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Scientific medicine and homeopathy are interesting case studies for the ongoing project of demarcating science from pseudoscience. Much of the demarcation literature formulates abstract criteria for demarcating science from pseudoscience generally. In service of a more localist approach to the demarcation problem, I reconstruct a specific demarcating difference, the like comparison criterion, invoked by nineteenth century adherents to an early model of scientific medicine. If it is to remain relevant today, I argue that the like comparison criterion must be updated in our current era of epidemiological, evidence-based medicine to recognize the importance of assessing study bias and mechanistic implausibility in contemporary medical science.
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Homeopatia , Ciência , História do Século XIX , Homeopatia/história , Ciência/história , Medicina Baseada em Evidências/história , MedicinaRESUMO
Medical interventions that cure or prevent medical conditions are central to medicine; and thus, understanding them is central to our understanding of medicine. My purpose in this paper is to explore the conceptual foundations of medicine by providing a singular analysis of the concept of a 'preventive or curative medical intervention'. Borrowing a general account of prevention from Phil Dowe (2000, 2001), I provide an analysis of prevention, cure, risk reduction, and a preventive or curative intervention, before turning to preventive and curative medical interventions. The resulting counterfactual-mechanistic account holds that preventive and curative medical interventions reduce the probability of a medical condition in an actual population compared to their counterfactual omission, commonly by disrupting an etiological or constitutive mechanism for the condition.
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COVID-19 epidemic models raise important questions for science and philosophy of science. Here I provide a brief preliminary exploration of three: what kinds of predictions do epidemic models make, are they causal models, and how do different kinds of epidemic models differ in terms of what they represent?
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COVID-19/epidemiologia , Epidemias , Modelos Teóricos , Filosofia , HumanosRESUMO
The dynamics of protein binding pockets are crucial for their interaction specificity. Structural flexibility allows proteins to adapt to their individual molecular binding partners and facilitates the binding process. This implies the necessity to consider protein internal motion in determining and predicting binding properties and in designing new binders. Although accounting for protein dynamics presents a challenge for computational approaches, it expands the structural and physicochemical space for compound design and thus offers the prospect of improved binding specificity and selectivity. A cavity on the surface or in the interior of a protein that possesses suitable properties for binding a ligand is usually referred to as a binding pocket. The set of amino acid residues around a binding pocket determines its physicochemical characteristics and, together with its shape and location in a protein, defines its functionality. Residues outside the binding site can also have a long-range effect on the properties of the binding pocket. Cavities with similar functionalities are often conserved across protein families. For example, enzyme active sites are usually concave surfaces that present amino acid residues in a suitable configuration for binding low molecular weight compounds. Macromolecular binding pockets, on the other hand, are located on the protein surface and are often shallower. The mobility of proteins allows the opening, closing, and adaptation of binding pockets to regulate binding processes and specific protein functionalities. For example, channels and tunnels can exist permanently or transiently to transport compounds to and from a binding site. The influence of protein flexibility on binding pockets can vary from small changes to an already existent pocket to the formation of a completely new pocket. Here, we review recent developments in computational methods to detect and define binding pockets and to study pocket dynamics. We introduce five different classes of protein pocket dynamics: (1) appearance/disappearance of a subpocket in an existing pocket; (2) appearance/disappearance of an adjacent pocket on the protein surface in the direct vicinity of an already existing pocket; (3) pocket breathing, which may be caused by side-chain fluctuations or backbone or interdomain vibrational motion; (4) opening/closing of a channel or tunnel, connecting a pocket inside the protein with solvent, including lid motion; and (5) the appearance/disappearance of an allosteric pocket at a site on a protein distinct from an already existing pocket with binding of a ligand to the allosteric binding site affecting the original pocket. We suggest that the class of pocket dynamics, as well as the type and extent of protein motion affecting the binding pocket, should be factors considered in choosing the most appropriate computational approach to study a given binding pocket. Furthermore, we examine the relationship between pocket dynamics classes and induced fit, conformational selection, and gating models of ligand binding on binding kinetics and thermodynamics. We discuss the implications of protein binding pocket dynamics for drug design and conclude with potential future directions for computational analysis of protein binding pocket dynamics.
