scholarly journals Structural basis for the biosynthesis of lovastatin

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jialiang Wang ◽  
Jingdan Liang ◽  
Lu Chen ◽  
Wei Zhang ◽  
Liangliang Kong ◽  
...  
Keyword(s):  
Structural Basis ◽  
Cholesterol Lowering ◽  
Enoyl Reductase ◽  
Face To Face ◽  
The Core ◽  
Catalytic Domains ◽  
Structural Details ◽  
Architectural Model ◽  
The Individual ◽  
Structural Insights

AbstractStatins are effective cholesterol-lowering drugs. Lovastatin, one of the precursors of statins, is formed from dihydromonacolin L (DML), which is synthesized by lovastatin nonaketide synthase (LovB), with the assistance of a separate trans-acting enoyl reductase (LovC). A full DML synthesis comprises 8 polyketide synthetic cycles with about 35 steps. The assembling of the LovB–LovC complex, and the structural basis for the iterative and yet permutative functions of the megasynthase have remained a mystery. Here, we present the cryo-EM structures of the LovB–LovC complex at 3.60 Å and the core LovB at 2.91 Å resolution. The domain organization of LovB is an X-shaped face-to-face dimer containing eight connected domains. The binding of LovC laterally to the malonyl-acetyl transferase domain allows the completion of a L-shaped catalytic chamber consisting of six active domains. This architecture and the structural details of the megasynthase provide the basis for the processing of the intermediates by the individual catalytic domains. The detailed architectural model provides structural insights that may enable the re-engineering of the megasynthase for the generation of new statins.

scholarly journals Structural basis for plazomicin antibiotic action and resistance

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Tolou Golkar ◽  
Angelia V. Bassenden ◽  
Krishnagopal Maiti ◽  
Dev P. Arya ◽  
T. Martin Schmeing ◽  
...  
Keyword(s):  
Mrna Translation ◽  
Structural Data ◽  
Structural Basis ◽  
Clinical Settings ◽  
Mechanisms Of Resistance ◽  
The Core ◽  
Clinical Resistance ◽  
A Site ◽  
The Impact ◽  
Structural Insights

AbstractThe approval of plazomicin broadened the clinical library of aminoglycosides available for use against emerging bacterial pathogens. Contrarily to other aminoglycosides, resistance to plazomicin is limited; still, instances of resistance have been reported in clinical settings. Here, we present structural insights into the mechanism of plazomicin action and the mechanisms of clinical resistance. The structural data reveal that plazomicin exclusively binds to the 16S ribosomal A site, where it likely interferes with the fidelity of mRNA translation. The unique extensions to the core aminoglycoside scaffold incorporated into the structure of plazomicin do not interfere with ribosome binding, which is analogously seen in the binding of this antibiotic to the AAC(2′)-Ia resistance enzyme. The data provides a structural rationale for resistance conferred by drug acetylation and ribosome methylation, i.e., the two mechanisms of resistance observed clinically. Finally, the crystal structures of plazomicin in complex with both its target and the clinically relevant resistance factor provide a roadmap for next-generation drug development that aims to ameliorate the impact of antibiotic resistance.

scholarly journals mSphere of Influence: Structural Insights into the Molecular Mechanism Underlying Placental Malaria

mSphere ◽  
2021 ◽  
Vol 6 (3) ◽  
Author(s):  
Maria del Pilar Quintana
Keyword(s):  
Plasmodium Falciparum ◽  
Chondroitin Sulfate ◽  
Placental Malaria ◽  
Structural Basis ◽  
Content Type ◽  
Link Type ◽  
Structural Details ◽  
Inhibitory Antibodies ◽  
Structural Insights ◽  
Insight Into

ABSTRACT Maria del Pilar Quintana works on immunology and pathogenesis of severe malaria. In this mSphere of Influence article, she reflects on how the papers “Structural basis for placental malaria mediated by Plasmodium falciparum VAR2CSA” (R. Ma, T. Lian, R. Huang, J. P. Renn, J. D. Petersen, J. Zimmerberg, P. E. Duffy, N. H. Tolia, Nat Microbiol 6:380–391, 2021, https://doi.org/10.1038/s41564-020-00858-9) and “Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding” (K. Wang, R. Dagil, T. Lavsten, S. K. Misra, C. B. Spliid, Y. Wang, T. Gustavsson, D. R. Sandoval, E. E. Vidal-Calvo, S. Choudary, M. O. Agerback, K. Lindorff-Larsen, M. A. Nielsen, T. G. Theander, J. S. Sharp, T. M. Clausen, P. Gourdon, A. Salanti [Research Square preprint], 2021, https://doi.org/10.21203/rs.3.rs-121821/v1) shed light on the precise structural details behind Plasmodium falciparum VAR2CSA binding to chondroitin sulfate A (CSA) in the placenta and how these novel insights have changed the way she will approach her work toward the discovery of new broadly cross-reactive/inhibitory antibodies targeting VAR2CSA.

