Lipoprotein-associated phospholipase A2: A paradigm for allosteric regulation by membranes

Lipoprotein-associated phospholipase A2 (Lp-PLA2) associates with low- and high-density lipoproteins in human plasma and specifically hydrolyzes circulating oxidized phospholipids involved in oxidative stress. The association of this enzyme with the lipoprotein’s phospholipid monolayer to access its substrate is the most crucial first step in its catalytic cycle. The current study demonstrates unequivocally that a significant movement of a major helical peptide region occurs upon membrane binding, resulting in a large conformational change upon Lp-PLA2 binding to a phospholipid surface. This allosteric regulation of an enzyme’s activity by a large membrane-like interface inducing a conformational change in the catalytic site defines a unique dimension of allosterism. The mechanism by which this enzyme associates with phospholipid interfaces to select and extract a single phospholipid substrate molecule and carry out catalysis is key to understanding its physiological functioning. A lipidomics platform was employed to determine the precise substrate specificity of human recombinant Lp-PLA2 and mutants. This study uniquely elucidates the association mechanism of this enzyme with membranes and its resulting conformational change as well as the extraction and binding of specific oxidized and short acyl-chain phospholipid substrates. Deuterium exchange mass spectrometry coupled with molecular dynamics simulations was used to define the precise specificity of the subsite for the oxidized fatty acid at the sn-2 position of the phospholipid backbone. Despite the existence of several crystal structures of this enzyme cocrystallized with inhibitors, little was understood about Lp-PLA2‘s specificity toward oxidized phospholipids.

Verismo opera: how bel canto technique protected the voices of its singers

<p>Verismo is a style of opera composition that was influenced by a significant movement in Italian literature from the end of the nineteenth century to the beginning of the twentieth century. It is characterised by the true-to-life portrayal of rural or urban poverty, often showing a robust regional lifestyle as well as serving as the introduction to the region's representative songs and dances. Historically, the singing of verismo opera posed some problems for singers in regards to their stamina and the longevity of their career. As a student, I attempted to sing this type of music, but I felt unable to sing it well; my difficulties and the problems associated with the performance of verismo, therefore, fascinated me. Rationalising that proper vocal technique was the answer to these problems, I then concentrated on long-term systematic bel canto training in China and New Zealand. In most cases, the study of bel canto technique is a fundamental part of the process of learning vocal music for classical singers. In addition to laying out the background of verismo and bel canto, my exegesis demonstrates how singers can learn to sing verismo opera well without damaging their voices, which will help them extend their stamina and the length of their career. I especially investigate the differing use of the body needed for singing each type of music. Researching bel canto, I have listened to different singers' recordings and have written short critiques of their voices, focusing on how they developed bel canto to sing verismo. I have focused on bel canto and verismo works for my repertoire and can apply the techniques safely based on bel canto training. To articulate this knowledge, I take three different arias (one bel canto aria, two verismo arias) as case studies to analyse, to demonstrate the points I want to make. In addition, as a native Mandarin Chinese speaker, I focus on how Mandarin native speakers deal with singing Italian, and I articulate techniques to help other Mandarin speakers learn bel canto. Overall, my research will have practical and artistic value for younger students in helping them to understand the challenges of singing verismo opera.</p>

Verismo opera: how bel canto technique protected the voices of its singers

<p>Verismo is a style of opera composition that was influenced by a significant movement in Italian literature from the end of the nineteenth century to the beginning of the twentieth century. It is characterised by the true-to-life portrayal of rural or urban poverty, often showing a robust regional lifestyle as well as serving as the introduction to the region's representative songs and dances. Historically, the singing of verismo opera posed some problems for singers in regards to their stamina and the longevity of their career. As a student, I attempted to sing this type of music, but I felt unable to sing it well; my difficulties and the problems associated with the performance of verismo, therefore, fascinated me. Rationalising that proper vocal technique was the answer to these problems, I then concentrated on long-term systematic bel canto training in China and New Zealand. In most cases, the study of bel canto technique is a fundamental part of the process of learning vocal music for classical singers. In addition to laying out the background of verismo and bel canto, my exegesis demonstrates how singers can learn to sing verismo opera well without damaging their voices, which will help them extend their stamina and the length of their career. I especially investigate the differing use of the body needed for singing each type of music. Researching bel canto, I have listened to different singers' recordings and have written short critiques of their voices, focusing on how they developed bel canto to sing verismo. I have focused on bel canto and verismo works for my repertoire and can apply the techniques safely based on bel canto training. To articulate this knowledge, I take three different arias (one bel canto aria, two verismo arias) as case studies to analyse, to demonstrate the points I want to make. In addition, as a native Mandarin Chinese speaker, I focus on how Mandarin native speakers deal with singing Italian, and I articulate techniques to help other Mandarin speakers learn bel canto. Overall, my research will have practical and artistic value for younger students in helping them to understand the challenges of singing verismo opera.</p>

