Physiologic cold shock of Moraxella catarrhalis affects the expression of genes involved in the iron acquisition, serum resistance and immune evasion

Background Moraxella catarrhalis, a major nasopharyngeal pathogen of the human respiratory tract, is exposed to rapid downshifts of environmental temperature when humans breathe cold air. It was previously shown that the prevalence of pharyngeal colonization and respiratory tract infections caused by M. catarrhalis are greatest in winter. The aim of this study was to investigate how M. catarrhalis uses the physiologic exposure to cold air to upregulate pivotal survival systems in the pharynx that may contribute to M. catarrhalis virulence. Results A 26°C cold shock induces the expression of genes involved in transferrin and lactoferrin acquisition, and enhances binding of these proteins on the surface of M. catarrhalis. Exposure of M. catarrhalis to 26°C upregulates the expression of UspA2, a major outer membrane protein involved in serum resistance, leading to improved binding of vitronectin which neutralizes the lethal effect of human complement. In contrast, cold shock decreases the expression of Hemagglutinin, a major adhesin, which mediates B cell response, and reduces immunoglobulin D-binding on the surface of M. catarrhalis. Conclusion Cold shock of M. catarrhalis induces the expression of genes involved in iron acquisition, serum resistance and immune evasion. Thus, cold shock at a physiologically relevant temperature of 26°C induces in M. catarrhalis a complex of adaptive mechanisms that enables the bacterium to target their host cellular receptors or soluble effectors and may contribute to enhanced growth, colonization and virulence.

Thoracic target volume delineation using various maximum-intensity projection computed tomography image sets for stereotactic body radiation therapy

The motion of lung tumors during respiration makes the accurate delivery of radiation therapy to the thorax difficult because it increases the uncertainty of target position. The adoption of four-dimensional computed tomography (4D-CT) has allowed us to determine how a tumor moves with respiration for each individual patient. Using information acquired during a 4D-CT scan, we can define the target, visualize motion, and calculate dose during the planning phase of the radiotherapy process. One image data set that can be created from the 4D-CT acquisition is the maximum-intensity projection (MIP). The MIP can be used as a starting point to define the volume that encompasses the motion envelope of the moving gross target volume (GTV). Because of the close relationship that exists between the MIP and the final target volume, we investigated four MIP data sets created with different methodologies (3 using various 4D-CT sorting implementations, and one using all available cine CT images) to compare target delineation. It has been observed that changing the 4D-CT sorting method will lead to the selection of a different collection of images; however, the clinical implications of changing the constituent images on the resultant MIP data set are not clear. There has not been a comprehensive study that compares target delineation based on different 4D-CT sorting methodologies in a patient population. We selected a collection of patients who had previously undergone thoracic 4D-CT scans at our institution, and who had lung tumors that moved at least 1 cm. We then generated the four MIP data sets and automatically contoured the target volumes. In doing so, we identified cases in which the MIP generated from a 4D-CT sorting process under-represented the motion envelope of the target volume by more than 10% than when measured on the MIP generated from all of the cine CT images. The 4D-CT methods suffered from duplicate image selection and might not choose maximum extent images. Based on our results, we suggest utilization of a MIP generated from the full cine CT data set to ensure a representative inclusive tumor extent, and to avoid geometric miss.

Acquisition of a natural resistance gene renders a clinical strain of methicillin-resistant Staphylococcus aureus resistant to the synthetic antibiotic linezolid.

Linezolid, which targets the ribosome, is a new synthetic antibiotic that is used for treatment of infections caused by Gram-positive pathogens. Clinical resistance to linezolid, so far, has been developing only slowly and has involved exclusively target site mutations. We have discovered that linezolid resistance in a methicillin-resistant Staphylococcus aureus hospital strain from Colombia is determined by the presence of the cfr gene whose product, Cfr methyltransferase, modifies adenosine at position 2503 in 23S rRNA in the large ribosomal subunit. The molecular model of the linezolid-ribosome complex reveals localization of A2503 within the drug binding site. The natural function of cfr likely involves protection against natural antibiotics whose site of action overlaps that of linezolid. In the chromosome of the clinical strain, cfr is linked to ermB, a gene responsible for dimethylation of A2058 in 23S rRNA. Coexpression of these two genes confers resistance to all the clinically relevant antibiotics that target the large ribosomal subunit. The association of the ermB/cfr operon with transposon and plasmid genetic elements indicates its possible mobile nature. This is the first example of clinical resistance to the synthetic drug linezolid which involves a natural resistance gene with the capability of disseminating among Gram-positive pathogenic strains.

