Lung transplantation can potentially be a life-saving treatment for patients with non-resolving COVID-19-associated respiratory failure. Concerns limiting lung transplantation include recurrence of SARS-CoV-2 infection in the allograft, technical challenges imposed by viral-mediated injury to the native lung, and the potential risk for allograft infection by pathogens causing ventilator-associated pneumonia in the native lung. Importantly, the native lung might recover, resulting in long-term outcomes preferable to those of transplant. Here, we report the results of lung transplantation in three patients with non-resolving COVID-19-associated respiratory failure. We performed single molecule fluorescent in situ hybridization (smFISH) to detect both positive and negative strands of SARS-CoV-2 RNA in explanted lung tissue from the three patients and in additional control lung tissue samples. We conducted extracellular matrix imaging and single cell RNA sequencing on explanted lung tissue from the three patients who underwent transplantation and on warm post-mortem lung biopsies from two patients who had died from COVID-19-associated pneumonia. Lungs from these five patients with prolonged COVID-19 disease were free of SARS-CoV-2 as detected by smFISH, but pathology showed extensive evidence of injury and fibrosis that resembled end-stage pulmonary fibrosis. Using machine learning, we compared single cell RNA sequencing data from the lungs of patients with late stage COVID-19 to that from the lungs of patients with pulmonary fibrosis and identified similarities in gene expression across cell lineages. Our findings suggest that some patients with severe COVID-19 develop fibrotic lung disease for which lung transplantation is their only option for survival.

Many diseases exhibit population-specific causal effect sizes with trans-ethnic genetic correlations significantly less than 1, limiting trans-ethnic polygenic risk prediction. We develop a new method, S-LDXR, for stratifying squared trans-ethnic genetic correlation across genomic annotations, and apply S-LDXR to genome-wide summary statistics for 31 diseases and complex traits in East Asians (average N = 90K) and Europeans (average N = 267K) with an average trans-ethnic genetic correlation of 0.85. We determine that squared trans-ethnic genetic correlation is 0.82× (s.e. 0.01) depleted in the top quintile of background selection statistic, implying more population-specific causal effect sizes. Accordingly, causal effect sizes are more population-specific in functionally important regions, including conserved and regulatory regions. In regions surrounding specifically expressed genes, causal effect sizes are most population-specific for skin and immune genes, and least population-specific for brain genes. Our results could potentially be explained by stronger gene-environment interaction at loci impacted by selection, particularly positive selection.

Background & Aims Krüppel-like factor 5 (KLF5) is transcription factor that is expressed by dividing epithelial cells of the intestinal epithelium. KLF5 promotes proliferation in vitro and in vivo and is induced by mitogens and various stress stimuli. To study the role of KLF5 in intestinal epithelial homeostasis, we examined the phenotype of mice with conditional deletion of Klf5 in the gut. Methods Mice were generated with intestinal-specific deletion of Klf5 (Vil-Cre;Klf5fl/fl). Morphological changes in the small intestine and colon were examined by immunohistochemistry, immunoblotting, and real-time PCR. Results Klf5 mutant mice were born at a normal Mendelian ratio but had high mortality compared to controls. Complete deletion of Klf5 from the intestinal mucosa resulted in neonatal lethality that corresponded with an absence of epithelial proliferation. Variegated intestinal-specific deletion of Klf5 in adult mice resulted in morphological changes that included a regenerative phenotype, impaired barrier function, and inflammation. Adult mutant mice exhibited defects in epithelial differentiation and migration. These changes were associated with reduced expression of Cdx 1, Cdx2, and Eph and ephrin signaling proteins. Concomitantly, Wnt signaling to β-catenin was reduced. Proliferation in regenerative crypts was associated with increased expression of the progenitor cell marker Sox9. Conclusions Deletion of Klf5 in the gut epithelium of mice demonstrated that KLF5 maintains epithelial proliferation, differentiation, and cell positioning along the crypt radial axis. Morphological changes that occur with deletion of Klf5 are associated with disruption of canonical Wnt signaling and increased expression of Sox9.

