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Abstract A sensitivity study for the search for the charged lepton flavor violating process $$\tau \rightarrow \gamma \mu $$ τ → γ μ at the Super $$\tau $$ τ -Charm Facility is performed with a fast simulation. With the expected performance of the current detector design and an integrated luminosity of $$1\,\textrm{ab}^{-1}$$ 1 ab - 1 corresponding to one-year of data taking, the sensitivity on the branching fraction (BF) of $$\tau \rightarrow \gamma \mu $$ τ → γ μ is estimated to be at the level of $$10^{-8}$$ 10 - 8 . The sensitivity under different detector performances are also studied. With ideal performance, the BF could be probed to be $$2.8\,\times \,10^{-8}$$ 2.8 × 10 - 8 at 90% confidence level. The sensitivity is expected to scale with the square root of the luminosity, therefore with a total luminosity of $$10\,\hbox {ab}^{-1}$$ 10 ab - 1 corresponding to ten-year of data taking, the sensitivity could reach $$8.8\,\times 10^{-9}$$ 8.8 × 10 - 9 , which is about one order of magnitude improvement upon the current best upper limit.

Abstract We report a feasibility study of pure leptonic decay $$D_s^+\rightarrow \mu ^+\nu _\mu $$ D s + → μ + ν μ by using a fast simulation software package at STCF. With an expected luminosity of $$1~\mathrm {ab}^{-1}$$ 1 ab - 1 collected at STCF at a center-of-mass energy of 4.009 GeV, the statistical sensitivity of the branching fraction is determined to be 0.3%. Combining this result with the $$c \rightarrow s$$ c → s quark mixing matrix element $$|V_{cs}|$$ | V cs | determined from the current global Standard Model fit, the statistical sensitivity of $$D_s^+$$ D s + decay constant, $$f_{D_s^+}$$ f D s + , is estimated to be 0.2%. Alternatively, combining the current results of $$f_{D_s^+}$$ f D s + calculated by lattice QCD, the statistical sensitivity of $$|V_{cs}|$$ | V cs | is determined to be 0.2%, which helps probe possible new physics beyond Standard Model. The unprecedented precision to be achieved at STCF will provide a precise calibration of QCD and rigorous test of Standard Model.

Abstract We report a sensitive study of measuring $$b\rightarrow s\gamma $$ b → s γ photon polarisation in $$D^{0}\rightarrow K_1(1270)^-e^+\nu _e$$ D 0 → K 1 ( 1270 ) - e + ν e with an integrated luminosity of $$\mathscr {L}$$ L = 1 ab $$^{-1}$$ - 1 at a center-of-mass energy of 3.773 GeV at a future Super Tau Charm Facility. More than 61,000 signals of $$D^{0}\rightarrow K_1(1270)^-e^+\nu _e$$ D 0 → K 1 ( 1270 ) - e + ν e are expected. Based on a fast simulation software package, the statistical sensitivity for the ratio of up-down asymmetry is estimated to be $$1.5\times 10^{-2}$$ 1.5 × 10 - 2 by performing a two-dimensional angular analysis in $$D^{0}\rightarrow K_1(1270)^-e^+\nu _e$$ D 0 → K 1 ( 1270 ) - e + ν e . Combining with measurements of up-down asymmetry in $$B\rightarrow K_1\gamma $$ B → K 1 γ , the photon polarisation in $$b\rightarrow s\gamma $$ b → s γ can be determined model-independently.

Abstract Background This study aimed to analyze the effects of ruxolitinib on children with secondary hemophagocytic lymphohistiocytosis (HLH). Methods Eleven pediatric patients diagnosed with HLH and treated with ruxolitinib (ruxolitinib group: group R) between November 2017 and August 2018 were retrospectively analyzed. Eleven age-matched pediatric patients with HLH undergoing conventional treatment (control group: group C) during the same period were also analyzed. Results In group R, three patients who did not respond to methylprednisolone (MP) pulse and intravenous immunoglobulin (IVIG) therapies were treated with Ruxolitinib and their temperature decreased to normal levels. Four patients had normal temperature after conventional treatment (dexamethasone and etoposide, with or without cyclosporine A), but they had severe organ involvement, including obvious yellowing of the skin, increased liver enzyme levels and neuropsychiatric symptoms, and they were all ameliorated with ruxolitinib treatment. Four patients were relieved with ruxolitinib therapy alone. In group C, the body temperatures of eleven patients decreased to normal levels after conventional treatment. The body temperature of group R patients decreased to normal levels more rapidly than that of group C patients. The glucocorticoid dosage in group R was significantly lower than that in group C. Both groups were followed-up for 2–2.5 years. No obvious adverse drug reactions to ruxolitinib were observed during treatment and follow-up. Conclusion Ruxolitinib might be an effective drug in controlling body temperature and reducing inflammation indicators. It might be a potential replacement for glucocorticoid therapy for HLH treatment in children, thereby reducing or avoiding glucocorticoid-related adverse reactions.

