Optimization of lactic acid production from apple and tomato pomaces by thermotolerant bacteria.

The production of lactic acid (LA) through biomass fermentation represents a promising alternative to the chemical synthesis. The use of agri-food by-products as fermentable carbohydrate sources can improve process sustainability by reducing waste and valorizing residual biomass. This study assessed the use of apple and tomato pomaces for producing LA through fermentation using thermotolerant bacteria under aerobic and non-sterile conditions. Three bacteria were evaluated and Heyndrickxia coagulans DSM 2314 was selected for its ability to produce LA from hydrolyzates of apple pomace (APH) and tomato pomace (TPH). The fermentation conditions were optimized to maximize LA production from APH, TPH and a mixture of both hydrolyzates. Therefore, LA productions ranged from 36.98 ± 0.41 to 40.72 ± 0.43 g/L, with yields from 0.86 ± 0.02 to 1.01 ± 0.01 g/g. Yeast extract was necessary as a nitrogen source for fermenting APH, while TPH and the mixture of both hydrolyzates did not require any supplementation. Other nitrogen sources, such as wine lees, urea and NH3Cl, were tested for fermenting APH. However, mixing this hydrolyzate with TPH proved to be the most viable alternative. This study demonstrates the potential for valorizing apple and tomato pomaces into LA under feasible fermentation conditions.

Evaluating the combined and individual cytotoxic effect of beauvericin, enniatin B and ochratoxin a on breast cancer cells, leukemia cells, and fresh peripheral blood mononuclear cells.

Beauvericin (BEA), Enniatin B (ENN B), and Ochratoxin A (OTA) are mycotoxins produced by fungi species. Their main effect on several organs and systems is associated with chronic exposure going from immunotoxicity, estrogenic disorders, and renal failure to cancer (in animals and humans). OTA belongs to Group 1 according to the International Agency for Research in Cancer (IARC) and it has legislated limited values; not happening for BEA nor ENN B. Exposure to mixtures of mycotoxins occurs through food intake in daily consumption. The aim of this study was to evaluate the implication of BEA, ENN B, and OTA individually and combined in producing cytotoxicity in cells for immunological studies and cancer cell lines (human leukemia cells (HL-60), fresh human peripheral blood mononuclear cells (PBMCs), and human breast cancer (MDA-MB-231) cells). Cells were treated for 4 h and 24 h at different concentrations of BEA, ENN B, and OTA, respectively. Viability assays were carried out by flow cytometry using DAPI (4',6-diamindino-2-phenylindole, dihydrochloride) as a viability dye and the potential effects of synergism, addition, and antagonism were assessed through the Chou and Talalay method. Individual OTA treatment exerted the greatest cytotoxicity for PBMC cells (IC50 0.5 µM) while ENN B for HL-60 (IC50 0.25 µM) and MDA-MB-231 (IC50 0.15 µM). In binary combination [ENN B + OTA] resulted in exerting the greatest cytotoxicity for HL-60 and MDA-MB-231 cells; while [BEA + OTA] in PBMC cells. The triple combination resulted in being highly cytotoxic for PBMC cells compared to HL-60 and MDA-MB-231 cells. In summary, PBMC cells were the most sensible cells for all three mycotoxins and the presence of OTA in any of the combinations had the greatest toxicity causing synergism as the most common cytotoxic effect.

Case Report: Common variable immunodeficiency phenotype and granulomatous-lymphocytic interstitial lung disease with a novel SOCS1 variant.

Common variable immunodeficiency is a heterogeneous symptomatic group of inborn errors of immunity that mainly affects antibodies production and/or function, predisposing patients to recurrent and severe infections. More than half of them usually develop autoimmunity, lymphoproliferation, enteropathy, and malignancies. Among these conditions, chronic lung disease such as granulomatous-lymphocytic interstitial lung disease is one of the leading causes of death in these patients. Recently, many genes that play a key role in B and T cells' development, maintenance, and/or cytokines signaling pathways have been implicated in the pathogenesis of the disease. Here, we describe the first Argentinian patient presenting with common variable immunodeficiency and granulomatous-lymphocytic interstitial lung disease, harboring two in cis heterozygous variants in the SOCS1 gene.

Diethyl phthalate and dibutyl phthalate disrupt sirtuins expression in the HepG2 cells.

