Analogue Treatment Research Articles

Modulating surface properties of Mn-Fe nanocube-like catalyst to activate peroxymonosulfate for effective benzalkonium chloride degradation

The increasing consumption of Benzalkonium chloride (BAC) require more available and efficient processing techniques for environmental protection. Here in, etched MnFe nanocubes (E-MnFe NC) with cubic-like structures were synthesized as peroxymonosulfate (PMS) activator for BAC degradation via etching and calcination treatment of MnFe Prussian blue analogues (MnFe PBA). In this E-MnFe NC/PMS system, more than 99% BAC was degraded with the mineralization efficiency of 59.8% under optimum condition in 60 min. For mechanism, quenching results and EPR analysis demonstrated that both SO4•− and HO• are main contributor in the oxidation process. The transformation of surface charge and hydrophobic properties boosted the BAC adsorption, thus contributing to subsequent oxidation reaction. Meanwhile, the enhancement of electron transfer efficiency dominated by oxygen vacancies promoted the catalytic performance. Finally, the degradation pathway of BAC was proposed based on density functional theory (DFT) analysis and GC–MS results. Meanwhile, E-MnFe NC/PMS system possessed ascendant stability and reusability, as well as certain feasibility in actual environmental application. Overall, this work provides valuable references for quaternary ammonium compounds (QACs) degradation via SR-AOP about Fe-Mn catalyst.

Moderate heat treatment of CoFe Prussian blue analogues for enhanced oxygen evolution reaction performance

Moderate heat treatment of CoFe Prussian blue analogues for enhanced oxygen evolution reaction performance

Burkholderia cepacia CS8 improves phytoremediation potential of Calendula officinalis for tannery solid waste polluted soil

Microbes have shown potential for the bioremediation of tannery waste polluted soil. During our previous study, it was observed that heavy metal resistant Burkholderia cepacia CS8 augmented growth and phytoremediation capability of an ornamental plant. Objective of the present research work was to evaluate the capability of B. cepacia CS8 assisted Calendula officinalis plants for the phytoremediation of tannery solid waste (TSW) polluted soil. The TSW treatment significantly reduced growth attributes and photosynthetic pigments in C. officinalis. However, supplementation of B. cepacia CS8 which exhibited substantial tolerance to the TSW amended soil, augmented growth traits, carotenoid, proline, and antioxidant enzymes level in C. officinalis under toxic and nontoxic regimes. Inoculation of B. cepacia CS8 augmented plant growth (shoot length 13%, root length 11%), physiological attributes (chlorophyll a 14%, chlorophyll b 17%), antioxidant enzyme activities (peroxidase 24%, superoxide dismutase 31% and catalase 19%), improved proline 36%, phenol 32%, flavonoids 14% and declined malondialdehyde (MDA) content 15% and hydrogen peroxide (H2O2) level 12% in C. officinalis at TSW10 stress compared with relevant un-inoculated plants of TSW10 treatment. Moreover, B. cepacia CS8 application enhanced labile metals in soil and subsequent metal uptake, such as Cr 19%, Cd 22%, Ni 35%, Fe 18%, Cu 21%, Pb 34%, and Zn 30%, respectively in C. officinalis plants subjected to TSW10 stress than that of analogous un-inoculated treatment. Higher plant stress tolerance and improved phytoremediation potential through microbial inoculation will assist in the retrieval of agricultural land in addition to the renewal of native vegetation.

Discontinuing Hepatitis Activity Reduced Hepatocellular Carcinoma Recurrence after Primary Curative Therapy

Hepatocellular carcinoma (HCC) tends to recur after curative treatment. This study aimed to identify the clinical factors associated with HCC recurrence after initial curative therapy. We retrospectively included patients with early stage HCC Barcelona Clinic Liver Cancer (BCLC) stages 0 and A who received curative surgical resection or local ablation at three different Chang Gung Memorial Hospitals in Taiwan (527 patients from Linkou, 150 patients from Keelung, and 127 patients from Chiayi) from 2000 to 2009. Pretreatment clinical data were subjected to univariate and multivariate logistic analyses to identify the risk factors for HCC recurrence within five years after the primary curative treatment. Recurrence and survival rates were assessed using Kaplan-Meier curves and log-rank tests. Patients with a history of nucleoside analog or peg-interferon treatment for hepatitis B or hepatitis C infection had lower HCC recurrence rates than did those without such treatment. By contrast, alcohol drinking habits (p = 0.0049, hazard ratio (HR): 1.508, 95%CI: 1.133-2.009), a platelet count of < 14 × 104/μL (p = 0.003, HR: 1.533, 95%CI: 1.155-2.035), and a serum alanine aminotransferase level > 40 U/L (p = 0.0450, HR: 1.305, 95%CI: 1.006-1.694) were independent risk factors for HCC recurrence. The five-year HCC recurrence rates did not differ between patients who received either local radiofrequency ablation or surgical resection at BCLC stages 0 and A. Factors contributing to persistent hepatitis activity and advanced fibrosis precipitate tumor recurrence. Active intervention to discontinue liver injury or hepatitis could reduce HCC recurrence.

