Molecular features of lipoprotein CD0873 - a potential vaccine against the human pathogen Clostridioides difficile

This is the final version. Available on open access from the American Society for Biochemistry and Molecular Biology via the DOI in this recordClostridioides difficile is the primary cause of antibiotic-associated diarrhoea and colitis, a healthcare-associated intestinal disease resulting in a significant fatality rate. Colonization of the gut is critical for C. difficile pathogenesis, and the bacterial molecules essential for efficient colonization therefore offer great potential as vaccine candidates. Here we present findings demonstrating that the C. difficile immunogenic lipoprotein CD0873 plays a critical role in pathogen success in vivo. We found that in a dixenic colonization model, a CD0873-positive strain of C. difficile significantly outcompeted a CD0873-negative strain. Immunization of mice with recombinant CD0873 prevented long-term gut colonization and was correlated with a strong secretory IgA immune response. We further present high-resolution crystal structures of CD0873, at 1.80-2.50 Å resolutions, offering a first view of the ligand-binding pocket of CD0873 and provide evidence that this lipoprotein adhesin is part of a tyrosine import system, an amino acid key in C. difficile infection. These findings suggest that CD0873 could serve as a effective component in a vaccine against C. difficile

Multiple generation of Bengali static signatures

Handwritten signature datasets are really necessary for the purpose of developing and training automatic signature verification systems. It is desired that all samples in a signature dataset should exhibit both inter-personal and intra-personal variability. A possibility to model this reality seems to be obtained through the synthesis of signatures. In this paper we propose a method based on motor equivalence model theory to generate static Bengali signatures. This theory divides the human action to write mainly into cognitive and motor levels. Due to difference between scripts, we have redesigned our previous synthesizer [1,2], which generates static Western signatures. The experiments assess whether this method can approach the intra and inter-personal variability of the Bengali-100 Static Signature DB from a performance-based validation. The similarities reported in the experimental results proof the ability of the synthesizer to generate signature images in this script

A novel image compression algorithm for high resolution 3D reconstruction

This research presents a novel algorithm to compress high-resolution images for accurate structured light 3D reconstruction. Structured light images contain a pattern of light and shadows projected on the surface of the object, which are captured by the sensor at very high resolutions. Our algorithm is concerned with compressing such images to a high degree with minimum loss without adversely affecting 3D reconstruction. The Compression Algorithm starts with a single level discrete wavelet transform (DWT) for decomposing an image into four sub-bands. The sub-band LL is transformed by DCT yielding a DC-matrix and an AC-matrix. The Minimize-Matrix-Size Algorithm is used to compress the AC-matrix while a DWT is applied again to the DC-matrix resulting in LL2, HL2, LH2 and HH2 sub-bands. The LL2 sub-band is transformed by DCT, while the Minimize-Matrix-Size Algorithm is applied to the other sub-bands. The proposed algorithm has been tested with images of different sizes within a 3D reconstruction scenario. The algorithm is demonstrated to be more effective than JPEG2000 and JPEG concerning higher compression rates with equivalent perceived quality and the ability to more accurately reconstruct the 3D models

Chemical Composition, Biological Activity, and Health-Promoting Effects of Withania somnifera for Pharma-Food Industry Applications

The Withania genus comes from the Solanaceae family and includes around 23 species, spread over some areas of the Mediterranean, Asia, and East Africa. Widely used in traditional medicine for thousands of years, these plants are rich in secondary metabolites, with special emphasis on steroidal lactones, named withanolides which are used as ingredients in numerous formulations for a plethora of diseases, such as asthma, diabetes, arthritis, impotence, amnesia, hypertension, anxiety, stress, cancer, neurodegenerative, and cardiovascular diseases, and many others. Among them, Withania somnifera (L.) Dunal is the most widely addressed species from a pharmacological and agroindustrial point of view. In this sense, this review provides an overview of the folk uses, phytochemical composition, and biological activity, such as antioxidant, antimicrobial, anti-inflammatory, and cytotoxic activity of W. somnifera, although more recently other species have also been increasingly investigated. In addition, their health-promoting effects, i.e., antistress, anxiolytic, adaptogenic, antirheumatoid arthritis, chemoprotective, and cardiorespiratory-enhancing abilities, along with safety and adverse effects are also discussed.N. C. -M. acknowledges the Portuguese Foundation for Science and Technology under the Horizon 2020 Program (PTDC/PSI-GER/28076/2017)

