Desensitization and remission after peanut sublingual immunotherapy in 1- to 4-year-old peanut-allergic children: A randomized, placebo-controlled trial.

BACKGROUND: Prior studies of peanut sublingual immunotherapy (SLIT) have suggested a potential advantage with younger age at treatment initiation. OBJECTIVE: We studied the safety and efficacy of SLIT for peanut allergy in 1- to 4-year-old children. METHODS: Peanut-allergic 1- to 4-year-old children were randomized to receive 4 mg peanut SLIT versus placebo. Desensitization was assessed by double-blind, placebo-controlled food challenge (DBPCFC) after 36 months of treatment. Participants desensitized to at least 443 mg peanut protein discontinued therapy for 3 months and then underwent DBPCFC to assess for remission. Biomarkers were measured at baseline and longitudinally during treatment. RESULTS: Fifty participants (25 peanut SLIT, 25 placebo) with a median age of 2.4 years were enrolled across 2 sites. The primary end point of desensitization was met with actively treated versus placebo participants having a significantly greater median cumulative tolerated dose (4443 mg vs 143 mg), higher likelihood of passing the month 36 DBPCFC (60% vs 0), and higher likelihood of demonstrating remission (48% vs 0). The highest rate of desensitization and remission was seen in 1- to 2-year-olds, followed by 2- to 3-year-olds and 3- to 4-year-olds. Longitudinal changes in peanut skin prick testing, peanut-specific IgG4, and peanut-specific IgG4/IgE ratio were seen in peanut SLIT but not placebo participants. Oropharyngeal itching was more commonly reported by peanut SLIT than placebo participants. Skin, gastrointestinal, upper respiratory, lower respiratory, and multisystem adverse events were similar between treatment groups. CONCLUSION: Peanut SLIT safely induces desensitization and remission in 1- to 4-year-old children, with improved outcomes seen with younger age at initiation.

Single-cell sequencing reveals the impact of endothelial cell PIEZO1 expression on thoracic aortic aneurysm.

INTRODUCTION: Thoracic aortic aneurysm (TAA) is a severe vascular disease that threatens human life, characterized by focal dilatation of the entire aortic wall, with a diameter 1.5 times larger than normal. PIEZO1, a mechanosensitive cationic channel, monitors mechanical stimulations in the environment, transduces mechanical signals into electrical signals, and converts them into biological signals to activate intracellular signaling pathways. However, the role of PIEZO1 in TAA is still unclear. METHODS: We analyzed a single-cell database to investigate the expression level of PIEZO1 in TAA. We constructed a conditional knockout mouse model of Piezo1 and used the PIEZO1 agonist Yoda1 to intervene in the TAA model mice established by co-administration of BAPN and ANG-II. Finally, we explored the effect of Yoda1 on TAA in vitro. RESULTS AND DISCUSSION: We observed decreased PIEZO1 expression in TAA at both RNA and protein levels. Single-cell sequencing identified a specific reduction in Piezo1 expression in endothelial cells. Administration of PIEZO1 agonist Yoda1 prevented the formation of TAA. In PIEZO1 endothelial cell conditional knockout mice, Yoda1 inhibited TAA formation by interfering with PIEZO1. In vivo and in vitro experiments demonstrated that the effect of Yoda1 on endothelial cells involved macrophage infiltration, extracellular matrix degradation, and neovascularization. This study highlights the role of PIEZO1 in TAA and its potential as a therapeutic target, providing opportunities for clinical translation.

Small-molecule caspase-1 inhibitor CZL80 terminates refractory status epilepticus via inhibition of glutamatergic transmission.

Status epilepticus (SE), a serious and often life-threatening medical emergency, is characterized by abnormally prolonged seizures. It is not effectively managed by present first-line anti-seizure medications and could readily develop into drug resistance without timely treatment. In this study, we highlight the therapeutic potential of CZL80, a small molecule that inhibits caspase-1, in SE termination and its related mechanisms. We found that delayed treatment of diazepam (0.5 h) easily induces resistance in kainic acid (KA)-induced SE. CZL80 dose-dependently terminated diazepam-resistant SE, extending the therapeutic time window to 3 h following SE, and also protected against neuronal damage. Interestingly, the effect of CZL80 on SE termination was model-dependent, as evidenced by ineffectiveness in the pilocarpine-induced SE. Further, we found that CZL80 did not terminate KA-induced SE in Caspase-1-/- mice but partially terminated SE in IL1R1-/- mice, suggesting the SE termination effect of CZL80 was dependent on the caspase-1, but not entirely through the downstream IL-1ß pathway. Furthermore, in vivo calcium fiber photometry revealed that CZL80 completely reversed the neuroinflammation-augmented glutamatergic transmission in SE. Together, our results demonstrate that caspase-1 inhibitor CZL80 terminates diazepam-resistant SE by blocking glutamatergic transmission. This may be of great therapeutic significance for the clinical treatment of refractory SE.

