Transfer learning in a biomaterial fibrosis model identifies in vivo senescence heterogeneity and contributions to vascularization and matrix production across species and diverse pathologies

Cellular senescence is a state of permanent growth arrest that plays an important role in wound healing, tissue fibrosis, and tumor suppression. Despite senescent cells’ (SnCs) pathological role and therapeutic interest, their phenotype in vivo remains poorly defined. Here, we developed an in vivo–derived senescence signature (SenSig) using a foreign body response–driven fibrosis model in a p16-CreERT2;Ai14 reporter mouse. We identified pericytes and “cartilage-like” fibroblasts as senescent and defined cell type–specific senescence-associated secretory phenotypes (SASPs). Transfer learning and senescence scoring identified these two SnC populations along with endothelial and epithelial SnCs in new and publicly available murine and human data single-cell RNA sequencing (scRNAseq) datasets from diverse pathologies. Signaling analysis uncovered crosstalk between SnCs and myeloid cells via an IL34–CSF1R–TGFβR signaling axis, contributing to tissue balance of vascularization and matrix production. Overall, our study provides a senescence signature and a computational approach that may be broadly applied to identify SnC transcriptional profiles and SASP factors in wound healing, aging, and other pathologies.</p

Transfer learning in a biomaterial fibrosis model identifies in vivo senescence heterogeneity and contributions to vascularization and matrix production across species and diverse pathologies

Cellular senescence is a state of permanent growth arrest that plays an important role in wound healing, tissue fibrosis, and tumor suppression. Despite senescent cells’ (SnCs) pathological role and therapeutic interest, their phenotype in vivo remains poorly defined. Here, we developed an in vivo–derived senescence signature (SenSig) using a foreign body response–driven fibrosis model in a p16-CreERT2;Ai14 reporter mouse. We identified pericytes and “cartilage-like” fibroblasts as senescent and defined cell type–specific senescence-associated secretory phenotypes (SASPs). Transfer learning and senescence scoring identified these two SnC populations along with endothelial and epithelial SnCs in new and publicly available murine and human data single-cell RNA sequencing (scRNAseq) datasets from diverse pathologies. Signaling analysis uncovered crosstalk between SnCs and myeloid cells via an IL34–CSF1R–TGFβR signaling axis, contributing to tissue balance of vascularization and matrix production. Overall, our study provides a senescence signature and a computational approach that may be broadly applied to identify SnC transcriptional profiles and SASP factors in wound healing, aging, and other pathologies.</p

Ran-dependent docking of importin-β to RanBP2/Nup358 filaments is essential for protein import and cell viability

RanBP2 captures RanGTP–importin-β complexes at cytoplasmic fibrils to ensure adequate classical NLS–mediated protein import and cell viability

Poor quality of reporting confounding bias in observational intervention studies:a systematic review

PURPOSE: To systematically review observational studies on medical interventions to determine the quality of reporting of confounding. METHODS: Articles on observational studies on medical interventions in five general medical journals and five epidemiological journals published between January 2004 and April 2007 were systematically reviewed. All relevant items pertaining to confounding bias were scored for each article. The overall quality of reporting was determined with an 8-point score. RESULTS: The MEDLINE search resulted in 2993 publications, and 174 (5.8%) articles were included in the analysis. In the majority of studies (>98%), the potential for confounding bias was reported. Details on the selection and inclusion of observed confounders were reported in 10% and 51%, respectively. The potential for unobserved confounding was reported in 60%, and 9% commented on the potential effect of such remaining confounding. The quality of reporting of confounding score was mediocre (a median score of 4 points; interquartile range 3 to 5), and scores were similar in all years. CONCLUSION: The quality of reporting of confounding in articles on observational medical intervention studies was poor. However, the STROBE statement for reporting of observational studies may considerably impact the reporting of such studies

Invasive pneumococcal disease and 7-valent pneumococcal conjugate vaccine, the Netherlands

