Correction: Dhaliwal et al. Developments and Prospects in Imperative Underexploited Vegetable Legumes Breeding: A Review. Int. J. Mol. Sci. 2020, 21, 9615.

In the publication [...].

Interobserver agreement and prognostic value of image-based scoring systems in patients with primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a cholestatic liver disease that progresses to cirrhosis and liver failure. The Anali and Amsterdam scores are based upon imaging features on MRI and ERCP, respectively. AIMS: We aimed to compare the interobserver variability and performances of these scores. METHODS: Patients with PSC with at least 1 MRCP were included. Images were independently scored by 2 experts. Agreement and prognostic performance with a primary end point of hepatic decompensation was assessed. RESULTS: Fifty-nine patients were included (67.8% male, 86.4% IBD). Interobserver agreement for the Anali and Amsterdam scores were moderate (k = 0.49; 95% CI 0.35-0.64 and k = 0.43; 95% CI 0.30-0.56, respectively). Among the Anali components, dysmorphy (caudate/right lobe ratio > 0.9) had fair agreement (k = 0.37; 95% CI 0.14-0.60) and portal hypertension (k = 0.64, 95% CI 0.32-0.89) and intrahepatic dilation (k = 0.70; 95% CI 0.53-0.87) had substantial agreement. The Amsterdam extrahepatic and intrahepatic scores had fair agreement (k = 0.38; 95% CI 0.23-0.52) and moderate agreement (k = 0.50; 95% CI 0.34-0.67), respectively. Anali score (HR 5.90, 95% CI 1.64-21.21), total bilirubin (HR = 3.23; 95% Cl 1.06-9.91), and age (HR = 1.05; 95% CI 1.00-1.11) were independent predictors of hepatic decompensation. Mayo risk score and Anali score had good discriminative ability with c-statistics of 0.78 (CI 0.59-0.96) and 0.76 (CI 0.56-0.91). Anali score remained an independent predictor after adjusting for Mayo risk score. CONCLUSION: Anali score adds additional predictive value for hepatic decompensation in patients with PSC.

A large-effect QTL introgressed from ricebean imparts resistance to Mungbean yellow mosaic India virus in blackgram (Vigna mungo (L.) Hepper).

KEY MESSAGE: Here, we report identification of a large effect QTL conferring Mungbean yellow mosaic India virus resistance introgressed from ricebean in blackgram variety Mash114. The tightly linked KASP markers would assist in marker-assisted-transfer of this region into Vigna species infected by MYMIV. Until recently, precise location of genes and marker-assisted selection was long thought in legumes such as blackgram due to lack of dense molecular maps. However, advances in next-generation sequencing based on high-throughput genotyping technologies such as QTL-seq have revolutionized trait mapping in marker-orphan crops. Using QTL-seq approach, we have identified a large-effect QTL for resistance to Mungbean yellow mosaic India virus (MYMIV) in blackgram variety Mash114. MYMIV is devastating disease responsible for huge yield losses in blackgram, greengram and other legumes. Mash114 showed consistent and high level of resistance to MYMIV since last nine years. Whole genome re-sequencing of MYMIV-resistant and susceptible bulks derived from RILs of cross KUG253 X Mash114 identified a large-effect QTL (qMYMIV6.1.1) spanning 3.4 Mb on chromosome 6 explaining 70% of total phenotypic variation. This region was further identified as an inter-specific introgression from ricebean. Linkage mapping using KASP markers developed from potent candidate genes involved in virus resistance identified the 500 kb genomic region equaling 1.9 cM on genetic map linked with MYMIV. The three KASP markers closely associated with MYMIV originated from serine threonine kinase, UBE2D2 and BAK1/BRI1-ASSOCIATED RECEPTOR KINASE genes. These KASPs can be used for marker-assisted transfer of introgressed segment into suitable backgrounds of Vigna species.

Decreased CD57 expression of natural killer cells enhanced cytotoxicity in patients with primary sclerosing cholangitis.