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Proteínas/metabolismo , Algoritmos , Sítios de Ligação , Ligação ProteicaRESUMO
Macromolecular interactions play a crucial role in biological systems. Simulation of diffusional association (SDA) is a software for carrying out Brownian dynamics simulations that can be used to study the interactions between two or more biological macromolecules. webSDA allows users to run Brownian dynamics simulations with SDA to study bimolecular association and encounter complex formation, to compute association rate constants, and to investigate macromolecular crowding using atomically detailed macromolecular structures. webSDA facilitates and automates the use of the SDA software, and offers user-friendly visualization of results. webSDA currently has three modules: 'SDA docking' to generate structures of the diffusional encounter complexes of two macromolecules, 'SDA association' to calculate bimolecular diffusional association rate constants, and 'SDA multiple molecules' to simulate the diffusive motion of hundreds of macromolecules. webSDA is freely available to all users and there is no login requirement. webSDA is available at http://mcm.h-its.org/webSDA/.
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DNA/química , Simulação de Dinâmica Molecular , Proteínas/química , RNA/química , Software , DNA/metabolismo , Difusão , Internet , Simulação de Acoplamento Molecular , Proteínas/metabolismo , RNA/metabolismoRESUMO
UNLABELLED: LigDig is a web server designed to answer questions that previously required several independent queries to diverse data sources. It also performs basic manipulations and analyses of the structures of protein-ligand complexes. The LigDig webserver is modular in design and consists of seven tools, which can be used separately, or via linking the output from one tool to the next, in order to answer more complex questions. Currently, the tools allow a user to: (i) perform a free-text compound search, (ii) search for suitable ligands, particularly inhibitors, of a protein and query their interaction network, (iii) search for the likely function of a ligand, (iv) perform a batch search for compound identifiers, (v) find structures of protein-ligand complexes, (vi) compare three-dimensional structures of ligand binding sites and (vii) prepare coordinate files of protein-ligand complexes for further calculations. AVAILABILITY AND IMPLEMENTATION: LigDig makes use of freely available databases, including ChEMBL, PubChem and SABIO-RK, and software programs, including cytoscape.js, PDB2PQR, ProBiS and Fconv. LigDig can be used by non-experts in bio- and chemoinformatics. LigDig is available at: http://mcm.h-its.org/ligdig. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Internet , Proteínas/química , Proteínas/metabolismo , Software , Sítios de Ligação , Bases de Dados Factuais , Frutosedifosfatos/metabolismo , Humanos , LigantesRESUMO
"Scientific community" refers to a group of people collaborating together on scientific-research-related activities who also share common goals, interests, and values. Such communities play a key role in many bioinformatics activities. Communities may be linked to a specific location or institute, or involve people working at many different institutions and locations. Education and training is typically an important component of these communities, providing a valuable context in which to develop skills and expertise, while also strengthening links and relationships within the community. Scientific communities facilitate: (i) the exchange and development of ideas and expertise; (ii) career development; (iii) coordinated funding activities; (iv) interactions and engagement with professionals from other fields; and (v) other activities beneficial to individual participants, communities, and the scientific field as a whole. It is thus beneficial at many different levels to understand the general features of successful, high-impact bioinformatics communities; how individual participants can contribute to the success of these communities; and the role of education and training within these communities. We present here a quick guide to building and maintaining a successful, high-impact bioinformatics community, along with an overview of the general benefits of participating in such communities. This article grew out of contributions made by organizers, presenters, panelists, and other participants of the ISMB/ECCB 2013 workshop "The 'How To Guide' for Establishing a Successful Bioinformatics Network" at the 21st Annual International Conference on Intelligent Systems for Molecular Biology (ISMB) and the 12th European Conference on Computational Biology (ECCB).
