Ultrasound Changes in the Enthesis and Peri-enthesis Area of the Patellar and Achilles Tendons in Response to Physical Exercise: Comparison Between Healthy Subjects and Patients with Spondyloarthritis in Clinical Remission.

RATIONALE AND OBJECTIVES: The goal of achieving clinical remission in patients with spondyloarthritis does not necessarily include the resolution of entheseal inflammation from a histological perspective. However, enthesis not clinically inflamed, under mechanical stress, may behave differently from healthy subjects considering the physiopathology of SpA. Our goal was to determine whether ultrasound changes in entheses differ between SpA patients in clinical remission and healthy subjects. METHODS: SpA patients in clinical remission and matched healthy controls were recruited. At baseline, the following variables were measured on the dominant side by ultrasound: thickness of the distal patellar enthesis (hDP), the deep infrapatellar bursa (hDIB), the Achilles enthesis (hA), the preachilleal bursa (hPAB), effusion in the preachileal bursa (hePAB), and the presence of power Doppler signal in both enthesis. All measurements except hDP and hA were collected again after exercise (post-stress ultrasound). RESULTS: 30 patients and 30 controls were enrolled. In all subjects, hDIB, hPAB, and the preachileal bursa occupancy index increased significantly after the exercise. The increase was significantly greater in patients for all variables. At baseline, in patients, hyperemia was detected in one patellar tendon (3.3%) and in two Achilles tendons (6.7%). After exercise, the number of tendons with hyperemia increased to 11/30 (36.7%) and 12/30 (40%), respectively. Among controls, there was no detectable basal hyperemia, but after exercise, it was detected in 1/30 patellar tendons (3.3%) and 2/30 Achilles tendons (6.7%). CONCLUSION: Exercise triggers a greater effusive and hyperemic synovial response in patients in remission than in healthy controls. These findings suggest that the definition of remission should also include an assessment of the synovial response to mechanical stress.

Sequential trypsin and ProAlanase digestions unearth immunological protein biomarkers shrouded by skeletal collagen.

This study investigates the efficacy of proteomic analysis of human remains to identify active infections in the past through the detection of pathogens and the host response to infection. We advance leprosy as a case study due to the sequestering of sufferers in leprosaria and the suggestive skeletal lesions that can result from the disease. Here we present a sequential enzyme extraction protocol, using trypsin followed by ProAlanase, to reduce the abundance of collagen peptides and in so doing increase the detection of non-collagenous proteins. Through our study of five individuals from an 11th to 18th century leprosarium, as well as four from a contemporaneous non-leprosy associated cemetery in Barcelona, we show that samples from 2 out of 5 leprosarium individuals extracted with the sequential digestion methodology contain numerous host immune proteins associated with modern leprosy. In contrast, individuals from the non-leprosy associated cemetery and all samples extracted with a trypsin-only protocol did not. Through this study, we advance a palaeoproteomic methodology to gain insights into the health of archaeological individuals and take a step toward a proteomics-based method to study immune responses in past populations.

Subclinical synovitis impact on the progression of lupus joint disease: A 10-year longitudinal multicenter study.

OBJECTIVE: To determine the effect of subclinical synovitis on the progression of joint disease in a cohort of patients with systemic lupus erythematosus over a mean follow-up of 10 years. METHODS: A longitudinal follow-up of 96 patients diagnosed with lupus was performed. All patients were considered clinically free of joint disease or with minimal joint impairment at baseline and were studied through ultrasound study of their dominant hand to assess the prevalence of subclinical synovitis. Now, over 10 years after we contacted them and reviewed their evolution to determine the impact of had or had not been diagnosed with subclinical synovitis in their current joint condition. RESULTS: Thirty-one of the 91 reached patients developed clinical progression in their joint manifestations (at least one ordinal degree of worsening). Of these, 23 (74,9%) had demonstrated subclinical synovitis at baseline. In the group of patients who did not progress clinically, 46 (76,6%) did not have this finding at the start of follow-up (p < .01, OR 9,44 95%CI 3,46-25,74). The patients in whom clinical progression was demonstrated had worse combined ultrasound scores than the rest of the patients: 6,41 SD 1,45 vs. 1,15 SD 0,97 (p < .01). CONCLUSIONS: The finding of subclinical synovitis in patients with systemic lupus erythematosus is associated with the development of joint disease progression both clinically and ultrasonographically.