Large-scale land acquisition and its effects on the water balance in investor and host countries

This study examines the validity of the assumption that international large-scale land acquisition (LSLA) is motivated by the desire to secure control over water resources, which is commonly referred to as ‘water grabbing’. This assumption was repeatedly expressed in recent years, ascribing the said motivation to the Gulf States in particular. However, it must be considered of hypothetical nature, as the few global studies conducted so far focused primarily on the effects of LSLA on host countries or on trade in virtual water. In this study, we analyse the effects of 475 intended or concluded land deals recorded in the Land Matrix database on the water balance in both host and investor countries. We also examine how these effects relate to water stress and how they contribute to global trade in virtual water. The analysis shows that implementation of the LSLAs in our sample would result in global water savings based on virtual water trade. At the level of individual LSLA host countries, however, water use intensity would increase, particularly in 15 sub-Saharan states. From an investor country perspective, the analysis reveals that countries often suspected of using LSLA to relieve pressure on their domestic water resources—such as China, India, and all Gulf States except Saudi Arabia—invest in agricultural activities abroad that are less water-intensive compared to their average domestic crop production. Conversely, large investor countries such as the United States, Saudi Arabia, Singapore, and Japan are disproportionately externalizing crop water consumption through their international land investments. Statistical analyses also show that host countries with abundant water resources are not per se favoured targets of LSLA. Indeed, further analysis reveals that land investments originating in water-stressed countries have only a weak tendency to target areas with a smaller water risk.

Determining acquisition and cessation antecedents to adolescent cigarette smoking for development of intervention strategies

Our national focus and emphasis on the promotion of healthy behavior choices regarding tobacco and other drugs continues to target adolescents. Multiple studies have shown that adolescence is the optimum period for the prevention of substance use initiation as life-long patterns of health behaviors are established during this critical developmental stage. Tobacco use is associated with an increase in morbid and mortal health conditions of which prevalence increases throughout the lifespan. Attention to the antecedents of preventable health conditions aims to modify the risks and identify health promotion factors. Modifying antecedent factors for tobacco initiation in youth and identifying protective factors for successful smoking cessation has major public health implications across the lifespan. Of foremost interest are those risk factors and resultant behaviors that predict a youth's probability of initiating cigarette use and their cessation of cigarette use. Specifically, this dissertation supports previous results identifying intervention variables on the initiation/cessation continuum model especially with the established predictors of smoking (decisional balance and susceptibility) and with more recently identified predictors of smoking (nicotine dependence and withdrawal symptoms) in current and former smokers in a sample of high school students in Austin and Houston, Texas. These results offer insight for the development of appropriate intervention program strategies for our youth. ^

Sequence scanning: A method for rapid sequence acquisition from large-fragment DNA clones.

A strategy of "sequence scanning" is proposed for rapid acquisition of sequence from clones such as bacteriophage P1 clones, cosmids, or yeast artificial chromosomes. The approach makes use of a special vector, called LambdaScan, that reliably yields subclones with inserts in the size range 8-12 kb. A number of subclones, typically 96 or 192, are chosen at random, and the ends of the inserts are sequenced using vector-specific primers. Then long-range spectrum PCR is used to order and orient the clones. This combination of shotgun and directed sequencing results in a high-resolution physical map suitable for the identification of coding regions or for comparison of sequence organization among genomes. Computer simulations indicate that, for a target clone of 100 kb, the scanning of 192 subclones with sequencing reads as short as 350 bp results in an approximate ratio of 1:2:1 of regions of double-stranded sequence, single-stranded sequence, and gaps. Longer sequencing reads tip the ratio strongly toward increased double-stranded sequence.