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Comunicação , Biologia Computacional/organização & administração , Humanos , Internet , Mídias SociaisRESUMO
Natural reward and drugs of abuse converge on the mesolimbic pathway and activate common mechanism of neural plasticity in the nucleus accumbens. Chronic exposure to opiates induces plasticity in dopaminergic neurons of the ventral tegmental area (VTA), which regulates morphine reward tolerance. Here, we test the hypotheses that mating-induced release of endogenous opioids in the VTA causes morphological changes of VTA dopamine cells in male rats, which in-turn regulate the long-term expression of experience-induced reinforcement of sexual behavior. First, sexual experience decreased VTA dopamine soma size 1 and 7 days, but not 30 days after the last mating session. This effect was blocked with naloxone before each mating session; thus, VTA dopamine cell plasticity was dependent on action of endogenous opioids. In turn, VTA plasticity was associated with altered opiate reward, as sexually experienced males did not form conditioned place preference for 0.5 mg/kg morphine. Next, it was determined whether endogenous opioid action mediates sexual reward and memory in male rats treated with naloxone during mating experience, either systemically or intra-VTA. Naloxone did not prevent the initial experience-induced facilitation of sexual behavior over repeated mating sessions, or conditioned place preference for mating. However, naloxone treatment attenuated the longer-term expression of experience-induced facilitation of sexual behavior and neural activation in mesolimbic areas induced by mating-associated conditioned cues. Together, these data demonstrate that endogenous opioids during mating induce neural plasticity in VTA dopamine neurons that appear critical for morphine reward and long-term memory for natural reward behavior.
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Copulação/fisiologia , Neurônios Dopaminérgicos/fisiologia , Plasticidade Neuronal/fisiologia , Recompensa , Área Tegmentar Ventral/fisiologia , Animais , Aprendizagem por Associação/efeitos dos fármacos , Aprendizagem por Associação/fisiologia , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Masculino , Morfina/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Área Tegmentar Ventral/efeitos dos fármacosRESUMO
The third Heidelberg Unseminars in Bioinformatics (HUB) was held on 18th October 2012, at Heidelberg University, Germany. HUB brought together around 40 bioinformaticians from academia and industry to discuss the 'Biggest Challenges in Bioinformatics' in a 'World Café' style event.
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Biologia Computacional , Animais , Biodiversidade , Especiação Genética , Humanos , Armazenamento e Recuperação da Informação , Gestão do Conhecimento , Filogenia , Medicina de PrecisãoRESUMO
The physiology of breath holding is complex, and voluntary breath-hold duration is affected by many factors, including practice, psychology, respiratory chemoreflexes, and lung stretch. In this activity, we outline a number of simple laboratory activities or classroom demonstrations that illustrate the complexity of the integrative physiology behind breath-hold duration. These activities require minimal equipment and are easily adapted to small-group demonstrations or a larger-group inquiry format where students can design a protocol and collect and analyze data from their classmates. Specifically, breath-hold duration is measured during a number of maneuvers, including after end expiration, end inspiration, voluntary prior hyperventilation, and inspired hyperoxia. Further activities illustrate the potential contribution of chemoreflexes through rebreathing and repeated rebreathing after a maximum breath hold. The outcome measures resulting from each intervention are easily visualized and plotted and can comprise a comprehensive data set to illustrate and discuss complex and integrated cardiorespiratory physiology.
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Suspensão da Respiração , Avaliação Educacional , Fisiologia/educação , Mecânica Respiratória/fisiologia , Fenômenos Fisiológicos Respiratórios , Gasometria/métodos , Dióxido de Carbono/sangue , Educação de Graduação em Medicina/métodos , Feminino , Humanos , Masculino , Oxigênio/sangue , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: The efficacy of bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) for medically refractory idiopathic generalized dystonia has been demonstrated repeatedly. More variable outcomes have been reported in the treatment of secondary dystonia with GPi DBS. OBJECTIVES: The present study seeks to examine the pallidal physiology and clinical outcome of GPi DBS in a case of secondary dystonia. METHODS: We report on a 43-year-old man who at the age of 9 suffered a left basal ganglia stroke and at the age of 21 developed severe disabling hemidystonia. Following unsuccessful medical management for many years and an axial involvement of the dystonia, he underwent bilateral GPi DBS with dual microelectrode mapping of cell firing and evoked field potentials (fEP). RESULTS: On the intact side we found regular firing of pallidal neurons and normal fEP indicative of functioning striatopallidal pathways. The affected side was found to include a higher frequency of bursting pallidal neurons. fEP could not be evoked on the affected side, suggesting their origin to be striatal GABAergic afferents. CONCLUSIONS: The patient had marked benefit from bilateral GPi DBS, which suggests that the therapeutic effects of DBS were mediated by the intact pathways in this case of hemidystonia.