A short-term manual for webcam-based telemedicine treatment of Internet use disorders.

In recent decades, the number of people who experience their Internet use behavior as problematic has risen dramatically. In Germany, a representative study from 2013 estimated the prevalence of Internet use disorder (IUD) to be about 1.0%, with higher rates among younger people. A 2020 meta-analysis shows a global weighted average prevalence of 7.02%. This indicates that developing effective IUD treatment programs is more critical than ever. Studies show that motivational interviewing (MI) techniques are widely used and effective in treating substance abuse and IUDs. In addition, an increasing number of online-based health interventions are being developed to provide a low-threshold treatment option. This article presents a short-term online-based treatment manual for IUDs that combines MI techniques with therapy tools from cognitive behavioral therapy (CBT) and acceptance and commitment therapy (ACT). The manual includes 12 webcam-based therapy sessions, each lasting 50 min. Each session is framed by a standardized beginning, conclusion, outlook, and flexible session content. In addition, the manual contains example sessions to illustrate the therapeutic intervention. Finally, we discuss the advantages and disadvantages of online-based therapy compared to analog treatment settings and provide recommendations for dealing with these challenges. By combining established therapeutic approaches with an online-based therapeutic setting based on flexibility and motivation, we aim to provide a low-threshold solution for treating IUDs.

Comparison of somatostatin receptor expression in patients with neuroendocrine tumours with and without somatostatin analogue treatment imaged with [18F]SiTATE.

Somatostatin analogues (SSA) are frequently used in the treatment of neuroendocrine tumours. Recently, [18F]SiTATE entered the field of somatostatin receptor (SSR) positron emission tomography (PET)/computed tomography (CT) imaging. The purpose of this study was to compare the SSR-expression of differentiated gastroentero-pancreatic neuroendocrine tumours (GEP-NET) measured by [18F]SiTATE-PET/CT in patients with and without previous treatment with long-acting SSAs to evaluate if SSA treatment needs to be paused prior to [18F]SiTATE-PET/CT. 77 patients were examined with standardised [18F]SiTATE-PET/CT within clinical routine: 40 patients with long-acting SSAs up to 28 days prior to PET/CT examination and 37 patients without pre-treatment with SSAs. Maximum and mean standardized uptake values (SUVmax and SUVmean) of tumours and metastases (liver, lymphnode, mesenteric/peritoneal and bones) as well as representative background tissues (liver, spleen, adrenal gland, blood pool, small intestine, lung, bone) were measured, SUV ratios (SUVR) were calculated between tumours/metastases and liver, likewise between tumours/metastases and corresponding specific background, and compared between the two groups. SUVmean of liver (5.4 ± 1.5 vs. 6.8 ± 1.8) and spleen (17.5 ± 6.8 vs. 36.7 ± 10.3) were significantly lower (p < 0.001) and SUVmean of blood pool (1.7 ± 0.6 vs. 1.3 ± 0.3) was significantly higher (p < 0.001) in patients with SSA pre-treatment compared to patients without. No significant differences between tumour-to-liver and specific tumour-to-background SUVRs were observed between both groups (all p > 0.05). In patients previously treated with SSAs, a significantly lower SSR expression ([18F]SiTATE uptake) in normal liver and spleen tissue was observed, as previously reported for 68Ga-labelled SSAs, without significant reduction of tumour-to-background contrast. Therefore, there is no evidence that SSA treatment needs to be paused prior to [18F]SiTATE-PET/CT.

Development and validation of a model for predicting the adult height of girls with idiopathic central precocious puberty.