Bacterial resistance to antibiotics:modified target sites

Alteration in the target sites of antibiotics is a common mechanism of resistance. Examples of clinical strains showing resistance can be found for every class of antibiotic, regardless of the mechanism of action. Target site changes often result from spontaneous mutation of a bacterial gene on the chromosome and selection in the presence of the antibiotic. Examples include mutations in RNA polymerase and DNA gyrase, resulting in resistance to the rifamycins and quinolones, respectively. In other cases, acquisition of resistance may involve transfer of resistance genes from other organisms by some form of genetic exchange (conjugation, transduction, or transformation). Examples of these mechanisms include acquisition of the mecA genes encoding methicillin resistance in Staphylococcus aureus and the various van genes in enterococci encoding resistance to glycopeptides. © 2005 Elsevier B.V. All rights reserved.

Knowledge acquisition from L2 specialist texts

This research aims to investigate knowledge acquisition and concept formation in the domain of economics and business studies through a foreign language, English, from the very initial to the very final stage of development in the context of Higher Education in Turkey. It traces both the processes as well as the product of acquisition in order to provide a detailed picture of how knowledge acquisition occurs. It aims to explore ways in which the acquisition process can be facilitated and promoted while prospective students of the Department of Economics and Business Administration receive a language training programme, following the completion of which they will join their academic community which offers part of its courses through the English language. The study draws upon (some) theories of mental representation of knowledge, such as schema, frame and script. The concept of discourse community with its characteristics is investigated, enculturation of prospective students to acquire knowledge of their domain through L2 is explored, and the crucial role of the constructivist theory in relation to knowledge acquisition is highlighted. The present study was conducted through a process of enculturation taking place partly at the language centre of Çukurova University and partly at the target discourse community. The data utilised for initiating knowledge acquisition was obtained by establishing a corpus of economics and business texts, which the learners are expected to read during their academic courses utilising computerised technology. The method of think aloud protocols was used to analyse processes taking place in knowledge acquisition, while the product of what was acquired was investigated by means of written recall protocols. It has been discovered that knowledge acquisition operates on the basis of analogical and to a certain extent metaphorical reasoning. The evidence obtained from the think aloud protocols showed that neophytes were able to acquire fundamental concepts of their future domain by reaching the level of shared understanding with the members of their target community of the faculty. Diaries and questionnaire analyses demonstrated that enculturation facilitated learners' transition from the language centre into the target community. Analyses of the written recall protocols and examinations from the post-enculturation stage of the research showed that neophytes' academic performances in their target community were much higher than those of their non-enculturated counterparts. Processes learners go through and strategies they spontaneously make use of, especially while acquiring knowledge of a specific domain through L2 have so far remained unexplored research areas. The present research makes a potential contribution to the language and knowledge acquisition theories by examining closely and systematically the language and the strategies they employ in acquiring such knowledge. The research findings offer useful implications to English language teaching at language schools. Language teachers are provided with useful guidelines as to how they can provide prospective students of a particular academic community with an experience of acquiring fundamental concepts of their discipline before they become members of their target community.

Exploring novel auditory displays for supporting accelerated skills acquisition and enhanced performance in motorsport

This paper explores the design, development and evaluation of a novel real-time auditory display system for accelerated racing driver skills acquisition. The auditory feedback provides concurrent sensory augmentation and performance feedback using a novel target matching design. Real-time, dynamic, tonal audio feedback representing lateral G-force (a proxy for tire slip) is delivered to one ear whilst a target lateral G-force value representing the ‘limit’ of the car, to which the driver aims to drive, is panned to the driver’s other ear; tonal match across both ears signifies that the ‘limit’ has been reached. An evaluation approach was established to measure the efficacy of the audio feedback in terms of performance, workload and drivers’ assessment of self-efficacy. A preliminary human subject study was conducted in a driving simulator environment. Initial results are encouraging, indicating that there is potential for performance gain and driver confidence enhancement based on the audio feedback.

