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Cell Sep 2021The hidden world of amyloid biology has suddenly snapped into atomic-level focus, revealing over 80 amyloid protein fibrils, both pathogenic and functional. Unlike... (Review)
Review
The hidden world of amyloid biology has suddenly snapped into atomic-level focus, revealing over 80 amyloid protein fibrils, both pathogenic and functional. Unlike globular proteins, amyloid proteins flatten and stack into unbranched fibrils. Stranger still, a single protein sequence can adopt wildly different two-dimensional conformations, yielding distinct fibril polymorphs. Thus, an amyloid protein may define distinct diseases depending on its conformation. At the heart of this conformational variability lies structural frustrations. In functional amyloids, evolution tunes frustration levels to achieve either stability or sensitivity according to the fibril's biological function, accounting for the vast versatility of the amyloid fibril scaffold.
Topics: Amyloidogenic Proteins; Animals; Disease; Evolution, Molecular; Humans; Polymorphism, Genetic; Protein Folding; Protein Stability
PubMed: 34534463
DOI: 10.1016/j.cell.2021.08.013 -
RSC Medicinal Chemistry Jan 2022In this opinion piece I share personal anecdotes from three drug discovery projects, sugammadex an anaesthetic reversal agent from Organon Scotland, and ribociclib and...
In this opinion piece I share personal anecdotes from three drug discovery projects, sugammadex an anaesthetic reversal agent from Organon Scotland, and ribociclib and erdafitinib, both oncology drugs arising from Astex UK collaborations with Novartis and Janssen respectively. These drugs have been used to treat millions of patients. The learnings from this research focus on innovation, teamwork, and collaborations. Drug discovery, even with its frustrations and disappointments can be a great career for scientists in industry, in academia, or in a not-for-profit institute, who want their research to alleviate human suffering.
PubMed: 35211673
DOI: 10.1039/d1md00279a -
Molecules (Basel, Switzerland) Jan 2023The development and application of new organoboron reagents as Lewis acids in synthesis and metal-free catalysis have dramatically expanded over the past 20 years. In... (Review)
Review
The development and application of new organoboron reagents as Lewis acids in synthesis and metal-free catalysis have dramatically expanded over the past 20 years. In this context, we will show the recent uses of the simple and relatively weak Lewis acid BPh-discovered 100 years ago-as a metal-free catalyst for various organic transformations. The first part will highlight catalytic applications in polymer synthesis such as the copolymerization of epoxides with CO, isocyanate, and organic anhydrides to various polycarbonate copolymers and controlled diblock copolymers as well as alternating polyurethanes. This is followed by a discussion of BPh as a Lewis acid component in the frustrated Lewis pair (FLP) mediated cleavage of hydrogen and hydrogenation catalysis. In addition, BPh-catalyzed reductive N-methylations and C-methylations with CO and silane to value-added organic products will be covered as well along with BPh-catalyzed cycloadditions and insertion reactions. Collectively, this mini-review showcases the underexplored potential of commercially available BPh in metal-free catalysis.
PubMed: 36771006
DOI: 10.3390/molecules28031340 -
HCA Healthcare Journal of Medicine 2023Description Our EMRs should empower us, but unfortunately, they often bully and frustrate us. This poem is an expression of my frustration and disappointment with my own...
Description Our EMRs should empower us, but unfortunately, they often bully and frustrate us. This poem is an expression of my frustration and disappointment with my own EMR. Creating it allowed me to channel my frustration and disappointment.
PubMed: 37434907
DOI: 10.36518/2689-0216.1581 -
Journal of Molecular Biology Feb 2023Proteins interact with other proteins, with nucleic acids, lipids, carbohydrates and various small molecules in the living cell. These interactions have been quantified... (Review)
Review
Proteins interact with other proteins, with nucleic acids, lipids, carbohydrates and various small molecules in the living cell. These interactions have been quantified and structurally characterized in numerous studies such that we today have a comprehensive picture of protein structure and function. However, proteins are dynamic and even folded proteins are likely more heterogeneous than they appear in most descriptions. One property of proteins that relies on dynamics and heterogeneity is allostery, the ability of a protein to change structure and function upon ligand binding to an allosteric site. Over the last decades the concept of allostery was broadened to embrace all types of long-range interactions across a protein including purely entropic changes without a conformational change in single protein domains. But with this re-definition came a problem: How do we measure allostery? In this opinion, we discuss some caveats arising from the quantitative description of single-domain allostery from an experimental perspective and how the limitations cannot be separated from the definition of allostery per se. Furthermore, we attempt to tie together allostery with the concept of frustration in an effort to investigate the links between these two complex, and yet general, properties of proteins. We arrive at the conclusion that the sensitivity to perturbation of allosteric networks in single protein domains is too large for the networks to be of significant biological relevance.
