The role of lymphoid tissue SPARC in the pathogenesis and response to treatment of multiple myeloma.

BACKGROUND: Despite the significant progress in the treatment of multiple myeloma (MM), the disease remains untreatable and its cure is still an unmet clinical need. Neoplastic transformation in MM is initiated in the germinal centers (GCs) of secondary lymphoid tissue (SLT) where B cells experience extensive somatic hypermutation induced by follicular dendritic cells (FDCs) and T-cell signals. OBJECTIVE: We reason that secreted protein acidic and rich in cysteine (SPARC), a common stromal motif expressed by FDCs at the origin (SLTs) and the destination (BM) of MM, plays a role in the pathogenesis of MM, and, here, we sought to investigate this role. METHODS: There were 107 BM biopsies from 57 MM patients (taken at different time points) together with 13 control specimens assessed for SPARC gene and protein expression and compared with tonsillar tissues. In addition, regulation of myeloma-promoting genes by SPARC-secreting FDCs was assessed in in vitro GC reactions (GCRs). RESULTS: SPARC gene expression was confirmed in both human primary (BM) and secondary (tonsils) lymphoid tissues, and the expression was significantly higher in the BM. Sparc was detectable in the BM and tonsillar lysates, co-localized with the FDC markers in both tissues, and stimulation of FDCs in vitro induced significantly higher levels of SPARC expression than unstimulated controls. In addition, SPARC inversely correlated with BM PC infiltration, ISS staging, and ECOG performance of the MM patients, and in vitro addition of FDCs to lymphocytes inhibited the expression of several oncogenes associated with malignant transformation of PCs. CONCLUSION: FDC-SPARC inhibits several myelomagenic gene expression and inversely correlates with PC infiltration and MM progression. Therapeutic induction of SPARC expression through combinations of the current MM drugs, repositioning of non-MM drugs, or novel drug discovery could pave the way to better control MM in clinically severe and drug-resistant patients

Risk factors of cervical intraepithelial lesion in Douala-Cameroon: Implications of Herpes Simplex Virus Type 2, Chlamydia Trachomatis and Treponema Pallidum

Infection with high risk oncogenic human papillomavirus (HPV) such as HPVs 16 and 18 is the main cause of cervical cancer. The objective of this study was to determine the impact of Chlamydia trachomatis, Herpes simplex virus 2 (HSV 2), Treponema pallidum and some sexual behaviour on malignant progression of cervical lesion in Douala, Cameroon. From July 2009 to January 2010, we performed routine cervical smears to 163 consenting women, who completed a questionnaire on risk factors of cervical cancer. Blood samples were obtained for each of these women and used for the detection of antibodies against Chlamydia trachomatis, HSV 2 and Treponema pallidum. Results obtained showed that 26/163 (17 LSIL and 9 HSIL) of women had abnormal cytology, 75.5% (123/163) had HSV 2 infection, 19% (31/163) infected by Chlamydia trachomatis and 4.3% (7/163) infected by Treponema pallidum. Among the LSIL-positive women 35.3% (6/17) and 94.1% (16/17) were infected with Chlamydia trachomatis and HSV 2 respectively. Among those with HSIL cytology, 22.2% (2/9), 66.7% (6/9) and 11.1% (1/9) respectively had Chlamydia trachomatis, HSV 2 and Treponema pallidum. High parity and pregnancy rate was observed among women with positive cytology. Our finding shown high rate of cervical abnormalities among women infected with HSV 2; and among those with a higher number of parities and pregnancies. These results suggest that further investigations should be made in Cameroon to access real burden of these risk factors in the progression and persistence of cervical lesion.Key words:risk factors, cervical cancer, HSV 2, Chlamydia trachomatis, sexually transmitted infections.doi: 10.4314/ajcem.v12i3.