A model for predicting the AH of girls with ICPP was developed incorporating the variables of height SDS, height SDS for bone age, and target height. The internal and external validation ensures an appropriate degree of discrimination and calibration of the prediction model. •Uncertainty prevails as how to predict the adult height of patients with central precocious puberty following gonadotropin-releasing hormone analog treatment. • Previous models for predicting adult height of girls with idiopathic central precocious puberty have not been proven translational to the Chinese population. •This study develops a new model for predicting the adult height of idiopathic central precocious puberty girls who underwent gonadotropin-releasing hormone analog treatment. • The internal and external validation assures a good degree of discrimination and calibration of the prediction model in this study.

Differential responsiveness of spermatogonia to retinoic acid dictates precocious differentiation but not meiotic entry during steady-state spermatogenesis†.

The foundation of mammalian spermatogenesis is provided by undifferentiated spermatogonia, which comprise of spermatogonial stem cells (SSCs) and transit-amplifying progenitors that differentiate in response to retinoic acid (RA) and are committed to enter meiosis. Our laboratory recently reported that the foundational populations of SSCs, undifferentiated progenitors, and differentiating spermatogonia are formed in the neonatal testis in part based on their differential responsiveness to RA. Here, we expand on those findings to define the extent to which RA responsiveness during steady-state spermatogenesis in the adult testis regulates the spermatogonial fate. Our results reveal that both progenitor and differentiating spermatogonia throughout the testis are capable of responding to exogenous RA, but their resulting fates were quite distinct-undifferentiated progenitors precociously differentiated and proceeded into meiosis on a normal timeline, while differentiating spermatogonia were unable to hasten their entry into meiosis. This reveals that the spermatogonia responding to RA must still complete the 8.6day differentiation program prior to their entry into meiosis. Addition of exogenous RA enriched testes with preleptotene and pachytene spermatocytes one and two seminiferous cycles later, respectively, supporting recent clinical studies reporting increased sperm production and enhanced fertility in subfertile men on long-term RA analog treatment. Collectively, our results reveal that a well-buffered system exists within mammalian testes to regulate spermatogonial RA exposure, that exposed undifferentiated progenitors can precociously differentiate, but must complete a normal-length differentiation program prior to entering meiosis, and that daily RA treatments increased the numbers of advanced germ cells by directing undifferentiated progenitors to continuously differentiate.

AN APPROACH TO TRANSMISSION AND DISTRIBUTION NETWORK CONNECTION CHARGES

The article sets out the results of elaboration and analysis of the basic features and premises for an approach to charges for connecting consumer and generator of electricity to the transmission and distribution network. The scope and significances of basic and modified versions of approaches to connection charge in the general context of electrical energy system and the electrical energy market are shown. All the aspects are illustrated from available world experience and practice as well as according to results of analogous methodological treatment applied to networked thermal energy and gas piping systems. It is the intention of the authors to draw attention to the essential features and assumptions of the different approaches to connection charges, the importance of transparency in the relations between connection charges and network use charges, and the consequences of different approaches to network users, particularly of renewable energy source generating plants.

Kinetics and predictive value of HBcrAg, HBV RNA and anti-HBc during bulevirtide treatment of chronic HDV-infected patients.

The entry inhibitor bulevirtide (BLV) is a new treatment option for patients with chronic hepatitis D virus (HDV) infection and compensated liver disease. The aim of this study was to investigate the kinetic and predictive value of markers reflecting HBV cccDNA transcriptional activity and host immune response activity during BLV treatment in a real-life cohort of HDV infected patients. Levels of HDV RNA, HBV RNA, hepatitis B core related antigen (HBcrAg) and hepatitis B core antibodies (anti-HBc) were measured in 16 patients before (BL), after three (3M) and six (6M) months of treatment with BLV. All patients received nucleos(t)ide analogue treatment. HDV RNA declined in all patients during treatment. 38% (6/16) showed ≥ 2 log HDV RNA decline from BL to 6M and 11 patients (69%) normalized ALT levels. HBV RNA levels were low and only detectable in two to four patients. HBcrAg levels declined in 75% (12/16) of patients. Median HBcrAg levels declined significantly from BL to 6M (3.75 logU/ml (IQR 2.93-4.78) vs. 3.4 logU/ml (IQR 2-4.68), p=0.002). A similar trend was shown for anti-HBc between BL and 6M. Levels of HBcrAg or anti-HBc did not differ significantly between patients with or without ≥ 2 log HDV RNA decline from BL to 6M.After 6 months treatment with BLV, levels of HBcrAg showed a significant decline, while HBV RNA and anti-HBc levels did not change. Reduction of HBV cccDNA transcriptional activity and immunological effects of antiviral treatment might explain these changes.

