Ethylene regulates auxin-mediated root gravitropic machinery and controls root angle in cereal crops.

Root angle is a critical factor in optimizing the acquisition of essential resources from different soil depths. The regulation of root angle relies on the auxin-mediated root gravitropism machinery. While the influence of ethylene on auxin levels is known, its specific role in governing root gravitropism and angle remains uncertain, particularly when Arabidopsis (Arabidopsis thaliana) core ethylene signaling mutants show no gravitropic defects. Our research, focusing on rice (Oryza sativa L.) and maize (Zea mays), clearly reveals the involvement of ethylene in root angle regulation in cereal crops through the modulation of auxin biosynthesis and the root gravitropism machinery. We elucidated the molecular components by which ethylene exerts its regulatory effect on auxin biosynthesis to control root gravitropism machinery. The ethylene-insensitive mutants ethylene insensitive2 (osein2) and ethylene insensitive like1 (oseil1), exhibited substantially shallower crown root angle compared to the wild type. Gravitropism assays revealed reduced root gravitropic response in these mutants. Hormone profiling analysis confirmed decreased auxin levels in the root tips of the osein2 mutant, and exogenous auxin (NAA) application rescued root gravitropism in both ethylene-insensitive mutants. Additionally, the auxin biosynthetic mutant mao hu zi10 (mhz10)/tryptophan aminotransferase2 (ostar2) showed impaired gravitropic response and shallow crown root angle phenotypes. Similarly, maize ethylene-insensitive mutants (zmein2) exhibited defective gravitropism and root angle phenotypes. In conclusion, our study highlights that ethylene controls the auxin-dependent root gravitropism machinery to regulate root angle in rice and maize, revealing a functional divergence in ethylene signaling between Arabidopsis and cereal crops. These findings contribute to a better understanding of root angle regulation and have implications for improving resource acquisition in agricultural systems.

Roles of auxin response factors in rice development and stress responses.

Auxin signalling plays a key role in various developmental processes ranging from embryogenesis to senescence in plants. Auxin response factor (ARF), a key component of auxin signalling, functions by binding to auxin response element within promoter of auxin response genes, activating or repressing the target genes. Increasing evidences show that ARFs are crucial for plant response to stresses. This review summarises the recent advance on the functions and their regulatory pathways of rice ARFs in development and responding to stresses. The importance of OsARFs is demonstrated by their roles in triggering various physiological, biochemical and molecular reactions to resist adverse environmental conditions. We also describe the transcriptional and post-transcriptional regulation of OsARFs, and discuss the major challenges in this area.

Clinical features of chronic hepatitis B patients with lean nonalcoholic fatty liver disease.

BACKGROUND: The clinical features have been well described in obese chronic hepatitis B (CHB) patients with nonalcoholic fatty liver disease (NAFLD). However, little is known about the clinical features of lean CHB-NAFLD patients. METHODS: The study retrospectively included treatment-naïve CHB patients who underwent ultrasound between 2015 and 2021. Liver fibrosis was assessed by aspartate aminotransferase (AST) to platelet ratio index (APRI), Fibrosis-4 score (FIB-4), NAFLD fibrosis score (NFS), and transient elastography. RESULTS: Among 1226 CHB-NAFLD patients, 25.0% patients were lean. The age, gender, and platelet, alanine aminotransferase, AST, and albumin levels were comparable between lean CHB-NAFLD and nonlean patients. The levels of plasma glucose, triglycerides, total cholesterol, and uric acid, as well as proportions of concurrent hypertension and diabetes, were lower in lean patients. Lean patients presented higher hepatitis B surface antigen (HBsAg) levels (3.4 log10 IU/ml vs. 3.2 log10 IU/ml, p = 0.006), hepatitis B virus (HBV) DNA levels (4.1 log10 IU/ml vs. 3.2 log10 IU/ml, p < 0.001), and hepatitis B e antigen (HBeAg) positive proportions (40.4% vs. 30.2%, p = 0.002) than nonlean patients. The values of APRI, FIB-4, and liver stiffness were comparable between two groups. However, lean patients had lower NFS values (-3.0 vs. -2.6, p < 0.001) and lower proportions (12.6% vs. 21.1%, p = 0.003) of advanced fibrosis (NFS ≥ -1.5) than nonlean patients. Similar results were observed in HBeAg-positive and HBeAg-negative subgroups. CONCLUSIONS: Nearly a quarter of CHB-NAFLD patients were lean. Lean patients had lower proportions of metabolic abnormalities and advanced liver fibrosis than nonlean patients. However, lean CHB-NAFLD patients had higher HBsAg levels, HBV DNA levels, and HBeAg-positive proportions. Registry and registration no. of the study/trial: Clinicaltrials.gov, Identifier: NCT03097952.