Reply to Connor and Evers (2020): Critique of the Bias of Crowds Model Simply Restates the Model

2020 ◽  
Author(s):  
Keith Payne ◽  
Heidi A. Vuletich ◽  
Kristjen B. Lundberg
Keyword(s):  
Implicit Bias ◽  
Group Level ◽  
Systemic Racism ◽  
Individual Level ◽  
The Core ◽  
Psychological Science ◽  
Implicit Biases ◽  
The Individual

The Bias of Crowds model (Payne, Vuletich, & Lundberg, 2017) argues that implicit bias varies across individuals and across contexts. It is unreliable and weakly associated with behavior at the individual level. But when aggregated to measure context-level effects, the scores become stable and predictive of group-level outcomes. We concluded that the statistical benefits of aggregation are so powerful that researchers should reconceptualize implicit bias as a feature of contexts, and ask new questions about how implicit biases relate to systemic racism. Connor and Evers (2020) critiqued the model, but their critique simply restates the core claims of the model. They agreed that implicit bias varies across individuals and across contexts; that it is unreliable and weakly associated with behavior at the individual level; and that aggregating scores to measure context-level effects makes them more stable and predictive of group-level outcomes. Connor and Evers concluded that implicit bias should be considered to really be noisily measured individual construct because the effects of aggregation are merely statistical. We respond to their specific arguments and then discuss what it means to really be a feature of persons versus situations, and multilevel measurement and theory in psychological science more broadly.

Pathways to Success Through Identity-Based Motivation

2015 ◽  
Author(s):  
Daphna Oyserman
Keyword(s):  
The Self ◽  
The Core ◽  
Very Young Children ◽  
The Future ◽  
Identity Based ◽  
Future Self ◽  
Fidelity Measures ◽  
The Individual ◽  
Taking Action ◽  
Minimal Effort

Everyone can imagine their future self, even very young children, and this future self is usually positive and education-linked. To make progress toward an aspired future or away from a feared future requires people to plan and take action. Unfortunately, most people often start too late and commit minimal effort to ineffective strategies that lead their attention elsewhere. As a result, their high hopes and earnest resolutions often fall short. In Pathways to Success Through Identity-Based Motivation Daphna Oyserman focuses on situational constraints and affordances that trigger or impede taking action. Focusing on when the future-self matters and how to reduce the shortfall between the self that one aspires to become and the outcomes that one actually attains, Oyserman introduces the reader to the core theoretical framework of identity-based motivation (IBM) theory. IBM theory is the prediction that people prefer to act in identity-congruent ways but that the identity-to-behavior link is opaque for a number of reasons (the future feels far away, difficulty of working on goals is misinterpreted, and strategies for attaining goals do not feel identity-congruent). Oyserman's book goes on to also include the stakes and how the importance of education comes into play as it improves the lives of the individual, their family, and their society. The framework of IBM theory and how to achieve it is broken down into three parts: how to translate identity-based motivation into a practical intervention, an outline of the intervention, and empirical evidence that it works. In addition, the book also includes an implementation manual and fidelity measures for educators utilizing this book to intervene for the improvement of academic outcomes.

scholarly journals Eye contact effect: The role of vagal regulation and reactivity, and self-regulation of attention

2021 ◽  
Author(s):  
Alicja Niedźwiecka
Keyword(s):  
Executive Functions ◽  
Cognitive Performance ◽  
Self Regulation ◽  
Eye Contact ◽  
Autonomic Regulation ◽  
Face To Face ◽  
Effective Strategies ◽  
Contact Effect ◽  
The Individual

AbstractEye contact is a crucial aspect of social interactions that may enhance an individual’s cognitive performance (i.e. the eye contact effect) or hinder it (i.e. face-to-face interference effect). In this paper, I focus on the influence of eye contact on cognitive performance in tasks engaging executive functions. I present a hypothesis as to why some individuals benefit from eye contact while others do not. I propose that the relations between eye contact and executive functioning are modulated by an individual’s autonomic regulation and reactivity and self-regulation of attention. In particular, I propose that individuals with more optimal autonomic regulation and reactivity, and more effective self-regulation of attention benefit from eye contact. Individuals who are less well regulated and over- or under-reactive and who do not employ effective strategies of self-regulation of attention may not benefit from eye contact and may perform better when eye contact is absent. I present some studies that justify the proposed hypothesis and point to a method that could be employed to test them. This approach could help to better understand the complex mechanisms underlying the individual differences in participant’s cognitive performance during tasks engaging executive functions.