Background: Phthalates are additives used as plasticizers among other uses, classified as endocrine disruptors and may contribute to some metabolic disorders. The aim of this work was to determine the effect of the exposure of diethyl phthalate (DEP) and dibutyl phthalate (DBP) on cell viability and reactive oxygen species (ROS) production, as well as the regulation of sirloins in HepG2 cells. Methods: HepG2 cells were exposed to DEP or DBP at 0.1, 1, 10 and 100 µg/mL, and after 48 or 72 h the gene and protein expression of sirtuins was quantified by qRT-PCR and Western-Blot, respectively. Results: Results showed that even at a low concentration of 0.1 µg/mL DEP affected the expression of Sirt3 and Sirt4, whereas DBP at 0.1 µg/mL affected Sirt3 and Sirt5 gene expression. Protein analysis showed a reduction in Sirt1 levels at a DEP concentration of 1 µg/mL and higher, while DBP at higher dose (100 µg/mL) decreased Sirt3 protein levels. Cell viability decreased by 20% only at higher dose (100 µg/mL) and ROS production increased at 10 and 100 µg/mL for both phthalates. Conclusion: These findings indicate that exposure to low concentrations (0.1 µg/mL) of DEP or DBP can negatively influence the expression of some sirtuins.

Influence of discontinuities on photonic waveguides.

Fabrication-induced imperfections in photonic wire waveguides, such as roughness, stitching errors, and discontinuities, degrade their performance and thereby lower the yield of large-scale systems. This degradation is primarily due to the high insertion losses induced by imperfections, which scale nonlinearly with the index contrast in wire waveguides. Here we investigate the influence of discontinuities in photonic waveguides and later show a platform that is robust to fabrication imperfections. Our platform is based on an array of silicon nano-pillars, arranged to form a sub-wavelength (SW) grating waveguide. We focus on investigating the robustness by considering an abrupt break in the waveguide, as an extreme case of discontinuity. We show that sub-wavelength silicon waveguides are robust against unwanted large discontinuities relative to the operating wavelength. We measure a transmission loss of <2.2 dB at 1550 n m, for a discontinuity of length 2.1 µ m, when compared to more than 7 d B of loss in conventional silicon wire waveguides for the same discontinuity. Our results show that this mode of protection is broadband, covering the entire telecommunication band (λ =1500-1600 nm). We believe that this investigation of the influence of discontinuities in photonic waveguides could be a step toward the realization of low-loss optical waveguides.

Potential bioaccessibility and bioavailability of polyphenols and functional properties of tiger nut beverage and its by-product during in vitro digestion.

"Horchata de chufa" is a beverage produced from tiger nut tubers, which yields a high amount of by-product. This study explored the functional properties of the Spanish tiger nut beverage (TNB) and its by-product (TNBP) together with the bioaccessibility and bioavailability of polyphenols in vitro. TNB and TNBP were characterized for polyphenols via LC/MS/MS and underwent in vitro digestion (INFOGEST). The total antioxidant capacity (TAC) of all bioaccessible fractions and digestion residues was assessed. Intestinal bioaccessible fractions were tested for the ability to inhibit the activity of digestive enzymes (α-amylase, α-glucosidase, and lipase) and the content of polyphenols, whose bioavailability was assessed in a Caco-2 cell model. Thirteen polyphenols were quantified and found to be more abundant in TNB (603 ± 1.4 µg g-1 DW) than in TNBP (187 ± 1.0 µg g-1 DW). Polyphenol bioaccessibility was higher for TNBP than that for TNB (57% vs. 27%), and despite a similar TAC of the intestinal bioaccessible fractions (10.2 ± 0.1 µmoL vs. 9.2 ± 0.03 µmoL eq. Trolox per g DW for TNB and TNBP, respectively), the different patterns of polyphenols released upon digestion suggested the higher ability of TNBP fraction to inhibit α-glucosidase and lipase. TNBP digestion residue showed higher TAC than TNB. Moreover, TNB polyphenols exhibited over 80% bioavailability, whereas TNBP polyphenols' bioavailability ranged from 62% to 84%. Overall, the findings demonstrated that TNBP maintains a high nutritional value, thus suggesting its possible reuse in innovative, healthy, and sustainable foods.