CTLA4+CD4+CXCR5−FOXP3+ T cells associate with unfavorable outcome in patients with chronic HBV infection

BackgroundA major barrier to achieving a favorable outcome of chronic HBV infection is a dysregulated HBV-specific immune response resulting from immunosuppressive features of FOXP3+ T cells. A better definition of FOXP3+ T cells is essential for improving the prognosis of HBV infection. We aimed to investigate the role of CD4+CXCR5−FOXP3+ T cells with CTLA4 expression in patients with chronic HBV infection.MethodsTreatment-naïve chronic HBV-infected patients, HBV-related hepatic failure, and a longitudinal cohort of chronic hepatitis B (CHB) patients with nucleos(t)ide analogue treatment were enrolled for analysis of CD4+CXCR5−FOXP3+ T cell responses by flow cytometry and single-cell RNA sequencing (scRNA-seq).ResultsScRNA-seq revealed that circulating CD4+CXCR5−FOXP3+ T cells presented distinct inhibitory features compared to spleen tissue. Meanwhile, patients with treatment-naïve chronic HBV infection or with HBV-related hepatic failure showed an upregulation of immune-suppressive features (PD-1, CTLA4, GITR) on CD4+CXCR5−FOXP3+T cells; in vitro analysis found HBeAg and HBcAg stimulation induced elevated levels of inhibitory molecules. Notably, the frequency of CTLA4+CD4+CXCR5−FOXP3+ T cells was positively correlated with HBV DNA levels, and longitudinal analysis demonstrated a high frequency of this subset at 12 weeks of antiviral treatment predicted unfavorable outcome in CHB patients.ConclusionsCTLA4+CD4+CXCR5−FOXP3+ T cells are related to unfavorable outcomes in HBV-infected patients; these data indicated that alleviating CTLA4+CD4+CXCR5−FOXP3+ T cells may improve the prognosis of HBV infection.

Effective Analysis of Antiviral Treatment in Patients with HBeAg-Seropositive Chronic Hepatitis B with ALT < 2 Upper Limits of Normal: A Multi-center Retrospective Cohort Study.

Although the indications for antiviral therapy for patients with chronic hepatitis B have been gradually expanded in different guidelines, antiviral treatment efficacy remains unclear among HBeAg-seropositive patients with alanine aminotransferase (ALT) < 2 upper limits of normal (ULN). This study aimed to evaluate the efficacy of antiviral therapy for these patients. In total, 102 treatment-naive patients who were HBeAg seropositive with ALT < 2 ULN and had received nucleotide analogs were included, and their clinical data were retrospectively analyzed. After 96-week treatment, 84.3% (n = 86), 26.5% (n = 27) and 20.6% (n = 21) patients achieved virological response, HBeAg seroclearance and HBeAg seroconversion, respectively. Logistic regression analysis revealed that baseline AST (odds ratio [OR] = 1.069, 95% confidence interval [CI] 1.014-1.127, p = 0.014), serum HBV DNA (OR = 0.540, 95% CI 0.309-0.946, p = 0.031) and quantitative HBsAg levels (OR = 0.147, 95% CI 0.036-0.597, p = 0.007) were independent factors for virological response. At baseline, HBsAg < 4.63 log10 IU/ml was identified as a strong predictor for the 96-week virological response, with a concordance rate of 0.902. Moreover, the levels of liver stiffness values (8.30 ± 3.86 vs. 6.17 ± 1.91, p < 0.001) at week 96 had significantly declined compared to baseline. Nucleotide analog treatment effectively suppressed HBV DNA in patients with HBeAg-seropositive chronic hepatitis B with ALT < 2 × ULN and greatly improved liver fibrosis. The study also found that HBsAg < 4.63 log10 IU/ml was a strong predictor of the virological response.

Expression of neuroendocrine markers predicts increased survival in triple-negative breast cancer patients.