Beneficial effect of temporary methotrexate interruption on B and T cell responses upon SARS-CoV-2 vaccination in patients with rheumatoid arthritis or psoriatic arthritis.

B and T cell responses were evaluated in patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) after 1 or 2 weeks of methotrexate (MTX) withdrawal following each COVID-19 vaccine dose and compared with those who maintained MTX. Adult RA and PsA patients treated with MTX were recruited and randomly assigned to 3 groups: MTX-maintenance (n = 72), MTX-withdrawal for 1 week (n = 71) or MTX-withdrawal for 2 weeks (n = 73). Specific antibodies to several SARS-CoV-2 antigens and interferon (IFN)-γ and interleukin (IL)-21 responses were assessed. MTX withdrawal in patients without previous COVID-19 was associated with higher levels of anti-RBD IgG and neutralising antibodies, especially in the 2-week withdrawal group and with higher IFN-γ secretion upon stimulation with pools of SARS-CoV-2 S peptides. No increment of RA/PsA relapses was detected across groups. Our data indicate that two-week MTX interruption following COVID-19 vaccination in patients with RA or PsA improves humoral and cellular immune responses.

RE-START: Exploring the effectiveness of anti-calcitonin gene-related peptide resumption after discontinuation in migraine.

BACKGROUND AND PURPOSE: According to the latest European guidelines, discontinuation of monoclonal antibodies against calcitonin gene-related peptide (anti-CGRP MAb) may be considered after 12-18 months of treatment. However, some patients may worsen after discontinuation. In this study, we assessed the response following treatment resumption. METHODS: This was a prospective study conducted in 14 Headache Units in Spain. We included patients with response to anti-CGRP MAb with clinical worsening after withdrawal and resumption of treatment. Numbers of monthly migraine days (MMD) and monthly headache days (MHD) were obtained at four time points: before starting anti-CGRP MAb (T-baseline); last month of first treatment period (T-suspension); month of restart due to worsening (T-worsening); and 3 months after resumption (T-reintroduction). The response rate to resumption was calculated. Possible differences among periods were analysed according to MMD and MHD. RESULTS: A total of 360 patients, 82% women, with a median (interquartile range [IQR]) age at migraine onset of 18 (12) years. The median (IQR) MHD at T-baseline was 20 (13) and MMD was 5 (6); at T-suspension, the median (IQR) MHD was 5 (6) and MMD was 4 (5); at T-worsening, the median (IQR) MHD was 16 (13) and MMD was 12 (6); and at T-reintroduction, the median (IQR) MHD was 8 (8) and MHD was 5 (5). In the second period of treatment, a 50% response rate was achieved by 57.4% of patients in MHD and 65.8% in MMD. Multivariate models showed significant differences in MHD between the third month after reintroduction and last month before suspension of first treatment period (p < 0.001). CONCLUSION: The results suggest that anti-CGRP MAb therapy is effective after reintroduction. However, 3 months after resumption, one third of the sample reached the same improvement as after the first treatment period.

Occurrence of SARS-CoV-2 viremia is associated with genetic variants of genes related to COVID-19 pathogenesis.