Building on the clinical applicability of ctDNA analysis in non-metastatic pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma represents one of the solid tumors showing the worst prognosis worldwide, with a high recurrence rate after adjuvant or neoadjuvant therapy. Circulating tumor DNA analysis raised as a promising non-invasive tool to characterize tumor genomics and to assess treatment response. In this study, surgical tumor tissue and sequential blood samples were analyzed by next-generation sequencing and were correlated with clinical and pathological characteristics. Thirty resectable/borderline pancreatic ductal adenocarcinoma patients treated at the Hospital Universitario de Navarra were included. Circulating tumoral DNA sequencing identified pathogenic variants in KRAS and TP53, and in other cancer-associated genes. Pathogenic variants at diagnosis were detected in patients with a poorer outcome, and were correlated with response to neoadjuvant therapy in borderline pancreatic ductal adneocarcinoma patients. Higher variant allele frequency at diagnosis was associated with worse prognosis, and thesum of variant allele frequency was greater in samples at progression. Our results build on the potential value of circulating tumor DNA for non-metastatic pancreatic ductal adenocarcinoma patients, by complementing tissue genetic information and as a non-invasive tool for treatment decision. Confirmatory studies are needed to corroborate these findings.

Validation of a Novel BCM Model for Recurrence Risk Prediction after Mucosectomy of Colorectal Lateral Spreading Tumors in a European Cohort.

BACKGROUND AND AIM: Piecemeal endoscopic mucosal resection (pEMR) is the best approach to resect large lateral spreading tumors (LST, > 20 mm width). However, it is associated with early recurrence (ER) and late recurrence (LR). This study aims to assess the risk factors associated with ER and LR and to validate different predictive scores (SMSA, SERT, and BCM) in identifying the risk of ER and LR after LST resected by pEMR in a European cohort. METHODS: Retrospective observational cohort study, based on a prospectively collected database, of large LST submitted to pEMR. RESULTS: A total of 108 patients were included in the study and the incidence rates of ER and LR were 22% and 8%, respectively. The lesion's size, SERT, and BCM scores were independent predictor factors of ER (p-value < 0.05), while the lesion's site and BCM score were independent predictor factors of LR (p-value < 0.05). For the prediction of ER, the SERT score (cut-off > 1) presented the highest AUROC (0.758 vs 0.697 from BCM and 0.647 from SMSA). Regarding LR, the BCM model (cut-off > 2) presented the highest AUROC (0.817 vs 0.708 from SERT and 0.691 from SMSA). CONCLUSIONS: We present the first external validation of the three scores mentioned in an European cohort. SERT and BCM scores had an acceptable performance in predicting ER and LR. However, the BCM model was the only score that proved to be an independent predictor of both ER and LR, proving to be valuable for both applications.

Diagnostic approach and monitoring of chronic kidney disease in the primary care pediatric population.

Chronic kidney disease (CKD) has severe consequences on the quality and expectancy of life and is considered a major health problem worldwide. This is, especially relevant in pediatric patients, as they have unique characteristics and a mortality rate 30 times higher (in advanced stages) than healthy people. This review aims to define the minimum components for the diagnostic approach and monitoring of CKD in the pediatric population from primary health care to promote comprehensive care and adequate risk management. For this purpose, we performed a systematic review of the literature with a panel of experts. Based on the evidence, to optimize the definition, diagnosis, and timely treatment of CKD in the pediatric population, we formulated 21 recommendations. These were approved by the research team and peer-reviewed by clinical experts. They will facilitate the definition of the diagnostic approach for CKD in the pediatric population in primary health-care settings, allowing for timely treatment intervention, comprehensive care, and monitoring of this disease.

La enfermedad renal crónica (ERC) tiene graves consecuencias en la calidad y la esperanza de vida, y se considera un importante problema de salud a nivel mundial. Esto es especialmente relevante en pacientes pediátricos, ya que presenta características únicas y una tasa de mortalidad en etapas avanzadas que es 30 veces mayor que en personas sanas. El objetivo de esta revisión fue definir los componentes mínimos para el abordaje diagnóstico y para el seguimiento de la ERC en la población pediátrica desde la atención primaria en salud, con el fin de promover la atención integral y una adecuada gestión del riesgo. Para esto, se realizó una revisión sistemática de la literatura con panel de discusión de expertos. Basándonos en la evidencia, y con el objetivo de optimizar la definición, diagnóstico y tratamiento oportuno de la ERC en la población pediátrica, se formularon 21 recomendaciones. Estas fueron aprobadas por el equipo desarrollador y los pares expertos clínicos evaluadores, y permitirán definir de manera oportuna el abordaje diagnóstico de la ERC en la población pediátrica desde la atención primaria en salud, facilitando la intervención temprana, una atención integral y el seguimiento de esta patología.

