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 The Human Cost of 'Caring' Care for Registered Nurses in Clinical Practice

2021 ◽  
Author(s):  
◽  
Sylvia Margaret Shona Blair
Keyword(s):  
Clinical Practice ◽  
Registered Nurses ◽  
Public Hospital ◽  
Elderly Population ◽  
Nursing Practice ◽  
Clinical Settings ◽  
Health Reforms ◽  
The Core ◽  
Human Cost ◽  
The Impact

<p>This research utilised a focus group methodology to discover what nurses in clinical practice considered 'caring' care meant for them. Six registered nurses volunteered to participate in the project. They practised over a variety of clinical settings within a public hospital, which provided both acute and elective surgical and medical services to the community, including an extensive elderly population.  Taking these important 'caring' care statements, I then explored with the group what factors in their work environment hindered or enhanced their identified 'caring' care. New Zealand nurses identified similar themes and concepts important to their 'caring' in clinical practice as did their overseas counterparts.  This study also highlighted the impact the health reforms had on individual clinical practice at this hospital. The effects of the institutional changes in response to the health reforms were far reaching at both a personal and professional level.  Caring is an important concept found in nursing practice. It has been widely documented by nurse scholars, researchers and nurse authors that care is at the core of nursing practice. Some have even referred to care as being the heart of nursing. The findings from the present research indicates the importance nurses place on caring in their day to day encounters with patients. It also demonstrates how nurses express their care and their perceptions of the importance care has in their clinical practice.</p>

scholarly journals The Human Cost of 'Caring' Care for Registered Nurses in Clinical Practice

2021 ◽  
Author(s):  
◽  
Sylvia Margaret Shona Blair
Keyword(s):  
Clinical Practice ◽  
Registered Nurses ◽  
Public Hospital ◽  
Elderly Population ◽  
Nursing Practice ◽  
Clinical Settings ◽  
Health Reforms ◽  
The Core ◽  
Human Cost ◽  
The Impact

<p>This research utilised a focus group methodology to discover what nurses in clinical practice considered 'caring' care meant for them. Six registered nurses volunteered to participate in the project. They practised over a variety of clinical settings within a public hospital, which provided both acute and elective surgical and medical services to the community, including an extensive elderly population.  Taking these important 'caring' care statements, I then explored with the group what factors in their work environment hindered or enhanced their identified 'caring' care. New Zealand nurses identified similar themes and concepts important to their 'caring' in clinical practice as did their overseas counterparts.  This study also highlighted the impact the health reforms had on individual clinical practice at this hospital. The effects of the institutional changes in response to the health reforms were far reaching at both a personal and professional level.  Caring is an important concept found in nursing practice. It has been widely documented by nurse scholars, researchers and nurse authors that care is at the core of nursing practice. Some have even referred to care as being the heart of nursing. The findings from the present research indicates the importance nurses place on caring in their day to day encounters with patients. It also demonstrates how nurses express their care and their perceptions of the importance care has in their clinical practice.</p>

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.

Soziale Disziplinierung im flexiblen Kapitalismus

2004 ◽  
Vol 34 (136) ◽  
pp. 339-356
Author(s):  
Tobias Wölfle ◽  
Oliver Schöller
Keyword(s):  
Social Welfare ◽  
Second Step ◽  
Social Rights ◽  
Federal Law ◽  
Capitalist Development ◽  
The Core ◽  
The Past ◽  
The Impact ◽  
Municipal Level

Under the term “Hilfe zur Arbeit” (aid for work) the federal law of social welfare subsumes all kinds of labour disciplining instruments. First, the paper shows the historical connection of welfare and labour disciplining mechanisms in the context of different periods within capitalist development. In a second step, against the background of historical experiences, we will analyse the trends of “Hilfe zur Arbeit” during the past two decades. It will be shown that by the rise of unemployment, the impact of labour disciplining aspects of “Hilfe zur Arbeit” has increased both on the federal and on the municipal level. For this reason the leverage of the liberal paradigm would take place even in the core of social rights.

Fictive Fathers in the Field

2020 ◽  
Vol 1 (3) ◽  
pp. 265-273
Author(s):  
Katrina Daly Thompson
Keyword(s):  
Cultural Studies ◽  
Ethnographic Research ◽  
A Site ◽  
The Impact

Through my own narrative about my relationship with my fictive father in Zanzibar and the impact of this relationship on my research, in this autoethnographic essay I explore three themes: fictiveness, fatherhood, and the field. These themes tie together different aspects of the term “patriography,” linking them to ethnography and its subgenre autoethnography. Drawing on the term “patriography” as the science or study of fathers, I use the concept of “the field” to examine the impact of narratives about fathers on not only the field as a site of ethnographic research but also on the field of African cultural studies.