Open-label study of the efficacy, safety, and durability of peanut sublingual immunotherapy in peanut-allergic children.

BACKGROUND: Studies on the efficacy of peanut sublingual immunotherapy (SLIT) are limited. The durability of desensitization after SLIT has not been well described. OBJECTIVE: We sought to evaluate the efficacy and safety of 4-mg peanut SLIT and persistence of desensitization after SLIT discontinuation. METHODS: Challenge-proven peanut-allergic 1- to 11-year-old children were treated with open-label 4-mg peanut SLIT for 48 months. Desensitization after peanut SLIT was assessed by a 5000-mg double-blind, placebo-controlled food challenge (DBPCFC). A novel randomly assigned avoidance period of 1 to 17 weeks was followed by the DBPCFC. Skin prick test results immunoglobulin levels, basophil activation test results, TH1, TH2, and IL-10 cytokines were measured longitudinally. Safety was assessed through patient-reported home diaries. RESULTS: Fifty-four participants were enrolled and 47 (87%) completed peanut SLIT and the 48-month DBPCFC per protocol. The mean successfully consumed dose (SCD) during the DBPCFC increased from 48 to 2723 mg of peanut protein after SLIT (P < .0001), with 70% achieving clinically significant desensitization (SCD > 800 mg) and 36% achieving full desensitization (SCD = 5000 mg). Modeled median time to loss of clinically significant desensitization was 22 weeks. Peanut skin prick test; peanut-specific IgE, IgG4, and IgG4/IgE ratio; and peanut-stimulated basophil activation test, IL-4, IL-5, IL-13, IFN-γ, and IL-10 changed significantly compared with baseline, with changes seen as early as 6 months. Median rate of reaction per dose was 0.5%, with transient oropharyngeal itching being the most common, and there were no dosing symptoms requiring epinephrine. CONCLUSIONS: In this open-label, prospective study, peanut SLIT was safe and induced clinically significant desensitization in most of the children, lasting more than 17 weeks after discontinuation of therapy.

Hedgehog signaling-related genomics signature for the accurate progress and prognosis prediction in gastric cancer.

The Hedgehog pathway is thought to be closely associated with the progression of GC; however, a specific link between the Hedgehog pathway on the prognosis and immune infiltration of gastric cancer is still lacking. This study collected Hedgehog pathway-related genes. The Hedgehog pathway-related pattern were identified by consensus cluster analysis. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were used to identify the biological functions which were significantly altered between predefined Cluster1 and Cluster2 in consensus clustering. The risk model of gastric cancer based on Hedgehog signaling pathway was constructed by univariate and multivariate COX regression, and the nomogram was constructed. The results showed that there were significant differences in the expression of Hedgehog pathway-related genes between the two groups. In addition, the constructed risk model was significantly correlated with the clinical prognosis and immune cell infiltration level of patients with gastric cancer. The model effectively predicted the efficacy of chemotherapy in GC patients and the sensitivity of drug treatment between groups. We systematically revealed the mechanism of Hedgehog pathway in gastric cancer and selected biomarkers with biological significance from a new perspective, providing potential direction for the treatment of gastric cancer.

Revealing the roles of egg darkness and nest similarity for a cryptic parasite egg versus host's cognition: an alternate coevolutionary trajectory.