Imbalance of SARS-CoV-2-specific CCR6+ and CXCR3+ CD4+ T cells and IFN-γ + CD8+ T cells in patients with Long-COVID.

Long-COVID (LC) is characterised by persistent symptoms for at least 3 months after acute infection. A dysregulation of the immune system and a persistent hyperinflammatory state may cause LC. LC patients present differences in activation and exhaustion states of innate and adaptive compartments. Different T CD4+ cell subsets can be identified by differential expression of chemokine receptors (CCR). However, changes in T cells with expression of CCRs such as CCR6 and CXCR3 and their relationship with CD8+ T cells remains unexplored in LC. Here, we performed unsupervised analysis and found CCR6+ CD4+ subpopulations enriched in COVID-19 convalescent individuals upon activation with SARS-CoV-2 peptides. SARS-CoV-2 specific CCR6+ CD4+ are decreased in LC patients, whereas CXCR3+ CCR6- and CCR4+ CCR6- CD4+ T cells are increased. LC patients showed lower IFN-γ-secreting CD8+ T cells after stimulation with SARS-CoV-2 Spike protein. This work underscores the role of CCR6 in the pathophysiology of LC.

Ketamine and fluoxetine exert similar actions on prelimbic and infralimbic responsivity to lateral septal nucleus stimulation in Wistar rats.

Ketamine is a dissociative anesthetic that has been proposed to be a useful alternative in cases of a poor response to other treatments in patients with depression. Remarkably, beneficial clinical actions of ketamine are detected once its psychotropic actions disappear. Therefore, clinical actions may occur independently of dose. Most current studies focus on actions of ketamine on neurotrophic factors, but few studies have investigated actions of ketamine on neural structures for which actions of antidepressants have been previously explored. Lateral septal nucleus (LSN) stimulation reduces neural activity in the prelimbic cortex (PL) and infralimbic cortex (IL) subregions of the medial prefrontal cortex (mPFC). Fluoxetine increases inhibitory responsivity of the LSN-IL connection. In the present study, actions of an anesthetic dose of ketamine were compared with a high dose of fluoxetine on behavior and neural responsivity 24 h after drug administration. Fluoxetine reduced immobility in the forced swim test without changing locomotor activity in the open field test. Ketamine strongly decreased locomotor activity and did not produce changes in immobility. In another set of Wistar rats that received similar drug treatment regimens, the results indicated that LSN stimulation in saline-treated animals produced a long-lasting inhibitory afterdischarge in these mPFC subregions. Actions of ketamine on the LSN-mPFC connection reproduced actions of fluoxetine, consisting of accentuated inhibition of the LSN action on the mPFC. These findings suggest that independent of different actions on neurotransmission, the common final pathway of antidepressants lies in their actions on forebrain structures that are related to emotional regulation.

Individual and contextual determinants associated with traumatic dental injuries in children eight to ten years of age: a multilevel analysis.

OBJECTIVE: Investigate individual and contextual determinants associated with traumatic dental injuries in schoolchildren. METHODS: A cross-sectional study with 739 pairs of parents and children. Parents answered a sociodemographic questionnaire, the Family Adaptability and Cohesion Evaluation Scale and a questionnaire on the child's use of electronic devices. Examinations of the children were conducted at the school by calibrated examiners using the diagnostic criteria proposed by Andreasen. Contextual variables of the school were also collected. Multilevel Poisson regression for complex samples was performed (p < 0.05). RESULTS: The individual factors associated with the outcome were children of single parents (PR = 2.33; 95% CI: 1.79-2.66), practice of sports (PR = 2.46; 95% CI: 1.70-3.22), the daily use of electronic devices (PR = 1.78; 95% CI: 1.31-1.81), more than 2 h per day of screen time (PR = 3.84; 95% CI: 1.94-4.28) and chaotic family adaptability (PR = 4.22; 95% CI: 3.44-4.99). The contextual variables were studying at a public school (PR = 1.77; 95% CI: 1.02-3.05) and the presence of rigid floor in the school courtyard (PR = 1.99; 95% CI: 1.15-3.15). CONCLUSION: Individual determinants, studying at a public school and the presence of rigid floor in the school courtyard were associated with traumatic dental.