Strategies for Developing an Inclusive Geriatric Physician Workforce for Older Adults in the U.S

The “geriatric imperative” has been part of the aging discourse for more than 30 years but neither geriatric practice nor older adults are homogenous. As the U.S. population ages, elders will become more racially and ethnically diverse; and, their health outcomes will be shaped by lifetime experiences with systemic discrimination and racism. Already, COVID-19 has made clear that older adults and non-Whites, particularly African Americans and Hispanics, disproportionately bear the burden of disease and illness. Research suggests health disparities will continue unless there is change within the health care system. The Institute of Medicine (2001) reported on the problematic nature of the stark contrast between the diversity of patients and the physicians caring for them, including issues with patient trust and communication, yet no significant movement has been made to diversify the physician workforce. Despite being 13% and 16% of the U.S. population, respectively, African Americans and Hispanics make up just 5% and 6% of the practicing physician workforce. Further, practicing geriatricians represent less than 1% of physicians with very few physicians of color. There is a need for more African American and Hispanic geriatricians. In this systematic review, we examine recruitment and retention efforts targeting students of color, and curricula of geriatric medical programs in the U.S. We offer recommendations toward incentivizing physicians of color to enter geriatrics, strategies to support decolonization of geriatric medical curricula in undergraduate medical education programs, and the development of mentorship and pipeline programs to increase diversity in the geriatric physician workforce.

A Mana Wahine Critical Analysis of New Zealand Legislation Concerning Education: Implications for Addressing Māori Social Disadvantage

<p>Theory and practice are intertwined, woven inextricably together by the way that each informs and is informed by the other (Moss 2002, Pihama 2001, Simmonds 2009). This research confronts and analyses the legal bases of gendered and race-based inequalities by critically analysing New Zealand social policy legislation through a mana wahine perspective. Mana wahine and critical policy analysis share common goals to challenge dominant theoretical and methodological norms in order to recognise unequal power distributions, of which colonisation is implicit (Tomlins-Jahnke 1997). This research has been guided by a reading of literature that suggests Māori social disadvantage has become ingrained and that policies designed to address this inequality and to include Māori people and Māori perspectives in mainstreamed systems are both confusing, and yet to be successful. This study has been designed to explore present policy legislation concerning social development. A case study of the education system has been used, which draws on historic and more contemporary Western political agendas as reflected in legislative shifts. Key findings of this research include the exclusion of mana wahine through the ongoing processes of colonisation that do not give rise to Māori cultural understandings. To summarise, the social policy context at present is characterised by: Māori demands for greater self-determination; an absence of Treaty rights for Māori; liberal interpretations of Treaty principles, and scant processes to implement them; a devoid of aspects pertinent to mana wahine, and; the contradiction between Government's articulated position on rights and inclusion in social policy and the language used in and concepts enforced by legislation. The findings are significant and reveal the ongoing complexities of Indigenous inequalities in the context of widespread policy ‘commitment’ to inclusion and equality. The central argument developed throughout this study is that there is an urgent need to shift policy thinking toward Māori if there is to be a significant movement toward justice for Māori women, which will involve Māori-centred decolonisation and the inclusion of aspects pertinent to mana wahine.</p>

A Mana Wahine Critical Analysis of New Zealand Legislation Concerning Education: Implications for Addressing Māori Social Disadvantage

<p>Theory and practice are intertwined, woven inextricably together by the way that each informs and is informed by the other (Moss 2002, Pihama 2001, Simmonds 2009). This research confronts and analyses the legal bases of gendered and race-based inequalities by critically analysing New Zealand social policy legislation through a mana wahine perspective. Mana wahine and critical policy analysis share common goals to challenge dominant theoretical and methodological norms in order to recognise unequal power distributions, of which colonisation is implicit (Tomlins-Jahnke 1997). This research has been guided by a reading of literature that suggests Māori social disadvantage has become ingrained and that policies designed to address this inequality and to include Māori people and Māori perspectives in mainstreamed systems are both confusing, and yet to be successful. This study has been designed to explore present policy legislation concerning social development. A case study of the education system has been used, which draws on historic and more contemporary Western political agendas as reflected in legislative shifts. Key findings of this research include the exclusion of mana wahine through the ongoing processes of colonisation that do not give rise to Māori cultural understandings. To summarise, the social policy context at present is characterised by: Māori demands for greater self-determination; an absence of Treaty rights for Māori; liberal interpretations of Treaty principles, and scant processes to implement them; a devoid of aspects pertinent to mana wahine, and; the contradiction between Government's articulated position on rights and inclusion in social policy and the language used in and concepts enforced by legislation. The findings are significant and reveal the ongoing complexities of Indigenous inequalities in the context of widespread policy ‘commitment’ to inclusion and equality. The central argument developed throughout this study is that there is an urgent need to shift policy thinking toward Māori if there is to be a significant movement toward justice for Māori women, which will involve Māori-centred decolonisation and the inclusion of aspects pertinent to mana wahine.</p>