Background/aims: Primary sclerosing cholangitis (PSC) is a chronic inflammatory biliary disease for which the immunopathological basis remains an enigma. Natural killer (NK) cells are key components of innate immunity and seemingly play diversified roles in different autoimmune disorders (AIDs). The aim of this study was to determine the role of NK cells in the pathogenesis of PSC. Methods: The frequency and phenotype of circulating NK cells in a large cohort of patients with PSC and healthy controls (HCs) were systematically examined. In addition, the functional capacity of NK cells including cytotoxicity and cytokine production was studied. Results: The frequency of CD3-CD56dimCD16+ (defined as CD56dim) NK cells in PSC patients was significantly lower in comparison to HCs. CD56dim NK cells from PSC displayed a more immature phenotype including high expression of the natural killing receptor NKp46 and downregulation of the highly differentiated NK cell marker CD57. Interestingly, the reduction of CD57 expression of NK cells was associated with the disease severity of PSC. In addition, PSC CD56dim NK cells exhibited increased CD107a degranulation and cytolytic activity toward target cells compared with HCs. Further analysis demonstrated that CD57-CD56dim NK cells from PSC had elevated expression of NKp46, NKp30, IL-2 receptor, and KLRG1 and higher cytotoxic capacity as compared to CD57+CD56dim NK cells. Conclusions: Our data demonstrate that the differentiation of PSC NK cells is dysregulated with enhanced cytotoxic activity. This change is likely to be functionally involved in pathogenesis and disease progression, deducing the potential of NK-directed immunotherapy for PSC.

Genome-wide Association Study for Yield and Yield-Related Traits in Diverse Blackgram Panel (Vigna mungo L. Hepper) Reveals Novel Putative Alleles for Future Breeding Programs.

Blackgram (Vigna mungo L. Hepper) is an important tropical and sub-tropical short-duration legume that is rich in dietary protein and micronutrients. Producing high-yielding blackgram varieties is hampered by insufficient genetic variability, absence of suitable ideotypes, low harvest index and susceptibility to biotic-abiotic stresses. Seed yield, a complex trait resulting from the expression and interaction of multiple genes, necessitates the evaluation of diverse germplasm for the identification of novel yield contributing traits. Henceforth, a panel of 100 blackgram genotypes was evaluated at two locations (Ludhiana and Gurdaspur) across two seasons (Spring 2019 and Spring 2020) for 14 different yield related traits. A wide range of variability, high broad-sense heritability and a high correlation of grain yield were observed for 12 out of 14 traits studied among all environments. Investigation of population structure in the panel using a set of 4,623 filtered SNPs led to identification of four sub-populations based on ad-hoc delta K and Cross entropy value. Using Farm CPU model and Mixed Linear Model algorithms, a total of 49 significant SNP associations representing 42 QTLs were identified. Allelic effects were found to be statistically significant at 37 out of 42 QTLs and 50 known candidate genes were identified in 24 of QTLs.

Developments and Prospects in Imperative Underexploited Vegetable Legumes Breeding: A Review.

Vegetable legumes are an essential source of carbohydrates, vitamins, and minerals, along with health-promoting bioactive chemicals. The demand for the use of either fresh or processed vegetable legumes is continually expanding on account of the growing consumer awareness about their well-balanced diet. Therefore, sustaining optimum yields of vegetable legumes is extremely important. Here we seek to present d etails of prospects of underexploited vegetable legumes for food availability, accessibility, and improved livelihood utilization. So far research attention was mainly focused on pulse legumes' performance as compared to vegetable legumes. Wild and cultivated vegetable legumes vary morphologically across diverse habitats. This could make them less known, underutilized, and underexploited, and make them a promising potential nutritional source in developing nations where malnutrition still exists. Research efforts are required to promote underexploited vegetable legumes, for improving their use to feed the ever-increasing population in the future. In view of all the above points, here we have discussed underexploited vegetable legumes with tremendous potential; namely, vegetable pigeon pea (Cajanus cajan), cluster bean (Cyamopsis tetragonoloba), winged bean (Psophocarpus tetragonolobus), dolichos bean (Lablab purpureus), and cowpea (Vigna unguiculata), thereby covering the progress related to various aspects such as pre-breeding, molecular markers, quantitative trait locus (QTLs), genomics, and genetic engineering. Overall, this review has summarized the information related to advancements in the breeding of vegetable legumes which will ultimately help in ensuring food and nutritional security in developing nations.

Glycomic analysis of antibody indicates distinctive glycosylation profile in patients with autoimmune cholangitis.