The significance of neuroendocrine (NE) markers in triple-negative breast cancer (TNBC) patients has not been investigated. This study aims to clarify the incidence and prognostic significance of NE marker expression in TNBC, determine its association with other clinicopathological parameters, and further explore the pathological features and potential treatment options for TNBC patients expressing NE markers. Clinicopathological data were collected from 396 TNBC patients undergoing radical breast cancer surgery at Peking Union Medical College Hospital from January 2002 to December 2014, with a final follow-up in July 2019. Immunohistochemistry (IHC) staining was performed for NE markers including chromogranin A (CgA) and synaptophysin (Syn). For TNBC patients with positive NE marker expression, IHC staining was then performed for alpha-thalassemia/mental retardation X-linked (ATRX), O(6)-methylguanine-methyltransferase (MGMT), somatostatin receptor 2 (SSTR2), and programmed death receptor-ligand 1 (PD-L1). The chi-square or Fisher exact test was used to evaluate the correlations between NE marker expression and other parameters. Survival curves were plotted using the Kaplan-Meier (K-M) method to assess the prognostic significance of NE markers in TNBC. NE marker-positive staining was observed in 7.6% (30/396) of all TNBC cases. Only 0.5% (2/396) cases had ≥ 90% neoplastic cells expressing NE markers. Positive NE marker expression was associated with negative basal-like marker expression. K-M survival analysis showed that the NE marker-positive TNBC patients had higher disease-free survival (DFS) rates than the NE marker-negative patients at the same stage. Among the 30 NE marker-positive TNBC cases, 13.3% and 26.7% showed negative IHC staining for ATRX and MGMT, respectively, while 13.3% had a 3+ score for SSTR2 IHC staining. For PD-L1 IHC staining, 13.3% of the 30 TNBC cases were higher than 10 scores in Combined Positive Score (CPS), and 10.0% were higher than 10% in Tumor Cell Proportion Score (TPS). There was a small proportion of TNBC patients expressing NE markers. TNBC patients with positive NE marker expression had a better prognosis than the negative group at the same stage. TNBC cases with positive NE marker expression may potentially benefit from immunotherapy or somatostatin analogue treatment.

Gonadotropin-releasing hormone analogue and recombinant human growth hormone treatment for idiopathic central precocious puberty in girls.

To investigate the effectiveness and safety of gonadotropin-releasing hormone analogue (GnRHa) in combination with recombinant human growth hormone (rhGH) in girls with central precocious puberty (CPP). Clinical data of 80 girls diagnosed with idiopathic central precocious puberty (ICPP) between January 2017 and June 2021 were retrospectively analyzed. Treatment strategy involved GnRHa alone (group A: n=34) and GnRHa+rhGH (group B: n=46). Children's heights (Ht), weights (Wt) and sex hormone levels were measured every 3 months after treatment and bone age (BA) every six months. Heights, growth velocity (GV), predicted adult height (PAH), weights, body mass index (BMI), sex hormone levels and bone age were compared between the two groups. Children in group B showed greater height gain at the 12th, 24th and 30th months after treatment (p<0.05) than those in group A, had faster growth rates in the first and second year following treatment (p<0.05) and better PAH (p<0.05). No statistical differences in weight or BMI were found between the two groups before treatment or at any time after treatment (p>0.05). Levels of LH and FSH were lower in both groups after treatment with no statistical differences between groups (p>0.05). The gap between bone age and chronological age gradually decreased in both groups and no abnormal progression of bone age or other adverse side effects occurred. The combination of GnRHa with rhGH produced better height gains than GnRHa alone for patients with CPP. The gonadal axis was suppressed and progression of bone age delayed with good safety and efficacy.

Real-world hepatitis B antiviral treatment trends and adherence to practice guidelines: a large cohort study

ABSTRACT Background Epidemiologic data regarding chronic hepatitis B virus infections in Israel is limited as extensive population-based studies have not been performed. Objective This work aimed to evaluate the current characteristics of hepatitis B infection among Israeli adults and evaluate adherence to the European Association for the Study of the Liver practice guidelines for antiviral treatment. Methods Clinical and demographic data of HBsAg-positive patients registered in the Leumit-Health-Service database (one of the four major health maintenance organizations in Israel) between 2000 and 2019 were retrieved. Patients were compared according to eligibility to antiviral treatment and type of nucleos(t)ide analogue (NA) treatment. Results In total, 1216 patients had documented HBsAg positivity (males 58.6%, mean age 40.2 ± 14.2 years), 90.6% of whom were HBeAg negative. Antiviral therapy eligibility was met by 37% of patients, among whom 89% received antiviral therapy. Antiviral therapies include NA with a high barrier to resistance (HBR) (64.5%) and NA with a low barrier to resistance (LBR) (35.5%). Compared to patients who received LBR NA, patients receiving HBR NA had shorter treatment (68.7 ± 50 vs. 161.5 ± 42.6 months, p < .001) and follow-up duration (125 ± 68 vs. 188 ± 48 months, p < .001); at the end of follow-up, ALT levels and APRI score were higher among patients on LBR NA compared to patients on HBR NA. Conclusion Most patients received antiviral treatment according to the international practice guidelines. However, one-third of them were treated with a less potent NA, probably due to their lower cost. These findings should encourage the optimization of HBV care and full compliance with the professional practice guideline recommendations.