Introduction: SARS-CoV-2 viral load has been related to COVID-19 severity. The main aim of this study was to evaluate the relationship between SARS-CoV-2 viremia and SNPs in genes previously studied by our group as predictors of COVID-19 severity. Materials and methods: Retrospective observational study including 340 patients hospitalized for COVID-19 in the University Hospital La Princesa between March 2020 and December 2021, with at least one viremia determination. Positive viremia was considered when viral load was above the quantifiable threshold (20 copies/ml). A total of 38 SNPs were genotyped. To study their association with viremia a multivariate logistic regression was performed. Results: The mean age of the studied population was 64.5 years (SD 16.6), 60.9% patients were male and 79.4% white non-Hispanic. Only 126 patients (37.1%) had at least one positive viremia. After adjustment by confounders, the presence of the minor alleles of rs2071746 (HMOX1; T/T genotype OR 9.9 p < 0.0001), rs78958998 (probably associated with SERPING1 expression; A/T genotype OR 2.3, p = 0.04 and T/T genotype OR 12.9, p < 0.0001), and rs713400 (eQTL for TMPRSS2; C/T + T/T genotype OR 1.86, p = 0.10) were associated with higher risk of viremia, whereas the minor alleles of rs11052877 (CD69; A/G genotype OR 0.5, p = 0.04 and G/G genotype OR 0.3, p = 0.01), rs2660 (OAS1; A/G genotype OR 0.6, p = 0.08), rs896 (VIPR1; T/T genotype OR 0.4, p = 0.02) and rs33980500 (TRAF3IP2; C/T + T/T genotype OR 0.3, p = 0.01) were associated with lower risk of viremia. Conclusion: Genetic variants in HMOX1 (rs2071746), SERPING1 (rs78958998), TMPRSS2 (rs713400), CD69 (rs11052877), TRAF3IP2 (rs33980500), OAS1 (rs2660) and VIPR1 (rs896) could explain heterogeneity in SARS-CoV-2 viremia in our population.

Galectin-1: A Potential Biomarker Differentiating between Early Rheumatoid Arthritis and Spondyloarthritis.

Galectin-1 (Gal1) plays a regulatory role in the immune system. We have recently validated that Gal1 serum (sGal1) levels are increased in rheumatoid arthritis (RA) patients compared to healthy donors (HDs); however, there is no information on Gal1 in spondyloarthritis (SpA). Objective: To compare Gal1 levels in patients with SpA versus RA as a diagnostic biomarker. Methods: We studied sGal1 levels in HD (n = 52), SpA (n = 80) and RA patients (n = 64) who were randomly divided into discovery and validation sets. Synovial fluid (SF) from osteoarthritis (OA) (n = 28), peripheral SpA (n = 28) and RA (n = 28) were studied. In SpA patients, we analyzed the association between clinical parameters and sGal1 levels. Results: sGal1 levels were significantly lower in patients with SpA with respect to RA and similar to those of the HD. A cut-off of 20.50 ng/mL (sGal1) allowed one to differentiate RA patients from SpA and HD (Odd Ratio (OR) 8.23 and 12.64, respectively). Gal1 SF levels in SpA were slightly lower than OA patients and significantly lower than RA patients. No correlation was observed between sGal1 levels and clinical parameters in SpA patients. Conclusion: Gal1 could act as a diagnostic biomarker of RA and would allow one to distinguish SpA and RA patients.

Condicionantes del éxito terapéutico de las infiltraciones de corticoides en el síndrome del dedo en resorte / Determinants of Therapeutic Success of Corticoids Injections in Trigger Finger Syndrome