Glycosylation of antibodies, particularly in the Fc domain, critically modulate the ability of antibodies to bind to FcRs, maintaining immune quiescence to achieve a finely orchestrated immune response. The removal of sialic acid and galactose residues dramatically alters the physiological function of IgGs, and alterations of Ig glycosylation have been associated with several autoimmune disorders. However, Ig glycosylation has not been extensively studied in autoimmune cholangitis. We applied triple quadruple mass spectroscopy with subsequent multiple reaction monitoring to elucidate the profile, composition and linkage of sugar residues of antibody glycans in patients with primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and healthy controls (HC). Agalactosylated, HexNAc terminated IgG1 glycoforms were enriched in both PBC and PSC. Levels of IgM glycans at site N439 and fucosylated glycans in J chain, were significantly decreased in PBC compared to PSC and HC. PSC patients had decreased bisecting glycoforms and increased biantennary glycoforms on IgA compared to PBC. Importantly, our data demonstrate the association of distinct branching and composition patterns of Ig glycoforms with disease severity and liver cirrhosis, which highlight the importance of glycan biology as a potential mechanism and/or a disease specific signal of inflammation.

Estimation of the hyperelastic parameters of fresh human oropharyngeal soft tissues using indentation testing.

Patient-specific finite element (FE) modeling of the upper airway is an effective tool for accurate assessment of obstructive sleep apnea (OSA) syndrome. It is also useful for planning minimally invasive surgical procedures under severe OSA conditions. A major requirement of FE modeling is having reliable data characterizing the biomechanical properties of the upper airway tissues, particularly oropharyngeal soft tissue. While some data characterizing this tissue's linear elastic regime is available, reliable data characterizing its hyperelasticity is scarce. The aim of the current study is to estimate the hyperelastic mechanical properties of the oropharyngeal soft tissues, including the palatine tonsil, soft palate, uvula, and tongue base. Fresh tissue specimens of human oropharyngeal tissue were acquired from 13 OSA patients who underwent standard surgical procedures. Indentation testing was performed on the specimens to obtain their force-displacement data. To determine the specimens' hyperelastic parameters using these data, an inverse FE framework was utilized. In this work, the hyperelastic parameters corresponding to the commonly used Yeoh and 2nd order Ogden models were obtained. Both models captured the experimental force-displacement data of the tissue specimens reasonably accurately with mean errors of 11.65% or smaller. This study has provided estimates of the hyperelastic parameters of all upper airway soft tissues using fresh human tissue specimens for the first time.

Role of voice rest following laser resection of vocal fold lesions: A randomized controlled trial.

OBJECTIVES/HYPOTHESIS: Voice rest is often prescribed following phonosurgery by most surgeons despite limited empiric evidence to support its practice. This study assessed the effect of postphonosurgery voice rest on vocal outcomes. STUDY DESIGN: Prospective, randomized controlled trial. METHODS: Patients with unilateral vocal fold lesions undergoing CO2 laser excision were recruited in a prospective manner and randomized into one of two groups: 1) an experimental arm consisting of 7 days of absolute voice rest, or 2) a control arm consisting of no voice rest. The primary outcome measure was the Voice Handicap Index-10 (VHI-10) questionnaire. Secondary outcomes included aerodynamic measurements (maximum phonation time), acoustic measures (fundamental frequency, jitter, shimmer, and harmonic-to-noise ratio), and auditory-perceptual measures. Primary and secondary outcomes were assessed preoperatively and reassessed postoperatively at the 1- and 3-month follow-up. Patient compliance to voice rest instructions were controlled for using subjective and objective parameters. RESULTS: Thirty patients were enrolled with 15 randomized to each arm of the study. Statistical analysis for the entire cohort showed a significant improvement in the mean preoperative VHI-10 compared to postoperative assessments at 1-month (19.0 vs. 7.3, P < .05) and 3-month (19.0 vs. 6.2, P < .05) follow-up. However, between-group comparisons showed no significant difference in postoperative VHI-10 at either time point. Similarly, secondary outcome measures yielded no significant difference in between-group comparisons. CONCLUSIONS: Our study shows no significant benefit to voice rest on postoperative voice outcomes as determined by patient self-perception, acoustic variables, and auditory-perceptual analysis. LEVEL OF EVIDENCE: 1b CLINICAL TRIAL NUMBER: NCT02788435 (clinicaltrials.gov) Laryngoscope, 130:1750-1755, 2020.

