brain Aβ−/+ status across the AD continuum. However, for models with and without the AD risk factors, a biomarker panel of Aβ1-42/Aβ1-40, p-tau181, and GFAP performed equivalent to or better than any of the biomarkers alone in predicting brain Aβ−/+ status across the AD continuum. Longitudinally, plasma Aβ1-42/Aβ1-40, p-tau181, and GFAP were altered in MCI compared with CU, and plasma GFAP and NfL were altered in AD compared with CU. In addition, lower plasma Aβ1-42/Aβ1-40 and higher p-tau181, GFAP, and NfL were associated with prospective cognitive decline and lower plasma Aβ1-42/Aβ1-40, and higher p-tau181 and GFAP were associated with increased Aβ-PET load prospectively. Discussion These findings suggest that plasma biomarkers are altered cross-sectionally and longitudinally, along the AD continuum, and are prospectively associated with cognitive decline and brain Aβ-PET load. In addition, although p-tau181 performed equivalent to or better than other biomarkers in predicting an Aβ−/+ status across the AD continuum, a panel of biomarkers may have superior Aβ−/+ status predictive capability across the AD continuum

Systemic perturbations of the kynurenine pathway precede progression to dementia independently of amyloid-β

Increasing evidence suggests that kynurenine pathway (KP) dyshomeostasis may promote disease progression in dementia. Studies in Alzheimer's disease (AD) patients confirm KP dyshomeostasis in plasma and cerebrospinal fluid (CSF) which correlates with amyloid-β and tau pathology. Herein, we performed the first comprehensive study assessing baseline levels of KP metabolites in participants enrolling in the Australian Imaging Biomarkers Flagship Study of Aging. Our purpose was to test the hypothesis that changes in KP metabolites may be biomarkers of dementia processes that are largely silent. We used a cross-sectional analytical approach to assess non-progressors (N = 73); cognitively normal (CN) or mild cognitive impairment (MCI) participants at baseline and throughout the study, and progressors (N = 166); CN or MCI at baseline but progressing to either MCI or AD during the study. Significant KP changes in progressors included increased 3-hydroxyanthranilic acid (3-HAA) and 3-hydroxyanthranilic acid/anthranilic acid (3-HAA/AA) ratio, the latter having the largest effect on the odds of an individual being a progressor (OR 35.3; 95% CI between 14 and 104). 3-HAA levels were hence surprisingly bi-phasic, high in progressors but low in non-progressors or participants who had already transitioned to MCI or dementia. This is a new, unexpected and interesting result, as most studies of the KP in neurodegenerative disease show reduced 3-HAA/AA ratio after diagnosis. The neuroprotective metabolite picolinic acid was also significantly decreased while the neurotoxic metabolite 3-hydroxykynurenine increased in progressors. These results were significant even after adjustment for confounders. Considering the magnitude of the OR to predict change in cognition, it is important that these findings are replicated in other populations. Independent validation of our findings may confirm the utility of 3-HAA/AA ratio to predict change in cognition leading to dementia in clinical settings

Plasma p217+tau versus NAV4694 amyloid and MK6240 tau PET across the Alzheimer's continuum

Introduction We evaluated a new Simoa plasma assay for phosphorylated tau (P-tau) at aa217 enhanced by additional p-tau sites (p217+tau). Methods Plasma p217+tau levels were compared to 18F-NAV4694 amyloid beta (Aβ) positron emission tomography (PET) and 18F-MK6240 tau PET in 174 cognitively impaired (CI) and 223 cognitively unimpaired (CU) participants. Results Compared to Aβ− CU, the plasma levels of p217+tau increased 2-fold in Aβ+ CU and 3.5-fold in Aβ+ CI. In Aβ− the p217+tau levels did not differ significantly between CU and CI. P217+tau correlated with Aβ centiloids P = .67 (CI, P = .64; CU, P = .45) and tau SUVRMT P = .63 (CI, P = .69; CU, P = .34). Area under curve (AUC) for Alzheimer's disease (AD) dementia versus Aβ− CU was 0.94, for AD dementia versus other dementia was 0.93, for Aβ+ versus Aβ− PET was 0.89, and for tau+ versus tau− PET was 0.89. Discussion Plasma p217+tau levels elevate early in the AD continuum and correlate well with Aβ and tau PET

Antibacterial Resistance Leadership Group 2.0: Back to Business

In December 2019, the Antibacterial Resistance Leadership Group (ARLG) was awarded funding for another 7-year cycle to support a clinical research network on antibacterial resistance. ARLG 2.0 has 3 overarching research priorities: infections caused by antibiotic-resistant (AR) gram-negative bacteria, infections caused by AR gram-positive bacteria, and diagnostic tests to optimize use of antibiotics. To support the next generation of AR researchers, the ARLG offers 3 mentoring opportunities: the ARLG Fellowship, Early Stage Investigator seed grants, and the Trialists in Training Program. The purpose of this article is to update the scientific community on the progress made in the original funding period and to encourage submission of clinical research that addresses 1 or more of the research priority areas of ARLG 2.0

All-particle cosmic ray energy spectrum measured with 26 IceTop stations

We report on a measurement of the cosmic ray energy spectrum with the IceTop air shower array, the surface component of the IceCube Neutrino Observatory at the South Pole. The data used in this analysis were taken between June and October, 2007, with 26 surface stations operational at that time, corresponding to about one third of the final array. The fiducial area used in this analysis was 0.122 km^2. The analysis investigated the energy spectrum from 1 to 100 PeV measured for three different zenith angle ranges between 0{\deg} and 46{\deg}. Because of the isotropy of cosmic rays in this energy range the spectra from all zenith angle intervals have to agree. The cosmic-ray energy spectrum was determined under different assumptions on the primary mass composition. Good agreement of spectra in the three zenith angle ranges was found for the assumption of pure proton and a simple two-component model. For zenith angles {\theta} < 30{\deg}, where the mass dependence is smallest, the knee in the cosmic ray energy spectrum was observed between 3.5 and 4.32 PeV, depending on composition assumption. Spectral indices above the knee range from -3.08 to -3.11 depending on primary mass composition assumption. Moreover, an indication of a flattening of the spectrum above 22 PeV were observed.Comment: 38 pages, 17 figure