O Problema dos Pares Contraditórios de Experimentos Mentais

Um dos principais problemas epistemológicos que podem ser encontrados no estudo dos experimentos mentais diz respeito ao critério de escolha entre casos que produzam resultados contraditórios. Que justificação possuímos para escolher entre C e ~C? James Roberto Brown argumenta a favor de um critério de probabilidade, onde se atribui probabilidade aos dois fenômenos e o mais provável de ser verdadeiro é o que aceitamos. John Norton argumenta que experimentos mentais são argumentos, por isso eles podem ser reconstruídos como argumentos. Através desse processo podemos encontrar as falhas na argumentação do experimento e decidir, através de justificação lógica, qual é a conclusão correta. A abordagem de Brown se mostra muito infrutífera por não apresentar como o cálculo de probabilidade deve funcionar, nem como é possível atribuir probabilidades a verdade dos resultados dos experimentos mentais. Por outro lado, para aceitar a resposta de Norton, necessitamos aceitar que experimentos mentais realmente façam uso de argumentos e que isso seja tudo o que podemos dizer sobre eles. Essa estruturação não permite nenhuma outra fonte epistêmica para justificar os resultados dos experimentos metais

Thought Experiments, Ethics And Emotions

This article aims to analyze the functioning of thought experiments in ethics. We will demonstrate that although many thought experiments in ethics can be reconstructed as arguments, according to the thesis defended by John Norton, its reconstructed version does not have the same epistemic force. We will argue that the reconstructed versions are not capable of bringing the same type of understanding in relation to thought experiments, which have an explanatory advantage that arguments do not have. Therefore, arguments are not a sufficient condition for solving problems within ethics and also within thought experiments in this area. We will argue that emotions can be one of the non-argumentative factors that can produce negative and positive interference on thought experimenters and thought experiment, which cannot be demonstrated accurately in the reconstructed version. In this way, the reconstructed version is not able to convey an adequate understanding of emotions and other influences. Finally, we will elaborate on two thought experiments that demonstrate the need to use emotions in moral actions based on the criticism produced by Flávio Williges against traditional moral theories. These thought experiments can be reconstructed as arguments, but without giving us the same understanding that thought experiments are capable of

Region Specific and Worldwide Distribution of Collagen-Binding M Proteins with PARF Motifs among Human Pathogenic Streptococcal Isolates

Some of the variety of Streptococcus pyogenes and Streptococcus dysgalactiae ssp. equisimilis (SDSE) M proteins act as collagen-binding adhesins that facilitate acute infection. Moreover, their potential to trigger collagen autoimmunity has been implicated in the pathogenesis of acute rheumatic fever and attributed to a collagen-binding motif called PARF (peptide associated with rheumatic fever). For the first time we determine the rate of clinical isolates with collagen-binding M proteins that use a PARF motif (A/T/E)XYLXX(L/F)N in a defined geographic region, Vellore in South India. In this region both, incidence of streptococcal infections and prevalence of acute rheumatic fever are high. M proteins with PARF motif conferred collagen-binding activity to 3.9% of 153 S. pyogenes and 10.6% of 255 SDSE clinical isolates from Vellore. The PARF motif occurred in three S. pyogenes and 22 SDSE M protein types. In one of the S. pyogenes and five of the SDSE M proteins that contained the motif, collagen-binding was impaired, due to influences of other parts of the M protein molecule. The accumulated data on the collagen binding activity of certain M protein types allowed a reanalysis of published worldwide emm-typing data with the aim to estimate the rates of isolates that bind collagen via PARF. The results indicate that M proteins, which bind collagen via a PARF motif, are epidemiologically relevant in human infections, not only in Vellore. It is imperative to include the most relevant collagen-binding M types in vaccines. But when designing M protein based vaccines it should be considered that collagen binding motifs within the vaccine antigen remain potential risk factors

A common theme in interaction of bacterial immunoglobulin-binding proteins with immunoglobulins illustrated in the equine system