Topics: Allosteric Regulation; Proteins; Allosteric Site; Entropy; Protein Domains
PubMed: 36586463
DOI: 10.1016/j.jmb.2022.167934 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... Nov 2022Preeclampsia-eclampsia is a common obstetric critical disease and obstetricians have studied it assiduously for hundreds of years. We have attempted to explore the... (Review)
Review
Preeclampsia-eclampsia is a common obstetric critical disease and obstetricians have studied it assiduously for hundreds of years. We have attempted to explore the etiology, pathology, prevention, intervention, and treatment of preeclampsia-eclampsia, but we still have not arrived at a thorough understanding of its causes, and it is difficult to find effective prevention and treatment methods. Although the research process has been fraught with difficulties and frustrations, we are nonetheless gradually gaining a better understanding of the disease. Perhaps, in the near future, we will be able to acquire a full understanding of the disease and find better ways to ensure the health and safety of mothers and fetuses.
Topics: Female; Pregnancy; Humans; Eclampsia; Pre-Eclampsia; Fetus
PubMed: 36443042
DOI: 10.12182/20221160203 -
Current Psychiatry Reports Nov 2020To review the current literature on biobehavioral mechanisms involved in reactive aggression in a transdiagnostic approach. (Review)
Review
PURPOSE OF REVIEW
To review the current literature on biobehavioral mechanisms involved in reactive aggression in a transdiagnostic approach.
RECENT FINDINGS
Aggressive reactions are closely related to activations in the brain's threat circuitry. They occur in response to social threat that is experienced as inescapable, which, in turn, facilitates angry approach rather than fearful avoidance. Provocation-induced aggression is strongly associated with anger and deficits in cognitive control including emotion regulation and inhibitory control. Furthermore, the brain's reward system plays a particular role in anger-related, tit-for-tat-like retaliatory aggression in response to frustration. More research is needed to further disentangle specific brain responses to social threat, provocation, and frustration. A better understanding of the psychological and neurobiological mechanisms involved in reactive aggression may pave the way for specific mechanism-based treatments, involving biological or psychotherapeutic approaches or a combination of the two.
Topics: Aggression; Anger; Brain; Humans; Reward
PubMed: 33180230
DOI: 10.1007/s11920-020-01208-6 -
The Liverpool Law Review 2022One of the key legal questions that COVID-19 has raised relates to the status of the traditional contractual doctrine of frustration. The pandemic and the ongoing...
One of the key legal questions that COVID-19 has raised relates to the status of the traditional contractual doctrine of frustration. The pandemic and the ongoing lockdowns across the globe have made it difficult for many contracts to perform. At the same time, there is a deep doctrinal and conceptual confusion with respect to the very essentials of this doctrine and its remedy - i.e., what happens after an adjudicative tribunal declares that a given contract has been frustrated. The paper offers a unified conceptual account of the frustration doctrine and claims that both the doctrine and its remedy crystallize a single unifying idea.
PubMed: 35757386
DOI: 10.1007/s10991-022-09305-7 -
Healthcare Policy = Politiques de Sante Aug 2022Recently, we have all seen myriad articles in the national newspapers announcing that provinces' healthcare systems are imploding, with authors describing systems in...
Recently, we have all seen myriad articles in the national newspapers announcing that provinces' healthcare systems are imploding, with authors describing systems in states of "crisis" (Laverly 2022), "visibly coming apart" (Tumilty 2022), "broken" (Urback 2022) and "a travesty" (Picard 2022). Without minimizing the hardships or frustrations that some patients and their families have been experiencing at the hands of provincial health systems, are the harsh descriptors apt or fair?
Topics: Canada; Delivery of Health Care; Humans
PubMed: 36103232
DOI: 10.12927/hcpol.2022.26910