Changes in Proteasome Structure and Function Caused by HAMLET in Tumor Cells

BACKGROUND: Proteasomes control the level of endogenous unfolded proteins by degrading them in the proteolytic core. Insufficient degradation due to altered protein structure or proteasome inhibition may trigger cell death. This study examined the proteasome response to HAMLET, a partially unfolded protein-lipid complex, which is internalized by tumor cells and triggers cell death. METHODOLOGY/PRINCIPAL FINDINGS: HAMLET bound directly to isolated 20S proteasomes in vitro and in tumor cells significant co-localization of HAMLET and 20S proteasomes was detected by confocal microscopy. This interaction was confirmed by co-immunoprecipitation from extracts of HAMLET-treated tumor cells. HAMLET resisted in vitro degradation by proteasomal enzymes and degradation by intact 20S proteasomes was slow compared to fatty acid-free, partially unfolded alpha-lactalbumin. After a brief activation, HAMLET inhibited proteasome activity in vitro and in parallel a change in proteasome structure occurred, with modifications of catalytic (beta1 and beta5) and structural subunits (alpha2, alpha3, alpha6 and beta3). Proteasome inhibition was confirmed in extracts from HAMLET-treated cells and there were indications of proteasome fragmentation in HAMLET-treated cells. CONCLUSIONS/SIGNIFICANCE: The results suggest that internalized HAMLET is targeted to 20S proteasomes, that the complex resists degradation, inhibits proteasome activity and perturbs proteasome structure. We speculate that perturbations of proteasome structure might contribute to the cytotoxic effects of unfolded protein complexes that invade host cells

IL-2 Regulates SEB Induced Toxic Shock Syndrome in BALB/c Mice

BACKGROUND:Toxic Shock Syndrome (TSS) is characterized by fever, rash, hypotension, constitutional symptoms, and multi-organ involvement and is caused by Staphylococcus aureus enterotoxins such as Staphylococcal Enterotoxin B (SEB). SEB binds to the MHC-IIalpha chain and is recognized by the TCRbeta chain of the Vbeta8 TCR(+) T cells. The binding of SEB to Vbeta chain results in rapid activation of T cells and production of inflammatory cytokines, such as Interleukin-2 (IL-2), Interferon-gamma and Tumor Necrosis Factor-alpha which mediate TSS. Although IL2 was originally identified as the T cell growth factor and was proposed to contribute to T cell differentiation, its role in TSS remains unexplored. METHODOLOGY/PRINCIPAL FINDINGS:Mice were injected with D-Gal (25 mg/mouse). One hour after D-Galactosamine (D-Gal) injection each mouse was injected with SEB (20 microg/mouse. Mice were then observed for 72 hrs and death was recorded at different times. We tested Interleukin-12, IFNgamma, and IL-2 deficient mice (IL-2(-/-)), but only the IL-2 deficient mice were resistant to SEB induced toxic shock syndrome. More importantly reconstitution of IL-2 in IL-2 deficient mice restored the shock. Interestingly, SEB induced IL-2 production from T cells was dependent on p38MAPK activation in macrophages as inhibition of it in macrophages significantly inhibited IL-2 production from T cells. CONCLUSION:This study shows the importance of IL -2 in TSS which has not been previously explored and it also shows that regulating macrophages function can regulate T cells and TSS