Bulevirtide monotherapy for 48 weeks in patients with HDV-related compensated cirrhosis and clinically significant portal hypertension.

Bulevirtide (BLV) has recently been conditionally approved for the treatment of chronic hepatitis delta (CHD) in Europe, but its effectiveness and safety in patients with compensated cirrhosis and clinically significant portal hypertension (CSPH) are unknown. Consecutive patients with HDV-related compensated cirrhosis and CSPH who started BLV 2mg/day were enrolled in this single-center study. Clinical/virological characteristics were collected at baseline, weeks 4, 8 and every 8 weeks thereafter. HDV RNA was quantified by Robogene 2.0 (lower limit of detection 6 IU/ml). Eighteen Caucasian patients with compensated cirrhosis and CSPH under nucleos(t)ide analogue treatment were enrolled: median (IQR) age was 48 (29-77) years, and 67% were male. Median (IQR) platelet count was 70 (37-227) x103/μl, liver stiffness measurement (LSM) 16.4 (7.8-57.8) kPa, alanine aminotransferase (ALT) 106 (32-222) U/L, HBsAg 3.7 (2.5-4.3) log IU/ml, HDV RNA 4.9 (3.3-6.6) log IU/ml. During 48 weeks of BLV monotherapy, HDV RNA declined by 3.1 (0.2-4.3) log IU/ml (p <0.001 vs. baseline), becoming undetectable in 5 patients (23%). A virological response was observed in 14 (78%) patients while a non-response was observed in 2 (11%). ALT decreased to 35 (15-86) U/L (p <0.001 vs. baseline), normalizing in 83% of patients. A combined response was observed in 67% of patients. Aspartate aminotransferase and gamma-glutamyltransferase levels significantly improved. Concerning liver function parameters, albumin values significantly increased and bilirubin remained stable. LSM significantly improved in patients with virological response, while platelet count was unchanged. None of the patients developed decompensating events or hepatocellular carcinoma. BLV was well tolerated, no patient discontinued treatment and the increase in bile acids was fully asymptomatic. A 48-week course of BLV 2mg/day monotherapy is safe and effective even for difficult-to treat patients with HDV-related compensated cirrhosis and CSPH. Hepatitis delta virus (HDV) is associated with the most severe form of viral hepatitis. A new treatment for HDV called bulevirtide has recently received conditional approval for patients with chronic HDV infection. However, its safety and effectiveness in patients with more advanced liver disease is not known. Herein, we show that it is safe and effective in patients with HDV-related cirrhosis and clinically significant portal hypertension.

Proteogenomic landscape and clinical characterization of GH-producing pituitary adenomas/somatotroph pituitary neuroendocrine tumors

The clinical characteristics of growth hormone (GH)-producing pituitary adenomas/somatotroph pituitary neuroendocrine tumors (GHomas/somatotroph PitNETs) vary across patients. In this study, we aimed to integrate the genetic alterations, protein expression profiles, transcriptomes, and clinical characteristics of GHomas/somatotroph PitNETs to identify molecules associated with acromegaly characteristics. Targeted capture sequencing and copy number analysis of 36 genes and nontargeted proteomics analysis were performed on fresh-frozen samples from 121 sporadic GHomas/somatotroph PitNETs. Targeted capture sequencing revealed GNAS as the only driver gene, as previously reported. Classification by consensus clustering using both RNA sequencing and proteomics revealed many similarities between the proteome and the transcriptome. Gene ontology analysis was performed for differentially expressed proteins between wild-type and mutant GNAS samples identified by nontargeted proteomics and involved in G protein–coupled receptor (GPCR) pathways. The results suggested that GNAS mutations impact endocrinological features in acromegaly through GPCR pathway induction. ATP2A2 and ARID5B correlated with the GH change rate in the octreotide loading test, and WWC3, SERINC1, and ZFAND3 correlated with the tumor volume change rate after somatostatin analog treatment. These results identified a biological connection between GNAS mutations and the clinical and biochemical characteristics of acromegaly, revealing molecules associated with acromegaly that may affect medical treatment efficacy.

