Gotowa bibliografia na temat „Protein Model Discrimination”

Abstract Black adults and women are more likely to experience serious cognitive decline in older age than their white and male counterparts. Evidence suggests perceived discrimination is associated with poor cognition in older adults, though the mechanisms remain unclear. Perceived discrimination has been linked to elevated inflammatory markers, such as C-reactive protein (CRP), which increases risk for worse cognitive functioning. Yet, little research has investigated whether CRP is implicated in the association between discrimination and cognition among Black older adults or if this relationship differs by gender. Using 2006-2016 data from Black adults ≥65 years old(N=1343) in the nationally representative Health and Retirement Study, random effects linear regression models (1) tested the association between discrimination and cognitive functioning; (2) explored whether this relationship differed for women and men; and (3) assessed whether elevated CRP mediated the association between discrimination and cognitive functioning. More frequent discrimination was associated with worse cognitive functioning (b= -0.24, SE=0.11, p<0.05), though gender did not moderate this relationship. Elevated CRP was significantly associated with worse cognitive functioning (b= 0.40, SE=0.18, p<0.05). Discrimination remained statistically significant in this model, indicating no mediation by CRP. Of note, inclusion of depressive symptoms and cardiometabolic conditions accounted for the association between both discrimination and CRP with cognitive functioning. These findings demonstrate the need for more within-group research on older Black adults documenting the complex relationship between discrimination, inflammation, and cognitive health. This approach will provide greater understanding of the biopsychosocial mechanisms underlying disparities in cognitive functioning in Black adults.

ABSTRACT IMPACT: Our findings could potentially identify CVD at-risk persons living with HIV who might benefit from aggressive risk-reduction. OBJECTIVES/GOALS: PWH have higher rates of CVD than the general population yet CVD risk prediction models rely on traditional risk factors and fail to capture the heterogeneity of CVD risk in PWH. Here we identify protein biomarkers that are able to discriminate between CVD cases and controls in PWH, and we assess their added benefit beyond traditional risk factors. METHODS/STUDY POPULATION: We analyzed 459 baseline protein expression levels from five OLINK panels in a matched CVD (MI, coronary revascularization, stroke, CVD death) case-control study with 390 PWH from INSIGHT trials (131 cases, 259 controls). We formed 200 datasets via bootstrap. For each bootstrap set, a two-component partial least squares discriminant model (PLSDA) was fit. The importance of each variable in the discrimination of cases and controls in the PLSDA projection was assessed by the variable importance in projection (VIP) score. Proteins with average VIP scores > 1 were used in penalized logistic regression models with elastic net penalty, and proteins were ranked based on the number of times the protein had a nonzero coefficient. Proteins in the top 25th percentile were considered to have high discrimination. RESULTS/ANTICIPATED RESULTS: Participants had mean age 47 years, 13% were females, 4.9% had CVD at baseline and 69% were on ART at baseline. Eight proteins including the hepatocyte growth factor and interleukin-6 were identified as able to distinguish between CVD cases and controls within PWH. A protein score (PS) of the top-ranked proteins was developed using the bootstrap (for weights) and the entire data. The PS was found to be predictive of CVD independent of established CVD and HIV factors (Odds ratio: 2.17 CI: 1.58-2.99). A model with the PS and traditional risk factors had a 5.9% improvement in AUC over the baseline model (AUC=0.731 vs 0.69), which is an increase in model predictive power of 18%. Individuals with a PS above the median score were 3.1 (CI: 1.83- 5.41) times more likely to develop CVD than those with a protein score below the median score. DISCUSSION/SIGNIFICANCE OF FINDINGS: A protein score developed improved discrimination of PWH with CVD and those without, and helped identify PWH with high risk for developing CVD. If validated, this score and/or the individual proteins could be used in addition with established factors to identify CVD at-risk individuals who might benefit from aggressive risk-reduction.

There is urgent need for biomarkers that provide early detection of pancreatic ductal adenocarcinoma (PDAC) as well as discrimination of autoimmune pancreatitis, as current clinical approaches are not suitably accurate for precise diagnosis. We used mass spectrometry to analyze protein profiles of more than 300 plasma specimens obtained from PDAC, noncancerous pancreatic diseases including autoimmune pancreatitis patients and healthy subjects. We obtained 1063 proteomic signals from 160 plasma samples in the training cohort. A proteomic signature consisting of 7 mass spectrometry signals was used for construction of a proteomic model for detection of PDAC patients. Using the test cohort, we confirmed that this proteomic model had discrimination power equal to that observed with the training cohort. The overall sensitivity and specificity for detection of cancer patients were 82.6% and 90.9%, respectively. Notably, 62.5% of the stage I and II cases were detected by our proteomic model. We also found that 100% of autoimmune pancreatitis patients were correctly assigned as noncancerous individuals. In the present paper, we developed a proteomic model that was shown able to detect early-stage PDAC patients. In addition, our model appeared capable of discriminating patients with autoimmune pancreatitis from those with PDAC.