In Vivo Three-dimensional Kinematics of Normal Knees During Sitting Sideways

Background The normal knee kinematics during asymmetrical kneeling such as the sitting sideways remains unknown. This study aimed to clarify in vivo kinematics during sitting sideways of normal knees. Methods Twelve knees from six volunteers were examined. Under fluoroscopy, each volunteer performed a sitting sideways. A two-dimensional/three-dimensional registration technique was used. The rotation angle, varus-valgus angle, anteroposterior translation of the medial and lateral sides of the femur relative to the tibia, and kinematic pathway in each flexion angle was evaluated. Results Bilateral knees during sitting sideways showed a femoral external rotation relative to the tibia with flexion. Whereas the ipsilateral knees showed valgus movement, and the contralateral knees showed varus movement. The medial side of the contralateral knees was more posteriorly located than that of the ipsilateral knees beyond 110° of flexion. The lateral side of the contralateral knees was more anteriorly located than that of the ipsilateral knees from 120° to 150° of flexion. In the ipsilateral knees, a medial pivot pattern followed by a bicondylar rollback was observed. In the contralateral knees, no significant movement followed by a bicondylar rollback was observed. Conclusion Even though the asymmetrical kneeling such as sitting sideways, the knees did not display asymmetrical movement.

Introduction

In the past few decades, in social work and other helping professions, there has been a significant movement toward establishing evidence-based practice (EBP) interventions for persons who experience a variety of mental, emotional, and behavioral problems. EBP interventions are those that have been empirically tested and found to be effective with persons who receive certain mental health diagnoses (...

The Blob and the Mob

This chapter explores social movements as a new lens through which to approach grand strategy. Although grand strategists and social movement strategists often view each other as opposites, they have more to learn from each other—and more in common—than either group might think. Within the realm of strategic thought, there has long been significant intellectual overlap between military, political, and social-movement approaches. Far from standing apart from questions of war and peace, stability and instability, conflict and diplomacy, nearly every significant movement for social change has actively engaged these questions, including the real or potential use of violence. Around the world, still more radical movements, many of them at least nominally Marxist in orientation, produced vast literatures on the virtues and vices of revolutionary strategy, as well as the complex task of transforming members and leaders, after victory, from revolutionaries into statesmen. In modern Western democratic societies, social-change strategists tend to favor non-violent methods, but debates rage nonetheless.

Glycoside hydrolase family 5: structural snapshots highlighting the involvement of two conserved residues in catalysis

The ability of retaining glycoside hydrolases (GHs) to transglycosylate is inherent to the double-displacement mechanism. Studying reaction intermediates, such as the glycosyl-enzyme intermediate (GEI) and the Michaelis complex, could provide valuable information to better understand the molecular factors governing the catalytic mechanism. Here, the GEI structure of RBcel1, an endo-1,4-β-glucanase of the GH5 family endowed with transglycosylase activity, is reported. It is the first structure of a GH5 enzyme covalently bound to a natural oligosaccharide with the two catalytic glutamate residues present. The structure of the variant RBcel1_E135A in complex with cellotriose is also reported, allowing a description of the entire binding cleft of RBcel1. Taken together, the structures deliver different snapshots of the double-displacement mechanism. The structural analysis revealed a significant movement of the nucleophilic glutamate residue during the reaction. Enzymatic assays indicated that, as expected, the acid/base glutamate residue is crucial for the glycosylation step and partly contributes to deglycosylation. Moreover, a conserved tyrosine residue in the −1 subsite, Tyr201, plays a determinant role in both the glycosylation and deglycosylation steps, since the GEI was trapped in the RBcel1_Y201F variant. The approach used to obtain the GEI presented here could easily be transposed to other retaining GHs in clan GH-A.