Influence of Healthcare Delivery Type on Patients' Mental Health: Is Hospitalization Always a Stressful Factor? Can Allostatic Load Help Assess a Patient's Psychological Disorders?

BACKGROUND: Psychological distress is a predictor of future health and disease data, with consequent implications for both the patient and the healthcare system. Taking advantage of the unprecedented situation caused by the COVID-19 pandemic we aimed to assess whether the type of medical care received by patients during the initial months of the pandemic influenced their evolution, particularly at the psychological level. Additionally, we investigated whether allostatic load was associated not only with physical but also psychological alterations. METHODS: All the patients diagnosed with COVID-19 infection at HM Madrid Hospital during the month of March 2020 were studied, both those hospitalized (110) and those treated on an outpatient basis (46). They were psychologically evaluated using the Profile of Mood States (POMS) test. We calculated the allostatic load using different laboratory parameters. RESULTS: Outpatient patients had significantly higher scores than hospitalized ones in Tension-Anxiety (52 ± 19.3 vs. 38 ± 4.3; p < 0.001). So, 36.9% of the outpatient patients exhibited anxiety. Allostatic load has not been correlated with patients' psychological alterations. CONCLUSIONS: Psychological distress of outpatient patients should be taken into account in their management to improve mental health planning. This knowledge could provide comprehensive care to patients including their mental health, in the face of subsequent epidemics/pandemics.

Genetic Diversity and Phylogeography of the Relict Tree Fern Culcita macrocarpa: Influence of Clonality and Breeding System on Genetic Variation.

The tree fern Culcita macrocarpa, a threatened Iberian-Macaronesian endemism, represents the sole European species of the order Cyatheales. Considered a Tertiary relict of European Palaeotropical flora, its evolutionary history and genetic diversity, potentially influenced by presumed high clonal propagation, remain largely unknown. This study elucidates the phylogeographic history of C. macrocarpa, assessing the impact of vegetative reproduction on population dynamics and genetic variability. We provide genetic data from eight newly identified nuclear microsatellite loci and one plastid DNA region for 17 populations spanning the species' range, together with species distribution modeling data. Microsatellites reveal pervasive clonality in C. macrocarpa, which has varied among populations. We assess the impact of clonality on genetic diversity and evaluate how estimates of intra-population genetic diversity indices and genetic structuring are affected by the chosen definition of "individual" (focusing exclusively on genetically distinct individuals, genets, as opposed to considering all independent clonal replicates, ramets). We identify two main population groups, one in the northern Iberian Peninsula and the other in the Macaronesian archipelagos and southern Iberian Peninsula. Within each group, we found relict populations (in the Azores and the Cantabrian Cornice) as well as recent originated populations. This population structure suggests colonization dynamics in which recent populations originated from one or a few genets of relict populations and became established through intra-gametophytic self-fertilization and vegetative expansion. DAPC analysis facilitated the identification of alleles that most significantly contributed to the observed population structure. The current Andalusian populations appear to have originated from colonization events from the Azores and the Cantabrian Cornice. Our findings suggest that C. macrocarpa persisted through the Last Glacial Maximum in two refugia: the Azores and the Cantabrian Cornice. Colonization into new areas occurred presumably from these refuges, generating two large population groups with structured genetic diversity. This study underscores the significance of clonality in establishing new populations and shaping genetic structure.

Mapping trends in preemptive analgesia related to oral surgery with the use of Ibuprofen: a comprehensive quantitative and qualitative analysis of bibliometric parameters.