Discrimination of high-risk types of human papillomaviruses plays an important role in the diagnosis and remedy of cervical cancer. Recently, several computational methods have been proposed based on protein sequence-based and structure-based information, but the information of their related proteins has not been used until now. In this paper, we proposed using protein “sequence space” to explore this information and used it to predict high-risk types of HPVs. The proposed method was tested on 68 samples with known HPV types and 4 samples without HPV types and further compared with the available approaches. The results show that the proposed method achieved the best performance among all the evaluated methods with accuracy 95.59% andF1-score 90.91%, which indicates that protein “sequence space” could potentially be used to improve prediction of high-risk types of HPVs.

Odor detection and discrimination in mammals is known to be initiated by membrane-bound G-protein-coupled receptors (GPCRs). The role that the lipid membrane may play in odor discrimination, however, is less well understood. Here, we used model membrane systems to test the hypothesis that phospholipid bilayer membranes may be capable of odor discrimination. The effect of S-carvone, R-carvone, and racemic lilial on the model membrane systems was investigated. The odorants were found to affect the fluidity of supported lipid bilayers as measured by fluorescence recovery after photobleaching (FRAP). The effect of odorants on surface-supported lipid multilayer microarrays of different dimensions was also investigated. The lipid multilayer micro- and nanostructure was highly sensitive to exposure to these odorants. Fluorescently-labeled lipid multilayer droplets of 5-micron diameter were more responsive to these odorants than ethanol controls. Arrays of lipid multilayer diffraction gratings distinguished S-carvone from R-carvone in an artificial nose assay. Our results suggest that lipid bilayer membranes may play a role in odorant discrimination and molecular recognition in general.

Improving thermostability of an enzyme can accelerate the relevant chemical reaction. Thus, the analysis and prediction of thermophilic proteins are conducive to protein engineering and enzyme design. In this study, a novel method based on two-step discrimination was proposed to distinguish between thermophilic and non-thermophilic proteins. The model was rigorously benchmarked on an objective dataset including 915 thermophilic proteins and 793 non-thermophilic proteins. Results showed that the overall accuracy of our method is 94.44% in 5-fold cross-validation, which is higher than those of other published methods. We believe that the two-step discriminated strategy will become a promising method in the relevant field of protein bioinformatics.

Matrix metalloproteinases (MMPs) network with other biological molecules to maintain the extracellular matrix (ECM) in normal physiology and perform different roles. Understanding and assigning specific role to each of 24 members of these endoproteinases is impeded because of lack of specific and efficient detection methods in biological samples. Moreover, MMP-based anti-cancer drug development has also been challenged because, currently, there is no robust methodology to distinguish the inactive pro-enzymes, active enzymes or those complexed with endogenous inhibitors in biological specimens. The objective of this project is to develop a chemical proteomics strategy based on Matrix assisted laser desorption ionization tandem mass spectrometry (MALDI-MS/MS) to help identify and discriminate the various MMP forms. Firstly, a triazine dye-based ligand immobilized on chromatography beads was utilized to assess whether it binds to recombinant human MMPs (rhMMPs). The results highlighted that the ligand interacts with latent forms of MMPs in agreement with the literature. Secondly, the potential of the ligand was assessed using MALDI-MS/MS based methodology in in vitro cancer models. Cell line culture supernatants were used in amounts to emulate the availability of tumour biopsies in clinical settings. The MS/MS spectral peaks specific to MMPs (MMP-2 and MMP- 14), and two endogenous inhibitors TIMP-1 and TIMP-2 were found in affinity chromatography eluates of cell culture supernatants with higher Mascot scores for the latter. While western blot detected MMP-2 in cell extracts, MALDI-MS/MS did not detect MMPs because of amounts below the limit of detection (LOD) of the instrument. Although the ligand was found to be interacting with MMPs and detergent-free salt elution buffers improved MALDI analysis, recovery of MMPs from biological samples was sub-optimal. The dye ligand was observed to bind other enzymes and despite various strategies to reduce non-specific binding of proteins or enable selective elution did not improve MMP enrichment. Further work using methodology described in this study is required after scaling up the MMP amounts in biological specimen and to resolve the issue of non-specific binding of proteins to the ligand by understanding its structure.