As a text-book example of coevolution, the escalating interactions between egg mimicry by parasitic cuckoos and egg recognition by their hosts constitute a key battlefield for parasitism and anti-parasitism strategies. However, some parasite-host systems have deviated from this coevolutionary trajectory because some cuckoos do not lay mimetic eggs, while the hosts do not recognize them, even under the high costs of parasitism. The cryptic egg hypothesis was proposed to explain this puzzle, but the evidence to date is mixed and the relationship between the two components of egg crypticity, egg darkness (dim egg coloration) and nest similarity (similarity to host nest appearance), remains unknown. Here, we developed a 'field psychophysics' experimental design to dissect these components while controlling for undesired confounding factors. Our results clearly show that both egg darkness and nest similarity of cryptic eggs affect recognition by hosts, and egg darkness plays a more influential role than nest similarity. This study provides unambiguous evidence to resolve the puzzle of absent mimicry and recognition in cuckoo-host systems and explains why some cuckoo eggs were more likely to evolve dim coloration rather than similarity to host eggs or host nests.

Characteristics of children with IgA nephropathy.

BACKGROUND: We analyzed the demographic and clinical characteristics of children with immunoglobulin A (IgA) nephropathy using data in the first pages of electronic health records of 22 hospitals from 2016 to 2018. METHODS: Information collected included gender, age, infection site, etiological infection, acute kidney injury (AKI), and chronic kidney disease (CKD) stages 2-5. We analyzed the gender and age distribution of children with IgA nephropathy, the characteristics of children complicated with AKI and CKD, and the influence of geographical distribution and economic status on the incidence of IgA nephropathy. RESULTS: We included a total of 4006 patients with IgA nephropathy. Incidence in males gradually increased with age. Seventy-nine cases (1.97%) had AKI. We found no significant difference in gender (P = 0.19) or age (P = 0.07) between the AKI and non-AKI groups. Twenty-nine patients had CKD (0.72%), who were significantly older than those in the non-CKD group (P < 0.0001). The incidence of IgA nephropathy in less-developed areas was significantly lower than that in developed areas (P = 0.0002). CONCLUSIONS: The incidence of IgA nephropathy was high mainly in males. Age was an important factor affecting CKD. The disease was related to environment and economic status. IMPACT: We analyze the demographic and clinical characteristics of children with immunoglobulin A (IgA) nephropathy using data in the first pages of electronic health records. This is a large sample, multi-center study. The incidence of IgA nephropathy in males increased gradually with age. Age was an important factor affecting CKD. The disease was related to environment and economic status.

Multi-centre, prospective randomized comparison of three different substrate ablation strategies for persistent atrial fibrillation.

AIMS: The optimal strategy for persistent atrial fibrillation (PerAF) is poorly defined. We conducted a multicentre, randomized, prospective trial to compare the outcomes of different ablation strategies for PerAF. METHODS AND RESULTS: We enrolled 450 patients and randomly assigned them in a 1:1:1 ratio to undergo pulmonary vein isolation and subsequently undergo the following three different ablation strategies: anatomical guided ablation (ANAT group, n = 150), electrogram guided ablation (EGM group, n = 150), and extensive electro-anatomical guided ablation (EXT group, n = 150). The primary endpoint was freedom from atrial fibrillation (AF) lasting longer than 30 s at 12 months after a single ablation procedure. After 12 months of follow-up, 72% (108) of patients in the EXT group were free from AF recurrence, as compared with the 64% (96) in the EGM group (P = 0.116), and 54% (81) in the ANAT group (P = 0.002). The EXT group showed less AF/atrial tachycardia recurrence than the EGM group (60% vs. 50%, P = 0.064) and the ANAT group (60% vs. 37.3%, P < 0.001). The EXT group showed the highest rate of AF termination (66.7%), followed by 56.7% in the EGM group, and 20.7% in the ANAT group. The AF termination signified less AF recurrence at 12 months compared to patients without AF termination (30.1% vs. 42.7%, P = 0.008). Safety endpoints did not differ significantly between the three groups (P = 0.924). CONCLUSIONS: Electro-anatomical guided ablation achieved the most favourable outcomes among the three ablation strategies. The AF termination is a reliable ablation endpoint.

Assessing causality between second-hand smoking and potentially associated diseases in multiple systems: A two-sample Mendelian randomization study.