Background Veno‐venous extracorporeal membrane oxygenation (V‐V ECMO) support is increasingly used in the management of COVID‐19‐related acute respiratory distress syndrome (ARDS). However, the clinical decision‐making to initiate V‐V ECMO for severe COVID‐19 still remains unclear. In order to determine the optimal timing and patient selection, we investigated the outcomes of both COVID‐19 and non‐COVID‐19 patients undergoing V‐V ECMO support. Methods Overall, 138 patients were included in this study. Patients were stratified into two cohorts: those with COVID‐19 and non‐COVID‐19 ARDS. Results The survival in patients with COVID‐19 was statistically similar to non‐COVID‐19 patients ( p = .16). However, the COVID‐19 group demonstrated higher rates of bleeding ( p = .03) and thrombotic complications ( p < .001). The duration of V‐V ECMO support was longer in COVID‐19 patients compared to non‐COVID‐19 patients (29.0 ± 27.5 vs 15.9 ± 19.6 days, p < .01). Most notably, in contrast to the non‐COVID‐19 group, we found that COVID‐19 patients who had been on a ventilator for longer than 7 days prior to ECMO had 100% mortality without a lung transplant. Conclusions These findings suggest that COVID‐19‐associated ARDS was not associated with a higher post‐ECMO mortality than non‐COVID‐19‐associated ARDS patients, despite longer duration of extracorporeal support. Early initiation of V‐V ECMO is important for improved ECMO outcomes in COVID‐19 ARDS patients. Since late initiation of ECMO was associated with extremely high mortality related to lack of pulmonary recovery, it should be used judiciously or as a bridge to lung transplantation.

BACKGROUND & AIMS-Krüppel-like factor 5 (KLF5) is a transcription factor that promotes proliferation; is highly expressed in dividing crypt cells of the gastrointestinal epithelium and is induced by various stress stimuli. We sought to determine the role of KLF5 in colonic inflammation and recovery by studying mice with dextran sulfate sodium (DSS)-induced colitis.

This roadmap outlines the role semiconductor-based materials play in understanding the complex biophysical dynamics at multiple length scales, as well as the design and implementation of next-generation electronic, optoelectronic, and mechanical devices for biointerfaces. The roadmap emphasizes the advantages of semiconductor building blocks in interfacing, monitoring, and manipulating the activity of biological components, and discusses the possibility of using active semiconductor-cell interfaces for discovering new signaling processes in the biological world.

Recent studies have highlighted the role of gene networks in disease biology. To formally assess this, we constructed a broad set of pathway, network, and pathway+network annotations and applied stratified LD score regression to 42 independent diseases and complex traits (average N =323K) to identify enriched annotations. First, we constructed annotations from 18,119 biological pathways, including 100kb windows around each gene. We identified 156 pathway-trait pairs whose disease enrichment was statistically significant (FDR < 5%) after conditioning on all genes and on annotations from the baseline-LD model, a stringent step that greatly reduced the number of pathways detected; most of the significant pathway-trait pairs were previously unreported. Next, for each of four published gene networks, we constructed probabilistic annotations based on network connectivity using closeness centrality, a measure of how close a gene is to other genes in the network. For each gene network, the network connectivity annotation was strongly significantly enriched. Surprisingly, the enrichments were fully explained by excess overlap between network annotations and regulatory annotations from the baseline-LD model, validating the informativeness of the baseline-LD model and emphasizing the importance of accounting for regulatory annotations in gene network analyses. Finally, for each of the 156 enriched pathway-trait pairs, for each of the four gene networks, we constructed pathway+network annotations by annotating genes with high network connectivity to the input pathway. For each gene network, these pathway+network annotations were strongly significantly enriched for the corresponding traits. Once again, the enrichments were largely explained by the baseline-LD model. In conclusion, gene network connectivity is highly informative for disease architectures, but the information in gene networks may be subsumed by regulatory annotations, such that accounting for known annotations is critical to robust inference of biological mechanisms.

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