Az ügyfélszerzési mód hatásának vizsgálata a vevőelégedettségre és a lojalitásra a szervezeti piacon (Analyzing the impact of the customer acquisition mode to the customer satisfaction and loyalty on the corporate market – assessing the effect of recommendation with applying structural equation modelling)

A kutatás célja a marketingeszközök hosszú távú hatásának pontosabb megértése szervezetközi viszonylatban a vevőértékelési modellek egyik nehezen számszerűsíthető tényezője, az ajánlás hatásának vizsgálata által. A hatások elemzésére a strukturális egyenlőségek módszerét (Structural Equation Modelling) alkalmazta a szerző. Rámutatott, hogy az ajánlással szerzett ügyfelek elégedettebbek, lojálisabbak és gyakrabban ajánlják a vállalatot a más módon szerzett ügyfeleknél. Az összefüggések feltárása és bizonyítása különösen az ajánlás kumulatív hatása miatt jelentős. Az eredmények gyakorlati alkalmazásával lehetőség nyílik az ügyfélkör differenciáltabb, értékalapú szegmentációjára, amely pontosabb célcsoport-meghatározást lesz lehetővé, és hosszú távon hozzájárul a vállalat optimális ügyfélportfóliójának kialakításához. ______ The research is aimed at more precise understanding of longterm effects of marketing tools in business to business relations by analysing the impacts of recommendation potential, one of the hardly measurable factors of customer value concept. Structural Equation Modelling is applied for conducting effect analysis. The results show that customers acquired with recommendation are more satisfied, more loyal, and make more recommendation that other customer. These results are more interesting if we take the cumulative effect of recommendation in account. They provide bases for a more differentiated segmentation of customers, which results in a more accurate identification of target groups. In the long-run, the application of the customer-value concept considerably contributes to creating an optimal customer portfolio for companies.

The art of building trust via e-communication channels: Post-acquisition integration as a special context

This study discusses the importance of establishing trust in post-acquisition integration context and how the use of e-channels facilitates or inhibits this process. The objective of this study is to analyze how the use of electronic communication channels influences the post-acquisition integration process in terms of trust establishment and overall integration efficiency, developing a framework as a result. Three sub-objectives are introduced: to find out the building blocks of trust in M&A’s, to analyse how the use of e-channels influence the process of trust establishment in post-acquisition integration context, and to define the consequences trust and use of e-channels have for the process. The theoretical background of the study includes literature and theories relating to trust establishment in post-acquisition integration context and how the use of e-channels influences the process of trust development on a general level. The empirical research is conducted as a single case study, based on key informant interviews. The interview data was collected between October 2015 and January 2016. Altogether nine interviews were realised; six with representatives from the acquiring firm and three with target firm members. Thematic analysis was selected as the main method for analysing and processing the qualitative data. This study finds that trust has an essential role in post-acquisition integration context, facilitating the integration process in various different ways. Hence, identifying the different building blocks of trust is important in order for members of the organisations to be better able establish and maintain trust. In today’s international business, the role of electronic communication channels has also increased in importance significantly and it was confirmed that these pose both challenges and possibilities for the development of interpersonal trust. One of the most important underlying factors influencing the trust levels via e-communication channels is the level of user’s comfort in using the different e-channels. Without sufficient and meaningful training, the communication conducted via these channels in inhibited in a number of ways. Hence, understanding the defining characteristics of e-communication together with the risks and opportunities related to the use of these can have far-reaching consequences for the post-acquisition integration process as a whole. The framework based on the findings and existing theory introduces the most central factors influencing the trust establishment together with the positive and negative consequences these have for the integration process. Moreover, organizational level consistency and the existence of shared guidelines on appropriate selection of communication channels according to the nature of the task at hand are seen as important

Continuous acquisition of MHC:peptide complexes by recipient cells contributes to the generation of anti-graft CD8+T cell immunity