Neutrophil-to-lymphocyte ratio is associated with 28-day mortality in patients with severe fever with thrombocytopenia syndrome.

OBJECTIVES: To determine the association of the neutrophil-to-lymphocyte ratio (NLR) with 28-day mortality in patients with severe fever with thrombocytopenia syndrome (SFTS). METHODS: A single-centre retrospective analysis was performed in an emergency department from January 01, 2018, to June 30, 2021. Univariate and multivariable Cox proportional hazards regression models were used to investigate the prognostic factors associated with 28-day mortality. Kaplan-Meier curves were analysed in patients stratified by the optimal cut-off point of the NLR determined using a receiver operating characteristic (ROC) curve. RESULTS: In total, 182 SFTS patients were included, and 24 (13.2%) died within 28 days. The median age of the included patients was 59.64 ± 12.74 years, and 48.4% (88/182) were male. The patients in the non-survival group had significantly higher NLRs than those in the survival group (6.91 ± 6.73 vs. 2.23 ± 1.83). The NLR was a significant predictor of 28-day mortality (adjusted HR: 1.121, 95% CI: 1.033, 1.215). The area under the ROC curve of the NLR for predicting 28-day mortality was 0.743 (95% CI: 0.624, 0.862), and the optimal cut-off value was 4.19 (sensitivity, 54.2%; specificity, 89.2%). In addition, 28-day mortality in the patients with an NLR ≥ 4.19 was notably higher than that in the patients with an NLR < 4.19 (43.3% vs. 7.2%), and Kaplan-Meier analysis showed that the patients with an NLR ≥ 4.19 had a significantly lower survival rate than those with an NLR < 4.19. CONCLUSIONS: The NLR was a significant, independent predictor of 28-day mortality in SFTS patients.

Gadd45 in Preeclampsia.

Preeclampsia is a pregnancy-induced complex of multiple pathological changes. Numerous stresses during pregnancy, including hypoxia, immune activation, inflammatory cytokines, and oxidative stress were reported as contributing factors to the preeclamptic pathology. Seeking common sensors of various stressors in preeclampsia is of new interest and can potentially benefit in disease prevention and treatment. Recent studies have highlighted the role of the Gadd45a protein as a stress sensor in preeclampsia. In response to various pathophysiological stressors, notably hypoxia, oxidative stress, inflammatory cytokines, and AT1-AAs, Gadd45a activates Mkk3-p38 and or JNK signaling. This, in turn, results in immunological and inflammatory changes as well as triggering the production of circulating factors such as sFlt-1, which are believed to account for many of the pathophysiological-related symptoms of preeclampsia. Activation of inflammatory/immune responses in preeclampsia may function in a feedback loop to maintain elevated expression of Gadd45a protein.

Aqueous Rechargeable Li+ /Na+ Hybrid Ion Battery with High Energy Density and Long Cycle Life.

The practical application of aqueous rechargeable batteries is hampered by the low energy density and poor cycle stability, which mostly arises from the corrosion of cathode current collector, exfoliation of active material, and narrow electrochemical stability window of aqueous electrolyte. A light-weight and low-cost cathode current collector composed of graphite and carbon nanotube coated on nylon membrane exhibiting corrosion resistance and strong adhesion is developed. Also, a modified aqueous electrolyte with the addition of urea whose window is expanded to ≈3.2 V is developed that contributes to the formation of solid-electrolyte interphase on surfaces of electrodes. LiMn2 O4 /NaTi2 (PO4 )3 Li+ /Na+ hybrid ion battery using such aqueous electrolyte and current collector is demonstrated to cycle up to 10 000 times with low cost (60 dollars per kWh) and high energy density (100 Wh kg-1 ) for stationary energy storage and electronic vehicles applications.

