Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells.

OBJECTIVE: The functional role of interleukin-22 (IL22) in chronic inflammation is controversial, and mechanistic insights into how it regulates target tissue are lacking. In this study, we evaluated the functional role of IL22 in chronic colitis and probed mechanisms of IL22-mediated regulation of colonic epithelial cells. DESIGN: To investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial cells, we employed a three-dimentional mini-gut epithelial organoid system, in vivo disease models and transcriptomic datasets in human IBD. RESULTS: As well as inducing transcriptional modules implicated in antimicrobial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional programme in colonic epithelial cells. In the colon of patients with active colonic Crohn's disease (CD), there was enrichment of IL22-responsive transcriptional modules and ER stress response modules. Strikingly, in an IL22-dependent model of chronic colitis, targeting IL22 alleviated colonic epithelial ER stress and attenuated colitis. Pharmacological modulation of the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response. CONCLUSIONS: Our data challenge perceptions of IL22 as a predominantly beneficial cytokine in IBD and provide novel insights into the molecular mechanisms of IL22-mediated pathogenicity in chronic colitis. Targeting IL22-regulated pathways and alleviating colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis. TRIAL REGISTRATION NUMBER: NCT02749630.

Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease.

The polarization of CD4+ T cells into distinct T helper cell lineages is essential for protective immunity against infection, but aberrant T cell polarization can cause autoimmunity. The transcription factor T-bet (TBX21) specifies the Th1 lineage and represses alternative T cell fates. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that may be causative for autoimmune diseases. The majority of these polymorphisms are located within non-coding distal regulatory elements. It is considered that these genetic variants contribute to disease by altering the binding of regulatory proteins and thus gene expression, but whether these variants alter the binding of lineage-specifying transcription factors has not been determined. Here, we show that SNPs associated with the mucosal inflammatory diseases Crohn's disease, ulcerative colitis (UC) and celiac disease, but not rheumatoid arthritis or psoriasis, are enriched at T-bet binding sites. Furthermore, we identify disease-associated variants that alter T-bet binding in vitro and in vivo. ChIP-seq for T-bet in individuals heterozygous for the celiac disease-associated SNPs rs1465321 and rs2058622 and the IBD-associated SNPs rs1551398 and rs1551399, reveals decreased binding to the minor disease-associated alleles. Furthermore, we show that rs1465321 is an expression quantitative trait locus (eQTL) for the neighboring gene IL18RAP, with decreased T-bet binding associated with decreased expression of this gene. These results suggest that genetic polymorphisms may predispose individuals to mucosal autoimmune disease through alterations in T-bet binding. Other disease-associated variants may similarly act by modulating the binding of lineage-specifying transcription factors in a tissue-selective and disease-specific manner.

T-bet as a key regulator of mucosal immunity.

Initially understood to be a key regulator of interferon-γ-producing helper T cells, our knowledge of T-bet's functional roles has expanded to encompass a growing range of cellular lineages. In addition to regulating other interferon-γ-producing adaptive immune cells, it is now clear that T-bet plays a fundamental role in the regulation of innate immune responses across mucosal surfaces. This homeostatic role is demonstrated by the spontaneous colitis that occurs when T-bet is deleted from innate immune cells in RAG(-/-) mice. Using this model as a focal point, we review our understanding of T-bet's regulation of adaptive and innate immune systems, focusing particularly on mucosal populations including innate lymphoid cells, dendritic cells and intraepithelial lymphocytes. With the increasingly diverse effects of T-bet on different lineages, the classical binding-centric paradigm of T-bet's molecular functionality has increasingly struggled to account for the versatility of T-bet's biological effects. Recent recognition of the synergistic interactions between T-bet and other canonical transcription factors has led to a co-operative paradigm that has provided greater explanatory power. Synthesizing insights from ChIP-seq and comparative biology, we expand the co-operative paradigm further and suggest a network approach as a powerful way to understand and model T-bet's diverse functionality.

Potential benefits of climate change on navigation in the northern sea route by 2050.

Climate change has been inducing a continuous increase in temperatures within the Arctic region, consequently leading to an escalation in the rates of Arctic ice depletion. These changes have profound implications for navigation along the Arctic Northern Sea Route (NSR). However, access to the NSR is constrained to specific temporal intervals when the sea ice thickness reaches a threshold that permits safe passage of ships. This research employs climate change model simulations and the Polar Operational Limit Assessment Risk Indexing System framework to investigate the navigational feasibility of diverse ship types along NSR during the calendar years 2030, 2040, and 2050, under SSP2-4.5 and SSP5-8.5 scenarios. Different ship categories were analyzed within the context of these two scenarios. Results indicate considerable variation in the navigability of different ship categories across different scenarios and years. In general, polar ships demonstrate a higher navigational potential throughout most of the year, while pleasure crafts are constrained to specific periods. These findings bear significant implications for the future of shipping along the NSR. As Arctic ice continues to melt, NSR is anticipated to become more accessible to ships, albeit with navigational availability remaining contingent on the ship category and seasonal considerations.