Antecedentes y objetivo: El dedo en resorte es un motivo de consulta frecuente en el que las infiltraciones de corticoides juegan un papel terapéutico relevante en los grados de severidad intermedios cuando el tratamiento conservador no ha funcionado. Sin embargo, no existen criterios que permitan seleccionar qué pacientes se beneficiarán más de este procedimiento. El objetivo de nuestro estudio es identificar los condicionantes de éxito terapéutico de las infiltraciones de corticoides en estos pacientes. Materiales y métodos: Diseñamos un estudio prospectivo longitudinal basado en práctica clínica habitual con pacientes adultos, con diagnóstico clínico de dedo en resorte grado II o III, a quienes se les realizó una infiltración de 20mg de acetato de triamcinolona. Las variables desenlace fueron el alcanzar un grado Quinnell I o reducir en al menos una categoría la severidad del cuadro clínico, 2 meses después del procedimiento. Para determinar los condicionantes del alcance de los objetivos se realizó una modelización predictiva de regresión logística binaria utilizando aquellas variables que tuvieron una satisfactoria correlación univariante. Resultados: Se incluyeron 74 pacientes a lo largo de 3 años, 42 de los cuales (61,8%) tenían un grado Quinnell III. Tras la infiltración, 22 (32,4%) alcanzaron la resolución completa y 50 (73,5%), la resolución parcial. Las variables engrosamiento tendinoso (HR: 10,72; IC 95%: 2,88-39,93; p<0,001) y tiempo de evolución (HR: 1,23; IC 95%: 1,02-1,49; p=0,027) demostraron ser condicionantes predictoras del éxito terapéutico en la resolución completa. Para la modelización para resolución parcial las mismas variables demostraron ser condicionantes predictoras (HR: 5,57; IC 95%: 1,38-22,41; p=0,016 y HR: 1,18; IC 95% 0,99-1,41; p=0,051, respectivamente). El engrosamiento de la polea no demostró capacidad predictiva en ninguno de los 2 modelos.(AU)

Background and objective: Trigger finger is a frequent complaint in which corticosteroid infiltrations play a relevant therapeutic role in intermediate degrees of severity when conservative treatment has not worked. However, there are no criteria to select which patients will benefit most from this procedure. The present study aimed to identify the factors leading to the therapeutic success of corticosteroid infiltration in these patients. Materials and methods: We designed a prospective longitudinal study based on routine clinical practice with adult patients with a clinical diagnosis of trigger finger grade II or III on the Quinnell scale, who underwent an infiltration of 20mg of triamcinolone acetate. The outcome variables were to achieve a Quinnell grade I or reduce the severity of the symptoms by at least one category two months after the procedure. To identify the determinants of complete or partial therapeutic success, binary logistic regression predictive modelling was performed using those variables that had a satisfactory univariate correlation. Results: 74 patients were included over three years, 42 of whom (61.8%) were classified as Quinnell grade III. After infiltration, 22 (32.4%) achieved complete resolution and 50 (73.5%) partial resolution. The variables tendon thickening (HR 10.72; 95%CI 2.88-39.93; P<.001) and progression time (HR 1.23; 95%CI 1.02-1.49; P=.027) proved to be predictors of therapeutic success in complete resolution. For the modelling for partial resolution, the same variables proved to be determining predictors (HR 5.57; 95%CI 1.38-22.41; P=.016 and HR 1.18; 95%CI .99-1.41; P=.051, respectively). Pulley thickening did not demonstrate predictive ability in either model.(AU)

Genetic LGALS1 Variants Are Associated with Heterogeneity in Galectin-1 Serum Levels in Patients with Early Arthritis.

Galectin 1 (Gal1) exerts immunomodulatory effects leading to therapeutic effects in autoimmune animal models. Patients with rheumatoid arthritis have been reported to show higher Gal1 serum levels than the healthy population. Our study aimed to find genetic variants on the Gal1 gene (LGALS1) modulating its expression and/or clinical features in patients with early arthritis (EA). LGALS1 was sequenced in 53 EA patients to characterize all genetic variants. Then, we genotyped rs9622682, rs929039, and rs4820293, which covered the main genetic variation in LGALS1, in 532 EA patients. Gal1 and IL-6 serum levels were measured by ELISA and Gal1 also by western blot (WB) in lymphocytes from patients with specific genotypes. Once disease activity improved with treatment, patients with at least one copy of the minor allele in rs9622682 and rs929039 or those with GG genotype in rs4820293 showed significantly higher Gal1 serum levels (p < 0.05). These genotypic combinations were also associated with higher Gal1 expression in lymphocytes by WB and lower IL-6 serum levels in EA patients. In summary, our study suggests that genetic variants studied in LGALS1 can explain heterogeneity in Gal1 serum levels showing that patients with higher Gal1 levels have lower serum IL-6 levels.

Ultrasound changes following controlled mechanical stress in synovial tissue in the hands of healthy individuals.

