The AaERF64-AaTPPA module participates in cold acclimatization of Actinidia arguta (Sieb. et Zucc.) Planch ex Miq.

Actinidia arguta (A. arguta, kiwiberry) is a perennial deciduous vine with a strong overwintering ability. We hypothesized that trehalose metabolism, which plays a pivotal role in the stress tolerance of plants, may be involved in the cold acclimatization of A. arguta. Transcriptome analysis showed that the expression of AaTPPA, which encodes a trehalose-6-phosphate phosphatase (TPP), was upregulated in response to low temperatures. AaTPPA expression levels were much higher in lateral buds, roots, and stem cambia than in leaves in autumn. In AaTPPA-overexpressing (OE) Arabidopsis thaliana (A. thaliana), trehalose levels were 8-11 times higher than that of the wild type (WT) and showed different phenotypic characteristics from WT and OtsB (Escherichia coli TPP) overexpressing lines. AaTPPA-OE A. thaliana exhibited significantly higher freezing tolerance than WT and OtsB-OE lines. Transient overexpression of AaTPPA in A. arguta leaves increased the scavenging ability of reactive oxygen species (ROS) and the soluble sugar and proline contents. AaERF64, an ethylene-responsive transcription factor, was induced by ethylene treatment and bound to the GCC-box of the AaTPPA promoter to activate its expression. AaTPPA expression was also induced by abscisic acid. In summary, the temperature decrease in autumn is likely to induce AaERF64 expression through an ethylene-dependent pathway, which consequently upregulates AaTPPA expression, leading to the accumulation of osmotic protectants such as soluble sugars and proline in the overwintering tissues of A. arguta. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01475-8.

Vitamin D Deficiency and the Presentation of Primary Hyperparathyroidism: A Mini Review.

The clinical presentation of primary hyperparathyroidism (PHPT) has evolved over the years from a symptomatic disorder to a predominantly asymptomatic condition. Altered vitamin D metabolism seems to play a role in the presentation of PHPT and may exacerbate the severity of disease. The epidemiology of PHPT differs in the developing versus the developed world, where more severe phenotypes occur in regions where vitamin D deficiency is common. Although it has been validated that patients with PHPT should be vitamin D sufficient, the threshold to supplement in relation to the severity of PHPT and the degree of vitamin D deficiency remains controversial. This review will highlight some of the controversy regarding vitamin D deficiency and the different phenotypes of PHPT.

Use of Patient-Reported Outcomes for Assessing Diabetes Outcomes.

The treatment of diabetes can be complex and overwhelming for patients as it demands persistent attention to lifestyle management, adherence to medications, monitoring of side effects of drugs, and management of devices for glucose monitoring and/or insulin infusion. Therefore, understanding patient-reported outcomes (PROs) that provide direct insight into the patient's experience with diabetes is crucial for optimizing diabetes management.This review provides an overview of commonly used PRO questionnaires that assess different aspects of diabetes management.

Pyrite bio-leachate, mine wastewater can sterilize the rice (Oryza sativa L.) seeds and promote the germination.

We developed the way to use pyrite bio-leachate (PBL), the wastewater of bioleaching of refractory gold ore in agriculture. PBL contains high amount of iron and at certain concentration, iron has toxicity on microorganisms. Therefore PBL can be used for rice seed sterilization. Method 1 is soaking rice seeds in 100%, 10%, and 2% PBL for 1, 2, 3, and 4 days (25℃) and drying them. Method 2 is soaking rice seeds in 100%, 10%, and 2% PBL for 30 min, 60 min, and 120 min (25℃), wetting for 2 days under the shade and drying for 5 days. Method 1 with 100%, 10%, and 2% PBL did not sterilize rice seeds completely. Method 2 with 100% and 10% PBL showed the complete sterilization effect and enhanced the germination of rice seeds in any soaking time. Similar results were achieved in seedbed experiments. PBL which has serious potential to pollute the environment can be used for rice seed sterilization. Soaking rice seeds in 100% and 10% PBL for 30 min, 60 min, and 120 min (25℃), wetting for 2 days under the shade and drying them for 5 days, can sterilize the rice seeds completely and enhance the germination.

Preoperative differentiation of hypophysitis and pituitary adenomas using a novel clinicoradiologic scoring system.