INTRODUCTION: The global disease burden may be exacerbated by exposure to passive smoking (SHS), with the workplace being a primary location for such exposure. Numerous epidemiological studies have identified SHS as a risk factor for diseases affecting various systems, including cardiovascular, respiratory, immune, endocrine, and nervous systems. The conventional observational study has certain methodological constraints which can be circumvented through a Mendelian randomization (MR) study. Our MR study intends to investigate the causal link between workplace exposure to SHS and the potential associated diseases. METHODS: Summary statistics data involving European participants was sourced from three databases: the UK Biobank, the FinnGen study, and the European Bioinformatics Institute. Genetic variants linked with exposure to SHS in the workplace were identified as instrumental variables. The MR was carried out using inverse variance weighted (IVW), MR-Egger, and weighted median methods. Sensitivity tests were also undertaken within the MR to evaluate the validity of the causality. RESULTS: According to the IVW model, genetically determined atrial fibrillation (AF) and stroke [P= 6.64E-04 and 5.68E-07, odds ratio = 2.030 and 2.494, 95% confidence interval = 1.350,3.051 and 1.743,3.569] were robustly associated with exposure to SHS in the workplace. Suggestive associations were found between workplace SHS and myocardial infarction (MI), asthma, and depression. CONCLUSIONS: The MR study demonstrates that exposure to SHS in the workplace is a significant risk factor for AF and stroke in European individuals. Whether workplace exposure to SHS influences other diseases and the causality between them requires further exploration. IMPLICATIONS: This study explored the causality between exposure to SHS in the workplace and potential associated diseases in multiple systems, including MI, AF, stroke, lung cancer, asthma, allergic disease, type 2 diabetes, and depression, using a MR study. The MR study can circumvent the methodological constraints of observational studies and establish a causal relationship. The two-sample MR analysis provides evidence supporting the causal association of frequent workplace SHS with AF and stroke. Individuals exposed to SHS in the workplace may also have a heightened risk of MI, asthma, and depression. However, whether SHS affects other diseases and the causality between them requires further investigation. To our knowledge, this is the first two-sample MR study to determine the causal relationship between SHS and potential diseases. As exposure to SHS in the workplace is a prevalent issue and may contribute to a global disease burden. The reduction of exposure following the introduction of smoke-free laws has led to a decrease in the admission rate for cardiac events and an improvement in health indicators. It is crucial to further advance smoke-free policies and their implementation.

Chemogenetic inhibition of subicular seizure-activated neurons alleviates cognitive deficit in male mouse epilepsy model.

Cognitive deficit is a common comorbidity in temporal lobe epilepsy (TLE) and is not well controlled by current therapeutics. How epileptic seizure affects cognitive performance remains largely unclear. In this study we investigated the role of subicular seizure-activated neurons in cognitive impairment in TLE. A bipolar electrode was implanted into hippocampal CA3 in male mice for kindling stimulation and EEG recording; a special promoter with enhanced synaptic activity-responsive element (E-SARE) was used to label seizure-activated neurons in the subiculum; the activity of subicular seizure-activated neurons was manipulated using chemogenetic approach; cognitive function was assessed in object location memory (OLM) and novel object recognition (NOR) tasks. We showed that chemogenetic inhibition of subicular seizure-activated neurons (mainly CaMKIIα+ glutamatergic neurons) alleviated seizure generalization and improved cognitive performance, but inhibition of seizure-activated GABAergic interneurons had no effect on seizure and cognition. For comparison, inhibition of the whole subicular CaMKIIα+ neuron impaired cognitive function in naïve mice in basal condition. Notably, chemogenetic inhibition of subicular seizure-activated neurons enhanced the recruitment of cognition-responsive c-fos+ neurons via increasing neural excitability during cognition tasks. Our results demonstrate that subicular seizure-activated neurons contribute to cognitive impairment in TLE, suggesting seizure-activated neurons as the potential therapeutic target to alleviate cognitive impairment in TLE.

Waldenstrom Macroglobulinemia Arising During Maintenance Therapy of Plasma Cell Myeloma.

BACKGROUND: Both plasma cell myeloma (PCM) and Waldenstrom's macroglobulinemia (WM) are mature B-cell neoplasms commonly involving bone marrow and usually related to paraproteinemia. METHODS: Secondary WM in a patient with PCM during maintenance therapy has not been previously reported. We herein report the first case of WM arising during maintenance therapy of PCM. RESULTS: The diagnosis of secondary WM during maintenance therapy of PCM was based on combination of medical history, morphology, flow cytometry, immunofixation electrophoresis, and molecular genetics. CONCLUSIONS: This case highlights the importance of an integrated diagnostic work-up, with an interesting role for morphology and flow immunotyping.

Elevated Blood Selenium Level has a Non-Linear Association with Risk of Anemia in U.S.A. Adults: Data from the NHANES 2011-2016.

