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Individual variation in pain sensation makes pain clinical trials quite challenging to interpret. Now, Michael Salter and colleagues report that genetic variation in the P2RX7 gene affects pore formation of the protein and pain sensation in humans. Chronic pain is highly variable between individuals, as is the response to analgesics. Although much of the variability in chronic pain and analgesic response is heritable, an understanding of the genetic determinants underlying this variability is rudimentary 1 . Here we show that variation within the coding sequence of the gene encoding the P2X7 receptor (P2X7R) affects chronic pain sensitivity in both mice and humans. P2X7Rs, which are members of the family of ionotropic ATP-gated receptors, have two distinct modes of function: they can function through their intrinsic cationic channel or by forming nonselective pores that are permeable to molecules with a mass of up to 900 Da 2 , 3 . Using genome-wide linkage analyses, we discovered an association between nerve-injury–induced pain behavior (mechanical allodynia) and the P451L mutation of the mouse P2rx7 gene, such that mice in which P2X7Rs have impaired pore formation as a result of this mutation showed less allodynia than mice with the pore-forming P2rx7 allele. Administration of a peptide corresponding to the P2X7R C-terminal domain, which blocked pore formation but not cation channel activity, selectively reduced nerve injury and inflammatory allodynia only in mice with the pore-forming P2rx7 allele. Moreover, in two independent human chronic pain cohorts, a cohort with pain after mastectomy and a cohort with osteoarthritis, we observed a genetic association between lower pain intensity and the hypofunctional His270 (rs7958311) allele of P2RX7 . Our findings suggest that selectively targeting P2X7R pore formation may be a new strategy for individualizing the treatment of chronic pain.

Galectin-8 (Gal-8) is a member of a glycan-binding protein family that regulates the immune system, among other functions, and is a target of antibodies in autoimmune disorders. However, its role in multiple sclerosis (MS), an autoimmune inflammatory disease of the central nervous system (CNS), remains unknown. We study the consequences of Gal-8 silencing on lymphocyte subpopulations and the development of experimental autoimmune encephalitis (EAE), to then assess the presence and clinical meaning of anti-Gal-8 antibodies in MS patients. Lgals8/Lac-Z knock-in mice lacking Gal-8 expression have higher polarization toward Th17 cells accompanied with decreased CCR6+ and higher CXCR3+ regulatory T cells (Tregs) frequency. These conditions result in exacerbated MOG35-55 peptide-induced EAE. Gal-8 eliminates activated Th17 but not Th1 cells by apoptosis and ameliorates EAE in C57BL/6 wild-type mice. β-gal histochemistry reflecting the activity of the Gal-8 promoter revealed Gal-8 expression in a wide range of CNS regions, including high expression in the choroid-plexus. Accordingly, we detected Gal-8 in human cerebrospinal fluid, suggesting a role in the CNS immune-surveillance circuit. In addition, we show that MS patients generate function-blocking anti-Gal-8 antibodies with pathogenic potential. Such antibodies block cell adhesion and Gal-8-induced Th17 apoptosis. Furthermore, circulating anti-Gal-8 antibodies associate with relapsing-remitting MS (RRMS), and not with progressive MS phenotypes, predicting clinical disability at diagnosis within the first year of follow-up. Our results reveal that Gal-8 has an immunosuppressive protective role against autoimmune CNS inflammation, modulating the balance of Th17 and Th1 polarization and their respective Tregs. Such a role can be counteracted during RRMS by anti-Gal-8 antibodies, worsening disease prognosis. Even though anti-Gal-8 antibodies are not specific for MS, our results suggest that they could be a potential early severity biomarker in RRMS.

This may be uncharted waters for Panthers fans, many of whom just a few weeks ago didn't know the difference between a blue line and the shoreline. But that doesn't mean they didn't know how to react when their team lunged into the Stanley Cup finals Saturday: they erupted with the unbridled enthusiasm reserved for the greatest of sporting events. \"It's been a great ride,\" said Rob Thomas, a ticket broker watching the game at Dicey Riley's in Fort Lauderdale. \"I've been to every major sporting event, including the Super Bowl, the Final Four, and the Indianapolis 500. And bar none, this is the best experience of them all.\"

Reading text in real-world scenarios often requires understanding the context surrounding it, especially when dealing with poor-quality text. However, current scene text recognizers are unaware of the bigger picture as they operate on cropped text images. In this study, we harness the representative capabilities of modern vision-language models, such as CLIP, to provide scene-level information to the crop-based recognizer. We achieve this by fusing a rich representation of the entire image, obtained from the vision-language model, with the recognizer word-level features via a gated cross-attention mechanism. This component gradually shifts to the context-enhanced representation, allowing for stable fine-tuning of a pretrained recognizer. We demonstrate the effectiveness of our model-agnostic framework, CLIPTER (CLIP TExt Recognition), on leading text recognition architectures and achieve state-of-the-art results across multiple benchmarks. Furthermore, our analysis highlights improved robustness to out-of-vocabulary words and enhanced generalization in low-data regimes.