Understanding the evolution of the direct and indirect pathways of allorecognition following tissue transplantation is essential in the design of tolerance-promoting protocols. On the basis that donor bone marrow-derived antigen presenting cells are eliminated within days of transplantation, it has been argued that the indirect response represents the major threat to long term transplant survival, and is consequently the key target for regulation. However, the detection of MHC transfer between cells, and particularly the capture of MHC:peptide complexes by dendritic cells, led us to propose a third, semi-direct, pathway of MHC allorecognition. Persistence of this pathway would lead to sustained activation of direct pathway T cells, arguably persisting for the life of the transplant. In this study, we focused on the contribution of acquired MHC class I, on recipient DCs, during the life span of a skin graft. We observed that MHC class I acquisition by recipient DCs occurs for at least one month following transplantation and may be the main source of alloantigen that drives CD8+ cytotoxic T cell responses. In addition, acquired MHC class I-peptide complexes stimulate T cell responses in vivo further emphasizing the need to regulate both pathways to induce indefinite survival of the graft.

Protein disulfide isomerase as a target for besnoitiosis therapy : molecular characterization and studies of its role in infection and host immune response

Tese de Doutoramento em Ciências Veterinárias na especialidade de Sanidade Animal

The FOOT experiment: Trigger and Data Acquisition (TDAQ) development and data analysis

Hadrontherapy employs high-energy beams of charged particles (protons and heavier ions) to treat deep-seated tumours: these particles have a favourable depth-dose distribution in tissue characterized by a low dose in the entrance channel and a sharp maximum (Bragg peak) near the end of their path. In these treatments nuclear interactions have to be considered: beam particles can fragment in the human body releasing a non-zero dose beyond the Bragg peak while fragments of human body nuclei can modify the dose released in healthy tissues. These effects are still in question given the lack of interesting cross sections data. Also space radioprotection can profit by fragmentation cross section measurements: the interest in long-term manned space missions beyond Low Earth Orbit is growing in these years but it has to cope with major health risks due to space radiation. To this end, risk models are under study: however, huge gaps in fragmentation cross sections data are currently present preventing an accurate benchmark of deterministic and Monte Carlo codes. To fill these gaps in data, the FOOT (FragmentatiOn Of Target) experiment was proposed. It is composed by two independent and complementary setups, an Emulsion Cloud Chamber and an electronic setup composed by several subdetectors providing redundant measurements of kinematic properties of fragments produced in nuclear interactions between a beam and a target. FOOT aims to measure double differential cross sections both in angle and kinetic energy which is the most complete information to address existing questions. In this Ph.D. thesis, the development of the Trigger and Data Acquisition system for the FOOT electronic setup and a first analysis of 400 MeV/u 16O beam on Carbon target data acquired in July 2021 at GSI (Darmstadt, Germany) are presented. When possible, a comparison with other available measurements is also reported.

Identification Of Target Genes Using Gene Expression Profile Of Granulocytes From Patients With Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors.

Differential gene expression analysis by suppression subtractive hybridization with correlation to the metabolic pathways involved in chronic myeloid leukemia (CML) may provide a new insight into the pathogenesis of CML. Among the overexpressed genes found in CML at diagnosis are SEPT5, RUNX1, MIER1, KPNA6 and FLT3, while PAN3, TOB1 and ITCH were decreased when compared to healthy volunteers. Some genes were identified and involved in CML for the first time, including TOB1, which showed a low expression in patients with CML during tyrosine kinase inhibitor treatment with no complete cytogenetic response. In agreement, reduced expression of TOB1 was also observed in resistant patients with CML compared to responsive patients. This might be related to the deregulation of apoptosis and the signaling pathway leading to resistance. Most of the identified genes were related to the regulation of nuclear factor κB (NF-κB), AKT, interferon and interleukin-4 (IL-4) in healthy cells. The results of this study combined with literature data show specific gene pathways that might be explored as markers to assess the evolution and prognosis of CML as well as identify new therapeutic targets.