OBJECTIVE: The physiological response of the synovium to acute mechanical stress has not been extensively studied. This response is interesting in terms of the morphological changes it can cause as any such changes should be taken into account during ultrasound examinations. The purpose of this study was to assess the extent of changes in ultrasound images of the synovial joint in the hands of healthy individuals after controlled mechanical stress. METHOD: We included 110 healthy volunteers on whom we carried out two ultrasound examinations of the non-dominant hand: one at baseline and the other after controlled handgrip exercise at 70% of the maximum voluntary contraction. RESULTS: The synovitis scores at baseline and after exercise were 0.472±0.798 and 0.772±1.162 t(109)=-3.791, respectively; p < 0.001. We observed no tenosynovitis in 88.2% of the participants at baseline, while after exercise the percentage fell to 70.9%; x2 (1, N=110) =10.0851, p = 0.0014. CONCLUSION: We conclude that synovitis and tenosynovitis are inducible by physical exercise and are detectable on ultrasound. This should be taken into account during ultrasound examinations for suspicion or follow-up of inflammatory rheumatism.

Determinants of therapeutic success of corticoids injections in trigger finger syndrome.

BACKGROUND AND OBJECTIVE: Trigger finger is a frequent complaint in which corticosteroid infiltrations play a relevant therapeutic role in intermediate degrees of severity when conservative treatment has not worked. However, there are no criteria to select which patients will benefit most from this procedure. The present study aimed to identify the factors leading to the therapeutic success of corticosteroid infiltration in these patients. MATERIALS AND METHODS: We designed a prospective longitudinal study based on routine clinical practice with adult patients with a clinical diagnosis of trigger finger grade II or III on the Quinnell scale, who underwent an infiltration of 20 mg of triamcinolone acetate. The outcome variables were to achieve a Quinnell grade I or reduce the severity of the symptoms by at least one category two months after the procedure. To identify the determinants of complete or partial therapeutic success, binary logistic regression predictive modelling was performed using those variables that had a satisfactory univariate correlation. RESULTS: 74 patients were included over three years, 42 of whom (61.8%) were classified as Quinnell grade III. After infiltration, 22 (32.4%) achieved complete resolution and 50 (73.5%) partial resolution. The variables tendon thickening (HR 10.72; 95%CI 2.88-39.93; P < .001) and progression time (HR 1.23; 95%CI 1.02-1.49; P = .027) proved to be predictors of therapeutic success in complete resolution. For the modelling for partial resolution, the same variables proved to be determining predictors (HR 5.57; 95%CI 1.38-22.41; P = .016 and HR 1.18; 95%CI .99-1.41; P = .051, respectively). Pulley thickening did not demonstrate predictive ability in either model. DISCUSSION AND CONCLUSIONS: Our results indicate that the demonstration of finger flexor apparatus thickening is the main determining factor for the success of corticosteroid infiltrations in this pathology. This is in agreement with the histological findings of specimens obtained from both tenosynovial and pulley tissue. In the former, in addition to an infiltrate of inflammatory characteristics, the presence of chondrocytoid cells producing hyaluronic acid is demonstrated. Although the therapeutic success of infiltrations in previous studies reaches 70%, the recurrence rate is similar after 12 months. The selection of patients with tendon thickening ensures therapeutic success in the short term, could reduce recurrence in the long term, and avoid delay in release surgery.

Mycobacterium leprae diversity and population dynamics in medieval Europe from novel ancient genomes.

