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Background The Src homology region 2 domain-containing phosphatase-1 (SHP-1) is known to exert negative regulatory effects on immune cell signaling. Mice with mutations in the Shp1 gene develop inflammatory skin disease and autoimmunity, but no arthritis. We sought to explore the role of SHP-1 in arthritis using an autoimmune mouse model of rheumatoid arthritis. We generated Shp1 transgenic ( Shp1 -Tg) mice to study the impact of SHP-1 overexpression on arthritis susceptibility and adaptive immune responses. Methods SHP-1 gene and protein expression as well as tyrosine phosphatase activity were evaluated in spleen cells of transgenic and wild type (WT) mice. WT and Shp1 -Tg (homozygous or heterozygous for the transgene) mice were immunized with human cartilage proteoglycan (PG) in adjuvant, and arthritis symptoms were monitored. Protein tyrosine phosphorylation level, net cytokine secretion, and serum anti-human PG antibody titers were measured in immune cells from WT and Shp1 -Tg mice. WT mice were treated with regorafenib orally to activate SHP-1 either before PG-induced arthritis (PGIA) symptoms developed (preventive treatment) or starting at an early stage of disease (therapeutic treatment). Data were statistically analyzed and graphs created using GraphPad Prism 8.0.2 software. Results SHP-1 expression and tyrosine phosphatase activity were elevated in both transgenic lines compared to WT mice. While all WT mice developed arthritis after immunization, none of the homozygous Shp1 -Tg mice developed the disease. Heterozygous transgenic mice, which showed intermediate PGIA incidence, were selected for further investigation. We observed differences in interleukin-4 and interleukin-10 production in vitro, but serum anti-PG antibody levels were not different between the genotypes. We also found decreased tyrosine phosphorylation of several proteins of the JAK/STAT pathway in T cells from PG-immunized Shp1 -Tg mice. Regorafenib administration to WT mice prevented the development of severe PGIA or reduced disease severity when started after disease onset. Conclusions Resistance to arthritis in the presence of SHP-1 overexpression likely results from the impairment of tyrosine phosphorylation (deactivation) of key immune cell signaling proteins in the JAK/STAT pathway, due to the overwhelming tyrosine phosphatase activity of the enzyme in Shp1 -Tg mice. Our study is the first to investigate the role of SHP-1 in autoimmune arthritis using animals overexpressing this phosphatase. Pharmacological activation of SHP-1 might be considered as a new approach to the treatment of autoimmune arthritis.

Lenz-Majewski syndrome (LMS) is a rare disease characterized by complex craniofacial, dental, cutaneous, and limb abnormalities combined with intellectual disability. Mutations in the PTDSS1 gene coding one of the phosphatidylserine (PS) synthase enzymes, PSS1, were described as causative in LMS patients. Such mutations render PSS1 insensitive to feedback inhibition by PS levels. Here we show that expression of mutant PSS1 enzymes decreased phosphatidylinositol 4-phosphate (PI4P) levels both in the Golgi and the plasma membrane (PM) by activating the Sac1 phosphatase and altered PI4P cycling at the PM. Conversely, inhibitors of PI4KA, the enzyme that makes PI4P in the PM, blocked PS synthesis and reduced PS levels by 50% in normal cells. However, mutant PSS1 enzymes alleviated the PI4P dependence of PS synthesis. Oxysterol-binding protein–related protein 8, which was recently identified as a PI4P-PS exchanger between the ER and PM, showed PI4P-dependent membrane association that was significantly decreased by expression of PSS1 mutant enzymes. Our studies reveal that PS synthesis is tightly coupled to PI4P-dependent PS transport from the ER. Consequently, PSS1 mutations not only affect cellular PS levels and distribution but also lead to a more complex imbalance in lipid homeostasis by disturbing PI4P metabolism.