PURPOSE: Hypophysitis can clinically and radiologically mimic other nonfunctioning masses of the sella turcica, complicating preoperative diagnosis. While sellar masses may be treated surgically, hypophysitis is often treated medically, so differentiating between them facilitates optimal management. The objective of our study was to develop a scoring system for the preoperative diagnosis of hypophysitis. METHODS: A thorough literature review identified published hypophysitis cases, which were compared to a retrospective group of non-functioning pituitary adenomas (NFA) from our institution. A preoperative hypophysitis scoring system was developed and internally validated. RESULTS: Fifty-six pathologically confirmed hypophysitis cases were identified in the literature. After excluding individual cases with missing values, 18 hypophysitis cases were compared to an age- and sex-matched control group of 56 NFAs. Diabetes insipidus (DI) (p < 0.001), infundibular thickening (p < 0.001), absence of cavernous sinus invasion (CSI) (p < 0.001), relation to pregnancy (p = 0.002), and absence of visual symptoms (p = 0.007) were significantly associated with hypophysitis. Stepwise logistic regression identified DI and infundibular thickening as positive predictors of hypophysitis. CSI and visual symptoms were negative predictors. A 6-point hypophysitis-risk scoring system was derived: + 2 for DI, + 2 for absence of CSI, + 1 for infundibular thickening, + 1 for absence of visual symptoms. Scores ≥ 3 supported a diagnosis of hypophysitis (AUC 0.96, sensitivity 100%, specificity 75%). The scoring system identified 100% of hypophysitis cases at our institution with an estimated 24.7% false-positive rate. CONCLUSIONS: The proposed scoring system may aid preoperative diagnosis of hypophysitis, preventing unnecessary surgery in these patients.

Incidence and Survival Outcomes of Colorectal Cancer in Long-Term Metformin Users with Diabetes: A Population-Based Cohort Study Using a Common Data Model.

BACKGROUND AND AIMS: Previous studies have reported that metformin use in patients with diabetes mellitus may reduce the risk of colorectal cancer (CRC) incidence and prognosis; however, the evidence is not definite. This population-based cohort study aimed to investigate whether metformin reduces the risk of CRC incidence and prognosis in patients with diabetes mellitus using a common data model of the Korean National Health Insurance Service database from 2002 to 2013. METHODS: Patients who used metformin for at least 6 months were defined as metformin users. The primary outcome was CRC incidence, and the secondary outcomes were the all-cause and CRC-specific mortality. Cox proportional hazard model was performed and large-scaled propensity score matching was used to control for potential confounding factors. RESULTS: During the follow-up period of 81,738 person-years, the incidence rates (per 1000 person-years) of CRC were 5.18 and 8.12 in metformin users and non-users, respectively (p = 0.001). In the propensity score matched cohort, the risk of CRC incidence in metformin users was significantly lower than in non-users (hazard ratio (HR), 0.58; 95% CI (confidence interval), 0.47-0.71). In the sensitivity analysis, the lag period extending to 1 year showed similar results (HR: 0.63, 95% CI: 0.51-0.79). The all-cause mortality was significantly lower in metformin users than in non-users (HR: 0.71, 95% CI: 0.64-0.78); CRC-related mortality was also lower among metformin users. However, there was no significant difference (HR: 0.55, 95% CI: 0.26-1.08). CONCLUSIONS: Metformin use was associated with a reduced risk of CRC incidence and improved overall survival.

Hepatitis B Core-Related Antigen Is Useful for Predicting Phase and Prognosis of Hepatitis B e Antigen-Positive Patients.

The role of hepatitis B core-related antigen (HBcrAg) level in defining clinical phase and predicting prognosis of chronic hepatitis B (CHB) has not been fully studied. CHB patients who had undergone liver biopsy in Korea University Medical Center were included. Patients with liver cirrhosis were excluded. The associations of HBcrAg level with CHB phase, and nucleos(t)ide analogue (NA)-induced hepatitis B e antigen (HBeAg) seroconversion were analyzed. In total, 387 patients (median follow-up of 82.4 months) were included. The CHB phases of patients were defined histologically as immune-tolerant (IT, n = 32, 8.3%), HBeAg-positive and immune-active (PIA, n = 211, 54.5%), HBeAg-negative and immune-active (n = 125, 32.3%), and inactive (n = 19, 4.9%), respectively. In HBeAg-positive patients, the mean HBV DNA levels were comparable between the two groups (p = 0.990). However, the mean HBsAg (7.4 log IU/mL and 6.9 log IU/mL, p = 0.002) and HBcrAg levels (8.2 log U/mL vs. 7.6 log U/mL, p < 0.001) of IT patients were significantly higher than that of PIA patients. In multivariate analysis, younger age (odds ratio [OR] 0.949, p = 0.025), lower alanine aminotransferase (OR 0.988, p = 0.002) and higher HBcrAg level (OR = 2.745 p = 0.022) were independent predictors of the IT phase. Of the patients in the PIA phase, 194 received NA after liver biopsy, and 61 (31.4%) had achieved HBeAg seroconversion after antiviral therapy. In Cox regression analysis, the higher HBcrAg level was the only independent predictor of the NA-induced HBeAg seroconversion (hazard ratio 1.285, p = 0.028). The HBcrAg level is useful for predicting clinical phase of CHB and NA-induced HBeAg seroconversion in HBeAg-positive patients.