Bioinformatics analysis of bacteriophage and prophage endolysin domains

Biologia ◽  
2014 ◽  
Vol 69 (5) ◽  
Author(s):  
Barbora Vidová ◽  
Zuzana Šramková ◽  
Lenka Tišáková ◽  
Michaela Oravkinová ◽  
Andrej Godány
Keyword(s):  
Antimicrobial Properties ◽  
In Silico Analysis ◽  
Multiple Sequence ◽  
Catalytic Domains ◽  
Binding Domains ◽  
Multiresistant Bacteria ◽  
Or Gene ◽  
The Individual ◽  
Conserved Amino Acids ◽  
Sequence Types

AbstractEndolysins as a class of antibacterial enzymes are expected to become a very useful tool for many purposes to control spreading of, e.g., multiresistant bacteria in different environments. Their antimicrobial properties could be broadened or altered by mutagenesis, domain swapping or gene shuffling. Therefore, the specific designing of endolysins to achieve their desired properties is challenging. This work is focused on the in silico analysis of protein domains presence in sequences of phage and prophage endolysins, followed by the study of variety of domain combinations in the individual endolysin types. The multiple sequence alignment of endolysin sequences revealed the recognition of sequence types with typical domain arrangement and conserved amino acids, divided according to the target substrate in bacterial cell walls. The five protein families of catalytic domains are specifically occurring in dependence of bacterial Gram-type. The presence, types and numbers of binding domains within endolysin sequences were also studied. The obtained results enable a more targeted design of endolysins with required antimicrobial properties.

scholarly journals Cognitive–behavioural therapy with older people

2007 ◽  
Vol 13 (2) ◽  
pp. 111-118 ◽  
Author(s):  
Ceri Evans
Keyword(s):  
Older People ◽  
Effective Treatment ◽  
Psychiatric Disorders ◽  
Cognitive Behavioural Therapy ◽  
Historical Context ◽  
Behavioural Therapy ◽  
Age Group ◽  
The Core ◽  
Cognitive Behavioural ◽  
The Individual

Cognitive–behavioural therapy (CBT) is an effective treatment for a number of psychiatric disorders in adults of all ages. With the proportion of the population aged 65 or over increasing steadily, it is important to be aware of how the CBT needs of this age group can be best met. This article provides an overview of CBT and the historical context of using it with older people. Although an understanding of the individual, irrespective of age, is at the core of CBT, potential modifications to the procedure and content aimed at optimising its effectiveness for older people are discussed.

ЦЕННОСТИ И СМЫСЛЫ НЕНАСИЛИЯ В ПОЛИТИЧЕСКОМ ПРОТЕСТЕ

2021 ◽  
Vol 15 (4) ◽  
pp. 58
Author(s):  
Л. Ю. Логунова ◽  
Е. А. Маженина
Keyword(s):  
Political Culture ◽  
New Left ◽  
Political Protest ◽  
Self Awareness ◽  
Sociological Study ◽  
The Core ◽  
Long Term Study ◽  
History Of ◽  
The Individual ◽  
Left Movement

The article presents the results of a long-term study of protest as a cultural phenomenon, the transformation of values, realized in the activities of the best people of the planet and their followers. These values have absorbed the experience of many generations and the behavior of people defending the rights of an individual to dignity, equality before the law, fair attitude, freedom of thought. In the history of the development of political thought, values have formed that constitute the core of civil culture. The genesis of the birth of the nucleus of civil culture from the thinkers of Antiquity, ideologists of nonviolent resistance, leaders of the French bourgeois revolution, activists of the “new left” movement to the protests of our time is shown. The basis for updating the protection of these values is the socio-political situation, characterized by the divergence of interests of civil society and ruling political groups. The values of the core of civil culture (freedom of speech, freedom of conscience, freedom of assembly, human rights) acquire an acute urgency in situations of power crisis. This is the time of the birth of new values that will mobilize new generations of protesters. Protest, as an act of protecting the values of the individual, is a measure of the level of development of political culture in the state. The protest — it's not just a mass exit of dissent on the area. This is an indicator of the level of self-awareness of citizens and the development of the political culture of society. The symbols of political protest actions are a special text that expresses the meanings of values. The authors present the results of a sociological study, which used comparative, value-semantic, interpretive approaches, studied the meanings and values of political protests of the 20th — early 19th centuries, analyzed visual and publicistic evidence of protest actions: photo and video materials, publications in the press.