The M protein of Streptococcus equi subsp. equi known as fibrinogen-binding protein (FgBP) is a cell wall-associated protein with antiphagocytic activity that binds IgG. Recombinant versions of the seven equine IgG subclasses were used to investigate the subclass specificity of FgBP. FgBP bound predominantly to equine IgG4 and IgG7, with little or no binding to the other subclasses. Competitive binding experiments revealed that FgBP could inhibit the binding of staphylococcal protein A and streptococcal protein G to both IgG4 and IgG7, implicating the Fc interdomain region in binding to FgBP. To identify which of the two IgG Fc domains contributed to the interaction with FgBP, we tested two human IgG1/IgA1 domain swap mutants and found that both domains are required for full binding, with the CH3 domain playing a critical role. The binding site for FgBP was further localized using recombinant equine IgG7 antibodies with single or double point mutations to residues lying at the CH2-CH3 interface. We found that interaction of FgBP with equine IgG4 and IgG7 was able to disrupt C1q binding and antibody-mediated activation of the classical complement pathway, demonstrating an effective means by which S. equi may evade the immune response. The mode of interaction of FgBP with IgG fits a common theme for bacterial Ig-binding proteins. Remarkably, for those interactions studied in detail, it emerges that all the Ig-binding proteins target the CH2-CH3 domain interface, regardless of specificity for IgG or IgA, streptococcal or staphylococcal origin, or host species (equine or human)

Crucial Role of the CB3-Region of Collagen IV in PARF-Induced Acute Rheumatic Fever

Acute rheumatic fever (ARF) and rheumatic heart disease are serious autoimmune sequelae to infections with Streptococcus pyogenes. Streptococcal M-proteins have been implicated in ARF pathogenesis. Their interaction with collagen type IV (CIV) is a triggering step that induces generation of collagen-specific auto-antibodies. Electron microscopy of the protein complex between M-protein type 3 (M3-protein) and CIV identified two prominent binding sites of which one is situated in the CB3-region of CIV. In a radioactive binding assay, M3-protein expressing S. pyogenes and S. gordonii bound the CB3-fragment. Detailed analysis of the interactions by surface plasmon resonance measurements and site directed mutagenesis revealed high affinity interactions with dissociation constants in the nanomolar range that depend on the recently described collagen binding motif of streptococcal M-proteins. Because of its role in the induction of disease-related collagen autoimmunity the motif is referred to as “peptide associated with rheumatic fever” (PARF). Both, sera of mice immunized with M3-protein as well as sera from patients with ARF contained anti-CB3 auto-antibodies, indicating their contribution to ARF pathogenesis. The identification of the CB3-region as a binding partner for PARF directs the further approaches to understand the unusual autoimmune pathogenesis of PARF-dependent ARF and forms a molecular basis for a diagnostic test that detects rheumatogenic streptococci

Inconsistent effects of parietal α-tACS on Pseudoneglect across two experiments:A failed internal replication

Transcranial electrical stimulation (tES) is being investigated as an experimental and clinical interventional technique in human participants. While promising, important limitations have been identified, including weak effect sizes and high inter- and intra-individual variability of outcomes. Here, we compared two “inhibitory” tES-techniques with supposedly different mechanisms of action as to their effects on performance in a visuospatial attention task, and report on a direct replication attempt. In two experiments, 2 × 20 healthy participants underwent tES in three separate sessions testing different protocols (10 min stimulation each) with a montage targeting right parietal cortex (right parietal–left frontal, electrode-sizes: 3cm × 3cm–7 cm × 5 cm), while performing a perceptual line bisection (landmark) task. The tES-protocols were compared as to their ability to modulate pseudoneglect (thought to be under right hemispheric control). In experiment 1, sham-tES was compared to transcranial alternating current stimulation at alpha frequency (10 Hz; α-tACS) (expected to entrain “inhibitory” alpha oscillations) and to cathodal transcranial direct current stimulation (c-tDCS) (shown to suppress neuronal spiking activity). In experiment 2, we attempted to replicate the findings of experiment 1, and establish frequency-specificity by adding a 45 Hz-tACS condition to α-tACS and sham. In experiment 1, right parietal α-tACS led to the expected changes in spatial attention bias, namely a rightward shift in subjective midpoint estimation (relative to sham). However, this was not confirmed in experiment 2 and in the complete sample. Right parietal c-tDCS and 45 Hz-tACS had no effect. These results highlight the importance of replication studies, adequate statistical power and optimizing tES-interventions for establishing the robustness and reliability of electrical stimulation effects, and best practice

