Search

Analysis of pulmonary function tests (PFTs) is an area where machine learning (ML) may benefit clinicians, researchers, and the patients. PFT measures spirometry, lung volumes, and carbon monoxide diffusion capacity of the lung (DLCO). The results are usually interpreted by the clinicians using discrete numeric data according to published guidelines. PFT interpretations by clinicians, however, are known to have inter-rater variability and the inaccuracy can impact patient care. This variability may be caused by unfamiliarity of the guidelines, lack of training, inadequate understanding of lung physiology, or simply mental lapses. A rules-based automated interpretation system can recapitulate expert’s pattern recognition capability and decrease errors. ML can also be used to analyze continuous data or the graphics, including the flow-volume loop, the DLCO and the nitrogen washout curves. These analyses can discover novel physiological biomarkers. In the era of wearables and telehealth, particularly with the COVID-19 pandemic restricting PFTs to be done in the clinical laboratories, ML can also be used to combine mobile spirometry results with an individual’s clinical profile to deliver precision medicine. There are, however, hurdles in the development and commercialization of the ML-assisted PFT interpretation programs, including the need for high quality representative data, the existence of different formats for data acquisition and sharing in PFT software by different vendors, and the need for collaboration amongst clinicians, biomedical engineers, and information technologists. Hurdles notwithstanding, the new developments would represent significant advances that could be the future of PFT, the oldest test still in use in clinical medicine.

Nazi Culture would seem at first to be a very esoteric subject to teach to the rather practical-minded and not very cosmopolitan students of a northern New Jersey state college. But of course it is really a distancing technique, a Verfremdungseffekt a la Brecht. Teaching fascism is not really teaching fascism per se, but an angle for teaching capitalism and socialism. And teaching Nazi culture is an angle for teaching some of the purposes of capitalist ideology.

Fibroblast-like synoviocytes mediate joint destruction in rheumatoid arthritis and exhibit sustained proinflammatory and invasive properties. CD44 is a polymorphic transmembrane protein with defined roles inmatrix interaction and tumor invasion that is also a signaling coreceptor for macrophage migration inhibitory factor (MIF), which engages cell surface CD74. High-expression MIF alleles (rs5844572) are associated with rheumatoid joint erosion, but whether MIF signaling through the CD74/CD44 receptor complex promotes upstream autoimmune responses or contributes directly to synovial joint destruction is unknown. We report here the functional regulation of CD44 by an autocrine pathway in synovial fibroblasts that is driven by high-expression MIF alleles to up-regulate an inflammatory and invasive phenotype. MIF increases CD44 expression, promotes its recruitment into a functional signal transduction complex, and stimulates alternative exon splicing, leading to expression of the CD44v3-v6 isoforms associated with oncogenic invasion. CD44 recruitment into the MIF receptor complex, downstream MAPK and RhoA signaling, and invasive phenotype require MIF and CD74 and are reduced by MIF pathway antagonists. These data support a functional role for high-MIF expression alleles and the two-component CD74/CD44 MIF receptor in rheumatoid arthritis and suggest that pharmacologic inhibition of this pathway may offer a specific means to interfere with progressive joint destruction. [ABSTRACT FROM AUTHOR]

The immunoregulatory cytokine macrophage migration inhibitory factor (MIF) is encoded in a functionally polymorphic locus that is linked to the susceptibility of autoimmune and infectious diseases. The MIF promoter contains a 4-nucleotide microsatellite polymorphism (-794 CATT) that repeats 5 to 8 times in the locus, with greater numbers of repeats associated with higher mRNA levels. Because there is no information about the transcriptional regulation of these common alleles, we used oligonucleotide affinity chromatography and liquid chromatography-mass spectrometry to identify nuclear proteins that interact with the -794 CATT5-8 site. An analysis of monocyte nuclear lysates revealed that the transcription factor ICBP90 (also known as UHRF1) is the major protein interacting with the MIF microsatellite. We found that ICBP90 is essential for MIF transcription from monocytes/macrophages, B and T lymphocytes, and synovial fibroblasts, and TLR-induced MIF transcription is regulated in an ICBP90- and -794 CATT5-8 length-dependent manner. Whole-genome transcription analysis of ICBP90 shRNA-treated rheumatoid synoviocytes uncovered a subset of proinflammatory and immune response genes that overlapped with those regulated by MIF shRNA. In addition, the expression levels of ICBP90 and MIF were correlated in joint synovia from patients with rheumatoid arthritis. These findings identify ICBP90 as a key regulator of MIF transcription and provide functional insight into the regulation of the polymorphic MIF locus. [ABSTRACT FROM AUTHOR]