BACKGROUND: Only a few epidemiological studies have reported the association between blood selenium and the prevalence of anemia. To date, the evidence is limited and inconsistent. METHODS: We enrolled 9,335 participants (≥ 20 years) who participated in the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2016 to assess the link between blood selenium and the risk of anemia. Multivariate logistic regression analysis and a generalized additive model (GAM) was applied to assess the relationship between blood selenium and anemia risk. RESULTS: We found a significant adverse association between blood selenium and the prevalence of anemia after adjusting for all potential covariates (OR = 0.98, 95% CI: 0.97, 0.98, p < 0.001). After a sequence of sensitive analyses, the conclusion remains stable (p for trend < 0.001). However, a non-linear relationship was detected based on GAM. We calculated a turning point of 205.89 µg/L using a two-piecewise linear regression model. CONCLUSIONS: When blood selenium level is lower than 205.89 µg/L, blood selenium level is inversely associated with the risk of anemia. Our results provide a new strategy to reduce the risk of anemia.

Comparing the clinical efficacy of three surgical methods for cesarean scar pregnancy.

BACKGROUND: We aimed to compare the clinical efficacy of three surgical methods in the treatment of various types of cesarean scar pregnancy (CSP). METHODS: Herein, 314 cases of CSP were treated in the department of Obstetrics and Gynecology of the First Affiliated Hospital of Gannan Medical University between June 2017 and June 2020. The patients were divided into three groups based on the treatment received: group A (n = 146; curettage by pituitrin combined with ultrasonic monitoring and hysteroscopy-guided surgery), group B [n = 90; curettage after methotrexate (MTX) injection into the local gestational sac], and group C (n = 78; laparoscopic, transvaginal, and transabdominal cesarean scar resection). These groups were divided into three subgroups (type I, type II, and type III) according to the CSP type of the patients. RESULTS: The intraoperative blood loss, length of hospital stay, hospitalization cost, menstrual recovery time, and serum ß-HCG normalization time were lower in groups A than in groups B or C with type I, II and III CSP (P < 0.05). Operative efficiency and Successful second pregnancy rate were higher in groups A than in groups B or C with type I and II CSP (P < 0.05). But in type III CSP, the complications were more serious in group A than group C. CONCLUSIONS: Curettage by pituitrin combined with ultrasonic monitoring and hysteroscopy-guided surgery is an effective and relatively safe treatment for patients with type I and II CSP. Laparoscopic surgery is more suitable for type III CSP.

Protective effect of wuzibushen recipe on follicular development via regulating androgen receptor in polycystic ovary syndrome model rats.

OBJECTIVES: The study aimed to explore the role and mechanism of WZBS recipe on PCOS. METHODS: PCOS model was established. After modeling, PCOS rats were intragastrically administered with Diane-35 or WZBS recipe (6.93 g/kg/d). Then, the ovarian and uterine morphology were observed, the estrous cycle was assessed. HE and oil red O staining were conducted for ovarian morphological analysis and counting ovarian follicle and corpora lutea number. Furthermore, the serum content of testosterone (T) and sex-hormone-binding globulin (SHBG) were assessed by ELISA kits. The androgen receptor (AR), CX43 mRNA and protein expression were measured by q-PCR and Western blot. RESULTS: WZBS recipe increased uterine implanted blastocysts, reduced cystic dilated follicles, and normalized estrous cycle in PCOS rats. Meanwhile, WZBS recipe alleviated ovarian injury, increased mature follicles and corpora lutea number in PCOS rats. Moreover, WZBS recipe decreased serum T content, AR expression and increased serum SHBG content, CX43 expression in PCOS rats. CONCLUSIONS: This study reveals that WZBS recipe may attenuate PCOS by protecting follicular development via down-regulating AR.

The Diagnostic Value of Serum TGF-ß1, p2PSA Combined with PSA in Prostate Cancer.

