There are two competing views regarding the role of mechanistic knowledge in inferences about the effectiveness of interventions. One view holds that inferences about the effectiveness of interventions should be based only on data from population-level studies (often statistical evidence from randomised trials). The other view holds that such inferences must be based in part on mechanistic evidence. The competing views are local principles of inference, the plausibility of which can be assessed by a more general normative principle of inference. Bayesianism tells us to base inferences on both the 'likelihood' and the 'prior'. The likelihood represents statistical evidence. One influence on the prior probability of a hypothesis like 'd causes x' is mechanistic knowledge of how d causes x. Thus, reasoning about such inferences by appealing to both statistical and mechanistic evidence is vindicated by our best general theory of inference. The primary contribution of this paper is to assess the merits and weaknesses of the arguments on both sides of the debate, using the Bayesian framework. This analysis lends support to those who argue that we should base our causal inferences about interventions in part on mechanistic evidence.
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http://dx.doi.org/10.1016/j.shpsa.2022.01.001 | DOI Listing |
mSphere
January 2025
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Unlabelled: During infection, bacterial pathogens rely on secreted virulence factors to manipulate the host cell. However, in gram-positive bacteria, the molecular mechanisms underlying the folding and activity of these virulence factors after membrane translocation are not clear. Here, we solved the protein structures of two secreted parvulin and two secreted cyclophilin-like peptidyl-prolyl isomerase (PPIase) ATP-independent chaperones found in gram-positive streptococcal species.
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January 2025
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK.
The excessive accumulation of intrahepatic triglyceride (IHTG) in the liver is a risk factor for metabolic diseases, including type 2 diabetes and cardiovascular disease. IHTG can excessively accumulate owing to imbalances in the delivery, synthesis, storage and disposal of fat to, in and from the liver. Although obesity is strongly associated with IHTG accumulation, emerging evidence suggests that the composition of dietary fat, in addition to its quantity, plays a role in mediating IHTG accumulation.
View Article and Find Full Text PDFAutophagy
January 2025
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
Glia contribute to the neuropathology of Parkinson disease (PD), but how they react opposingly to be beneficial or detrimental under pathological conditions, like promoting or eliminating SNCA/α-syn (synuclein alpha) inclusions, remains elusive. Here we present evidence that aux (auxilin), the homolog of the PD risk factor GAK (cyclin G associated kinase), regulates the lysosomal degradation of SNCA/α-syn in glia. Lack of glial GAK/aux increases the lysosome number and size, regulates lysosomal acidification and hydrolase activity, and ultimately blocks the degradation of substrates including SNCA/α-syn.
View Article and Find Full Text PDFFront Pharmacol
January 2025
Department of Gastroenterology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
Introduction: Ulcerative colitis (UC), a form of inflammatory irritable bowel disease, is characterized by a recurrent and persistent nonspecific inflammatory response. Polydatin (PD), a natural stilbenoid polyphenol with potent properties, exhibits unexpected beneficial effects beyond its well-documented anti-inflammatory and antioxidant activities. In this study, we presented evidence that PD confers protection against dextran sodium sulfate (DSS)-induced ulcerative colitis.
View Article and Find Full Text PDFFront Immunol
January 2025
Department of Odontology, Section for Molecular Periodontology, Umeå University, Umeå, Sweden.
Introduction: Periodontitis is associated with rheumatoid arthritis (RA). One hypothesis posits that this connection arises from the formation of autoantibodies against citrullinated proteins (ACPA) in inflamed gums, possibly triggered by . We previously demonstrated an increased antibody response to arginine gingipains (anti-Rgp IgG), not only in individuals with severe periodontitis compared to controls, but in RA versus controls, with an association to ACPA.
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