Superior thermoelectric properties of ternary chalcogenides CsAg5Q3 (Q = Te, Se) predicted using first-principles calculations.

Tailoring novel thermoelectric materials (TEMs) with a high efficiency is challenging due to the difficulty in realizing both low thermal conductivity and high thermopower factor. In this work, we propose ternary chalcogenides CsAg5Q3 (Q = Te, Se) as promising TEMs based on first-principles calculations of their thermoelectric properties. Using lattice dynamics calculations within self-consistent phonon theory, we predict their ultralow lattice thermal conductivities below 0.27 W m-1 K-1, revealing the strong lattice anharmonicity and rattling vibrations of Ag atoms as the main origination. By using the mBJ exchange-correlation functional, we calculate the electronic structures with the direct band gaps in good agreement with experiments, and evaluate the charge carrier lifetime as a function of temperature within the deformation potential theory. Our calculations to solve Boltzmann transport equations demonstrate high thermopower factors of 2.5 mW m-1 K-2 upon p-type doping at 300 K, comparable to the conventional dichalcogenide thermoelectric GeTe. With these ultralow thermal conductivities and high thermopower factors, we determine a relatively high thermoelectric figure of merit ZT along the z-axis, finding the maximum value of ZTz to be 2.5 at 700 K for CsAg5Se3 by optimizing the hole concentration. Our computational results highlight the great potentiality of CsAg5Q3 (Q = Te, Se) for high-performance thermoelectric devices operating at room temperature.

Combination of intramuscular transplantation of autologous mononuclear bone marrow cells with sympathectomy (L2, 3) in patients with peripheral arterial disease(PAD).

BACKGROUND: In most patients with severe, chronic extremity ischemic diseases, intervention or surgical treatment is often not suitable. Combination of intramuscular transplantation of autologous monocular bone marrow cells (AMBMCs) and sympathectomy (L2, 3) has been proved therapeutically beneficial. METHODS: We studied 170 patients (combined group 80, control group 90) with extremity ischemia (TAO, ASO FontaineⅡ,Ⅲ, Ⅳ) between January 2013 and September 2019. RESULTS: In contrast to pre-operation, the walking distance of patients increased significantly (from 61.34 ± 52.23 m to 156.0 ± 32.4 m, p < 0.01), and the ankle-brachial index (ABI) remarkably improved (from 0.28 ± 0.13 to 0.59 ± 0.23, p < 0.05). CONCLUSION: Combined therapy is feasible and effective for patients with peripheral arterial disease (PAD).

Radiology report language positively influences adrenal incidentaloma guideline adherence.

BACKGROUND: Adrenal incidentalomas are common radiographic findings. Guidelines recommend biochemical and radiographic surveillance of adrenal incidentalomas. We investigated if patients were appropriately referred for outpatient evaluation. METHODS: Retrospective chart review was performed to identify patients with adrenal masses on imaging between November 7, 2016 and November 7, 2017. Demographic information, medical history, and outpatient referral information was collected. RESULTS: 11,723 computed tomography (CT) scans of the chest and/or abdomen/pelvis were performed. 246 patients were noted to have adrenal incidentalomas and met inclusion criteria. The CT report recommended follow-up in 63/246 cases (25.6%). 38/246 (15.4%) patients were referred for evaluation. Age, adrenal nodule size, and type of evaluating provider did not affect referral. A radiology report recommending follow-up was associated with increased referral rate (OR 5.441, 95% CI: 2.491-11.887). CONCLUSION: There was low outpatient referral for adrenal incidentalomas. Language in the radiology report significantly influenced referral rates and may be an important resource for improving guideline adherence.

Aspirin, metformin, and statin use on the risk of gastric cancer: A nationwide population-based cohort study in Korea with systematic review and meta-analysis.