Fatty Acid Composition of Growing Kiko X Spanish Crossbred Intact Male Goats Fed Varying Levels of Peanut Skins

Abstract The objective was to evaluate the effects of feeding peanut skins (PS) on fatty acid profile of goat meat. The diets used contained 0, 10, 20, and 30% of PS. After 92 days, longissimus muscle (LM), mesenteric adipose (MA), and subcutaneous (SA) tissue samples were analyzed for fatty acid profile. Eighteen (18), 21, and 21 fatty acids were detected in LM, MS and SC adipose tissues, respectively. No changes were detected in the fatty acid profile, but C18:0 increased linearly in LM (p \u3c 0.05) with increasing level of PS whereas C18:1 decreased in the similar manner (p = 0.05). Total saturated fatty acid and monounsaturated fatty acid percentage increased linearly (p \u3c 0.05) in LM fat, but polyunsaturated fatty acids were not different (p \u3e 0.05) among treatments. The results showed that the fatty acid composition of goat carcass can be altered with the dietary addition of PS. Keywords: Meat Goats, Peanut Skins, Fatty Acid

Mechanisms underlying the exquisite sensitivity of Candida albicans to combinatorial cationic and oxidative stress that enhances the potent fungicidal activity of phagocytes

This is the final version. Available on open access from the American Society for Microbiology via the DOI in this recordImmune cells exploit reactive oxygen species (ROS) and cationic fluxes to kill microbial pathogens, such as the fungus Candida albicans. Yet, C. albicans is resistant to these stresses in vitro. Therefore, what accounts for the potent antifungal activity of neutrophils? We show that simultaneous exposure to oxidative and cationic stresses is much more potent than the individual stresses themselves and that this combinatorial stress kills C. albicans synergistically in vitro. We also show that the high fungicidal activity of human neutrophils is dependent on the combinatorial effects of the oxidative burst and cationic fluxes, as their pharmacological attenuation with apocynin or glibenclamide reduced phagocytic potency to a similar extent. The mechanistic basis for the extreme potency of combinatorial cationic plus oxidative stress—a phenomenon we term stress pathway interference— lies with the inhibition of hydrogen peroxide detoxification by the cations. In C. albicans this causes the intracellular accumulation of ROS, the inhibition of Cap1 (a transcriptional activator that normally drives the transcriptional response to oxidative stress), and altered readouts of the stress-activated protein kinase Hog1. This leads to a loss of oxidative and cationic stress transcriptional outputs, a precipitous collapse in stress adaptation, and cell death. This stress pathway interference can be suppressed by ectopic catalase (Cat1) expression, which inhibits the intracellular accumulation of ROS and the synergistic killing of C. albicans cells by combinatorial cationic plus oxidative stress. Stress pathway interference represents a powerful fungicidal mechanism employed by the host that suggests novel approaches to potentiate antifungal therapy.IMPORTANCE The immune system combats infection via phagocytic cells that recognize and kill pathogenic microbes. Human neutrophils combat Candida infections by killing this fungus with a potent mix of chemicals that includes reactive oxygen species (ROS) and cations. Yet, Candida albicans is relatively resistant to these stresses in vitro. We show that it is the combination of oxidative plus cationic stresses that kills yeasts so effectively, and we define the molecular mechanisms that underlie this potency. Cations inhibit catalase. This leads to the accumulation of intracellular ROS and inhibits the transcription factor Cap1, which is critical for the oxidative stress response in C. albicans. This triggers a dramatic collapse in fungal stress adaptation and cell death. Blocking either the oxidative burst or cationic fluxes in human neutrophils significantly reduces their ability to kill this fungal pathogen, indicating that combinatorial stress is pivotal to immune surveillance.Biotechnology and Biological Sciences Research Council (BBSRC)Wellcome TrustEuropean CommissionNIAI

Lactate signalling regulates fungal β-glucan masking and immune evasion

AJPB: This work was supported by the European Research Council (STRIFE, ERC- 2009-AdG-249793), The UK Medical Research Council (MR/M026663/1), the UK Biotechnology and Biological Research Council (BB/K017365/1), the Wellcome Trust (080088; 097377). ERB: This work was supported by the UK Biotechnology and Biological Research Council (BB/M014525/1). GMA: Supported by the CNPq-Brazil (Science without Borders fellowship 202976/2014-9). GDB: Wellcome Trust (102705). CAM: This work was supported by the UK Medical Research Council (G0400284). DMM: This work was supported by UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/K000306/1). NARG/JW: Wellcome Trust (086827, 075470,101873) and Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology (097377). ALL: This work was supported by the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1).Peer reviewedPostprin

Особенности конструкции термической печи с барабанным механизмом перемещения заготовок