A High-Energy and Long-Life Aqueous Zn/Birnessite Battery via Reversible Water and Zn2+ Coinsertion.

Aqueous rechargeable Zn/birnessite batteries have recently attracted extensive attention for energy storage system because of their low cost and high safety. However, the reaction mechanism of the birnessite cathode in aqueous electrolytes and the cathode structure degradation mechanics still remain elusive and controversial. In this work, it is found that solvation water molecules coordinated to Zn2+ are coinserted into birnessite lattice structure contributing to Zn2+ diffusion. However, the birnessite will suffer from hydroxylation and Mn dissolution with too much solvated water coinsertion. Through engineering Zn2+ primary solvation sheath with strong-field ligand in aqueous electrolyte, highly reversible [Zn(H2 O)2 ]2+ complex intercalation/extraction into/from birnessite cathode is obtained. Cathode-electrolyte interface suppressing the Mn dissolution also forms. The Zn metal anode also shows high reversibility without formation of "death-zinc" and detrimental dendrite. A full cell coupled with birnessite cathode and Zn metal anode delivers a discharge capacity of 270 mAh g-1 , a high energy density of 280 Wh kg-1 (based on total mass of cathode and anode active materials), and capacity retention of 90% over 5000 cycles.

Plateletcrit as a potential index for predicting liver fibrosis in chronic hepatitis B.

Noninvasive tests (NITs) for liver fibrosis are highly needed for chronic hepatitis B (CHB) patients. We aimed to investigate whether plateletcrit (PCT) could be used as a NIT in predicting liver fibrosis for CHB patients. Five hundred and sixty-seven treatment-naïve CHB patients with available liver biopsies were included. Patients were randomly divided into a derivation cohort (n = 378) and a validation cohort (n = 189). The diagnostic accuracy of PCT was evaluated using receiver operating characteristic (ROC) curves. In the derivation cohort, PCT in CHB patients with S2-S4 (0.14%), S3-S4 (0.13%) and S4 (0.12%) was lower than patients with S0-S1 (0.17%, P < .001), S0-S2 (0.17%, P < .001) and S0-S3 (0.16%, P < .001), respectively. PCT was an independent predictor of significant fibrosis (≥S2), advanced fibrosis (≥S3) and cirrhosis (S4). The area under the ROC curve (AUROC) of PCT in predicting significant fibrosis, advanced fibrosis and cirrhosis was 0.645, 0.709 and 0.714, respectively. The AUROC of PCT was higher than the aspartate transaminase to platelet ratio index (APRI) in identifying advanced fibrosis and cirrhosis, while this was comparable with APRI in identifying significant fibrosis. The diagnostic value of PCT was comparable with fibrosis-4 score (FIB-4) in predicting significant fibrosis, advanced fibrosis and cirrhosis. In the validation cohort, PCT could also identify significant fibrosis, advanced fibrosis and cirrhosis with similar diagnostic accuracy as in the derivation cohort. PCT represents a simple and inexpensive indictor for liver fibrosis in CHB patients. PCT is just as good or better than other more complex tools for staging liver fibrosis in CHB patients.

HBeAg Negativity Is Associated With More Advanced Liver Fibrosis in Patients With Chronic Hepatitis B: A Propensity Score-Matching Analysis.

BACKGROUND: Serum hepatitis B e antigen (HBeAg) status is associated with the progression of chronic hepatitis B (CHB). The authors aimed to investigate the relationship between HBeAg status and liver pathology in CHB patients. METHODS: A total of 683 treatment-naive CHB patients who had undergone liver biopsy were retrospectively enrolled from 2 medical centers. Propensity score-matching (PSM) method was performed to adjust the imbalance of baseline confounders between HBeAg-positive and HBeAg-negative CHB patients. RESULTS: HBeAg-negative CHB patients (n=338) exhibited more advanced liver fibrosis than HBeAg-positive CHB patients (n=345) before PSM (P<0.001). However, there were no significant differences in the distribution of inflammation grades between HBeAg-positive and HBeAg-negative CHB patients (P=0.051). Of these 683 CHB patients, 123 patients were included in each group after PSM. HBeAg-negative CHB patients still showed significantly advanced liver fibrosis as compared with HBeAg-positive CHB patients (P=0.03) after PSM. Furthermore, the distribution of liver inflammation grades in the HBeAg-negative CHB patients was also more severe than patients with HBeAg-positive (P=0.037). HBeAg-negative status was identified as an independent risk factor of significant liver fibrosis (P=0.011) by multivariate analysis. CONCLUSIONS: HBeAg negativity is associated with more advanced liver fibrosis in CHB patients.