Citizen Deliberation Online

2019 ◽  
pp. 689-712
Author(s):  
Patrícia Rossini ◽  
Jennifer Stromer-Galley
Keyword(s):  
Political Engagement ◽  
Future Research ◽  
The Internet ◽  
Digital Platforms ◽  
The Core ◽  
Political Conversation ◽  
Political Talk ◽  
Citizen Deliberation ◽  
The Impact

Political conversation is at the heart of democratic societies, and it is an important precursor of political engagement. As society has become intertwined with the communication infrastructure of the Internet, we need to understand its uses and the implications of those uses for democracy. This chapter provides an overview of the core topics of scholarly concern around online citizen deliberation, focusing on three key areas of research: the standards of quality of communication and the normative stance on citizen deliberation online; the impact and importance of digital platforms in structuring political talk; and the differences between formal and informal political talk spaces. After providing a critical review of these three major areas of research, we outline directions for future research on online citizen deliberation.

Static and dynamic response of sandwich beams with lattice and pantographic cores

2021 ◽  
pp. 109963622110338
Author(s):  
Yury Solyaev ◽  
Arseniy Babaytsev ◽  
Anastasia Ustenko ◽  
Andrey Ripetskiy ◽  
Alexander Volkov
Keyword(s):  
Mechanical Performance ◽  
Lattice Structure ◽  
Unit Length ◽  
Experimental Tests ◽  
Plane Geometry ◽  
Sandwich Beams ◽  
Static Tests ◽  
Three Point Bending ◽  
The Core ◽  
The Impact

Mechanical performance of 3d-printed polyamide sandwich beams with different type of the lattice cores is investigated. Four variants of the beams are considered, which differ in the type of connections between the elements in the lattice structure of the core. We consider the pantographic-type lattices formed by the two families of inclined beams placed with small offset and connected by stiff joints (variant 1), by hinges (variant 2) and made without joints (variant 3). The fourth type of the core has the standard plane geometry formed by the intersected beams lying in the same plane (variant 4). Experimental tests were performed for the localized indentation loading according to the three-point bending scheme with small span-to-thickness ratio. From the experiments we found that the plane geometry of variant 4 has the highest rigidity and the highest load bearing capacity in the static tests. However, other three variants of the pantographic-type cores (1–3) demonstrate the better performance under the impact loading. The impact strength of such structures are in 3.5–5 times higher than those one of variant 4 with almost the same mass per unit length. This result is validated by using numerical simulations and explained by the decrease of the stress concentration and the stress state triaxiality and also by the delocalization effects that arise in the pantographic-type cores.

Comparative crosstalk performance analysis of different configurations of heterogeneous multicore fiber

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Umar Farooque ◽  
Rakesh Ranjan
Keyword(s):  
Refractive Index ◽  
Mode Coupling ◽  
The Other ◽  
Heterogeneous Multicore ◽  
Coupled Mode ◽  
The Core ◽  
Bending Radius ◽  
Multicore Fiber ◽  
The Impact ◽  
Core Pitch

AbstractIn order to select the heterogeneous multicore fiber (MCF) configuration with ultra-low crosstalk and low peak bending radius, comparative crosstalk analysis have been done for the three possible core configurations, namely, Configuration 1 - different refractive index (R.I.) and different radius, Configuration 2 - different R.I., and Configuration 3 - different radius. Using the coupled mode equation and the simplified expressions of mode coupling coefficient (MCC) for different configurations of heterogeneous cores, the crosstalk performance of all the heterogeneous MCF configurations along with the homogeneous MCF have been investigated analytically with respect to core pitch (D) and fiber bending radius (${R}_{b}$). Further, these expressions of MCC have been extended to obtain the simplified expressions of MCC for the estimation of crosstalk levels in respective trench-assisted (TA) heterogeneous MCF configurations. It is observed from the analysis that in Configuration 1, crosstalk level is lowest and the rate of decrease in the crosstalk with respect to the core pitch is highest compared to the other configurations of heterogeneous MCF. The values of crosstalk obtained analytically have been validated by comparing it with the values obtained from finite element method (FEM) based numerical simulation results. Further, we have investigated the impact of a fixed percent change (5%) in the core parameters (radius and/or R.I.) of one of the core of a homogeneous MCF, to realize the different heterogeneous MCF configurations, on the variations in crosstalk levels, difference in the mode effective refractive index of the core 1 and core 2 ($\Delta {n}_{eff}={n}_{eff1}-{n}_{eff2}$), and the peak bending radius (${R}_{pk}$). For the same percent variations (5%) in the core parameters (radius and/or R.I.) of different configurations of cores (Config. 1-Config. 3), Config. 1 MCF has highest variation in $\Delta {n}_{eff}$ value compared to other configurations of MCF. Further, this highest variation in $\Delta {n}_{eff}$ value of Config. 1 MCF results in smallest peak bending radius. The smaller value of peak bending radius allows MCF to bend into smaller radius. Therefore, Configuration 1 is the potential choice for the design of MCF with smaller peak bending radius and ultra-low crosstalk level compared to the other configurations of SI-heterogeneous MCF.