Disruption of the RICTOR/mTORC2 complex enhances the response of head and neck squamous cell carcinoma cells to PI3K inhibition.

Phosphoinositide 3-kinase (PI3K) is aberrantly activated in head and neck squamous cell carcinomas (HNSCC) and plays a pivotal role in tumorigenesis by driving Akt signaling, leading to cell survival and proliferation. Phosphorylation of Akt Thr308 by PI3K-PDK1 and Akt Ser473 by mammalian target of rapamycin complex 2 (mTORC2) activates Akt. Targeted inhibition of PI3K is a major area of preclinical and clinical investigation as it reduces Akt Thr308 phosphorylation, suppressing downstream mTORC1 activity. However, inhibition of mTORC1 releases feedback inhibition of mTORC2, resulting in a resurgence of Akt activation mediated by mTORC2. While the role of PI3K-activated Akt signaling is well established in HNSCC, the significance of mTORC2-driven Akt signaling has not been thoroughly examined. Here we explore the expression and function of mTORC2 and its obligate subunit RICTOR in HNSCC primary tumors and cell lines. We find RICTOR to be overexpressed in a subset of HNSCC tumors, including those with PIK3CA or EGFR gene amplifications. Whereas overexpression of RICTOR reduced susceptibility of HNSCC tumor cells to PI3K inhibition, genetic ablation of RICTOR using CRISPR/Cas9 sensitized cells to PI3K inhibition, as well as to EGFR inhibition and cisplatin treatment. Further, mTORC2 disruption led to reduced viability and colony forming abilities of HNSCC cells relative to their parental lines and induced loss of both activating Akt phosphorylation modifications (Thr308 and Ser473). Taken together, our findings establish RICTOR/mTORC2 as a critical oncogenic complex in HNSCC and rationalize the development of an mTORC2-specific inhibitor for use in HNSCC, either combined with agents already under investigation, or as an independent therapy.

Therapeutic trials of biologics in primary biliary cholangitis: An open label study of abatacept and review of the literature.

Primary biliary cholangitis (PBC) is a classic autoimmune disease in which humoral, cytotoxic, and innate immune responses have been implicated with the specific targeting of a mitochondrial antigen. The mainstay of treatment remains the bile acid ursodeoxycholic acid (UDCA). Corticosteroids may have some benefits, but to date, clinical trials of biologics targeting B cells and IL-12/23 have not shown any efficacy. Because activated T cells target the intrahepatic bile ducts in PBC and pre-clinical models suggested that blocking CD80/CD86 with CTLA-4 Ig might have therapeutic benefit in PBC, we performed an open-label trial to determine if CTLA-4 Ig (abatacept) is safe and potentially efficacious in PBC patients with an incomplete response to UDCA. PBC patients with an alkaline phosphatase (ALP) > 1.67 × the upper limit of normal after 6 months on UDCA treatment or who were intolerant of UDCA received abatacept 125 mg s.q. weekly for 24 weeks. The co-primary endpoint was ALP normalization or a >40% reduction from baseline. Among 16 subjects enrolled and who received at least 1 dose of abatacept, 1 (6.3%) met the co-primary endpoint. Absolute and percent changes in ALP [median (95% CI)] were +2.8 U/L (-90.9-96.6) and -0.28% (-21.1-15.5), respectively. No significant changes were observed in ALP, ALT, total bilirubin, albumin, immunoglobulins, or liver stiffness. Abatacept treatment decreased several non-terminally differentiated CD4+ but not CD8+ T cell populations, including decreases in CD4+ CCR5+ (p = 0.02) and CD4+ PD1+ (p = 0.03) lymphocytes. In contrast there were increases in CD4+ CCR7+ lymphocytes (p = 0.034). Treatment emergent adverse events occurred in 4 subjects. Abatacept was well tolerated in this population of PBC patients but like other biologics in PBC was ineffective in achieving biochemical responses associated with improved clinical outcomes.

Estimation of the Young's moduli of fresh human oropharyngeal soft tissues using indentation testing.