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Corpo Estriado/patologia , Estimulação Encefálica Profunda/métodos , Distúrbios Distônicos/terapia , Globo Pálido/cirurgia , Acidente Vascular Cerebral/complicações , Adulto , Distúrbios Distônicos/etiologia , Humanos , Masculino , Acidente Vascular Cerebral/patologia , Resultado do TratamentoRESUMO
The virtues of learning medical history for medical students have long been argued. Surveys of Canadian medical schools were done in 1939, 1968, and 1999 to discover details about the inclusion of medical history in undergraduate medical education (UME). In 2012, we completed our own survey. While medical history is more commonly included in the core UME curriculum now than in the past, half of Canada's schools still do not require it. An analysis of trends over time reveals the central importance of longstanding and emergent prejudices and cultural influences as barriers to more widespread inclusion of medical history.
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Plastid number and morphology vary dramatically between cell types and at different developmental stages. Furthermore, in C4 plants such as maize, chloroplast ultrastructure and biochemical functions are specialized in mesophyll and bundle sheath cells, which differentiate acropetally from the proplastid form in the leaf base. To develop visible markers for maize plastids, we have created a series of stable transgenics expressing fluorescent proteins fused to either the maize ubiquitin promoter, the mesophyll-specific phosphoenolpyruvate carboxylase (PepC) promoter, or the bundle sheath-specific Rubisco small subunit 1 (RbcS) promoter. Multiple independent events were examined and revealed that maize codon-optimized versions of YFP and GFP were particularly well expressed, and that expression was stably inherited. Plants carrying PepC promoter constructs exhibit YFP expression in mesophyll plastids and the RbcS promoter mediated expression in bundle sheath plastids. The PepC and RbcS promoter fusions also proved useful for identifying plastids in organs such as epidermis, silks, roots and trichomes. These tools will inform future plastid-related studies of wild-type and mutant maize plants and provide material from which different plastid types may be isolated.
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Proteínas Luminescentes/genética , Plastídeos/genética , Ribulose-Bifosfato Carboxilase/genética , Zea mays/genética , Regulação da Expressão Gênica de Plantas , Microscopia Confocal , Dados de Sequência Molecular , Fosfoenolpiruvato Carboxilase/genética , Plantas Geneticamente Modificadas/genética , Regiões Promotoras GenéticasRESUMO
PURPOSE: To characterize how residents employ rhetorical appeals (i.e., the strategic use of communication to achieve specifiable goals) when discussing unnecessary diagnostic tests with patients. METHOD: In 2015, senior hematology residents from 10 Canadian universities participating in a national formative objective structured clinical examination (OSCE) completed a resource stewardship communication station. In this communication scenario, a standardized patient (SP) portrayed a patient requesting unnecessary thrombophilia testing following early pregnancy loss. The authors performed a thematic analysis of audio transcripts using a qualitative description approach to identify residents' rhetorical appeals to logic (rational appeals), credibility, and emotion. RESULTS: For persuasive communication, residents (n = 27) relied primarily on rational appeals that fit into 3 categories (with themes) focused on medical evidence (poor utility, professional guidelines and recommendations), avoidance of harm (insurance implications, unnecessary or potentially harmful interventions, patient anxiety), and reassurance to patient (normalizing, clinical pretest probability, criteria for reconsidering testing). Appeals to credibility and emotion were rarely used. CONCLUSIONS: In an OSCE setting, residents relied predominantly on rational appeals when engaging SPs in conversations about unnecessary tests. These observations yield insights into how recent emphasis within residency education on appropriate test utilization may manifest when residents put recommendations into practice in conversations with patients. This study's framework of rational appeals may be helpful in designing communication curricula about unnecessary testing. Future studies should explore rhetoric about unnecessary testing in the clinical environment, strategies to teach and coach residents leading these conversations, and patients' preferences and responses to different appeals.