scholarly journals HPF1 remodels the active site of PARP1 to enable the serine ADP-ribosylation of histones

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Fa-Hui Sun ◽  
Peng Zhao ◽  
Nan Zhang ◽  
Lu-Lu Kong ◽  
Catherine C. L. Wong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Active Site ◽  
Negative Charge ◽  
Structural Data ◽  
Dna Breaks ◽  
Adp Ribosylation ◽  
Local Conformation ◽  
Key Residues ◽  
Structural Insights

AbstractUpon binding to DNA breaks, poly(ADP-ribose) polymerase 1 (PARP1) ADP-ribosylates itself and other factors to initiate DNA repair. Serine is the major residue for ADP-ribosylation upon DNA damage, which strictly depends on HPF1. Here, we report the crystal structures of human HPF1/PARP1-CAT ΔHD complex at 1.98 Å resolution, and mouse and human HPF1 at 1.71 Å and 1.57 Å resolution, respectively. Our structures and mutagenesis data confirm that the structural insights obtained in a recent HPF1/PARP2 study by Suskiewicz et al. apply to PARP1. Moreover, we quantitatively characterize the key residues necessary for HPF1/PARP1 binding. Our data show that through salt-bridging to Glu284/Asp286, Arg239 positions Glu284 to catalyze serine ADP-ribosylation, maintains the local conformation of HPF1 to limit PARP1 automodification, and facilitates HPF1/PARP1 binding by neutralizing the negative charge of Glu284. These findings, along with the high-resolution structural data, may facilitate drug discovery targeting PARP1.

scholarly journals Formation of GW190521 from stellar evolution: the impact of the hydrogen-rich envelope, dredge-up and 12C(α, γ)16O rate on the pair-instability black hole mass gap

2020 ◽  
Author(s):  
Guglielmo Costa ◽  
Alessandro Bressan ◽  
Michela Mapelli ◽  
Paola Marigo ◽  
Giuliano Iorio ◽  
...  
Keyword(s):  
Stellar Evolution ◽  
Reaction Rate ◽  
Primary Component ◽  
Mass Reduction ◽  
Black Hole Mass ◽  
Core Mass ◽  
The Core ◽  
Mass Gap ◽  
M Stars ◽  
The Impact

Abstract Pair-instability (PI) is expected to open a gap in the mass spectrum of black holes (BHs) between ≈40 − 65 M⊙ and ≈120 M⊙. The existence of the mass gap is currently being challenged by the detection of GW190521, with a primary component mass of $85^{+21}_{-14}$ M⊙. Here, we investigate the main uncertainties on the PI mass gap: the 12C(α, γ)16O reaction rate and the H-rich envelope collapse. With the standard 12C(α, γ)16O rate, the lower edge of the mass gap can be 70 M⊙ if we allow for the collapse of the residual H-rich envelope at metallicity Z ≤ 0.0003. Adopting the uncertainties given by the starlib database, for models computed with the 12C(α, γ)16O rate −1 σ, we find that the PI mass gap ranges between ≈80 M⊙ and ≈150 M⊙. Stars with MZAMS &gt; 110 M⊙ may experience a deep dredge-up episode during the core helium-burning phase, that extracts matter from the core enriching the envelope. As a consequence of the He-core mass reduction, a star with MZAMS = 160 M⊙ may avoid the PI and produce a BH of 150 M⊙. In the −2 σ case, the PI mass gap ranges from 92 M⊙ to 110 M⊙. Finally, in models computed with 12C(α, γ)16O −3 σ, the mass gap is completely removed by the dredge-up effect. The onset of this dredge-up is particularly sensitive to the assumed model for convection and mixing. The combined effect of H-rich envelope collapse and low 12C(α, γ)16O rate can lead to the formation of BHs with masses consistent with the primary component of GW190521.

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