IBR5 Regulates Leaf Serrations Development via Modulation of the Expression of PIN1.

Biodiversity in plant shape is mainly attributable to the diversity of leaf shape, which is largely determined by the transient morphogenetic activity of the leaf margin that creates leaf serrations. However, the precise mechanism underlying the establishment of this morphogenetic capacity remains poorly understood. We report here that INDOLE-3-BUTYRIC ACID RESPONSE 5 (IBR5), a dual-specificity phosphatase, is a key component of leaf-serration regulatory machinery. Loss-of-function mutants of IBR5 exhibited pronounced serrations due to increased cell area. IBR5 was localized in the nucleus of leaf epidermis and petiole cells. Introducing a C129S mutation within the highly conserved VxVHCx2GxSRSx5AYLM motif of IBR5 rendered it unable to rescue the leaf-serration defects of the ibr5-3 mutant. In addition, auxin reporters revealed that the distribution of auxin maxima was expanded ectopically in ibr5-3. Furthermore, we found that the distribution of PIN1 on the plasma membrane of the epidermal and cells around the leaf vein was compromised in ibr5-3. We concluded that IBR5 is essential for the establishment of PIN-FORMED 1 (PIN1)-directed auxin maxima at the tips of leaf serration, which is vital for the elaborated regulation during its formation.

First trimester noninvasive fetal RHD genotyping using maternal dried blood spots.

OBJECTIVE: This study was aimed to evaluate whether maternal dried blood spots could be a potential source for the noninvasive fetal RHD genotyping, serving as a combined one-step test for both the First Trimester Screen and the fetal RHD genotyping. METHOD: Both the maternal dried blood spots and the peripheral blood samples from 19 RhD-negative pregnant women were obtained during the First Trimester Screen. DNA was extracted and sequential real-time PCRs were performed to determine the fetal RHD genotypes. Fetal RhD serological types were obtained after delivery. This study was approved by the Institutional Review Board, and informed consents were obtained. RESULTS: A total of 19/19 fetal RHD genotyping with maternal DBS were consistent with the follow-up serological RhD test results after birth. Eleven were RhD positive, and eight were RhD negative (RHD deletion or RHD-CE-D = 6, RHD pseudogene = 1, RHDVI = 1). Sensitivity = 100%, specificity = 100%, positive predictive value = 100%, negative predictive value = 100%. A total of 18/19 fetal gender were determined correctly with maternal DBS. One female fetus was falsely determined as male. Sensitivity = 100%, specificity = 91.6%, positive predictive value = 87.5%, negative predictive value = 100%. CONCLUSION: Maternal dried blood spots, with the benefits of flexible sample transportation and processing, could be utilized for the noninvasive prenatal fetal RHD genotyping and potentially be incorporated into the routine First Trimester Screen. Larger scale study is in progress to implement fetal RHD genotyping in routine prenatal care. © 2017 John Wiley & Sons, Ltd.

Soluble CD40 ligand-activated B cells from patients with chronic hepatitis B virus infection as antigen presenting cells to induce hepatitis B virus specific cytotoxic T lymphocytes.

Chronic hepatitis B virus (HBV) infection is the result of an inadequate antiviral immune response to the virus. In this study, we aimed to investigate whether the soluble CD40 ligand-activated B (CD40-B) cells could present antigen and induce specific cytotoxic T lymphocytes (CTLs) in patients with chronic HBV infection. We observed that after activated by sCD40L, the expression of CD80, CD86, major histocompatibility complex (MHC) I and II molecules on the CD40-B cells was significantly increased. Cytometry and fluorescence microscopy showed that more than 41.34% CD40-B cells were loaded by the HBcAg peptide. Furthermore, after been activated and HBcAg18-27 antigen peptide pulsed, B cells obtained from patients with chronic HBV infection could induce HBcAg18-27 specific CTLs in vitro. Taken together, our results show that B cells from patients with chronic HBV infection can be activated by sCD40L and may function as antigen presenting cells and induce HBV-specific CTLs.