In the Netherlands, the national immunization program includes 7-valent pneumococcal conjugate vaccine (PCV7) for all newborns born after April 1, 2006. We compared the incidence of invasive pneumococcal disease (IPD) and patient and disease characteristics before PCV7 introduction (June 2004-June 2006) with those after PCV7 introduction (June 2008-June 2010). Culture-confirmed IPD cases were identified by 9 sentinel laboratories covering ≈25% of the Dutch population. Significant declines in overall IPD incidence were observed in children 65 (13%) years of age. A trend toward gradual increases in non-PCV7 serotype IPD infections was observed in all age groups; the largest increases were among persons 50-64 (37%) and >65 (25%) years of age. In adults, the proportion of immunocompromised persons increased among IPD patients. Overall, deaths from IPD decreased from 16% to 12% because of a lower case-fatality rate for persons with non-PCV7 serotype IP

The impact of the 13-valent pneumococcal conjugate vaccine on pneumococcal carriage in the Community Acquired Pneumonia Immunization Trial in Adults (CAPiTA) Study

Background: The impact of pneumococcal conjugate vaccination on the prevalence of nasopharyngeal carriage with pneumococci and other bacteria in adults is unknown. The direct effects of the 13-valent pneumococcal conjugate vaccine (PCV13) in community dwelling older adults was investigated as part of the randomized controlled Community Acquired Pneumonia immunization Trial in Adults (CAPiTA). Methods: We determined the carriage of S. pneumoniae, S. aureus, H. influenzae, and M. catarrhalis before and at 6, 12 and 24 months post-vaccination using PCR-based methods and conventional cultures of naso- and oropharyngeal swabs in 1,006 PCV13-recipients and 1,005 controls. Serotyping of the 13 vaccine-type (VT) pneumococci was performed by PCR targeting capsular synthesis genes and quellung reaction of isolates. Findings: Before randomization and based on PCR, 339 of 1891 subjects had nasopharyngeal carriage with any pneumococci (17.9%), and 114 of 1891 subjects (6.0%) carried a VT-pneumococci. At six months post-vaccination, VT-pneumococcal carriage was significantly lower in PCV13-recipients than in the placebo-group (RR 0.53 95%CI: 0.35-0.80; p=0.04). There was no difference between the groups at 12 and 24 months post-vaccination. Carriage of non-VT-pneumococci, S. aureus, H. influenzae, and M. catarrhalis did not change between groups. Interpretations: In community-dwelling adults of 65 years and older, a single dose of PCV13 appears to elicit a small and temporary reduction in VT-carriage at 6 months post-vaccination. Neither replacement by non-vaccine serotypes nor impact on other nasopharyngeal bacteria was observed

The impact of the 13-valent pneumococcal conjugate vaccine on pneumococcal carriage in the Community Acquired Pneumonia Immunization Trial in Adults (CAPiTA) Study

Background: The impact of pneumococcal conjugate vaccination on the prevalence of nasopharyngeal carriage with pneumococci and other bacteria in adults is unknown. The direct effects of the 13-valent pneumococcal conjugate vaccine (PCV13) in community dwelling older adults was investigated as part of the randomized controlled Community Acquired Pneumonia immunization Trial in Adults (CAPiTA). Methods: We determined the carriage of S. pneumoniae, S. aureus, H. influenzae, and M. catarrhalis before and at 6, 12 and 24 months post-vaccination using PCR-based methods and conventional cultures of naso- and oropharyngeal swabs in 1,006 PCV13-recipients and 1,005 controls. Serotyping of the 13 vaccine-type (VT) pneumococci was performed by PCR targeting capsular synthesis genes and quellung reaction of isolates. Findings: Before randomization and based on PCR, 339 of 1891 subjects had nasopharyngeal carriage with any pneumococci (17.9%), and 114 of 1891 subjects (6.0%) carried a VT-pneumococci. At six months post-vaccination, VT-pneumococcal carriage was significantly lower in PCV13-recipients than in the placebo-group (RR 0.53 95%CI: 0.35-0.80; p=0.04). There was no difference between the groups at 12 and 24 months post-vaccination. Carriage of non-VT-pneumococci, S. aureus, H. influenzae, and M. catarrhalis did not change between groups. Interpretations: In community-dwelling adults of 65 years and older, a single dose of PCV13 appears to elicit a small and temporary reduction in VT-carriage at 6 months post-vaccination. Neither replacement by non-vaccine serotypes nor impact on other nasopharyngeal bacteria was observed