Contribution of Streptococcus anginosus to Infections Caused by Groups C and G Streptococci, Southern India

This neglected pathogen causes a large portion of these infections

The implications of state-dependent tDCS effects in aging:Behavioural response is determined by baseline performance

Young adults typically display a processing advantage towards the left side of space (“pseudoneglect”), possibly as a result of right parietal dominance for spatial attention. This bias is ameliorated with age, with older adults displaying either no strongly lateralised bias, or a slight bias towards the right. This may represent an age-related reduction of right hemispheric dominance and/or increased left hemispheric involvement. Here, we applied anodal transcranial direct current stimulation (atDCS) to the right posterior parietal cortex (PPC; R-atDCS), the left PPC (L-atDCS) and a Sham protocol in young and older adults during a titrated lateralised visual detection task. We aimed to facilitate visual detection sensitivity in the contralateral visual field with both R-atDCS and L-atDCS relative to Sham. We found no differences in the effects of stimulation between young and older adults. Instead the effects of atDCS were state-dependent (i.e. related to task performance at baseline). Relative to Sham, poor task performers were impaired in both visual fields by anodal stimulation of the left posterior parietal cortex (PPC). Conversely, good performers maintained sensitivity in both visual fields in response to R-atDCS, although this effect was small. We highlight the importance of considering baseline task ability when designing tDCS experiments, particularly in older adults

Non-linear effects of transcranial direct current stimulation as a function of individual baseline performance:Evidence from biparietal tDCS influence on lateralized attention bias

Transcranial direct current stimulation (tDCS) is a well-established technique for non-invasive brain stimulation (NIBS). However, the technique suffers from a high variability in outcome, some of which is likely explained by the state of the brain at tDCS-delivery but for which explanatory, mechanistic models are lacking. Here, we tested the effects of bi-parietal tDCS on perceptual line bisection as a function of tDCS current strength (1 mA vs 2 mA) and individual baseline discrimination sensitivity (a measure associated with intrinsic uncertainty/signal-to-noise balance). Our main findings were threefold. We replicated a previous finding (Giglia et al., 2011) of a rightward shift in subjective midpoint after Left anode/Right cathode tDCS over parietal cortex (sham-controlled). We found this effect to be weak over our entire sample (n = 38), but to be substantial in a subset of participants when they were split according to tDCS-intensity and baseline performance. This was due to a complex, nonlinear interaction between these two factors. Our data lend further support to the notion of state-dependency in NIBS which suggests outcome to depend on the endogenous balance between task-informative ‘signal’ and task-uninformative ‘noise’ at baseline. The results highlight the strong influence of individual differences and variations in experimental parameters on tDCS outcome, and the importance of fostering knowledge on the factors influencing tDCS outcome across cognitive domains

Bdellovibrio bacteriovorus Inhibits Staphylococcus aureus Biofilm Formation and Invasion into Human Epithelial Cells

Bdellovibrio bacteriovorus HD100 is a predatory bacterium that attacks many Gram-negative human pathogens. A serious drawback of this strain, however, is its ineffectiveness against Gram-positive strains, such as the human pathogen Staphylococcus aureus. Here we demonstrate that the extracellular proteases produced by a host-independent B. bacteriovorus (HIB) effectively degrade/inhibit the formation of S. aureus biofilms and reduce its virulence. A 10% addition of HIB supernatant caused a 75% or greater reduction in S. aureus biofilm formation as well as 75% dispersal of pre-formed biofilms. LC-MS-MS analyses identified various B. bacteriovorus proteases within the supernatant, including the serine proteases Bd2269 and Bd2321. Tests with AEBSF confirmed that serine proteases were active in the supernatant and that they impacted S. aureus biofilm formation. The supernatant also possessed a slight DNAse activity. Furthermore, treatment of planktonic S. aureus with the supernatant diminished its ability to invade MCF-10a epithelial cells by 5-fold but did not affect the MCF-10a viability. In conclusion, this study illustrates the hitherto unknown ability of B. bacteriovorus to disperse Gram-positive pathogenic biofilms and mitigate their virulence.open6