Finite element (FE)-based biomechanical simulations of the upper airway are promising computational tools to study abnormal upper airway deformations under obstructive sleep apnea (OSA) conditions and to help guide minimally invasive surgical interventions in case of upper airway collapse. To this end, passive biomechanical properties of the upper airway tissues, especially oropharyngeal soft tissues, are indispensable. This research aimed at characterizing the linear elastic mechanical properties of the oropharyngeal soft tissues including palatine tonsil, soft palate, uvula, and tongue base. For this purpose, precise indentation experiments were conducted on freshly harvested human tissue samples accompanied by FE-based inversion schemes. To minimize the impact of the probable nonlinearities of the tested tissue samples, only the first quarter of the measured force-displacement data corresponding to the linear elastic regime was utilized in the FE-based inversion scheme to improve the accuracy of the tissue samples' Young's modulus calculations. Measured Young's moduli of the oropharyngeal soft tissues obtained in this study are presented. They include first estimates for palatine tonsil tissue samples while measured Young's moduli of other upper airway tissues were obtained for the first time using fresh human tissue samples.

Constructing a patient-specific computer model of the upper airway in sleep apnea patients.

OBJECTIVE: The use of computer simulation to develop a high-fidelity model has been proposed as a novel and cost-effective alternative to help guide therapeutic intervention in sleep apnea surgery. We describe a computer model based on patient-specific anatomy of obstructive sleep apnea (OSA) subjects wherein the percentage and sites of upper airway collapse are compared to findings on drug-induced sleep endoscopy (DISE). STUDY DESIGN: Basic science computer model generation. METHODS: Three-dimensional finite element techniques were undertaken for model development in a pilot study of four OSA patients. Magnetic resonance imaging was used to capture patient anatomy and software employed to outline critical anatomical structures. A finite-element mesh was applied to the volume enclosed by each structure. Linear and hyperelastic soft-tissue properties for various subsites (tonsils, uvula, soft palate, and tongue base) were derived using an inverse finite-element technique from surgical specimens. Each model underwent computer simulation to determine the degree of displacement on various structures within the upper airway, and these findings were compared to DISE exams performed on the four study patients. RESULTS: Computer simulation predictions for percentage of airway collapse and site of maximal collapse show agreement with observed results seen on endoscopic visualization. CONCLUSION: Modeling the upper airway in OSA patients is feasible and holds promise in aiding patient-specific surgical treatment. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:277-282, 2018.

Management of Psychosis in Parkinson's Disease: Emphasizing Clinical Subtypes and Pathophysiological Mechanisms of the Condition.

Investigation into neuropsychiatric symptoms in Parkinson's disease (PD) is sparse and current drug development is mainly focused on the motor aspect of PD. The tight association of psychosis with an impaired quality of life in PD, together with an important underreporting of this comorbid condition, contributes to its actual insufficient assessment and management. Furthermore, the withdrawal from access to readily available treatment interventions is unacceptable and has an impact on PD prognosis. Despite its impact, to date no standardized guidelines to the adequate management of PD psychosis are available and they are therefore highly needed. Readily available knowledge on distinct clinical features as well as early biomarkers of psychosis in PD justifies the potential for its timely diagnosis and for early intervention strategies. Also, its specific characterisation opens up the possibility of further understanding the underlying pathophysiological mechanisms giving rise to more targeted therapeutic developments in the nearer future. A literature review on the most recent knowledge with special focus on specific clinical subtypes and pathophysiological mechanisms will not only contribute to an up to date practical approach of this condition for the health care providers, but furthermore open up new ideas for research in the near future.

Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas.

Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs) are deadly and common cancers. Recent genomic studies implicate multiple genetic pathways, including cell signaling, cell cycle and immune evasion, in their development. Here we analyze public data sets and uncover a previously unappreciated role of epigenome deregulation in the genesis of 13% of HPV-negative HNSCCs. Specifically, we identify novel recurrent mutations encoding p.Lys36Met (K36M) alterations in multiple H3 histone genes. histones. We further validate the presence of these alterations in multiple independent HNSCC data sets and show that, along with previously described NSD1 mutations, they correspond to a specific DNA methylation cluster. The K36M substitution and NSD1 defects converge on altering methylation of histone H3 at K36 (H3K36), subsequently blocking cellular differentiation and promoting oncogenesis. Our data further indicate limited redundancy for NSD family members in HPV-negative HNSCCs and suggest a potential role for impaired H3K36 methylation in their development. Further investigation of drugs targeting chromatin regulators is warranted in HPV-negative HNSCCs driven by aberrant H3K36 methylation.

Spontaneous intrathyroidal hematoma causing airway obstruction: A case report.