Red cell distribution width as a potential index to assess the severity of hepatitis B virus-related liver diseases.

AIM: To investigate the association between red cell distribution width (RDW) and the severity of hepatitis B virus (HBV)-related liver diseases. METHODS: Sixty-nine patients with chronic hepatitis B (CHB) and 61 patients with HBV-related liver cirrhosis were enrolled in the present study. Forty-one healthy individuals were included as controls. Hematological parameters, hepatitis B e-antigen (HBeAg) status, HBV DNA levels and liver biochemistry were analyzed. Child-Pugh scores and Model for End-Stage Liver Disease (MELD) scores of the patients with HBV-related liver cirrhosis were calculated. RESULTS: The RDW was significantly higher in patients with HBV-related liver cirrhosis as compared with CHB patients and healthy controls. RDW was slightly higher in CHB patients as compared with healthy controls. An increasing correlation of RDW with Child-Pugh grades was found. RDW was positively correlated with Child-Pugh scores and MELD scores. In patients with HBV-related liver cirrhosis, RDW was also positively correlated with total bilirubin and negatively correlated with hemoglobin and serum albumin concentration. However, no significant difference was found between HBeAg positive and negative patients and no significant correlation between RDW and HBV DNA levels was found. CONCLUSION: The RDW was elevated in CHB patients and patients with HBV-related liver cirrhosis and was positively correlated with the severity of HBV-related liver cirrhosis. RDW is a potential index to assess the severity of HBV-related liver diseases.

Root hairs facilitate rice root penetration into compacted layers.

Compacted soil layers adversely affect rooting depth and access to deeper nutrient and water resources, thereby impacting climate resilience of crop production and global food security. Root hair plays well-known roles in facilitating water and nutrient acquisition. Here, we report that root hair also contributes to root penetration into compacted layers. We demonstrate that longer root hair, induced by elevated auxin response during a root compaction response, improves the ability of rice roots to penetrate harder layers. This compaction-induced auxin response in the root hair zone is dependent on the root apex-expressed auxin synthesis gene OsYUCCA8 (OsYUC8), which is induced by compaction stress. This auxin source for root hair elongation relies on the auxin influx carrier AUXIN RESISTANT 1 (OsAUX1), mobilizing this signal from the root apex to the root hair zone. Mutants disrupting OsYUC8 and OsAUX1 genes exhibit shorter root hairs and weaker penetration ability into harder layers compared with wild type (WT). Root-hair-specific mutants phenocopy these auxin-signaling mutants, as they also exhibit an attenuated root penetration ability. We conclude that compaction stress upregulates OsYUC8-mediated auxin biosynthesis in the root apex, which is subsequently mobilized to the root hair zone by OsAUX1, where auxin promotes root hair elongation, improving anchorage of root tips to their surrounding soil environment and aiding their penetration ability into harder layers.

Association of liver function and prognosis in patients with severe fever with thrombocytopenia syndrome.

OBJECTIVES: Severe fever with thrombocytopenia syndrome (SFTS) is an epidemic emerging infectious disease with high mortality rate. We investigated the association between liver injury and clinical outcomes in patients with SFTS. METHODS: A total of 291 hospitalized SFTS patients were retrospectively included. Cox proportional hazards model was adopted to identify risk factors of fatal outcome and Kaplan-Meier curves were used to estimate cumulative risks. RESULTS: 60.1% of patients had liver injury at admission, and the median alanine transaminase, aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBil) levels were 76.4 U/L, 152.3 U/L, 69.8 U/L and 9.9 µmol/L, respectively. Compared to survivors, non-survivors had higher levels of AST (253.0 U/L vs. 131.1 U/L, P < 0.001) and ALP (86.2 U/L vs. 67.9 U/L, P = 0.006), higher proportion of elevated ALP (20.0% vs. 4.4%, P < 0.001) and liver injury (78.5% vs. 54.9%, P = 0.001) at admission. The presence of liver injury (HR 2.049, P = 0.033) at admission was an independent risk factor of fatal outcome. CONCLUSIONS: Liver injury was a common complication and was strongly associated with poor prognosis in SFTS patients. Liver function indicators should be closely monitored for SFTS patients.