scholarly journals Effectiveness of the Nutritional App “MyNutriCart” on Food Choices Related to Purchase and Dietary Behavior: A Pilot Randomized Controlled Trial

Nutrients ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 1967 ◽  
Author(s):  
Cristina Palacios ◽  
Michelle Torres ◽  
Desiree López ◽  
Maria Trak-Fellermeier ◽  
Catherine Coccia ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Intervention Group ◽  
Smartphone Application ◽  
Analysis Of Covariance ◽  
Baseline Body Mass Index ◽  
Traditional Group ◽  
Face To Face ◽  
Cured Meats ◽  
Food Recalls ◽  
The Individual

Objective: To pilot test the effectiveness of “MyNutriCart”, a smartphone application (app) that generates healthy grocery lists, on diet and weight. Methods: A pilot randomized trial was conducted to test the efficacy of using the “MyNutriCart” app compared to one face-to-face counseling session (Traditional group) in Hispanic overweight and obese adults. Household food purchasing behavior, three 24-h food recalls, Tucker’s semi-quantitative food frequency questionnaire (FFQ), and weight were assessed at baseline and after 8 weeks. Statistical analyses included t tests, a Poisson regression model, and analysis of covariance (ANCOVA) using STATA. Results: 24 participants in the Traditional group and 27 in the App group completed the study. Most participants were women (>88%), with a mean age of 35.3 years, more than a high school education (>80%), a family composition of at least three members, and a mean baseline body mass index (BMI) of 34.5 kg/m2. There were significant improvements in household purchasing of vegetables and whole grains, in individual intakes of refined grains, healthy proteins, whole-fat dairies, legumes, 100% fruit juices, and sweets and snacks; and in the individual frequency of intake of fruits and cold cuts/cured meats within the intervention group (p < 0.05). However, no significant differences were found between groups. No changes were detected in weight. Conclusions: “MyNutriCart” app use led to significant improvements in food-related behaviors compared to baseline, with no significant differences when compared to the Traditional group. Cost and resource savings of using the app compared to face-to-face counseling may make it a good option for interventionists.

Structural insights into the substrate specificity of a glycoside hydrolase family 5 lichenase from Caldicellulosiruptor sp. F32

2017 ◽  
Vol 474 (20) ◽  
pp. 3373-3389 ◽  
Author(s):  
Dong-Dong Meng ◽  
Xi Liu ◽  
Sheng Dong ◽  
Ye-Fei Wang ◽  
Xiao-Qing Ma ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Substrate Specificity ◽  
Glycoside Hydrolase ◽  
Complex Structure ◽  
Dynamics Simulation ◽  
Structural Basis ◽  
Glycoside Hydrolase Family ◽  
Substrate Selectivity ◽  
Glucose Residue ◽  
Structural Insights

Glycoside hydrolase (GH) family 5 is one of the largest GH families with various GH activities including lichenase, but the structural basis of the GH5 lichenase activity is still unknown. A novel thermostable lichenase F32EG5 belonging to GH5 was identified from an extremely thermophilic bacterium Caldicellulosiruptor sp. F32. F32EG5 is a bi-functional cellulose and a lichenan-degrading enzyme, and exhibited a high activity on β-1,3-1,4-glucan but side activity on cellulose. Thin-layer chromatography and NMR analyses indicated that F32EG5 cleaved the β-1,4 linkage or the β-1,3 linkage while a 4-O-substitued glucose residue linked to a glucose residue through a β-1,3 linkage, which is completely different from extensively studied GH16 lichenase that catalyses strict endo-hydrolysis of the β-1,4-glycosidic linkage adjacent to a 3-O-substitued glucose residue in the mixed-linked β-glucans. The crystal structure of F32EG5 was determined to 2.8 Å resolution, and the crystal structure of the complex of F32EG5 E193Q mutant and cellotetraose was determined to 1.7 Å resolution, which revealed that the exit subsites of substrate-binding sites contribute to both thermostability and substrate specificity of F32EG5. The sugar chain showed a sharp bend in the complex structure, suggesting that a substrate cleft fitting to the bent sugar chains in lichenan is a common feature of GH5 lichenases. The mechanism of thermostability and substrate selectivity of F32EG5 was further demonstrated by molecular dynamics simulation and site-directed mutagenesis. These results provide biochemical and structural insights into thermostability and substrate selectivity of GH5 lichenases, which have potential in industrial processes.

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