Keeping Patients Safe Online: A Study of Refractive Surgery Advertisements on Social Media.

Introduction Refractive error is the leading cause of visual impairment and blindness globally. Increasingly, patients are exposed to information about refractive surgery through social media advertisements. While national guidelines specify how refractive surgery should be advertised in traditional media, it is unclear to what extent these standards are adhered to in the emerging commercial arena of social media. The adherence of refractive surgery advertisements on social media to professional standards is poorly studied. Method We retrospectively analyzed the content of refractive surgery advertisements on the social media platform "TikTok," shown in the United Kingdom (UK) from October 2022 to October 2023, and compared them to the guidelines set out by The Royal College of Ophthalmologists (RCOphth) and the Advertising Standards Authority (ASA). Results We found that 39/51 (76%) of advertisements did not state the specific pathology to be corrected, and 41/51 (80%) did not specify a surgical procedure. Additionally, 33/51 (65%) of advertisements included at least one financial inducement, 44/51 (86%) contained misleading claims. None of the analyzed advertisements provided specific prices, offered refractive surgery as a competition prize, or featured celebrity endorsements. No medical jargon was found in any of the advertisements. The most viewed advertisement was seen by over 1.2 million unique users, with the median number of views for all advertisements being 34,000. Conclusion In conclusion, our analysis revealed that none of the refractive surgery advertisements on a popular social media platform met the standards set by RCOphth or ASA. This study presents the first qualitative analysis of social media refractive surgery advertisements, offering insights into what users can expect and providing recommendations for patients, doctors, social media platforms, and regulators to enhance refractive surgery advertising in the future.

Rapid invasion and expansion of the invasive macroalgae Rugulopteryx okamurae in the Mediterranean and Atlantic: A 10-year review.

This review seeks to establish a baseline on the current knowledge and gaps in the scientific literature on the invasive macroalgae Rugulopteryx okamurae. Through a systematic literature analysis we summarize the insights regarding distribution and potential impacts as non-indigenous species associated with its expansion from the Strait of Gibraltar since first detected by 2015. After 10 years, this invasive alien macroalgae has broadly expanded across the Mediterranean Sea (France, Spain, Morocco and Italy) and the Atlantic coasts (Morocco, Spain, Portugal, Madeira, Azores and Canary Islands). The developed research mainly shows early new detections of R. okamurae, the negative effects including both economic and ecological impacts on native biota, monitoring efforts, as well as potential applications of the biomass generated. Most of the research is mainly focused on the Strait of Gibraltar adjacent waters, making other vulnerable regions impacted unknown. These findings demonstrate R. okamurae highly invasive behavior, the need of more research regarding its spatial monitoring, impacts and potential uses, as well the complexity of cross-border coastal management. The potential invasion of broader areas in both Mediterranean and Atlantic coasts from the European and African continent requires international efforts to monitor and mitigate its ecological and economic impact, developing both scientific applications stretching efforts with specialized private companies and adapting public policies. The gaps identified in the current knowledge of R. okamurae as an invasive alien species reveal as a priority the development and implementation of an international monitoring program, integrating public participation to identify early-warnings, that could be used to quantify impacts transferable to public policies and cross-border coastal management between both continents, filling the identified management gaps opening management opportunities in the industrial sector.

[Hypomania under corticotherapy. About 50 cases]. / Hypomanie sous corticothérapie. A propos de 50 cas.

AIM: Our study was to determine the prevalence of hypomania as a complication of corticotherapy and to discuss its clinical and etiopathogenic aspects, but also to heighten the practitioners on the importance of screening this disorder, which become easy with psychometric scales, such Angst one. Our final purpose was the secondary and tertiary prevention of this disorder, which may cause many complications. PATIENTS AND METHODS: We have applied the Angst scale of hypomania to 50 patients, aged between 18 and 80 years, and put under corticotherapy, at dose varying between 10 and 100 mg of prednisone per day. A score superior or equals 10 was taken as a sign of hypomania. RESULTS: Fourteen patients (28%), at 43.35 year of mean age, have presented an episode of hypomania under corticoids. This prevalence was more important in patients with lupus (38.89%) in comparison with other patients (21.86%). The symptomatology has begun in 12 cases (85.7% of all cases), during the first month of treatment. The average posology used varies between 60 and 100 mg of prednisone per day. CONCLUSION: The prevalence of psychiatric problems under oral corticotherapy is difficult to estimate, but is almost 15%, according to other studies. Actually, we know that this prevalence in under estimated. This underline the importance of doing an active research of these problems in patients under corticotherapy, either by direct questioning or clinical observation, or by passing appropriate questionnaires and an adapted evaluation scale, with the aim of secondary and tertiary prevention.

Primary omental torsion in children: case report.

Primary omental torsion is a rare cause of acute abdominal pain, we report a case of 10-year-old boy admitted with crampy abdominal pain, routine laboratory tests and plain abdominal radiography was normal, the patient underwent surgical exploration with the initial diagnosis of appendicitis, primary omental torsion was confirmed and the omentum was untwisted, with good postoperative evolution.