Clinical outcomes of treatment-naïve HBeAg-negative patients with chronic hepatitis B virus infection with low serum HBsAg and undetectable HBV DNA.

Serum hepatitis B surface antigen (HBsAg) level < 100 IU/ml and undetectable hepatitis B virus (HBV) DNA have been recently proposed as an alternate endpoint of "partial cure" in chronic hepatitis B (CHB). We investigated clinical outcomes of hepatitis B e antigen (HBeAg)-negative CHB patients with HBsAg <100 IU/ml and undetectable HBV DNA. Treatment-naïve HBeAg-negative CHB patients with undetectable HBV DNA and normal alanine aminotransferase were retrospectively included from three institutions. Patients were classified into the low HBsAg group (<100 IU/ml) and the high HBsAg group (≥100 IU/ml). Liver fibrosis was evaluated by noninvasive tests (NITs). A total of 1218 patients were included and the median age was 41.5 years. Patients with low HBsAg were older (45.0 vs. 40.0 years, P < 0.001) than those in the high HBsAg group, while the NIT parameters were comparable between groups. During a median follow-up of 25.7 months, patients with low HBsAg achieved a higher HBsAg clearance rate (13.0% vs. 0%, P < 0.001) and a lower rate of significant fibrosis development (2.2% vs. 7.0%, P = 0.049) compared to patients with high HBsAg. No patient developed HCC in either group. HBsAg level was negatively associated with HBsAg clearance (HR 0.213, P < 0.001) and patients with HBsAg < 100 IU/ml had a low risk of significant fibrosis development (HR 0.010, P = 0.002). The optimal cutoff value of HBsAg for predicting HBsAg clearance was 1.1 Log10 IU/ml. Treatment-naïve HBeAg-negative CHB patients with HBsAg <100 IU/ml and undetectable HBV DNA had favourable outcomes with a high rate of HBsAg clearance and a low risk of fibrosis progression.

Preeclampsia-associated stresses activate Gadd45a signaling and sFlt-1 in placental explants.

Accumulating evidence suggests that placental stresses during pregnancy can play an important role in the pathogenesis of preeclampsia. A common signal pathway that senses and converts placental stresses into intracellular stress response may be contributing to this pathology. Based on our previous findings, we extended our investigation to establish that Gadd45a stress signaling regulates sFlt-1 levels, particularly in placenta, when exposed to various preeclampsia-associated stresses including AT-1 receptor agonist (Angiotensin II), hypoxia, and inflammatory cytokines. Using a placental explant model, we found that Gadd45a was induced in response to all the preeclampsia stresses stated above. Although stress induced Gadd45a was associated with the activation of its downstream effectors phospho-p38 and phospho-JNK, the subsequent regulation of sFlt-1 levels occurred through either one of these effectors, but not both. These observations indicate that Gadd45a signaling may work as a hub connecting placental stresses and the pathogenesis of preeclampsia. It also provides evidence to justify testing the role of Gadd45 in the etiology of preeclampsia using in vivo mouse (i.e., Gadd45a null mice) models.

Gadd45 stress sensors in preeclampsia.

Preeclampsia is a pregnancy-induced complex of multiple pathological changes. Numerous stresses during pregnancy, including hypoxia, immune activation, inflammatory cytokines, and oxidative stress were reported as contributing factors to the preeclamptic pathology. Seeking common sensors of various stressors in preeclampsia is of new interest and can potentially benefit in disease prevention and treatment. Recent studies have highlighted the role of the Gadd45a protein as a stress sensor in preeclampsia. In response to various pathophysiological stressors, notably hypoxia, inflammatory cytokines, and AT1-AAs, Gadd45a activates Mkk3-p38 and or JNK signaling. This, in turn, results in immunological and inflammatory changes as well as triggering the production of circulating factors such as sFlt-1, which are believed to account for many of the pathophysiological-related symptoms of preeclampsia. Activation of inflammatory/immune responses in preeclampsia may function in a feedback loop to maintain elevated expression of Gadd45a protein.

