The main protease, M
(or 3CL
) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide. Feline infectious peritonitis, a fatal coronavirus ...infection in cats, was successfully treated previously with a prodrug GC376, a dipeptide-based protease inhibitor. Here, we show the prodrug and its parent GC373, are effective inhibitors of the M
from both SARS-CoV and SARS-CoV-2 with IC
values in the nanomolar range. Crystal structures of SARS-CoV-2 M
with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 replication in cell culture. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals. The work here lays the framework for their use in human trials for the treatment of COVID-19.
The evolution of misbelief McKay, Ryan T; Dennett, Daniel C
Behavioral and brain sciences,
12/2009, Letnik:
32, Številka:
6
Journal Article
Recenzirano
Odprti dostop
From an evolutionary standpoint, a default presumption is that true beliefs are adaptive and misbeliefs maladaptive. But if humans are biologically engineered to appraise the world accurately and to ...form true beliefs, how are we to explain the routine exceptions to this rule? How can we account for mistaken beliefs, bizarre delusions, and instances of self-deception? We explore this question in some detail. We begin by articulating a distinction between two general types of misbelief: those resulting from a breakdown in the normal functioning of the belief formation system (e.g., delusions) and those arising in the normal course of that system's operations (e.g., beliefs based on incomplete or inaccurate information). The former are instances of biological dysfunction or pathology, reflecting "culpable" limitations of evolutionary design. Although the latter category includes undesirable (but tolerable) by-products of "forgivably" limited design, our quarry is a contentious subclass of this category: misbeliefs best conceived as design features. Such misbeliefs, unlike occasional lucky falsehoods, would have been systematically adaptive in the evolutionary past. Such misbeliefs, furthermore, would not be reducible to judicious - but doxastically noncommittal - action policies. Finally, such misbeliefs would have been adaptive in themselves, constituting more than mere by-products of adaptively biased misbelief-producing systems. We explore a range of potential candidates for evolved misbelief, and conclude that, of those surveyed, only positive illusions meet our criteria.
Over the past two decades, nuclear magnetic resonance (NMR) has emerged as one of the three principal analytical techniques used in metabolomics (the other two being gas chromatography coupled to ...mass spectrometry (GC-MS) and liquid chromatography coupled with single-stage mass spectrometry (LC-MS)). The relative ease of sample preparation, the ability to quantify metabolite levels, the high level of experimental reproducibility, and the inherently nondestructive nature of NMR spectroscopy have made it the preferred platform for long-term or large-scale clinical metabolomic studies. These advantages, however, are often outweighed by the fact that most other analytical techniques, including both LC-MS and GC-MS, are inherently more sensitive than NMR, with lower limits of detection typically being 10 to 100 times better. This review is intended to introduce readers to the field of NMR-based metabolomics and to highlight both the advantages and disadvantages of NMR spectroscopy for metabolomic studies. It will also explore some of the unique strengths of NMR-based metabolomics, particularly with regard to isotope selection/detection, mixture deconvolution via 2D spectroscopy, automation, and the ability to noninvasively analyze native tissue specimens. Finally, this review will highlight a number of emerging NMR techniques and technologies that are being used to strengthen its utility and overcome its inherent limitations in metabolomic applications.
Identifying and understanding COVID-19 vaccine hesitancy within distinct populations may aid future public health messaging. Using nationally representative data from the general adult populations of ...Ireland (N = 1041) and the United Kingdom (UK; N = 2025), we found that vaccine hesitancy/resistance was evident for 35% and 31% of these populations respectively. Vaccine hesitant/resistant respondents in Ireland and the UK differed on a number of sociodemographic and health-related variables but were similar across a broad array of psychological constructs. In both populations, those resistant to a COVID-19 vaccine were less likely to obtain information about the pandemic from traditional and authoritative sources and had similar levels of mistrust in these sources compared to vaccine accepting respondents. Given the geographical proximity and socio-economic similarity of the populations studied, it is not possible to generalize findings to other populations, however, the methodology employed here may be useful to those wishing to understand COVID-19 vaccine hesitancy elsewhere.
It has been claimed that delusional and delusion-prone individuals have a tendency to gather less data before forming beliefs. Most of the evidence for this "jumping to conclusions" (JTC) bias comes ...from studies using the "beads task" data-gathering paradigm. However, the evidence for the JTC bias is mixed. We conducted a random-effects meta-analysis of individual participant data from 38 clinical and nonclinical samples (n = 2,237) to investigate the relationship between data gathering in the beads task (using the "draws to decision" measure) and delusional ideation (as indexed by the "Peters et al Delusions Inventory"; PDI). We found that delusional ideation is negatively associated with data gathering (r(s) = -0.10, 95% CI -0.17, -0.03) and that there is heterogeneity in the estimated effect sizes (Q-stat P = .03, I(2) = 33). Subgroup analysis revealed that the negative association is present when considering the 23 samples (n = 1,754) from the large general population subgroup alone (r(s) = -0.10, 95% CI -0.18, -0.02) but not when considering the 8 samples (n = 262) from the small current delusions subgroup alone (r(s) = -0.12, 95% CI -0.31, 0.07). These results provide some provisional support for continuum theories of psychosis and cognitive models that implicate the JTC bias in the formation and maintenance of delusions.