Online counterconditioning with COVID-19-relevant stimuli in lockdown: Impact on threat expectancy, fear, and persistent avoidance

Background and objectivesIn counterconditioning, a conditioned aversive stimulus (CS) is paired with an appetitive stimulus to reduce fear and avoidance. Findings are, however, mixed on the relative impact of counterconditioning versus standard extinction, where the CS is presented in the absence of the aversive event. This analogue treatment study investigated the impact of counterconditioning relative to standard extinction on threat expectancy, fear, and persistent avoidance with an online fear-conditioning task conducted with COVID-19-relevant appetitive stimuli during the pandemic. MethodsFollowing habituation, in which two CSs (male faces wearing face-coverings) were presented in the absence of the unconditioned stimulus (US; a loud female scream), participants (n = 123) underwent threat-conditioning where one stimulus (CS+) was followed by the US and another (CS-) was not. In avoidance learning, the US could be prevented by making a simple response in the presence of the CS+. Next, participants received either counterconditioning in which trial-unique positively rated images of scenes from before the COVID-19 pandemic and its associated restrictions (e.g., hugging others and holding hands) were presented with the CS + or no-counterconditioning (i.e., extinction). In the final test phase, avoidance was available, and all US deliveries were withheld. ResultsCounterconditioning led to diminished threat expectancy and reduced avoidance relative to no-counterconditioning. Fear ratings did not differ between groups. LimitationsNo physiological measures were obtained. ConclusionsImplemented online during the pandemic with COVID-19-relevant appetitive stimuli, counterconditioning was effective at reducing persistent avoidance and threat expectancy.

P-body dynamics revealed by DDX6 protein knockdown via the auxin-inducible degron system.

The transcriptome dynamically changes via several transcriptional and post-transcriptional mechanisms. RNA-binding proteins contribute to such mechanisms to regulate the cellular status. DDX6 is one such protein and a core component of processing bodies (P-bodies), membrane-less cytosolic substructures where RNA and proteins localize and are functionally regulated. Despite the importance of DDX6, owing to the lack of tightly controlled methods for protein knockdown, it was difficult to assess in high time resolution how its depletion exactly affects the P-body assembly structure. Therefore, we adopted an advanced protein degradation method, the auxin-induced degron (AID) system, to degrade DDX6 acutely in ES cells. By introducing AID-tagged DDX6 and the E3 ligase subunit of OsTIR1 into ES cells, we successfully degraded DDX6 following auxin analog (indole-3-acetic acid, IAA) treatment. The degradation rate of DDX6 was slower than that of the cytosolic reporter protein EGFP but was enhanced by increasing the OsTIR1 dosage. Lastly, we confirmed that a substantial portion of P-bodies disappears around the time of 1hr after IAA addition consistent with DDX6 depletion detected by western blot. In accordance with this, we detected transcriptome changes by 6hr after IAA treatment. Therefore, we demonstrated the applicability of the AID method to gain insight into the function of P-bodies and their protein components.

Hepatitis B functional cure and immune response.

Hepatitis B virus (HBV) is a hepatotropic virus, which damage to hepatocytes is not direct, but through the immune system. HBV specific CD4+ T cells can induce HBV specific B cells and CD8+ T cells. HBV specific B cells produce antibodies to control HBV infection, while HBV specific CD8+ T cells destroy infected hepatocytes. One of the reasons for the chronicity of HBV infection is that it cannot effectively activate adoptive immunity and the function of virus specific immune cells is exhausted. Among them, virus antigens (including HBV surface antigen, e antigen, core antigen, etc.) can inhibit the function of immune cells and induce immune tolerance. Long term nucleos(t)ide analogues (NAs) treatment and inactive HBsAg carriers with low HBsAg level may "wake up" immune cells with abnormal function due to the decrease of viral antigen level in blood and liver, and the specific immune function of HBV will recover to a certain extent, thus becoming the "dominant population" for functional cure. In turn, the functional cure will further promote the recovery of HBV specific immune function, which is also the theoretical basis for complete cure of hepatitis B. In the future, the complete cure of chronic HBV infection must be the combination of three drugs: inhibiting virus replication, reducing surface antigen levels and specific immune regulation, among which specific immunotherapy is indispensable. Here we review the relationship, mechanism and clinical significance between the cure of hepatitis B and immune system.