Objective: To investigate the diagnostic value of transforming growth factor-ß1 (TGF-ß1), prostate-specific antigen isomer 2 (p2PSA) combined with a prostate-specific antigen (PSA) in prostate cancer (PCa). Methods: From October 1, 2019 to September 1, 2022 we enrolled a total of 90 patients with PCa90 patients with PCa in the urology department of our hospital were selected as the PCa group, 90 patients with benign prostatic hyperplasia (BPH) were selected as the BPH group, and 90 healthy people were selected as a healthy control group. The levels of TGF-ß1, p2PSA and PSA in serum were detected, and the differences in TGF-ß1, p2PSA and PSA levels among the three groups and PCa patients with different pathological parameters were compared. Univariate and Logistic regression analyses were used to analyze the independent risk factors affecting the occurrence of PCa. With pathological results as the 'gold standard', the diagnostic efficacy of TGF-ß1, p2PSA and PSA alone and their combination for PCa was analyzed by the receiver operating characteristic (ROC) curve. Results: The levels of serum PSA, p2PSA, and TGF-ß1 in the PCa group were higher than those in the BPH group and control group (P < .001), and those in BPH group were higher than those in the control group (P < .001). The serum indexes of PCa group increased with the increase of Glerson grade and TNM stage (P < .001). The serum indexes of patients with lymph and bone metastasis were significantly higher than those without lymph and bone metastasis (P < .001). Logistic regression analysis showed that PSA, p2PSA and TGF-ß1 were independent risk factors for PCa (P < .001). The area under the ROC curve (AUC) of PSA, p2PSA, TGF-ß1 and combined detection were 0.738, 0.862, 0.821 and 0.932, respectively. The AUC of combined detection was greater than that of single detection (P < .001). Conclusion: The expression levels of serum TGF-ß1, p2PSA and PSA are related to PCa and are independent risk factors for PCa. The combined detection of the three groups can improve the diagnostic efficacy of PCa. Combined testing improves diagnostic accuracy for prostate cancer, allows for early intervention, and improves patient survival and confidence in treatment options. This will significantly improve the clinical management of prostate cancer. Future studies could explore other biomarkers or molecular indicators to further improve the accuracy of diagnosis and grading of prostate cancer. Additionally, differences between different populations and subtypes can be studied to better understand the heterogeneity of prostate cancer.

Kinetics of basophil hyporesponsiveness during short-course peanut oral immunotherapy.

BACKGROUND: Oral immunotherapy (OIT) leads to suppression of mast cell and basophil degranulation along with changes in the adaptive immune response. OBJECTIVES: This study aimed to determine how rapidly these effects occur during OIT and more broadly, the kinetics of basophil and mast cell suppression throughout the course of therapy. METHODS: Twenty participants, age 4 to 12 years, were enrolled in a peanut OIT trial and assessed for desensitization and sustained unresponsiveness after 9 months of therapy. Blood was collected 5 times in the first month and then intermittently throughout to quantify immunoglobulins and assess basophil activation by CD63, CD203c, and phosphorylated SYK (pSYK). RESULTS: Twelve of 16 participants that completed the trial were desensitized after OIT, with 9 achieving sustained unresponsiveness after discontinuing OIT for 4 weeks. Basophil hyporesponsiveness, defined by lower CD63 expression, was detected as early as day 90. pSYK was correlated with CD63 expression, and there was a significant decrease in pSYK by day 250. CD203c expression remained unchanged throughout therapy. Interestingly, although basophil activation was decreased across the cohort during OIT, basophil activation did not correlate with individual clinical outcomes. Serum peanut-specific IgG4 and IgA increased throughout therapy, whereas IgE remained unchanged. CONCLUSIONS: Suppression of basophil activation occurs within the first 90 days of peanut OIT, ultimately leading to suppression of signaling through pSYK.

PBMC transcriptomics identifies immune-metabolism disorder during the development of HBV-ACLF.