Proteins play a central role in all the biological processes. The immense diversity in protein structures and functions despite similar underlying composition is intriguing. The work presented in this thesis aims to provide a deeper understanding of protein structure-function relationships. It describes some techniques that were developed in order to probe these relationships. Chapter 1 provides a general introduction to the topics discussed in the thesis. Chapter 2 focuses on an important aspect of protein structures, the cavities. Although proteins are composed of regular arrangements of secondary structures, namely, α helices and β sheets, there are some irregularities. The packing density is not uniform throughout the protein resulting into formation of cavities. The role of cavities has been previously probed using mutagenesis studies. The mutations designed to fill the cavities were observed to improve stability and cavity creating mutations adversely affected the stability. Cavities are thus reported to be important contributors to stability. In chapter 2, we refine and benchmark a method for prediction of protein cavities based on molecular dynamics simulations. The insights derived from the mutagenesis studies provide some basic understanding of substitution preferences in proteins. The exposed non-active site positions are more tolerant to mutations whereas, the buried positions are not. Introducing cavity filling and disulfide mutations in proteins have been demonstrated to improve stability. Engineering protein variants with improved stability has immense applications in biology. In chapter 3, we discuss an important application, i.e., immunogen designing. Surface glycoproteins of several viruses exhibit two conformations, namely the metastable prefusion conformation and the highly stable postfusion conformation adopted during the fusion of the virus with the host cell membrane. Stable immunogens exhibiting the prefusion conformation are promising candidates for subunit vaccines. In chapter 3, we discuss immunogen designing for the respiratory syncytial virus (RSV). In addition to stabilized mutants, temperature sensitive (Ts) mutants are another class of engineered proteins. The Ts mutants exhibit reduced activity levels above the permissive temperature. They have been extensively used in developmental biology. Ts mutants are excellent tools to modulate protein expression levels in cells. A model for prediction of Ts positions was developed previously. This model exploits residue hydrophobicity to infer residue burial in the structure solely based on the protein sequence. In the current work, we improved the accuracy of the model by incorporating structural information in the model. Chapter 4 describes the development and benchmarking of a server for the prediction of Ts mutants (TSpred). The TSpred server suggests a stereochemically diverse set of mutations at the putative buried positions which are would produce destabilization to different extents and at least one of them is likely to be Ts. The TSpred predictions were employed for designing live attenuated vaccine candidates for RSV. The work thus far elaborates on factors contributing to protein stability and application of that information for rationally designing mutants to modulate protein structure and function. In order to gain a deeper understanding of the role of each protein residue in its function, simultaneous analysis of multiple mutants is essential. Site saturation mutagenesis techniques generate all nineteen mutations at each residue position of the protein and the mutant function is linked to a phenotypic readout like cell viability or binding to a ligand. The mutant libraries are deep sequenced using one of the available platforms like Illumina, SOLiD, 454 and Ion torrent, and analysed to estimate the relative proportions of each of the mutants in the library. Automated programs are necessary to analyse the large amount of data generated after deep sequencing. A pipeline for analysis of data generated from the Illumina sequencing platform is discussed in chapter 5. A mutational sensitivity measure denoted as MSseq was previously derived for the Controller of Cell division or Death B protein (CcdB). The values of the MSseq parameter reflect mutant activity. The active or inactive phenotypes of various mutants were analysed as a function of residue burial. Additional insights about substitution preferences at buried positions were gained from this analysis. In addition to residue burial, the substitution preferences varied with the physico-chemical nature and the size of the wild type (WT) and the mutant side chains. The active site of the CcdB protein could be inferred based on the trends in the mutational sensitivity values. We quantitated these effects and developed a model, detailed in chapter 6, for prediction of the mutant phenotypes using a fraction of the CcdB mutational data. The model was observed to perform better than two other machine learning based predictors, SNAP2 and SuSPect. Chapter 7 describes an additional application of the mutational sensitivity data. By analysing the population distribution of the MSseq values, an empirical parameter, RankScore, was previously derived for each residue in CcdB. RankScore can be interpreted as a weighted average of the MSseq values. RankScore was found to correlate well with residue depth which measures the extent of burial of a residue. As the residue depths in the native structure correlated well (r = 0.6) with the RankScores, the residue depths in native-like models would also correlate well with RankScores. Based on this principle, native-like models could be distinguished from low quality decoys. In the analysis reported in chapter 7, we examine this methodology using decoy datasets for ~200 proteins. We also consider additional information like predicted secondary structure and model quality score to achieve better model discrimination. Studies thus far describe analyses performed using single protein mutants. Furthermore, information about residue interactions is also important. During the course of evolution, as the maintenance of specific interactions is essential for protein function, residues participating in such interactions are either conserved or varied in a correlated manner. Several computational models analysing such correlations among mutations are available. Experimental techniques are also available for identification of the spatially proximal residues. In chapter 8, we analyse various computational programs using CcdB and Diacylglycerol kinase A (DgkA) proteins and the results are then compared with the available experimental data. Overall little overlap was observed between the predictions based on the natural sequence co-variation and the experimental data. Both the computational and experimental approaches can be applied in conjugation as they provide complementary information. The analyses described in the current work would provide useful guidelines for rational design of mutations to modulate protein stability. This has important implications in immunogen designing. The tools developed as part of the current work can be applied for (i) rational designing of Ts mutants, (ii) the analysis of site saturation libraries, (iii) calculation or prediction of substitution preferences, (iv) structure prediction using correlated mutations as constraints, or (v) protein model discrimination. A small appendix section is also included in the thesis. Synonymous mutations with differential phenotypes were observed in our deep sequenced library. In order to analyse them further, we performed a multiple sequence alignment and analysed codon frequencies at different positions. However, only preliminary results are available and those are included in Appendix I section of this thesis.