BACKGROUND: Hansen's disease (leprosy), widespread in medieval Europe, is today mainly prevalent in tropical and subtropical regions with around 200,000 new cases reported annually. Despite its long history and appearance in historical records, its origins and past dissemination patterns are still widely unknown. Applying ancient DNA approaches to its major causative agent, Mycobacterium leprae, can significantly improve our understanding of the disease's complex history. Previous studies have identified a high genetic continuity of the pathogen over the last 1500 years and the existence of at least four M. leprae lineages in some parts of Europe since the Early Medieval period. RESULTS: Here, we reconstructed 19 ancient M. leprae genomes to further investigate M. leprae's genetic variation in Europe, with a dedicated focus on bacterial genomes from previously unstudied regions (Belarus, Iberia, Russia, Scotland), from multiple sites in a single region (Cambridgeshire, England), and from two Iberian leprosaria. Overall, our data confirm the existence of similar phylogeographic patterns across Europe, including high diversity in leprosaria. Further, we identified a new genotype in Belarus. By doubling the number of complete ancient M. leprae genomes, our results improve our knowledge of the past phylogeography of M. leprae and reveal a particularly high M. leprae diversity in European medieval leprosaria. CONCLUSIONS: Our findings allow us to detect similar patterns of strain diversity across Europe with branch 3 as the most common branch and the leprosaria as centers for high diversity. The higher resolution of our phylogeny tree also refined our understanding of the interspecies transfer between red squirrels and humans pointing to a late antique/early medieval transmission. Furthermore, with our new estimates on the past population diversity of M. leprae, we gained first insights into the disease's global history in relation to major historic events such as the Roman expansion or the beginning of the regular transatlantic long distance trade. In summary, our findings highlight how studying ancient M. leprae genomes worldwide improves our understanding of leprosy's global history and can contribute to current models of M. leprae's worldwide dissemination, including interspecies transmissions.

Disease Activity Indices in Rheumatoid Arthritis: Comparative Performance to Detect Changes in Function, IL-6 Levels, and Radiographic Progression.

Objective: To compare the capacity of various disease activity indices to evaluate changes in function, IL-6 levels, and radiographic progression in early and established rheumatoid arthritis (RA). Methods: Secondary data analysis of a clinical trial assessing the efficacy of tocilizumab in patients with established RA (ACT-RAY) and a longitudinal prospective register of early arthritis (PEARL). Targeted outcomes were changes in physical function, measured with the health assessment questionnaire (HAQ), IL-6 serum levels, and radiographic progression. The "Hospital Universitario La Princesa Index" (HUPI), DAS28 using erythrocyte sedimentation rate and SDAI were the disease activity indices compared. Models adjusted for age and sex were fitted for each outcome and index and ranked based on the R 2 parameter and the quasi-likelihood under the independence model criterion. Results: Data from 8,090 visits (550 patients) from ACT-RAY and 775 visits (534 patients) from PEARL were analyzed. The best performing models for HAQ were the HUPI (R 2 = 0.351) and SDAI ones (R 2 = 0.329). For serum IL-6 levels, the SDAI (R 2 = 0.208) followed by the HUPI model (R 2 = 0.205). For radiographic progression in ACT-RAY, the HUPI (R 2 = 0.034) and the DAS28 models (R 2 = 0.026) performed best whereas the DAS28 (R 2 = 0.030) and HUPI models (R 2 = 0.023) did so in PEARL. Conclusions: HUPI outperformed other indices identifying changes in HAQ and radiographic progression and performed similarly to SDAI for IL-6 serum levels.

Host population structure for tolerance determines the evolution of plant-virus interactions.

Heterogeneity for plant defences determines both the capacity of host populations to buffer the effect of infection and the pathogen´s fitness. However, little information is known on how host population structure for tolerance, a major plant defence, impacts the evolution of plant-pathogen interactions. By performing 10 serial passages of Turnip mosaic virus (TuMV) in Arabidopsis thaliana populations with varying proportion of tolerant genotypes simulating different structures for this trait, we analysed how host heterogeneity for this defence shapes the evolution of both virus multiplication, the effect of infection on plant fecundity and mortality, and plant tolerance and resistance. Results indicated that a higher proportion of tolerant genotypes in the host population promotes virus multiplication and reduces the effect of infection on plant mortality, but not on plant fecundity. These changes resulted in more effective plant tolerance to virus infection. Conversely, a lower proportion of tolerant genotypes reduced virus multiplication, boosting plant resistance. Our work for the first time provides evidence of the main role of host population structure for tolerance on pathogen evolution and on the subsequent feedback loops on plant defences.