Knowledge driven decomposition of tumor expression profiles

<p>Abstract</p> <p>Background</p> <p>Tumors have been hypothesized to be the result of a mixture of oncogenic events, some of which will be reflected in the gene expression of the tumor. Based on this hypothesis a variety of data-driven methods have been employed to decompose tumor expression profiles into component profiles, hypothetically linked to these events. Interpretation of the resulting data-driven components is often done by post-hoc comparison to, for instance, functional groupings of genes into gene sets. None of the data-driven methods allow the incorporation of that type of knowledge directly into the decomposition.</p> <p>Results</p> <p>We present a linear model which uses knowledge driven, pre-defined components to perform the decomposition. We solve this decomposition model in a constrained linear least squares fashion. From a variety of options, a lasso-based solution to the model performs best in linking single gene perturbation data to mouse data. Moreover, we show the decomposition of expression profiles from human breast cancer samples into single gene perturbation profiles and gene sets that are linked to the hallmarks of cancer. For these breast cancer samples we were able to discern several links between clinical parameters, and the decomposition weights, providing new insights into the biology of these tumors. Lastly, we show that the order in which the Lasso regularization shrinks the weights, unveils consensus patterns within clinical subgroups of the breast cancer samples.</p> <p>Conclusion</p> <p>The proposed lasso-based constrained least squares decomposition provides a stable and relevant relation between samples and knowledge-based components, and is thus a viable alternative to data-driven methods. In addition, the consensus order of component importance within clinical subgroups provides a better molecular characterization of the subtypes.</p

Use of ER/PR/HER2 subtypes in conjunction with the 2007 St Gallen Consensus Statement for early breast cancer

<p>Abstract</p> <p>Background</p> <p>The 2007 St Gallen international expert consensus statement describes three risk categories and provides recommendations for treatment of early breast cancer. The set of recommendations on how to best treat primary breast cancer is recognized and used by clinicians worldwide. We now examine the variability of five-year survival of the 2007 St Gallen Risk Classifications utilizing the ER/PR/HER2 subtypes.</p> <p>Methods</p> <p>Using the population-based California Cancer Registry, 114,786 incident cases of Stages 1-3 invasive breast cancer diagnosed between 2000 and 2006 were identified. Cases were assigned to Low, Intermediate, or High Risk categories. Five-year-relative survival was computed for the three St Gallen risk categories and for the ER/PR/HER2 subtypes for further differentiation.</p> <p>Results and Discussion</p> <p>There were 9,124 (13%) cases classified as Low Risk, 44,234 (65%) cases as Intermediate Risk, and 14,340 (21%) as High Risk. Within the Intermediate Risk group, 33,735 (76%) were node-negative (Intermediate Risk 2) and 10,499 (24%) were node-positive (Intermediate Risk 3). For the High Risk group, 6,149 (43%) had 1 to 3 positive axillary lymph nodes (High Risk 4) and 8,191 (57%) had four or more positive lymph nodes (High Risk 5).</p> <p>Using five-year relative survival as the principal criterion, we found the following: a) There was very little difference between the Low Risk and Intermediate Risk categories; b) Use of the ER/PR/HER2 subtypes within the Intermediate and High Risk categories separated each into a group with better five-year survival (ER-positive) and a group with worse survival (ER-negative), irrespective of HER2-status; c) The heterogeneity of the High Risk category was most evident when one examined the ER/PR/HER2 subtypes with four or more positive axillary lymph nodes; (d) HER2-positivity did not always translate to worse survival, as noted when one compared the triple positive subtype (ER+/PR+/HER2+) to the triple negative subtype (ER-/PR-/HER2-); and (e) ER-negativity appeared to be a stronger predictor of poor survival than HER2-positivity.</p> <p>Conclusion</p> <p>The use of ER/PR/HER2 subtype highlights the marked heterogeneity of the Intermediate and High Risk categories of the 2007 St Gallen statements. The use of ER/PR/HER2 subtypes and correlation with molecular classification of breast cancer is recommended.</p

Asymmetric properties of long-term and total heart rate variability

We report on two new physiological phenomena: the long-term and total heart rate asymmetry, which describe a significantly larger contribution of heart rate accelerations to long-term and total heart rate variability. In addition to the existing pair of indices, \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text {SD1}}_{\rm d}, {\text {SD1}}_{\rm a},$$\end{document} which are based on partitioning short-term variance, we introduce two other pairs of descriptors based on partitioning long-term (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text {SD2}}_{\rm d}, {\text {SD2}}_{\rm a}$$\end{document}) and total (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text {SDNN}}_{\rm d}, {\text {SDNN}}_{\rm a}$$\end{document}) heart rate variability. The new asymmetric descriptors are used to analyze RR intervals time series derived from the 30-min ECG recordings of 241 healthy subjects resting in supine position. It is shown that both new types of asymmetry are present in 76% of the subjects. The new phenomena reported here are real physiological findings rather than artifacts of the method since they vanish after data shuffling