BACKGROUND/AIMS: Although several chemopreventive drugs against gastric cancer have been proposed, their effects have not been fully evaluated. We examined the impacts of aspirin, metformin, and statin use on gastric cancer development in a population-based cohort in Korea. METHODS: We analyzed the association between potential chemopreventive drugs-aspirin, metformin, and statin-and gastric cancer through the Observational Medical Outcomes Partnership Common Data Model-based Korean nationwide cohort. Use of aspirin, metformin, and statin was defined by ≥365 days of prescriptions for each drug in the general population. To summarize the current evidence, we further performed a systematic review and meta-analysis of the impact of aspirin, metformin, and statin on gastric cancer development. RESULTS: After propensity score matching, 31,839, 6764, and 10,251 subjects were observed for medians of 4.7, 4.2, and 4.2 years for aspirin, metformin, and statin analysis, respectively. Use of aspirin or statin was associated with lower risks of gastric cancer compared to their non-use, respectively (hazard ratio [HR] [95% confidence interval [CI]]: aspirin, 0.72 [0.60-0.85], p < 0.01; statin, 0.67 [0.49-0.92], p = 0.01). However, no association was observed between metformin use and gastric cancer development (HR [95% CI]: 0.85 [0.59-1.23], p = 0.40). A subgroup of subjects with diabetes mellitus showed a lower risk of gastric cancer development with statin use. The meta-analysis showed the highest effect size of gastric cancer development for statin, followed by aspirin and metformin. CONCLUSIONS: Statin and aspirin use were associated with significantly reduced risks of gastric cancer development, while the use of metformin was not associated with the gastric cancer risk. The protective effect of statin against gastric cancer was also significant in patients with diabetes mellitus.

Current laboratory tests for diagnosis of hepatitis B virus infection.

BACKGROUND: Hepatitis B virus (HBV) has a long history in human infectious diseases. HBV infection can progress chronically, leading to cancer. After introduction of a vaccine, the overall incidence rate of HBV infection has decreased, although it remains a health problem in many countries. PURPOSE: The aim of this review was to summarise current diagnostic efforts for HBV infection and future HBV diagnosis perspectives. METHODS: We reviewed and summarised current laboratory diagnosis related with HBV infection in clinical practice. RESULTS: There have been various serologic- and molecular-based methods to diagnose acute or chronic HBV infection. Since intrahepatic covalently closed circular DNAs (cccDNAs) function as robust HBV replication templates, cure of chronic HBV infection is limited. Recently, new biomarkers such as hepatitis B virus core-related antigen (HBcrAg) and HBV RNA have emerged that appear to reflect intrahepatic cccDNA status. These new biomarkers should be validated before clinical usage. CONCLUSION: An effective diagnostic approach and current updated knowledge of treatment response monitoring are important for HBV infection management. Brand new ultrasensitive and accurate immunologic methods may pave the way to manage HBV infection in parallel with immunotherapy era.

Comparative evaluation of Elecsys, Atellica, and Alinity assays for measuring the anti-Hepatitis C virus (HCV) antibody.

BACKGROUND: Hepatitis C virus (HCV) infection is a major cause of liver diseases in Korea. Anti-HCV assays are used to screen for HCV infection. Here, we assessed the agreement and diagnostic performances of three different anti-HCV assays. METHODS: We analyzed 1180 samples using three assay systems-Elecsys Anti-HCV II (Roche Diagnostics), Atellica IM aHCV (Siemens Healthineers), and Alinity s Anti-HCV (Abbott Diagnostics)-and evaluated the agreements between the results and diagnostic performances. RESULTS: The Cohens kappa coefficients between the Roche and Siemens, Siemens and Abbott, and Roche and Abbott systems were 0.837, 0.961, and 0.849, respectively. The Fleiss kappa coefficient among the three systems was 0.883. The sensitivities and positive predictive values were 86.5 and 89.8 for Roche, 97.5 and 98.1 for Siemens, and 99.4 and 98.2 for Abbott, respectively. The area under the curves of the anti-HCV signal to cutoff (S/Co) ratios or cutoff index for predicting viremia in the Roche, Siemens, and Abbott systems were 0.432, 0.641, and 0.676, respectively; the optimal S/Co ratio was 14.715 for Siemens and 14.42 for Abbott. CONCLUSIONS: All three assays showed excellent diagnostic performance; however, anti-HCV values need to be used with caution to predict viremia; therefore, supplementary tests are necessary to confirm viremia status, especially for samples with low values.