Arabidopsis thaliana Genes Associated with Cucumber mosaic virus Virulence and Their Link to Virus Seed Transmission.

Virulence, the effect of pathogen infection on progeny production, is a major determinant of host and pathogen fitness as it affects host fecundity and pathogen transmission. In plant-virus interactions, ample evidence indicates that virulence is genetically controlled by both partners. However, the host genetic determinants are poorly understood. Through a genome-wide association study (GWAS) of 154 Arabidopsis thaliana genotypes infected by Cucumber mosaic virus (CMV), we identified eight host genes associated with virulence, most of them involved in response to biotic stresses and in cell wall biogenesis in plant reproductive structures. Given that virulence is a main determinant of the efficiency of plant virus seed transmission, we explored the link between this trait and the genetic regulation of virulence. Our results suggest that the same functions that control virulence are also important for CMV transmission through seeds. In sum, this work provides evidence of a novel role for some previously known plant defense genes and for the cell wall metabolism in plant virus interactions.

Validation of galectin-1 as potential diagnostic biomarker of early rheumatoid arthritis.

Galectin 1 (Gal1) is a lectin with a wide cellular expression that functions as a negative regulator of the immune system in several animal models of autoimmune diseases. Identification of patients with rheumatoid arthritis (RA) has improved during the last decade, although there is still a need for biomarkers allowing an early diagnosis. In this regard, it has been recently proposed that Gal1 serum levels are increased in patients with RA compared to the general population. However, this topic is controversial in the literature. In this work, we provide additional information about the potential usefulness of Gal1 serum levels as a biomarker for RA diagnosis. We studied Gal1 serum and synovial fluid levels and clinical parameters in samples from 62 patients with early arthritis belonging to the PEARL study. In addition, 24 healthy donors were studied. We found that both patients fulfilling RA criteria and patients with undifferentiated arthritis showed higher Gal1 levels than healthy donors. Similar findings were observed in synovial fluid, which showed even higher levels than serum. However, we did not find correlation between Gal1 levels and disease activity or disability. Therefore, our results suggest that Gal1 could be a diagnostic but not a severity biomarker.

Expression of miR-135b in Psoriatic Skin and Its Association with Disease Improvement.

miRNAs have been associated with psoriasis since just over a decade. However, we are far from a complete understanding of their role during the development of this disease. Our objective was to characterize the cutaneous expression of miRNAs not previously described in psoriasis, the changes induced following the treatment with biologicals and their association with disease improvement. Next generation sequencing was performed from five skin samples from psoriasis patients (lesional and non-lesional skin) and five controls, and from this cohort, 12 microRNAs were selected to be analyzed in skin samples from 44 patients with plaque psoriasis. In 15 patients, an additional sample was obtained after three months of biological treatment. MiR-9-5p, miR-133a-3p and miR-375 were downregulated in the lesional skin of psoriasis patients. After treatment, expression of miR-133a-3p, miR-375, miR-378a and miR-135b in residual lesions returned towards the levels observed in non-lesional skin. The decrease in miR-135b levels after treatment with biologics was associated with both the improvement of patients evaluated through Psoriasis Area and Severity Index score and the decrease in local inflammatory response. Moreover, basal expression of miR-135b along with age was associated with the improvement of psoriasis, suggesting its possible usefulness as a prognostic biomarker.

Trade-offs between host tolerances to different pathogens in plant-virus interactions.

Although accumulating evidence indicates that tolerance is a plant defence strategy against pathogens as widespread as resistance, how plants evolve tolerance is poorly understood. Theory predicts that hosts will evolve to maximize tolerance or resistance, but not both. Remarkably, most experimental works failed in finding this trade-off. We tested the hypothesis that the evolution of tolerance to one virus is traded-off against tolerance to others, rather than against resistance and identified the associated mechanisms. To do so, we challenged eighteen Arabidopsis thaliana genotypes with Turnip mosaic virus (TuMV) and Cucumber mosaic virus (CMV). We characterized plant life-history trait modifications associated with reduced effects of TuMV and CMV on plant seed production (fecundity tolerance) and life period (mortality tolerance), both measured as a norm of reaction across viral loads (range tolerance). Also, we analysed resistance-tolerance and tolerance-tolerance trade-offs. Results indicate that tolerance to TuMV is associated with changes in the length of the pre-reproductive and reproductive periods, and tolerance to CMV with resource reallocation from growth to reproduction; and that tolerance to TuMV is traded-off against tolerance to CMV in a virulence-dependent manner. Thus, this work provides novel insights on the mechanisms of plant tolerance and highlights the importance of considering the combined effect of different pathogens to understand how plant defences evolve.

