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摘要： Background: Immune factors underlie approximately 20% of patients exhibiting platelet transfusion refractoriness (PTR). PTR can be mitigated by supplying HLA-A and B compatible platelets to these patients. Since 2019, Canadian Blood Services has managed a program to provide compatible platelets to alloimmunized patients. This study evaluates donor pool size and ethnic diversity options to serve Canada's population. Study Design and Methods: We adapted simulation-based stem cell matching methods by generating simulated patients and matching them to existing and simulated donors using a Python algorithm. Recruitment scenarios included census-aligned, single-group, and meta-heuristic-optimized distributions to enhance match rates and equity. Results: More typed donors increase match rates, but rates vary significantly by ethnicity. Non-Black patients achieved 95% coverage with 13,000-18,000 new donors, whereas Black patients required similar to 55,000 new donors. Single-ethnicity recruitment improved the targeted group's rate but reduced overall match rates and disadvantaged other populations. A Pareto-optimal donor mix-augmenting Black, Hispanic, Asian Pacific Islander, and Native American/First Nations donors while modestly reducing White typing-preserved or improved rates but yielded only modest gains for Black patients. A balanced strategy further prioritizing Black and Hispanic donors with slight reductions in White, Asian, and Native American/First Nations typing achieved improvements for the Black population with minimal losses for others. Discussion: While Pareto-optimal allocation enhances overall efficiency, targeted trade-offs, focusing on underrepresented groups, are essential to correct persistent disparities and achieve equitable HLA-matched platelet availability.

关键词： italic>Yersinia   infectious disease   tumor necrosis factor   gastrointestinal infection   infection dynamics   bacterial infection   innate immunity  

摘要： Enteroinvasive bacterial pathogens are responsible for an enormous worldwide disease burden that critically affects the young and immunocompromised. Yersinia pseudotuberculosis is a gram-negative enteric pathogen closely related to the plague agent Y. pestis that colonizes intestinal tissues, induces the formation of pyogranulomas along the intestinal tract, and disseminates to systemic organs following oral infection of experimental rodents. Prior studies proposed that systemic tissues were colonized by a pool of intestinal replicating bacteria distinct from populations within Peyer's patches and mesenteric lymph nodes. Whether bacteria within intestinal pyogranulomas serve as the source for systemic dissemination and the relationship between bacterial populations within different tissue sites is poorly defined. Moreover, the host factors that regulate Yersinia colonization and dissemination are not well understood. Here, we demonstrate using sequence tag-based analysis of microbial populations in R (STAMPR) that remarkably small founder populations independently colonize intestinal and systemic tissues. Notably, intestinal pyogranulomas contain clonal populations of bacteria that are restricted and do not spread to other tissues. However, Yersinia populations are shared among systemic organs and the blood, suggesting that systemic dissemination occurs via hematogenous spread. Finally, we demonstrate that TNF signaling is a key contributor to the bottlenecks limiting both initial colonization and subsequent dissemination of orally acquired bacterial populations. Altogether, this study reveals previously undescribed aspects of infection dynamics of enteric bacterial *** of bacteria following intestinal infection can lead to severe disease, including sepsis, organ damage, and death. However, the intestinal bacterial population dynamics governing the colonization of mucosal and systemic tissues and the intestinal sites that seed systemic

关键词： NMOSD   Cytokines   Disability   IL-1 beta   Aquaporin-4   Neuroinflammation  

摘要： Background Neuromyelitis Optica Spectrum Disorder (NMOSD) is a central nervous system inflammatory disease that causes severe disability. Differently from relapsing-remitting multiple sclerosis (RRMS) a group of patients present aqua-porin-4 (AQP4) antibodies in the serum. Although its pathogenesis is unclear, cytokine profiles may impact disease activity and severity. Objective To analyze cerebrospinal fluid (CSF) cytokine levels in NMOSD AQP4 + and their relationship with neurological disability, comparing findings with RRMS patients and non-inflammatory controls (NIC).Methods Sixty-four participants were recruited: 11 NMOSD AQP4+, 29 RRMS, and 24 NIC. CSF cytokine levels were measured using a multiplex assay. Group comparisons were performed with Kruskal-Wallis and Mann-Whitney U tests, while linear regression models evaluated the association between cytokine levels and Expanded Disability Status Scale (EDSS) scores. Results NMOSD AQP4 + patients displayed significantly higher CSF levels of IL-1 beta (p = 0.040), TNF-alpha (p < 0.001), G-CSF (p = 0.003), Eotaxin (p = 0.008), and MIP-1 alpha (p = 0.005) compared to RRMS and NIC. Moreover, IL-1 beta CSF levels were positively associated with disability at the time of lumbar puncture (beta = 22.24, SE = 7.73, p = 0.018), a relationship that remained significant after adjusting for age (beta = 18.96, SE = 6.33, p = 0.040). Conclusions Expression of proinflammatory cytokines may differ between NMOSD and RRMS. Elevated IL-1 beta levels in NMOSD AQP4 + patients are associated with neurological disability, suggesting a potential role as a biomarker of disease severity. Further studies are needed to confirm these findings and evaluate the therapeutic potential of targeting IL-1 beta in NMOSD. Highlights circle NMOSD AQP4 + patients show distinct cytokine profiles compared to RRMS and NIC. circle Elevated IL-1 beta levels are associated with disability in NMOSD AQP4 + patients. circle IL-1 beta could serve as a potential b