Delusional belief Coltheart, Max; Langdon, Robyn; McKay, Ryan
Annual review of psychology,
01/2011, Letnik:
62
Journal Article
Recenzirano
Delusional beliefs are seen in association with a number of neuropathological conditions, including schizophrenia, dementia, and traumatic brain injury. A key distinction exists between polythematic ...delusion (here the patient exhibits delusional beliefs about a variety of topics that are unrelated to each other) and monothematic delusion (here the patient exhibits just a single delusional belief or else a small set of delusional beliefs that are all related to a single theme). A great deal of recent research has focused on identifying and investigating various different forms of monothematic delusion. We discuss a general theoretical approach to the understanding of monothematic delusions--a two-factor approach according to which understanding the nature and genesis of any kind of monothematic delusion involves seeking answers to two questions. The first question is, what brought the delusional idea to mind in the first place? The second question is, why is this idea accepted as true and adopted as a belief when the belief is typically bizarre and when so much evidence against its truth is available to the patient? We discuss in detail six different kinds of monothematic delusion, showing for each how neuropsychological considerations allow a first factor (responsible for the content of the belief) and a second factor (responsible for the failure to reject the belief) to be plausibly identified. Five difficulties confronting this two-factor account of monothematic delusion are then identified, and attempts are made to address each one.
Understanding how individuals revise their political beliefs has important implications for society. In a preregistered study (N = 900), we experimentally separated the predictions of 2 leading ...theories of human belief revision-desirability bias and confirmation bias-in the context of the 2016 U.S. presidential election. Participants indicated who they desired to win, and who they believed would win, the election. Following confrontation with evidence that was either consistent or inconsistent with their desires or beliefs, they again indicated who they believed would win. We observed a robust desirability bias-individuals updated their beliefs more if the evidence was consistent (vs. inconsistent) with their desired outcome. This bias was independent of whether the evidence was consistent or inconsistent with their prior beliefs. In contrast, we found limited evidence of an independent confirmation bias in belief updating. These results have implications for the relevant psychological theories and for political belief revision in practice.
Vaccines are a powerful and relatively safe tool to protect against a range of serious diseases. Nonetheless, a sizeable minority of people express ‘vaccination hesitancy’. Accordingly, understanding ...the bases of this hesitancy represents a significant public health opportunity. In the present study we sought to examine the role of Big Five personality traits and general intelligence as predictors of vaccination hesitancy across two vaccination types in a large (N = 9667) sample of UK adults drawn from the Understanding Society longitudinal household study. We found that lower levels of general intelligence were associated with COVID-19 and seasonal flu vaccination hesitancy, and lower levels of neuroticism was associated with COVID-19 vaccination hesitancy. Although the self-reported reasons for being vaccine hesitant indicated a range of factors were important to people, lower general intelligence was associated with virtually all of these reasons. In contrast, Big Five personality traits showed more nuanced patterns of association.
Studying disease models at the molecular level is vital for drug development in order to improve treatment and prevent a wide range of human pathologies. Microbial infections are still a major ...challenge because pathogens rapidly and continually evolve developing drug resistance. Cancer cells also change genetically, and current therapeutic techniques may be (or may become) ineffective in many cases. The pathology of many neurological diseases remains an enigma, and the exact etiology and underlying mechanisms are still largely unknown. Viral infections spread and develop much more quickly than does the corresponding research needed to prevent and combat these infections; the present and most relevant outbreak of SARS-CoV-2, which originated in Wuhan, China, illustrates the critical and immediate need to improve drug design and development techniques. Modern day drug discovery is a time-consuming, expensive process. Each new drug takes in excess of 10 years to develop and costs on average more than a billion US dollars. This demonstrates the need of a complete redesign or novel strategies. Nuclear Magnetic Resonance (NMR) has played a critical role in drug discovery ever since its introduction several decades ago. In just three decades, NMR has become a "gold standard" platform technology in medical and pharmacology studies. In this review, we present the major applications of NMR spectroscopy in medical drug discovery and development. The basic concepts, theories, and applications of the most commonly used NMR techniques are presented. We also summarize the advantages and limitations of the primary NMR methods in drug development.
Metabolomics is a rapidly expanding field of systems biology that is gaining significant attention in many areas of biomedical research. Also known as metabonomics, it comprises the analysis of all ...small molecules or metabolites that are present within an organism or a specific compartment of the body. Metabolite detection and quantification provide a valuable addition to genomics and proteomics and give unique insights into metabolic changes that occur in tangent to alterations in gene and protein activity that are associated with disease. As a novel approach to understanding disease, metabolomics provides a "snapshot" in time of all metabolites present in a biological sample such as whole blood, plasma, serum, urine, and many other specimens that may be obtained from either patients or experimental models. In this article, we review the burgeoning field of metabolomics in its application to acute lung diseases, specifically pneumonia and acute respiratory disease syndrome (ARDS). We also discuss the potential applications of metabolomics for monitoring exposure to aerosolized environmental toxins. Recent reports have suggested that metabolomics analysis using nuclear magnetic resonance (NMR) and mass spectrometry (MS) approaches may provide clinicians with the opportunity to identify new biomarkers that may predict progression to more severe disease, such as sepsis, which kills many patients each year. In addition, metabolomics may provide more detailed phenotyping of patient heterogeneity, which is needed to achieve the goal of precision medicine. However, although several experimental and clinical metabolomics studies have been conducted assessing the application of the science to acute lung diseases, only incremental progress has been made. Specifically, little is known about the metabolic phenotypes of these illnesses. These data are needed to substantiate metabolomics biomarker credentials so that clinicians can employ them for clinical decision-making and investigators can use them to design clinical trials.
PDF