Within-Host Multiplication and Speed of Colonization as Infection Traits Associated with Plant Virus Vertical Transmission.

Although vertical transmission from parents to offspring through seeds is an important fitness component of many plant viruses, very little is known about the factors affecting this process. Viruses reach the seed by direct invasion of the embryo and/or by infection of the ovules or the pollen. Thus, it can be expected that the efficiency of seed transmission would be determined by (i) virus within-host multiplication and movement, (ii) the ability of the virus to invade gametic tissues, (iii) plant seed production upon infection, and (iv) seed survival in the presence of the virus. However, these predictions have seldom been experimentally tested. To address this question, we challenged 18 Arabidopsis thaliana accessions with Turnip mosaic virus and Cucumber mosaic virus Using these plant-virus interactions, we analyzed the relationship between the effect of virus infection on rosette and inflorescence weights; short-, medium-, and long-term seed survival; virulence; the number of seeds produced per plant; virus within-host speed of movement; virus accumulation in the rosette and inflorescence; and efficiency of seed transmission measured as a percentage and as the total number of infected seeds. Our results indicate that the best estimators of percent seed transmission are the within-host speed of movement and multiplication in the inflorescence. Together with these two infection traits, virulence and the number of seeds produced per infected plant were also associated with the number of infected seeds. Our results provide support for theoretical predictions and contribute to an understanding of the determinants of a process central to plant-virus interactions.IMPORTANCE One of the major factors contributing to plant virus long-distance dispersal is the global trade of seeds. This is because more than 25% of plant viruses can infect seeds, which are the main mode of germplasm exchange/storage, and start new epidemics in areas where they were not previously present. Despite the relevance of this process for virus epidemiology and disease emergence, the infection traits associated with the efficiency of virus seed transmission are largely unknown. Using turnip mosaic and cucumber mosaic viruses and their natural host Arabidopsis thaliana as model systems, we have identified the within-host speed of virus colonization and multiplication in the reproductive structures as the main determinants of the efficiency of seed transmission. These results contribute to shedding light on the mechanisms by which plant viruses disperse and optimize their fitness and may help in the design of more-efficient strategies to prevent seed infection.

Light Intensity Modulates the Efficiency of Virus Seed Transmission through Modifications of Plant Tolerance.

Increased light intensity has been predicted as a major consequence of climate change. Light intensity is a critical resource involved in many plant processes, including the interaction with viruses. A central question to plant-virus interactions is understanding the determinants of virus dispersal among plants. However, very little is known on the effect of environmental factors on virus transmission, particularly through seeds. The fitness of seed-transmitted viruses is highly dependent on host reproductive potential, and requires higher virus multiplication in reproductive organs. Thus, environmental conditions that favor reduced virus virulence without controlling its level of within-plant multiplication (i.e., tolerance) may enhance seed transmission. We tested the hypothesis that light intensity conditions that enhance plant tolerance promote virus seed transmission. To do so, we challenged 18 Arabidopsis thaliana accessions with Turnip mosaic virus (TuMV) and Cucumber mosaic virus (CMV) under high and low light intensity. Results indicated that higher light intensity increased TuMV multiplication and/or plant tolerance, which was associated with more efficient seed transmission. Conversely, higher light intensity reduced plant tolerance and CMV multiplication, and had no effect on seed transmission. This work provides novel insights on how environmental factors modulate plant virus transmission and contributes to understand the underlying processes.