关键词： Adaptive immunity   Cytokines   Immunology   Inflammation   Ophthalmology   T cells  

摘要： Recurrent acute anterior uveitis is a frequent extra-articular manifestation of the axial spondyloarthropathies (AxSpA): chronic inflammatory diseases affecting the spine, enthesis, peripheral joints, skin, and gastrointestinal tract. Pathology in AxSpA has been associated with local tissue-resident populations of IL-23 responsive lymphoid cells. Here we characterize a population of ocular T cell defined by CD3+CD4-CD8-CD69+gamma delta TCR+IL-23R+ that reside within the anterior uvea as an ocular entheseal analogue of the mouse eye. Localized cytokine expression demonstrates that uveal IL-23R+ IL-17A-producing cells are both necessary and sufficient to drive uveitis in response to IL-23. This T cell population is also present in humans, occupying extravascular tissues of the anterior uveal compartment. Consistent with the concept of IL-23 as a unifying mediator in AxSpA, we present evidence that IL-23 can also act locally on tissue resident T cells in the anterior compartment of the eye at sites analogous to the enthesis to drive ocular inflammation.

关键词： Toxoplasma gondii   cytokines   polymorphism   pregnant women  

摘要：

关键词： ADP-ribosylation   PARP   macrodomain   coronavirus   HSV-1   VSV   LCMV   interferon   interferon-stimulated genes  

摘要： PARP14 is a 203 kDa multi-domain protein that is primarily known as an ADP-ribosyltransferase and is involved in a variety of cellular functions, including DNA damage, microglial activation, inflammation, and cancer progression. In addition, PARP14 is upregulated by interferon (IFN), indicating a role in the antiviral response. Furthermore, PARP14 has evolved under positive selection, again indicating that it is involved in host-pathogen conflict. We found that PARP14 is required for increased IFN-I production in response to coronavirus infection lacking ADP-ribosylhydrolase (ARH) activity and poly(I:C);however, whether it has a direct antiviral function remains unclear. Here, we demonstrate that the catalytic activity of PARP14 enhances IFN-beta and IFN-gamma responses and independently restricts ARH-deficient murine hepatitis virus (MHV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. To determine if PARP14's antiviral functions extended beyond CoVs, we tested the ability of herpes simplex virus 1 (HSV-1), a DNA virus, vesicular stomatitis virus (VSV), a negative-sense RNA virus, and lymphocytic choriomeningitis virus (LCMV), an ambisense RNA virus, to infect A549 PARP14 knockout (KO) cells. While LCMV infection was unaffected, HSV-1 replication was increased in PARP14 KO cells, and VSV replication was decreased. These results indicate that PARP14 restricts HSV-1 replication but enhances the replication of VSV. A PARP14 active site inhibitor had no impact on HSV-1 or VSV replication, indicating that its effect on these viruses was independent of its catalytic activity. These data demonstrate that PARP14 promotes IFN production and has both proviral and antiviral functions targeting multiple *** antiviral response is largely regulated by post-translational modifications (PTM), including ADP-ribosylation. PARP14 is an ADP-ribosyltransferase that is upregulated by interferon and is under positive selection, indicating t

关键词： AGEING   ISCHAEMIA-REPERFUSION   LIVER TRANSPLANTATION  

摘要： BACKGROUND:With population ageing, elderly patients account for a growing proportion of hepatic surgery recipients. Hepatic ischaemia-reperfusion injury (HIRI) is a major cause of postoperative liver dysfunction, particularly in aged livers, yet its mechanisms remain poorly understood. OBJECTIVE:We aimed to elucidate critical cellular interactions and molecular mechanisms underlying aggravated HIRI in aged livers to uncover therapeutic targets. DESIGN:Single-cell RNA sequencing and spatial transcriptomics were performed on liver tissues from humans, rats and mice across ages to define key cell types and intercellular signalling. HIRI and liver transplantation animal models, primary cell co-cultures and adeno-associated virus-mediated gene knockdown were used to prove cellular function and mechanisms. Neutralising antibody was used to assess therapeutic efficacy. RESULTS:Integrated analyses revealed a significant enrichment of senescent liver sinusoidal endothelial cells (LSECs) in aged livers, with the most prominent age-associated increase in crosstalk with hepatocytes, thereby promoting inflammation. Further investigation demonstrated increased transcriptional activity of myeloid ecotropic viral integration site 2 (MEIS2) in senescent LSECs, driving interleukin (IL)-1α expression via promoter binding and the IL-1α-IL1R1 axis subsequently activated NF-κB signalling in hepatocytes, enhancing inflammatory cytokine production. Interestingly, LSECs were also most strongly influenced by hepatocytes during liver ageing, as hepatocyte-derived TNF-α further enhanced MEIS2 transcriptional activity in LSECs, establishing a proinflammatory positive feedback loop. Furthermore, we confirmed that neutralising IL-1α effectively alleviated HIRI in aged livers. CONCLUSION:Our findings identify the crosstalk between LSECs and hepatocytes in aged livers aggravating HIRI via MEIS2/IL-1α/IL1R1/TNF-α axis, suggesting that IL-1α neutralising antibody can be exploited as a promising thera