PURPOSE: This study aims to conduct a thorough analysis, both quantitative and qualitative, of bibliometric parameters related to preemptive analgesia (PA) in oral surgical procedures (OSP). METHODS: Research trends on PA in OSP using ibuprofen were reviewed through bibliometric analysis of 68 journal articles published from 1991 to 2022 in the Web of Science database. Bibliometric indicators were applied to analyze the journal article data, including the annual distribution of publications and literature growth, document types, citation indicators to measure qualitative research performance, and keyword mapping to identify research trends. The results were imported into RStudio, and the Bibliometrix package was used to prepare and analyze the metadata. RESULTS: The 68 included articles received a total of 900 citations, ranging from 1 source to 72 citations with some fluctuations. The papers on PA in OSP using ibuprofen had an average of 16.85 citations per paper. These publications were originated from 25 countries, with the highest contributions from Brazil (n = 17), the USA (n = 13), and Turkey (n = 8). The top five major contributing journals were the International Journal of Oral and Maxillofacial Surgery, Journal of Oral and Maxillofacial Surgery, Journal of Cranio-Maxillo-Facial Surgery, Journal of Periodontology, and Acta Odontologica Scandinavica, representing more than half of all selected papers. CONCLUSION: Papers focused on PA in OSP received numerous citations. The citation per article correlated with the number of publications at the affiliation, author, country, and journal levels. However, there is still a scarcity of studies in this field.

Kidney Transplantation Outcomes of Patients With Chronic Hypotension in Dialysis.

Introduction: Persistent chronic hypotension affects 5-10% of dialysis patients. It seems to be reversible after receiving a functioning graft, but data regarding its influence on transplant outcomes are scarce. We analyze the evolution of patients with chronic hypotension in dialysis who undergo kidney transplantation at our center. Methods: A retrospective observational study was conducted. Sixty-six patients with chronic hypotension (defined as systolic blood pressure ≤ 100 mm Hg at the time of transplantation) were identified. A control group of 66 non-hypotensive patients was assigned. The evolution of both groups was compared. Results: Hypotensive patients had higher rates of primary non-function (18.2% vs. 6.1%; P = 0.03) mainly due to venous thrombosis of the allograft, worse renal function at the end of follow-up (eGFR of 35 mL/min/1.73 m2 vs 48 mL/min/1.73 m2, P = 0.001) but there was no statistical difference in graft survival after censoring for primary non-function. After multivariable adjustment, chronic hypotension remained an independent predictor factor for graft failure (adjusted HR of 2.85; 95% CI: 1.24-6.57; P = 0.014). Use of vasoactive drugs and anticoagulation in hypotensive patients was associated with 7.1% of venous graft thrombosis compared to 17.3% in those with no intervention (P = 0.68). Receiving a functioning graft implied blood pressure normalization in patients with chronic hypotension. Conclusion: Chronic hypotension in dialysis has a negative impact on short-term kidney transplant outcomes but a lower impact on long-term results. It is reversible after receiving a functioning graft. Identifying this subgroup of patients seems crucial to implement measures aimed at improving transplant results.

Pathological autoantibody internalisation in myositis.

OBJECTIVES: Autoantibodies targeting intracellular proteins are common in various autoimmune diseases. In the context of myositis, the pathologic significance of these autoantibodies has been questioned due to the assumption that autoantibodies cannot enter living muscle cells. This study aims to investigate the validity of this assumption. METHODS: Confocal immunofluorescence microscopy was employed to localise antibodies and other proteins of interest in myositis muscle biopsies. Bulk RNA sequencing was used to examine the transcriptomic profiles of 669 samples, including those from patients with myositis, disease controls and healthy controls. Additionally, antibodies from myositis patients were introduced into cultured myoblasts through electroporation, and their transcriptomic profiles were analysed using RNA sequencing. RESULTS: In patients with myositis autoantibodies, antibodies accumulated inside myofibres in the same subcellular compartment as the autoantigen. Bulk RNA sequencing revealed that muscle biopsies from patients with autoantibodies targeting transcriptional regulators exhibited transcriptomic patterns consistent with dysfunction of the autoantigen. For instance, in muscle biopsies from patients with anti-PM/Scl autoantibodies recognising components of the nuclear RNA exosome complex, an accumulation of divergent transcripts and long non-coding RNAs was observed; these RNA forms are typically degraded by the nuclear RNA exosome complex. Introducing patient antibodies into cultured muscle cells recapitulated the transcriptomic effects observed in human disease. Further supporting evidence suggested that myositis autoantibodies recognising other autoantigens may also disrupt the function of their targets. CONCLUSIONS: This study demonstrates that, in myositis, autoantibodies are internalised into living cells, causing biological effects consistent with the disrupted function of their autoantigen.