An easy-to-use AIHF-nomogram to predict advanced liver fibrosis in patients with autoimmune hepatitis.

Background: The evaluation of liver fibrosis is essential in the management of patients with autoimmune hepatitis (AIH). We aimed to establish and validate an easy-to-use nomogram to identify AIH patients with advanced liver fibrosis. Methods: AIH patients who underwent liver biopsies were included and randomly divided into a training set and a validation set. The least absolute shrinkage and selection operator (LASSO) regression was used to select independent predictors of advanced liver fibrosis from the training set, which were utilized to establish a nomogram. The performance of the nomogram was evaluated using the receiver characteristic curve (ROC), calibration curve, and decision curve analysis (DCA). Results: The median age of 235 patients with AIH was 54 years old, with 83.0% of them being female. Six independent factors associated with advanced fibrosis, including sex, age, red cell distribution width, platelets, alkaline phosphatase, and prothrombin time, were combined to construct a predictive AIH fibrosis (AIHF)-nomogram. The AIHF-nomogram showed good agreement with real observations in the training and validation sets, according to the calibration curve. The AIHF-nomogram performed significantly better than the fibrosis-4 and aminotransferase-to-platelet ratio scores in the training and validation sets, with an area under the ROCs for predicting advanced fibrosis of 0.804 in the training set and 0.781 in the validation set. DCA indicated that the AIHFI-nomogram was clinically useful. The nomogram will be available at http://ndth-zzy.shinyapps.io/AIHF-nomogram/as a web-based calculator. Conclusions: The novel, easy-to-use web-based AIHF-nomogram model provides an insightful and applicable tool to identify AIH patients with advanced liver fibrosis.

Dynamic SARS-CoV-2-specific B-cell and T-cell responses following immunization with an inactivated COVID-19 vaccine.

OBJECTIVE: The dynamic adaptive immune responses elicited by the inactivated virus vaccine CoronaVac remain elusive. METHODS: In a prospective cohort of 100 healthcare professionals naïve for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who received two doses of CoronaVac, we analysed SARS-CoV-2-specific humoral and cellular responses at four different timepoints, including before vaccination (T1), 2 weeks after the first dose (T2), 2 weeks after the booster dose (T3), and 8-10 weeks after the booster dose (T4). SARS-CoV-2-specific antibodies, serum neutralizing activities, peripheral B cells, CD4+ and CD8+ T cells and their memory subsets were simultaneously measured in this cohort. RESULTS: SARS-CoV-2 spike-specific IgG responses reached a peak (geometric mean titre (GMT) 54827, 30969-97065) after two doses and rapidly declined (GMT 502, 212-1190) at T4, whereas suboptimal IgA responses were detected (GMT 5, 2-9). Spike-specific circulating B cells (0.60%, 0.46-0.73% of total B cells) and memory B cells (1.18%, 0.92-1.44% of total memory B cells) were effectively induced at T3 and sustained over time (0.33%, 0.23-0.43%; 0.87%, 0.05-1.67%, respectively). SARS-CoV-2-specific circulating CD4+ T cells (0.57%, 0.47-0.66%) and CD8+ T cells (1.29%, 1.04-1.54%) were detected at T3. At T4, 0.78% (0.43-1.20%) of memory CD4+ T cells and 0.68% (0.29-1.30%) of memory CD8+ T cells were identified as SARS-CoV-2-specific, while 0.62% (0.51-0.75%) of CD4+ T cells and 0.47% (0.38-0.58%) of CD8+ T cells were SARS-CoV-2-specific terminally differentiated effector memory cells. Furthermore, age and interval between doses affected the magnitude of CoronaVac-induced immune responses. SARS-CoV-2 memory CD4+ T cells were strongly associated with both receptor binding domain (RBD)-specific memory B cells (r 0.87, p <0.0001) and SARS-CoV-2-specific memory CD8+ T cells (r 0.48, p <0.0001). CONCLUSIONS: CoronaVac induced robust circulating and memory B cell and T cell responses. Our study offers new insight into the underlying immunobiology of inactivated virus vaccines in humans and may have implications for vaccine strategies in the future.