Systematic review of studies generating individual participant data on the efficacy of drugs for treating soil-transmitted helminthiases and the case for data-sharing

Preventive chemotherapy and transmission control (PCT) by mass drug administration is the cornerstone of the World Health Organization (WHO)’s policy to control soil-transmitted helminthiases (STHs) caused by Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm) and hookworm species (Necator americanus and Ancylostama duodenale) which affect over 1 billion people globally. Despite consensus that drug efficacies should be monitored for signs of decline that could jeopardise the effectiveness of PCT, systematic monitoring and evaluation is seldom implemented. Drug trials mostly report aggregate efficacies in groups of participants, but heterogeneities in design complicate classical meta-analyses of these data. Individual participant data (IPD) permit more detailed analysis of drug efficacies, offering increased sensitivity to identify atypical responses potentially caused by emerging drug resistance

Disordered T cell-B cell interactions in autoantibody-positive inflammatory arthritis

T peripheral helper (Tph) cells, identified in the synovium of adults with seropositive rheumatoid arthritis, drive B cell maturation and antibody production in non-lymphoid tissues. We sought to determine if similarly dysregulated T cell-B cell interactions underlie another form of inflammatory arthritis, juvenile oligoarthritis (oligo JIA). Clonally expanded Tph cells able to promote B cell antibody production preferentially accumulated in the synovial fluid (SF) of oligo JIA patients with antinuclear antibodies (ANA) compared to autoantibody-negative patients. Single-cell transcriptomics enabled further definition of the Tph gene signature in inflamed tissues and showed that Tph cells from ANA-positive patients upregulated genes associated with B cell help to a greater extent than patients without autoantibodies. T cells that co-expressed regulatory T and B cell-help factors were identified. The phenotype of these Tph-like Treg cells suggests an ability to restrain T cell-B cell interactions in tissues. Our findings support the central role of disordered T cell-help to B cells in autoantibody-positive arthritides

Astrocytes of the optic nerve exhibit a region-specific and temporally distinct response to elevated intraocular pressure

Abstract Background The optic nerve is an important tissue in glaucoma and the unmyelinated nerve head region remains an important site of many early neurodegenerative changes. In both humans and mice, astrocytes constitute the major glial cell type in the region, and in glaucoma they become reactive, influencing the optic nerve head (ONH) microenvironment and disease outcome. Despite recognizing their importance in the progression of the disease, the reactive response of optic nerve head astrocytes remains poorly understood. Methods To determine the global reactive response of ONH astrocytes in glaucoma we studied their transcriptional response to an elevation in IOP induced by the microbead occlusion model. To specifically isolate astrocyte mRNA in vivo from complex tissues, we used the ribotag method to genetically tag ribosomes in astrocytes, restricting analysis to astrocytes and enabling purification of astrocyte-associated mRNA throughout the entire cell, including the fine processes, for bulk RNA-sequencing. We also assessed the response of astrocytes in the more distal myelinated optic nerve proper (ONP) as glaucomatous changes manifest differently between the two regions. Results Astrocytes of the optic nerve exhibited a region-specific and temporally distinct response. Surprisingly, ONH astrocytes showed very few early transcriptional changes and ONP astrocytes demonstrated substantially larger changes over the course of the experimental period. Energy metabolism, particularly oxidative phosphorylation and mitochondrial protein translation emerged as highly upregulated processes in both ONH and ONP astrocytes, with the former showing additional upregulation in antioxidative capacity and proteolysis. Interestingly, optic nerve astrocytes demonstrated a limited neuroinflammatory response, even when challenged with a more severe elevation in IOP. Lastly, there were a greater number of downregulated processes in both astrocyte populations compared to upregulated processes. Conclusion Our findings demonstrate an essential role for energy metabolism in the response of optic nerve astrocytes to elevated IOP, and contrary to expectations, neuroinflammation had a limited overall role. The transcriptional response profile is supportive of the notion that optic nerve astrocytes have a beneficial role in glaucoma. These previously uncharacterized transcriptional response of optic nerve astrocytes to injury reveal their functional diversity and a greater heterogeneity than previously appreciated

Additional file 1 of Astrocytes of the optic nerve exhibit a region-specific and temporally distinct response to elevated intraocular pressure

Additional file 1: Supplementary Figure 1. (A-B) In-situ hybridization (A, A’) and immunohistochemical staining (B) of the mouse optic nerve for LCN2. We observed very sparse labeling of LCN2 at 7 days after microbead injections (arrowheads). (C-H) Longitudinal sections of the mouse ONH region immunostained for NDUFC2 and COX5B in untreated and microbead injected mice at 30 days. (I, J) Gene set enrichment analysis using the gene ontology (GO) and KEGG database

Additional file 4 of Astrocytes of the optic nerve exhibit a region-specific and temporally distinct response to elevated intraocular pressure

Additional file 4: Supplementary Table 2. Differential expression analysis using a likelihood ratio test (LRT) focusing on genes in the ONH that differ over time (0, 7 and 30 days) in microbead injected mice

Additional file 5 of Astrocytes of the optic nerve exhibit a region-specific and temporally distinct response to elevated intraocular pressure

Additional file 5: Supplementary Table 3. Differentially expressed genes in pairwise comparisons of ONH 7 vs 0 days

Additional file 12 of Astrocytes of the optic nerve exhibit a region-specific and temporally distinct response to elevated intraocular pressure

Additional file 12: Supplementary Table 10. Pathways differentiating ONH astrocytes from those in the ONP at 30 days

Additional file 2 of Astrocytes of the optic nerve exhibit a region-specific and temporally distinct response to elevated intraocular pressure

Additional file 2: Supplementary Figure 2. (A) Heatmap showing the per-sample activity score for each transcription factor identified as significantly different between ONH 30 vs 0 days.  While there are significant differences based on the log2 fold change of genes as input, the heatmap showed limited clustering by condition. (B) Table summarizing the known motifs found to be enriched in the transcription start site +/- 2kb region of our input gene list, with a p-value < 0.001.  For each known motif, the corresponding transcription factor is specified. (B) Table summarizing the known motifs found to be enriched in the transcription start site +/- 2kb region of our input gene list, with a p-value < 0.001.  For each known motif, the corresponding transcription factor is specified. (D) In-situ hybridization showing the localization of Cartpt mRNA in the optic nerve of a microbead injected mouse at 30 days. (E) Longitudinal sections of the mouse ONH region showing immunostaining for CARTPT and SOX9 in microbead injected mice at 30 days

Additional file 3 of Astrocytes of the optic nerve exhibit a region-specific and temporally distinct response to elevated intraocular pressure

Additional file 3: Supplementary Table 1. The quantity and quality of RNA and cDNA measured using the Agilent 2100 Bioanalyzer

Additional file 10 of Astrocytes of the optic nerve exhibit a region-specific and temporally distinct response to elevated intraocular pressure

Additional file 10: Supplementary Table 8. Common differentially expressed genes in all three timpoint comparisons in the ONP