Sulfotransferases (SULTs) are phase II drug-metabolizing enzymes catalyzing the sulfoconjugation from the co-factor 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to a substrate. It has been previously suggested that a considerable shift of SULT structure caused by PAPS binding could control the capability of SULT to bind large substrates. We employed molecular dynamics (MD) simulations and the recently developed approach of MD with excited normal modes (MDeNM) to elucidate molecular mechanisms guiding the recognition of diverse substrates and inhibitors by SULT1A1. MDeNM allowed exploring an extended conformational space of PAPS-bound SULT1A1, which has not been achieved up to now by using classical MD. The generated ensembles combined with docking of 132 SULT1A1 ligands shed new light on substrate and inhibitor binding mechanisms. Unexpectedly, our simulations and analyses on binding of the substrates estradiol and fulvestrant demonstrated that large conformational changes of the PAPS-bound SULT1A1 could occur independently of the co-factor movements that could be sufficient to accommodate large substrates as fulvestrant. Such structural displacements detected by the MDeNM simulations in the presence of the co-factor suggest that a wider range of drugs could be recognized by PAPS-bound SULT1A1 and highlight the utility of including MDeNM in protein–ligand interactions studies where major rearrangements are expected.

PurposeIn cardiac interventions, such as cardiac resynchronization therapy (CRT), image guidance can be enhanced by involving preoperative models. Multimodality 3D/2D registration for image guidance, however, remains a significant research challenge for fundamentally different image data, i.e., MR to X-ray. Registration methods must account for differences in intensity, contrast levels, resolution, dimensionality, field of view. Furthermore, same anatomical structures may not be visible in both modalities. Current approaches have focused on developing modality-specific solutions for individual clinical use cases, by introducing constraints, or identifying cross-modality information manually. Machine learning approaches have the potential to create more general registration platforms. However, training image to image methods would require large multimodal datasets and ground truth for each target application.MethodsThis paper proposes a model-to-image registration approach instead, because it is common in image-guided interventions to create anatomical models for diagnosis, planning or guidance prior to procedures. An imitation learning-based method, trained on 702 datasets, is used to register preoperative models to intraoperative X-ray images.ResultsAccuracy is demonstrated on cardiac models and artificial X-rays generated from CTs. The registration error was 2.92±2.22mm on 1000 test cases, superior to that of manual ( 6.48±5.6mm ) and gradient-based ( 6.79±4.75mm ) registration. High robustness is shown in 19 clinical CRT cases.ConclusionBesides the proposed methods feasibility in a clinical environment, evaluation has shown good accuracy and high robustness indicating that it could be applied in image-guided interventions.

Background: The predictive value of thrombus standard perviousness (SP) in acute ischemic stroke (AIS) for the technical success rates of mechanical thrombectomy (MT) or functional outcomes is not yet conclusive. We investigated the relationship between dynamic perviousness (DP) and revascularization results using time-dependent enhancement curve types determined with computed tomography (CT). Methods: A retrospective analysis of 137 AIS patients was performed. DP was calculated as the thrombus attenuation increase (TAI) using three time points and categorized into four groups: (1) no enhancement (CNE); (2) late enhancement (CLE); (3) early enhancement with washout (CW); (4) early enhancement without washout (CNW). Associations with the technical success rate and functional outcomes were assessed. Results: Late enhancement (CLE) had approximately two times higher odds for successful MT as compared to clots with other enhancement dynamics. The odds ratios (logistic regression model with CNW as the reference) for the TICI III scores were 4.04 (p = 0.067), 1.82 (p = 0.3), and 1.69 (p = 0.4) for CLE, CW, and CNE, respectively. The NIHSS scores at discharge and mRS scores at three months showed regression coefficients (linear regression model with CNW as reference) of −3.05 (p = 0.10), −1.17 (p = 0.51), and −1.24 (p = 0.47); and −1.30 (p = 0.097), −0.85 (p = 0.25), and −0.15 (p = 0.83) for CLE, CW, and CNE, respectively. Conclusions: Thrombi with late enhancement patterns showed a higher revascularization rate and better outcomes as compared to clots with early uptake or no washout.