Effects of Nature-Based Group Art Therapy Programs on Stress, Self-Esteem and Changes in Electroencephalogram (EEG) in Non-Disabled Siblings of Children with Disabilities.

The purpose of the present study was to examine changes in brain waves, stress, and self-esteem after a continuous eight-week nature-based art therapy program in the forest in non-disabled siblings of children with disabilities. A total of 29 participants participated in this study (art therapy program group, n = 18; control group, n = 11). The art therapy program group received eight weekly sessions of art therapy lasting 60 min each. Pre- and post-test results showed positive changes in the brain function index and stress levels of the participants in the art therapy program group. On the self-esteem scale, overall and social self-esteem increased significantly. In conclusion, creative activities in the forest can increase resistance to diseases through mechanisms that relieve stress and increase self-esteem. If art therapy that emphasizes somatosensory experience, creative expression, and self-motivation is accompanied by forest activities, this combined intervention can elicit positive physical and psychological changes.

Comparison of two ß-D-glucan assays for detecting invasive fungal diseases in immunocompromised patients.

(1-3)-ß-D-glucan (BDG) is a major biomarker of invasive fungal diseases (IFDs), which are life-threatening for immunodeficient patients. We compared the clinical performance of two BDG-detection assays. The precision, linearity, reference interval, and limit of quantitation of the Wako BDG assay were analyzed and the performance was compared with that of the Goldstream BDG assay using 272 clinical serum samples. The repeatability, within-laboratory imprecision, and limit of quantitation of the Wako BDG assay were 3.8%, 5.9%, and 7.35 pg/mL, respectively (linearity, 23.8-557 pg/mL; R2 = 0.998). The correlation coefficient, slope, and y-intercept for the Wako BDG assay versus Goldstream BDG assay were 0.29, 3.82, and 0.04, respectively. The sensitivity and specificity were 43.8% and 94.9% for the Wako BDG assay and 39.6% and 83.5% for the Goldstream BDG assay, respectively. In clinical settings, the Wako BDG assay is suitable for diagnosing patients with IFDs.

Comparison of antinuclear antibody profiles obtained using line immunoassay and fluorescence enzyme immunoassay.

OBJECTIVE: LIA-ANA-Profile-17S is a multiplex line immunoassay that simultaneously detects 17 antinuclear antibodies (ANAs) against extractable nuclear antigens (ENAs). We evaluated the utility of LIA-ANA-Profile-17S as a supplement to ANA indirect immunofluorescence (IIF) and EliA ENA (a fluorescence enzyme immunoassay) for diagnosis of ANA-associated rheumatic diseases. METHODS: Sera were collected from 245 patients referred for an ANA IIF test. LIA-ANA-Profile-17S results were compared with those of EliA ENA. The kappa coefficients, agreement rates, and diagnostic performance of these tests were assessed for systemic lupus erythematosus (SLE) and Sjögren's syndrome (SjS). RESULTS: We observed almost perfect interassay agreement for antibodies against Ro52/Ro60, CENP-B, and Scl-70 (kappa = 0.91, 0.97, and 1.00, respectively); strong agreement for anti-SS-B/La antibody (kappa = 0.81); and relatively low agreement for other antibodies, including those against dsDNA, Sm, RNP, and Jo-1. For SLE diagnosis, LIA-ANA-Profile-17S showed lower sensitivity and similar specificity compared with EliA ENA. The sensitivity and specificity of these two assays were similar for SjS diagnosis. CONCLUSIONS: The specificity of LIA-ANA-Profile-17S was enhanced when combined with ANA IIF and was comparable with that of EliA ENA. LIA-ANA-Profile-17S showed relatively good agreement with EliA ENA. In combination with ANA IIF, these assays showed enhanced diagnostic performance.

False-positive reactivity of anti-human leukocyte antigen antibodies detected using the single-antigen bead assay.