One of the most energy-intensive industries is ferrous metallurgy. The metallurgical sector in industrially developed countries is reducing its specific energy consumption per one ton of products by approximately 1.0 - 1.5 % per annum. In Russia, obsolete technology is the main reason for the high-energy intensity of industrial product. Energy saving in industrial production is associated with production technology and the scope of fuel and energy resources consumption. Therefore, ways to improve energy efficiency focus on reducing energy consumption of any kind during a specific process in a specific process or thermal unit. Ensuring the economical operation of furnace units requires detailed preliminary and verification analyses, upgrading and introduction of state-of-the-art equipment. The study presents a flow diagram and features of thermal operation of a new drum-type chamber furnace for heating metal products for quenching. The technical parameters of the furnace, the results of the thermo-technical analysis, the heat balance and the specific fuel consumption as applicable to the created design are also presented. The flow diagram of the furnace has significant advantages in terms of the energy efficiency of fuel as compared to the roller and conveyor methods of metal transportation. Placing blanks on the drum significantly reduces the complexity of their transportation. Thanks to its small length the proposed design is compact and easy to place in a workshop. The use of a recuperative fuel burning device allows the efficient use of the heat of waste gases in the heating process. The proposed design and method of products transportation in the furnace working space can be used for the heat treatment of bars, pipes, strips, as well as rolled steel of various shapes. © 2021 National University of Science and Technology MISIS. All rights reserved

Outer-Sphere Contributions to the Electronic Structure of Type Zero Copper Proteins

Bioinorganic canon states that active-site thiolate coordination promotes rapid electron transfer (ET) to and from type 1 copper proteins. In recent work, we have found that copper ET sites in proteins also can be constructed without thiolate ligation (called “type zero” sites). Here we report multifrequency electron paramagnetic resonance (EPR), magnetic circular dichroism (MCD), and nuclear magnetic resonance (NMR) spectroscopic data together with density functional theory (DFT) and spectroscopy-oriented configuration interaction (SORCI) calculations for type zero Pseudomonas aeruginosa azurin variants. Wild-type (type 1) and type zero copper centers experience virtually identical ligand fields. Moreover, O-donor covalency is enhanced in type zero centers relative that in the C112D (type 2) protein. At the same time, N-donor covalency is reduced in a similar fashion to type 1 centers. QM/MM and SORCI calculations show that the electronic structures of type zero and type 2 are intimately linked to the orientation and coordination mode of the carboxylate ligand, which in turn is influenced by outer-sphere hydrogen bonding

Fungal model systems and the elucidation of pathogenicity determinants

This is the final version of the article. Available from Elsevier via the DOI in this record.Fungi have the capacity to cause devastating diseases of both plants and animals, causing significant harvest losses that threaten food security and human mycoses with high mortality rates. As a consequence, there is a critical need to promote development of new antifungal drugs, which requires a comprehensive molecular knowledge of fungal pathogenesis. In this review, we critically evaluate current knowledge of seven fungal organisms used as major research models for fungal pathogenesis. These include pathogens of both animals and plants; Ashbya gossypii, Aspergillus fumigatus, Candida albicans, Fusarium oxysporum, Magnaporthe oryzae, Ustilago maydis and Zymoseptoria tritici. We present key insights into the virulence mechanisms deployed by each species and a comparative overview of key insights obtained from genomic analysis. We then consider current trends and future challenges associated with the study of fungal pathogenicity.This review was carried out by members of the EU-Initial Training Network Ariadne (PITN-GA-2009-237936), which provided financial support for C.B., S.D., M.E.G., E.G., E.M., P.V.M., M.M., V.N., M.F.A.N., T.O., M.O.R., K.S. and L.W

Revisión bibliográfica de implantología bucofacial del año 2007

Se expone una revisión de la literatura científica publicada en revistas indexadas durante el año 2007 sobre Implantología Bucofacial. La escasez de tiempo de que disponen los profesionales para consultar las múltiples fuentes de información, ha motivado a los autores a resumir los artículos publicados y clasificarlos en los siguientes apartados: generalidades, pacientes especiales, superficies y diseños, tejidos blandos, implantes inmediatos, carga inmediata, complicaciones, elevación sinusal, técnicas avanzadas, plasma rico en plaquetas y factores de crecimiento, cirugía guiada, cirugía mínimamente invasiva y miniimplantes, con la intención de facilitar una puesta al día