Background: Acute ischemic stroke (AIS) is one of the leading causes of death in the industrialized world and causes a heavy personal and economic burden. Thrombus perviousness, measured with pre-interventional computed tomography (CT), is a relatively new imaging biomarker with the potential to estimate clinical outcome in AIS and optimize therapy. However, reported findings on the relationship between thrombus perviousness and clinical parameters in AIS are conflicting. In this study, we investigated the characteristics of the time-resolved contrast agent uptake in thrombi and the predictive potential for clinical outcomes. Methods: We analyzed 55 AIS patients who underwent pre-interventional CT perfusion and recanalization with mechanical thrombectomy. A thrombus with a visible hyperdense artery sign was segmented in 2D. Thrombus standard perviousness was measured as the mean thrombus attenuation increase (TAI) between CT angiography (CTA) and NCCT. For dynamic perviousness, the time-resolved contrast agent uptake curve (CAU) was derived from a 30-phase CT perfusion (CTP) measurement. The rise time (trise) and the TAI increase rate per second (∆d), as well as the time window for the 10th (tW10), 20th (tW20), and 30th (tW30) percentiles of the CAU peak, were calculated. The standard and dynamic perviousness (trise, ∆d, tW10, tW20, and tW30) were analyzed for their associations with clinical outcomes (3-month mRS) with the Wilcoxon signed rank test. Results: Dynamic perviousness was associated with the clinical outcome. The group mean trise and ∆d for thrombi with good clinical outcomes (mRS ≤ 2) were approximately 20% lower (p = 0.04) and 36% higher (p = 0.02) than those for thrombi with poor outcomes (mRS > 2). The time windows for the 10, 20, and 30% maximum contrast agent concentrations in the thrombus were approximately 40% (p = 0.004), 18% (p = 0.02) and 33% (p = 0.004) lower in thrombi with good outcomes than in thrombi with poor outcomes, respectively. Standard perviousness showed no association with clinical outcome. Conclusion: Dynamic perviousness from perfusion imaging retrieves the CAU characteristics of thrombi with greater resolution detail than standard perviousness. Thrombi with relatively fast contrast agent uptake dynamics are more prone to good clinical outcomes than thrombi with slow uptake dynamics.

Relatively low travel costs and abundant opportunities for research funding in Switzerland and other developed countries allow researchers large amounts of international travel and collaborations, leading to a substantial carbon footprint. Increasing willingness to tackle this issue, in combination with the desire of many academic institutions to become carbon-neutral, calls for an in-depth understanding of academic air travel. In this study, we quantified and analyzed the carbon footprint of air travel by researchers from the École Polytechnique Fédérale de Lausanne (EPFL) from 2014 to 2016, which is responsible for about one third of EPFL’s total CO2 emissions. We find that the air travel impact of individual researchers is highly unequally distributed, with 10% of the EPFL researchers causing almost 60% of the total emissions from EPFL air travel. The travel footprint increases drastically with researcher seniority, increasing 10-fold from PhD students to professors. We found that simple measures such as restricting to economy class, replacing short trips by train and avoiding layovers already have the potential to reduce emissions by 36%. These findings can help academic institutions to implement travel policies which can mitigate the climate impact of their air travel.

Rheumatoid arthritis (RA) can be initiated and driven by immune responses to multiple antigenic epitopes including those in cartilage proteoglycan (PG, aggrecan) and type II collagen. RA is driven by T helper 1 (Th1) or Th17 pro-inflammatory T cell responses. LEAPS (Ligand Epitope Antigen Presentation System) DerG peptide conjugate vaccines were prepared using epitopes from PG that elicit immune responses in RA patients: epitope PG70 (DerG-PG70, also designated CEL-4000) and the citrullinated form of another epitope (PG275Cit). The LEAPS peptides were administered alone or together in Seppic ISA51vg adjuvant to mice with PG G1 domain-induced arthritis (GIA), a mouse model of RA. Each of these LEAPS peptides and the combination modulated the inflammatory response and stopped the progression of arthritis in the GIA mouse model. Despite having a therapeutic effect, the DerG-PG275Cit vaccine did not elicit significant antibody responses, whereas DerG-PG70 (alone or with DerG-PG275Cit) induced both therapy and antibodies. Spleen T cells from GIA mice, vaccinated with the DerG LEAPS peptides, preferentially produced anti-inflammatory (IL-4 and IL-10) rather than pro-inflammatory (IFN-γ or IL-17) cytokines in culture. Similarly, cytokines secreted by CD4+ cells of unvaccinated GIA mice, differentiated in vitro to Th2 cells and treated with either or both DerG vaccine peptides, exhibited an anti-inflammatory (IL-4, IL-10) profile. These results suggest that the two peptides elicit different therapeutic immune responses by the immunomodulation of disease-promoting pro-inflammatory responses and that the combination of the two LEAPS conjugates may provide broader epitope coverage and, in some cases, greater efficacy than either conjugate alone.