The single-antigen bead assay (SABA) demonstrates high sensitivity and specificity for detecting anti-human leukocyte antigen (HLA) antibodies. However, SABA may produce false-positive results for anti-HLA antibodies. Herein, we analyzed the data of patients with complement-dependent cytotoxic crossmatch-/flow cytometric crossmatch-/SABA+/- results to determine false-positive results for anti-HLA antibodies. We also determined the prevalence of false-positive results by comparing false-positive data from our laboratory and national allele frequency data obtained with high-resolution HLA typing. For HLA-A, -B, -C, and -DR, a ratio of positive frequency to allele frequency of ≥3 in our laboratory was considered a false-positive result. For HLA-DQA1/DQB1 and HLA-DPA1/DPB1, we considered the positive frequency of ≥3 as a false positive result due to lack of haplotype frequency data. SABA results from 284 patients (78.0%) demonstrated false reactivity. The antibody against HLA-C*17:01 displayed the highest frequency ratio (298.3). If false-positive reactivity is suspected, results should be confirmed using different methods. If confirmation tests are unfeasible, comparing the allele frequency with the positive rate of detected anti-HLA antibodies and using a ratio ≥3 may facilitate the interpretation of SABA results. The positive rate of anti-HLA antibodies can be validated using the HLA allele frequency of the population to determine false-positive results.

Expanding the Non-Invasive Diagnosis of Acute Rejection in Kidney Transplants Through Detection of Donor-Derived DNA in Urine: Proof-of-Concept Study.

BACKGROUND: Approximately 10%-20% of kidney transplant (KT) recipients suffer from acute rejection (AR); thus, sensitive and accurate monitoring of allograft status is recommended. We evaluated the clinical utility of donor-derived DNA (dd-DNA) detection in the urine of KT recipients as a non-invasive means for diagnosing AR. METHODS: Urine samples serially collected from 39 KT recipients were tested for 39 single-nucleotide variant loci selected according to technical criteria (i.e., high minor allele frequency and low analytical error) using next-generation sequencing. The fraction of dd-DNA was calculated and normalized by the urine creatinine (UCr) level (%dd-DNA/UCr). The diagnostic performance of %dd-DNA/UCr for AR was assessed by ROC curve analysis. RESULTS: There was an increasing trend of %dd-DNA/UCr in the AR group before subsequent graft injury, which occurred before (median of 52 days) histological rejection. The serum creatinine (SCr) level differed significantly between the AR and non-AR groups at two and four months of follow-up, whereas %dd-DNA/UCr differed between the groups at six months of follow-up. The combination of %dd-DNA/UCr, SCr, and spot urine protein (UPtn)/UCr showed high discriminating power, with an area under the ROC curve of 0.93 (95% confidence interval: 0.81-1.00) and a high negative predictive value of 100.0%. CONCLUSIONS: Although the dd-DNA-based test cannot eliminate the need for biopsy, the high negative predictive value of this marker could increase the prebiopsy probability of detecting treatable injury to make biopsy an even more effective diagnostic tool.

Investigation of Basophil Activation Test for Diagnosing Milk and Egg Allergy in Younger Children.

In children with concomitant food allergy and atopic dermatitis (AD), uncovering the causative food allergen is more arduous. We evaluated the basophil activation test (BAT) for its diagnostic value in children, including those with AD, for milk or egg allergy. We simultaneously measured serum-specific immunoglobulin E (sIgE) levels and performed BATs for cow's milk and egg white. We compared their overall diagnostic performance using the area under the receiver operating characteristic curve (AUC) with the Delong method and compared them in children with AD. Analyses were completed for 75 children for milk allergy and for 85 children for egg allergy. The sIgE and percentage of basophils with the expression of CD63 were correlated for both milk (r = 0.384, p < 0.001) and egg (r = 0.557, p < 0.001). The AUC of sIgE (0.701) for milk allergy was significantly increased when combined with the BAT (0.805; p = 0.029). In children with AD, the AUC of the BAT (0.924) for milk allergy was significantly larger than that of sIgE (0.701; p = 0.017). The BAT is a potentially useful diagnostic tool for milk allergy in children when combined with sIgE. Moreover, it may be a surrogate marker for milk allergy in children with AD.

Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop.

Activin A functions in BMP signaling in two ways: it either engages ACVR1B to activate Smad2/3 signaling or binds ACVR1 to form a non-signaling complex (NSC). Although the former property has been studied extensively, the roles of the NSC remain unexplored. The genetic disorder fibrodysplasia ossificans progressiva (FOP) provides a unique window into ACVR1/Activin A signaling because in that disease Activin can either signal through FOP-mutant ACVR1 or form NSCs with wild-type ACVR1. To explore the role of the NSC, we generated 'agonist-only' Activin A muteins that activate ACVR1B but cannot form the NSC with ACVR1. Using one of these muteins, we demonstrate that failure to form the NSC in FOP results in more severe disease pathology. These results provide the first evidence for a biological role for the NSC in vivo and pave the way for further exploration of the NSC's physiological role in corresponding knock-in mice.