OBJECTIVE: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) pathophysiology remains unclear. This study aims to characterise the molecular basis of HBV-ACLF using transcriptomics. METHODS: Four hundred subjects with HBV-ACLF, acute-on-chronic hepatic dysfunction (ACHD), liver cirrhosis (LC) or chronic hepatitis B (CHB) and normal controls (NC) from a prospective multicentre cohort were studied, and 65 subjects (ACLF, 20; ACHD, 10; LC, 10; CHB, 10; NC, 15) among them underwent mRNA sequencing using peripheral blood mononuclear cells (PBMCs). RESULTS: The functional synergy analysis focusing on seven bioprocesses related to the PBMC response and the top 500 differentially expressed genes (DEGs) showed that viral processes were associated with all disease stages. Immune dysregulation, as the most prominent change and disorder triggered by HBV exacerbation, drove CHB or LC to ACHD and ACLF. Metabolic disruption was significant in ACHD and severe in ACLF. The analysis of 62 overlapping DEGs further linked the HBV-based immune-metabolism disorder to ACLF progression. The signatures of interferon-related, neutrophil-related and monocyte-related pathways related to the innate immune response were significantly upregulated. Signatures linked to the adaptive immune response were downregulated. Disruptions of lipid and fatty acid metabolism were observed during ACLF development. External validation of four DEGs underlying the aforementioned molecular mechanism in patients and experimental rats confirmed their specificity and potential as biomarkers for HBV-ACLF pathogenesis. CONCLUSIONS: This study highlights immune-metabolism disorder triggered by HBV exacerbation as a potential mechanism of HBV-ACLF and may indicate a novel diagnostic and treatment target to reduce HBV-ACLF-related mortality.

Heterogeneity of transposon expression and activation of the repressive network in human fetal germ cells.

Epigenetic resetting in germ cells during development de-represses transposable elements (TEs). piRNAs protect fetal germ cells by targeted mRNA destruction and deposition of repressive epigenetic marks. Here, we provide the first evidence for an active piRNA pathway and TE repression in germ cells of human fetal testis. We identify pre-pachytene piRNAs with features of secondary amplification that map most abundantly to the long interspersed element type 1 (L1) family of TEs. L1-ORF1p expression is heterogeneous in fetal germ cells, peaks at mid-gestation and declines concomitantly with increases in piRNAs, nuclear localization of HIWI2 and an increase in H3K9me3. Surprisingly, the same cells with accumulation of L1-ORF1p display highest levels of HIWI2 and H3K9me3. Conversely, the earliest germ cells with high levels of L1-ORF1p express low levels of the chaperone HSP90α. We propose that a subset of germ cells resists L1 expression, whereas L1-expressing germ cells activate the repression pathway that leads to epigenetic silencing of L1 via H3K9me3.

Berry-Phase Switch in Electrostatically Confined Topological Surface States.

Here, we visualize the trapping of topological surface states in the circular n-p junctions on the top surface of the seven-quintuple-layer three dimensional (3D) topological insulator (TI) Sb_{2}Te_{3} epitaxial films. As shown by spatially dependent and field-dependent tunneling spectra, these trapped resonances show field-induced splittings between the degenerate time-reversal-symmetric states at zero magnetic field. These behaviors are attributed unambiguously to Berry-phase switch by comparing the experimental data with both numerical and semiclassical simulations. The successful electrostatic trapping of topological surface states in epitaxial films and the observation of Berry-phase switch provide a rich platform of exploiting new ideas for TI-based quantum devices.

Effects of Long-Acting Somatostatin Analogues on Lipid Metabolism in Patients with Newly Diagnosed Acromegaly: A Retrospective Study of 120 Cases.

The short-term effects of long-acting somatostatin analogues (SSAs) on lipid profiles in patients with acromegaly are not well studied. We retrospectively analyzed the effects of SSAs on lipid profiles and associated cardiovascular risk factors in a cohort of 120 newly diagnosed acromegaly patients. In this study, 69 females and 51 males were included. These patients were treated with either octreotide LAR (OCT) or lanreotide SR (LAN) for 3 months. After SSAs treatment, both GH and IGF-1 significantly decreased (p<0.001). Triglyceride (TG), total to high-density lipoprotein cholesterol (HDL-C) ratio, and lipoprotein (a) [Lp(a)] levels were significantly decreased, while HDL-C levels were increased (p<0.05). The reduction of mean serum GH (GHm) was positively associated with the decrease of TG (r=0.305, p=0.001) and Lp(a) (r=0.257, p=0.005), as well as the increase of HDL-C (r=-0.355, p<0.001). The changes of lipid profiles were observed only in OCT group, but not in LAN group. In addition, systolic blood pressure (SBP) had significantly declined after SSAs treatment, with an average reduction of 4.4 mmHg (126.7±1.28 vs. 122.3±1.44 mmHg, p=0.003), while no change was observed regarding diastolic blood pressure (DBP) (p>0.05). Fasting insulin, fasting C-peptide, and HOMA-IR were significantly decreased after SSAs treatment. In conclusion, our current study revealed that short-term SSAs treatment improves lipid profiles and other cardiovascular risk factors in patients with acromegaly.