Catheter ablation is the preferred treatment for typical atrial flutter (AFl), but it can be challenging due to anatomical abnormalities. The use of 3D electroanatomical mapping systems (EAMS) has reduced fluoroscopy exposure during AFl ablation. Intracardiac echocardiography (ICE) has also shown benefits in reducing radiation exposure during AFl ablation. However, there is a lack of evidence on the feasibility of ICE-guided, zero-fluoroscopy AFl ablation without the use of EAMS. In this prospective study, we enrolled 80 patients with CTI-dependent AFl. The first 40 patients underwent standard fluoroscopy + ICE-guided ablation (Standard ICE group), while the other 40 patients underwent zero-fluoroscopy ablation using only ICE (Zero ICE group). Procedure outcomes, including acute success, procedure time, fluoroscopy time, radiation dose, and complications, were compared between the groups. The acute success rate was 100% in both groups. Out of the 40 cases, the zero-fluoroscopy strategy was successfully implemented in 39 cases (97.5%) in the Zero ICE group. There were no significant differences in procedure time [55.5 (46.5; 66.8) min vs. 51.5 (44.0; 65.5),  = 0.50] and puncture to first ablation time [18 (13.5; 23) min vs. 19 (15; 23.5) min,  = 0.50] between the groups. The Zero ICE group had significantly lower fluoroscopy time [57 (36.3; 90) sec vs. 0 (0; 0) sec,  < 0.001] and dose [3.17 (2.27; 5.63) mGy vs. 0 (0; 0) mGy,  < 0.001] compared to the Standard ICE group. Total ablation time was longer in the Standard ICE group [597 (447; 908) sec vs. 430 (260; 750),  = 0.02], but total ablation energy [22,458 (14,836; 31,116) Ws vs. 17,043 (10,533; 29,302) Ws,  = 0.10] did not differ significantly. First-pass bidirectional conduction block of the CTI and acute reconnection rates were similar between the groups. No complications or recurrences were observed during the follow-up period. Our study suggests that zero-fluoroscopy CTI ablation guided solely by ICE for AFl is feasible and safe. Further investigation is warranted for broader validation.

Background: The predictive value of thrombus perviousness in acute ischemic stroke (AIS), as measured by computed tomography (CT), has been intensively studied with conflicting results. In this study, we investigate the predictive potential of the novel concept of dynamic perviousness using three-dimensional (3D) volumetric evaluation of occlusive thrombi. Methods: The full thrombus volume in 65 patients with a hyperdense artery sign on non-contrast CT (NCCT), who underwent mechanical thrombectomy (MT), was segmented. Perviousness maps were computed voxel-wise for the entire thrombus volume as thrombus attenuation increase (TAI) between NCCT and CT angiography (CTA) as well as between CTA and late venous phase CT (CTV). Perviousness was analyzed for its association with NIHSS at admission, Thrombolysis In Cerebral Infarction (TICI) score, and number of MT passes. Results: The mean late-uptake TAI of thrombi with NIHSS scores greater than 21 at admission was approximately 100% higher than for lower scored NIHSS (p between 0.05 and 0.005). Concerning revascularization results, thrombi requiring less than four MT passes had ca. 80% higher group mean late-uptake TAI than clots requiring four or more passes (p = 0.03), and thrombi with TICI score III had ca. 95% higher group mean late-uptake TAI than thrombi with TICI II (p = 0.03). Standard perviousness showed no significant correlation with MT results. Conclusion: Standard thrombus perviousness of 3D clot volume is not associated with revascularization results in AIS. In contrast, dynamic perviousness assessed with a voxel-wise characterization of 3D thrombi volume may be a better predictor of MT outcomes than standard perviousness.