RESUMEN
Recent case reports and studies on treating COVID-19 in patients with chronic sarcoidosis describe different treatment modalities ranging from glucocorticoids to biologic medications. This review article summarizes seven case series and reports totaling 46 patients. While one case report suggested that sarcoidosis medications such as glucocorticoids may lengthen the COVID-19 disease course, another study with a larger registry suggests they do not. More studies are needed to elucidate an improvement in outcomes. It is possible that addition of TNF-alpha inhibitors at COVID-19 diagnosis decreases hospitalization rate. Overall, it is difficult to make firm conclusions regarding treatment given the heterogeneity of treatment modalities in the current literature. Our summarized findings are outlined with the opinions of sarcoidosis, pulmonary, and infectious disease experts in a flow chart that provides clinicians with our proposed management algorithm for sarcoidosis patients who develop COVID-19. We emphasize a need for exchange of information regarding management of COVID-19 in the setting of sarcoidosis to further improve treatment in this vulnerable population of patients.
RESUMEN
Computational protein design (CPD) can address the inverse folding problem, exploring a large space of sequences and selecting ones predicted to fold. CPD was used previously to redesign several proteins, employing a knowledge-based energy function for both the folded and unfolded states. We show that a PDZ domain can be entirely redesigned using a "physics-based" energy for the folded state and a knowledge-based energy for the unfolded state. Thousands of sequences were generated by Monte Carlo simulation. Three were chosen for experimental testing, based on their low energies and several empirical criteria. All three could be overexpressed and had native-like circular dichroism spectra and 1D-NMR spectra typical of folded structures. Two had upshifted thermal denaturation curves when a peptide ligand was present, indicating binding and suggesting folding to a correct, PDZ structure. Evidently, the physical principles that govern folded proteins, with a dash of empirical post-filtering, can allow successful whole-protein redesign.
RESUMEN
The canonical Scribble polarity complex is implicated in regulation of epithelial junctions and apical polarity. Here, we show that SGEF, a RhoG-specific GEF, forms a ternary complex with Scribble and Dlg1, two members of the Scribble complex. SGEF targets to apical junctions in a Scribble-dependent fashion and functions in the regulation of actomyosin-based contractility and barrier function at tight junctions as well as E-cadherin-mediated formation of adherens junctions. Surprisingly, SGEF does not control the establishment of polarity. However, in 3D cysts, SGEF regulates the formation of a single open lumen. Interestingly, SGEF's nucleotide exchange activity regulates the formation and maintenance of adherens junctions, and in cysts the number of lumens formed, whereas SGEF's scaffolding activity is critical for regulation of actomyosin contractility and lumen opening. We propose that SGEF plays a key role in coordinating junctional assembly and actomyosin contractility by bringing together Scribble and Dlg1 and targeting RhoG activation to cell-cell junctions.