AbstractThis chapter explains the development of international and European law from a gender perspective and describes how the process from a gender-neutral to a gender-sensitive approach was developed.Since 1945 and the adoption of the UN Charter, the idea of achieving greater gender equality was merged into many international documents, including the first catalog of women’s rights—Convention on the Elimination of all Forms of Discrimination against Women. Many principal and subsidiary bodies were established, contributing to the elimination of gender discrimination and to awareness-raising on some critical issues which were an impediment to achieving gender equality. Twenty years ago, UN Security Council Resolution 1325 was adopted, due to a global effort to establish a platform as a foundation to national and international policies to ensure greater protection of women and girls, during and after, armed conflicts. International Humanitarian Law, enshrined in the Geneva Conventions, also has rules that specifically seek to protect women during armed conflicts. Also, International Criminal Law has been developed to recognize extreme forms of sexual violence as international crimes.On the European level, under the auspices of the Council of Europe, several international conventions were adopted to achieve gender equality. One of the main instruments, the European Convention on Human Rights, provides broad protection from discrimination based on gender, established in a comprehensive jurisprudence of the European Court of Human Rights. The EU has a set of primary and secondary sources on anti-discrimination, which provides comprehensive protection from gender discrimination and serves as an inspiring model to States candidates and other European countries.

AbstractThe chapter presents an overview of key labour law institutions, aiming at discussing the importance of the gender perspective in labour law. Therefore, the introductory section of the chapter will put this issue into the context of historical and conceptual framework genesis of regulating employment relationships. These issues are connected with the legal subordination and economic dependence of employees, which produce the need to create and implement norms that protect employees, as a weaker party to the employment relationship. This includes the limitation of employers’ (managerial, normative and disciplinary) prerogatives, in order to create the conditions for effective enjoyment of the right of jobseekers and employees for protection against gender-based discrimination. The labour law is, in this regard, traditionally conceived according to the model of a male worker, who is employed on the basis of a standard employment contract (open-ended full time employment contract). This then results in a failure to recognise or provide sufficient consideration of the specific needs that women have as participants in the labour market. The use of the feminist method, which included the understanding of gender as an analytical category in the field of labour law, opened up a new set of labour law issues. For example, in easing the ban on women working in physically demanding jobs, and the conceptualisation of the need to reconcile the professional and family duties of employees.. On the other hand, contemporary labour law, when creating conditions for achieving gender equality, is aimed primarily at women’s empowerment in the world of work. Persisting with this approach can lead to an oversimplified understanding of the principle of gender equality, ignoring the special needs of men in the world of work, as well as ignoring the importance of their role for consistent implementation of the principle of gender equality and women’s empowerment. The second section of the chapter will provide analysis of gender-based discrimination during the hiring process. Other sections will cover the risk of gender-based discrimination regarding rights, obligations and duties deriving from employment relationship, labour law measures to encourage improvements in the occupational safety and health, work-life balance for parents and caregivers, sexual harassment at work and promotion of gender equality in collective labour law.