关键词： Baicalin   Pre-eclampsia   Endothelial cells   Oxidative stress   Mitogen-activated protein kinase kinases   Peroxidase  

摘要： Preeclampsia (PE) is a leading cause of morbidity and mortality among pregnant women, postpartum mothers, and perinatal infants worldwide. Currently, there are no effective pharmacological interventions for the prevention or treatment of PE. Oxidative stress in vascular endothelial cells represents a key pathophysiological mechanism underlying PE. Baicalin, a flavonoid compound derived from the traditional Chinese medicine Scutellaria baicalensis, exhibits anti-inflammatory, antioxidant, antiapoptotic, and immunoregulatory properties. However, its potential application in PE remains insufficiently investigated. In vitro experiments were conducted to establish an oxidative stress model using human umbilical vein endothelial cells (HUVECs) exposed to hydrogen peroxide. Transcriptomic analysis was employed to identify genes significantly expressed differently. The effects of baicalin on HUVEC viability were assessed using the CCK-8 assay. Myeloperoxidase (MPO) levels were quantified via ELISA and colorimetric assays;while, the expression of MAPK/ERK1/2 signaling pathway components was analyzed using RT-qPCR and Western blotting. Cell apoptosis was evaluated by flow cytometry. Clinical studies have shown elevated MPO levels in the peripheral blood of patients with PE. Transcriptomic analysis identified the MAPK/ERK1/2 signaling pathway as a central pathway associated with oxidative stress model. Exposure to H2O2 (800 mu M) for 30 min reduced cell viability to 66.36%, confirming the successful establishment of the oxidative stress model in HUVECs. Treatment with baicalin at concentrations of 100/200/400 mu M significantly downregulated MAPK/ERK1/2 expression (P < 0.05). Moreover, baicalin reduced apoptosis at all tested concentrations (P < 0.01). Notably, while 200 and 400 mu M baicalin de-creased MPO secretion, 100 mu M baicalin increased MPO release (P < 0.05). Co-administration of 200 mu M baicalin with TNF-alpha antagonists did not produce additive effects on these p

关键词： oral mucositis   irradiation   head-neck irradiation   interleukin-23   candidiasis  

摘要： Targeted head and neck irradiation (HNI) used for cancer therapy causes mucosal damage and immune dysregulation, leaving cancer patients highly susceptible to infections of the oral mucosa. Oropharyngeal candidiasis (OPC) is an opportunistic infection caused by Candida albicans, a commensal fungus found in up to 80% of the population at any given time. High colonization levels of C. albicans are known to worsen damage caused by HNI. The interleukin-23 (IL-23)-T-helper 17 (Th17) axis is a central and non-redundant mediator of immunity to OPC, and anti-cytokine biologics targeting IL-23 have come into widespread clinical use for treating various autoimmune conditions. Here, we sought to understand the consequences of IL-23 deficiency in the setting of HNI, taking advantage of a mouse model of radiation-induced oral mucositis (OM) which we combined with fungal infection. Surprisingly, mice lacking IL-23 did not show increased signs of injury to the oral mucosa when subjected to HNI. However, in mice subjected to HNI and exposed to oral C. albicans, damage to the oral mucosa was markedly exacerbated, accompanied by substantially increased fungal susceptibility when IL-23 was absent. Thus, IL-23-driven control of fungal infections is needed to mitigate susceptibility to OM in the high proportion of individuals who carry C. albicans in the ***-23 plays key roles in expanding the T-helper 17 (Th17) cell subset during differentiation and promoting expression of cytokines, including the subset-defining cytokine IL-17 (IL-17A). While the effector cytokines produced by Th17 cells are required for host defense against extracellular microbes, especially Candida albicans, these can also be pathogenic during inflammatory and autoimmune disorders including psoriasis, psoriatic arthritis, and ankylosing spondylitis, among others. While IL-23 and IL-17 are similarly required for protection against oropharyngeal candidiasis (OPC), they can exert divergent functions in o