INTRODUCTION: Spontaneous thyroid hemorrhage is a rare occurrence that results in pain, discomfort, and occasionally compressive symptoms. Infrequently, extensive thyroid hemorrhage can result in a rapidly expanding hematoma resulting in airway compromise. This is a case of an otherwise healthy young woman, 3 months postpartum, with a slowly expanding spontaneous thyroid hemorrhage that measured at 7 × 5.5 × 5 cm by computed tomography. She ultimately required intubation to manage respiratory distress and subsequently a hemithyroidectomy for definitive treatment. The case presentation is followed by a literature review where known etiologies of thyroid hematoma including traumatic and nontraumatic causes, precipitating anticoagulation, and spontaneous rupture of branches of the external carotid artery are outlined. The potential links to pregnancy are explored. The roles of bedside thyroid ultrasound in the emergency department and lateral neck roentgenogram in diagnosis are explored. The importance of airway management and indications for conservative versus surgical treatments are discussed. CONCLUSIONS: This is a case of a spontaneous intrathyroidal hemorrhage, which progressed over days to ultimately cause airway compromise. It is imperative that physicians are educated on the appropriate detection and management of the potentially life-threatening spontaneous thyroid hematoma.

Timing of endoscopic surgical decompression in traumatic optic neuropathy: a systematic review of the literature.

BACKGROUND: Traumatic optic neuropathy (TON) represents a rare but devastating complication of closed head injuries. No accepted guidelines are available for medical and surgical management algorithms. A systematic review of the literature was performed to determine the optimal timing and candidacy for endoscopic surgical intervention. METHODS: A systematic review of multiple databases was performed including Medline-Ovid, EMBASE, and PubMed. Data was extracted and patients stratified based on surgical delay from trauma (≤3 days, >3 days, ≤7 days, or >7 days) as well as preoperative and postoperative vision testing (no light perception [NLP]; light perception [LP]; hand motion [HM]; or finger counting [FC] or better). RESULTS: The literature review identified 24 studies meeting inclusion criteria. In the group of patients receiving surgery ≤3 days after the antecedent event, 57% (105/183) had visual improvement, whereas in the >7-days group 51% (145/283) of patients improved. In those with NLP preoperatively, 41% (172/411) saw improvement, whereas those with LP (89%), HM (93%), or FC (85%) fared better. CONCLUSION: The literature suggests that surgical intervention for TON is indicated despite delayed presentation, and is a better choice than no intervention at all. Patients with complete blindness on presentation (NLP) tend to have a poorer surgical outcome.

Ongoing activation of autoantigen-specific B cells in primary biliary cirrhosis.

UNLABELLED: The serologic hallmark of primary biliary cirrhosis (PBC), the antimitochondrial response to the E2 component of the pyruvate dehydrogenase complex (PDC-E2), has unique features, including continuous high titers of immunoglobulin M (IgM) and IgG reactivity throughout all stages of disease, capable not only of target enzyme inhibition, but also crossreactive with chemical xenobiotics that share molecular homology with the inner lipoyl domain of PDC-E2; such chemicals have been proposed as potential etiological agents. We used flow cytometry and enzyme-linked immunospot assay (ELISPOT) to examine B-cell subsets in 59 subjects, including 28 with PBC, 13 with primary sclerosing cholangitis (PSC), and 18 healthy controls. Strikingly, in PBC, although there were no significant differences in B-cell phenotype subpopulations, 10% of the total IgG and IgA plasmablast population and 23% of the IgM plasmablast population were uniquely reactive with PDC-E2, detected in the CXCR7+ CCR10low plasmablast population. In contrast, plasmablast reactivity to a control antigen, tetanus toxoid, was minimal and similar in all groups. Additionally, we isolated plasmablast-derived polyclonal antibodies and compared reactivity with plasma-derived antibodies and noted a distinct noncirculating tissue source of xenobiotic crossreacting antibodies. The high levels of autoantigen specific peripheral plasmablasts indicate recent activation of naive or memory B cells and a continuous and robust activation. The presence of CXCR7+ CCR10low PDC-E2-specific ASCs suggests a mechanistic basis for the migration of circulating antigen specific plasmablasts to the mucosal epithelial ligands CXCL12 and CCL28. CONCLUSION: Our findings suggest a sustained rigorous B-cell response in PBC, likely activated and perpetuated by cognate autoantigen.