ACS Medicinal Chemistry Letters最新文献

A new device applies a single-colour electronic injection to create the brightest multi-colour phonon laser, with ten times more power and much narrower linewidth than others.

Objectives: Belimumab is a putative disease-modifying agent in systemic lupus erythematosus (SLE), yet the molecular underpinnings of its effects and the ability to predict early clinical response remain unexplored. To address these, we undertook a longitudinal, in-depth blood transcriptome study.

Methods: RNA-sequencing was performed in the blood of active SLE patients at baseline and following 6 months of belimumab treatment (n=45 paired samples). Clinical response was determined according to the SLE Responder Index (SRI)-4 and Lupus Low Disease Activity State (LLDAS). Weighted correlation network analysis (WGCNA) was used to uncover gene module trait associations. Reversibility of SLE susceptibility and severity gene signatures was assessed. Machine learning was used to build models predictive of response.

Results: Belimumab induced widespread transcriptome changes with downregulation of pathways related to B cells, type I/II interferon, IL-6/STAT3 and neutrophil activation. These effects were more pronounced among patients with LLDAS+ compared with to SRI-4+/LLDAS- response, with amelioration of the SLE 'susceptibility' signature observed in the former group. Unsupervised analysis unveiled gene modules enriched in neutrophil degranulation, type I interferon signalling and cytokine production to correlate positively with response at 6 months. Using neural networks, a set of 50 genes (including CCL4L2, CARD10, MMP15 and KLRC2) predicted response to belimumab with a cross-validated 84% specificity (test set). Lack of response was linked to perturbations of the cell cycle checkpoints, PI3K/Akt/mammalian target of rapamycin and TGF-beta signalling pathways.

Conclusion: Belimumab treatment ameliorates multiple innate and adaptive immunity dysregulations of SLE and may reverse the disease signature, consistent with the drug effects on reducing activity and preventing flares. Fingerprints of innate immunity correlate with robust improvement whereas DNA damage response with less responsive disease to BAFF inhibition.

Nature Photonics 18, 1147–1154 (2024)

Understanding the morphology and function of large-scale cerebrovascular networks is crucial for studying brain health and disease. However, reconciling the demands for imaging on a broad scale with the precision of high-resolution volumetric microscopy has been a persistent challenge. In this study, we introduce Bessel beam optical coherence microscopy with an extended focus to capture the full cortical vascular hierarchy in mice over 1000 × 1000 × 360 μm³ field-of-view at capillary level resolution. The post-processing pipeline leverages a supervised deep learning approach for precise 3D segmentation of high-resolution angiograms, hence permitting reliable examination of microvascular structures at multiple spatial scales. Coupled with high-sensitivity Doppler optical coherence tomography, our method enables the computation of both axial and transverse blood velocity components as well as vessel-specific blood flow direction, facilitating a detailed assessment of morpho-functional characteristics across all vessel dimensions. Through graph-based analysis, we deliver insights into vascular connectivity, all the way from individual capillaries to broader network interactions, a task traditionally challenging for in vivo studies. The new imaging and analysis framework extends the frontiers of research into cerebrovascular function and neurovascular pathologies.