The article deals with the issue of accent discrimination – the focus on prejudice against regional accents. It has been noted that lack of regional lexicon is one of the main reasons as to why ‘accentism’ is still going strong. It has been articulated that the reasons for glottophobia are hegemony of the monolingualism in France and class divisions in Britain that can lead to a skewed view of the world. Examples of accent bias are given. It has been found that there is currently no legislation to protect someone from accent discrimination. It has been studied that ‘Received Pronunciation’ or the ‘Queen’s English’ in Britain and standardized French in France seem to sound ‘very intelligent’ and it is a wide held view. It is being identified that academic institutions still support the idea of a single language model and accent prejudice. It has been concluded that in multicultural and multilingual Britain and France the solution is reasonable accommodation. It is required that the speaker is to make themselves understood whatever accent they choose.

In the United States, historical oppression and discrimination have barred certain groups based on their gender, race, religion, sexuality, and socioeconomic class from full participation in higher education. While there has been a long history of protest and pressure to diversify, progress has been mixed. After a recent wave of protests at Brown University, Richard M. Locke faced the task of developing a realistic and coherent university plan for addressing concerns and demands. Implementing insights from Joshua Cohen’s work on deliberation, Locke led a process that resulted in one of the most ambitious university diversity and inclusion action plans in the country. In this chapter, Locke describes the process undertaken and seeks to generalize from the experience at Brown to argue that collective deliberation can be an effective model for how universities can address an array of complex issues faced today.

After World War II and through the 1960s, Asian Americans began a transformative process, from being the “yellow peril” to becoming the model minority, and Asian Americans in the South experienced, to some degree, the same transformation. The war and its mottos of fighting for freedom and democracy at home and abroad affected the way Americans viewed their own hypocrisy toward minorities in the United States. African Americans were the largest minority group to use the aims of the war to demand attention to their plight with Jim Crow, prompting the growth of a nationwide civil rights movement, but Americans also came to view the century-old forms of legal discrimination against Asian immigrants and Asian Americans in a new light. Not only did Congress repeal the Chinese Exclusion Act in 1943 (making it legal for some Chinese to naturalize and allowing a small number of Chinese immigrants to enter the United States), but Filipino Americans and Indian Americans received similar treatment during and after World War II. In 1952, the McCarran-Walter Act (or the Immigration and Nationality Act of 1952), although designed to protect American security during the early Cold War by prohibiting and deporting subversive aliens, also made it possible for Asian immigrants of all ethnicities to become American citizens (while the number of Asians admitted to the United States did not drastically increase). Americans also viewed the ability of Japanese Americans to overcome the massive civil rights violations of wartime imprisonment and achieve economic and educational success as a model for all minorities to follow. Asian Americans came through the fires of World War II and proved that they were loyal Americans and deserving of equal treatment and respect, and while more subtle and sometimes not so subtle forms of racism and discrimination ...

Liberal scholars have historically stressed the role of NGOs, including churches, in world politics. Recently, scholars have also stressed the normative influence of religious actors as agents in international relations. The seventh chapter examines the role of the Catholic Church in the Northern Ireland peace process by analysing the theological basis of Catholic attitudes and beliefs regarding peace and the manifestations of these teachings as applied by bishops in Northern Ireland. The chapter demonstrates that faith creates action and explains how an important religious tradition in Northern Ireland promoted peace by recognizing and responding to the new kind of wars and political conflicts that have emerged in recent decades. As the nature of conflict changed from a state-centred model into one which saw civil wars and ethnic-conflict becoming the norm, so too did Catholic responses; national Churches began to realise that protest and non-violent action was no longer enough to create a more peaceful world. Consequently, the Catholic hierarchy in Northern Ireland sought to achieve peace by working for justice, especially for political prisoners and those who suffered discrimination.

Proteomic studies or studies of protein expression levels are growing swiftly with the steady improvement in technology and knowledge on understanding various anomalies affecting humans. Since differentially expressed proteins have an influence on overall cell functionality, this improves discrimination between healthy and diseased states. Identifying prime proteins offers prospective insights for developing optimized and targeted treatment methods. This research involves analyzing data from an early-stage study whose main purpose was to identify differentially expressed proteins. The presence of 3 progressively serious states of disease (healthy to mild to severe) escalates the importance of this study because there is not much research literature that considers ordinal outcomes in studies of this nature. The analysis can be segregated into 2 stages, univariate and multiprotein analysis. Approach of the univariate analysis was to implement continuation ratio model considering one protein at a time to pick those that exhibits potential ordinality. Penalized continuation ratio model using lasso regularization incorporated with bootstrapping proteins was performed as the next stage to identify protein combinationsthat perform well together. Compound results of the univariate and multi-protein analysis identified 20 most dominant proteins that have the capability to discriminate between the disease states in an ordinal manner satisfactorily. Keywords: Proteomic studies; Ordinal nature; Trend tests; Lasso regularization; Bootstrapping