BackgroundThe clinical features of urticaria have not been fully illustrated.ObjectivesTo demonstrate clinical features of urticaria in different areas of southern and northern China.MethodsIn this hospital-based multicenter study, outpatients with urticaria filled in a questionnaire during the initial visit and follow-up (once per week, lasting for a month).ResultsOverall, 1,715 outpatients with urticaria with a mean age of 37.86 ± 16.08 years (range = 0.5–87 years) were recruited. The median disease duration was 1.94 ± 4.31 years (range = 0–58 years). More itching was observed in the northern areas higher than that in the southern areas (99.5 vs 94.1%, P < 0.001). The incidence of pain, arthralgia, and family history in southern areas was higher than that in northern areas (5.1 vs 1.1%, 9.6 vs 0, 10.6% vs 3.2%, P < 0.001). The leading subtypes of specified urticaria were chronic spontaneous urticaria (81.4%) and symptomatic dermographism (35.9%). The incidence of symptomatic dermographism and cold urticaria in the southern areas was lower than that in the northern areas (31.8 vs. 50.3%, 4 vs. 8.5%, P < 0.001). Allergic diseases were the most common concomitant disorders of urticaria. More than half of the patients had to avoid certain food, such as fish-prawn-crab (30.7%) and alcohol (20%). Ebastine (41.1%) was the most commonly prescribed drug. The disease duration negatively correlated with the severity of itching and number of wheals (>50/24H) (Spearman’s rank correlation test, p < 0.001).ConclusionThis study provides a profile of clinical characteristics of urticaria in China and filled the gap in the field of regional comparative studies on urticaria.

Rheumatoid arthritis (RA) is considered to be a chronic autoimmune disease, pathogenesis of RA is complex and effective treatments for RA is still lacking. Previous studies found that microRNAs (miRNAs) play important roles in the pathogenesis of RA, and miR-223-3p is considered to be one of the possible biomarkers of RA. Recent studies have revealed that icariin alleviates RA in murine models, but the underlying mechanism needs to be further investigated. MiR-223-3p expression levels in fibroblast-like synoviocyte (RA-FLS) and patients with RA were quantified by qRT-PCR, cell proliferation was analyzed by CCK-8 and BrdU assay. Cell apoptosis was assessed by flow cytometry and western blotting. TNF-α, IL-1β and IL-6 concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Dual luminescence-based reporter gene assay was conducted to confirm the possible interaction between miR-223-3p and NLRP3. Icariin inhibits proliferation and inflammation cytokines secretion, promotes apoptosis of RA-FLS cells and upregulated the expression of miR-223-3p. MiR-223-3p targets to 3’-UTR of NRLP3 and regulates its expression. MiR-223-3p inhibitor reversed the effect of icariin on RA-FLS cells function. Additionally, anti-RA activity of icariin was restored by NLRP3 inhibitor MCC950 in miR-223-3p knockdown RA-FLS cells. Icariin inhibits proliferation and inflammation, promotes apoptosis of RA-FLS cells by regulating miR-223-3p/NLRP3 signalling, which may serve as a potential therapeutic target to alleviate RA.

Oxidative stress in adipose tissue is a crucial pathogenic mechanism of obesity-associated cardiovascular diseases. Chronic low-grade inflammation caused by obesity increases ROS production and dysregulation of adipocytokines. Leonurine (LEO) is an active alkaloid extracted from Herba Leonuri and plays a protective role in the cardiovascular system. The present study tested whether LEO alleviates inflammation and oxidative stress, and improves vascular function in an obese mouse model. Here, we found that obesity leads to inflammation and oxidative stress in epididymal white adipose tissue (EWAT), as well as vascular dysfunction. LEO significantly improved inflammation and oxidative stress both in vivo and in vitro. Obesity-induced vascular dysfunction was also improved by LEO as evidenced by the ameliorated vascular tone and decreased mesenteric artery fibrosis. Using mass spectrometry, we identified YTHDF1 as the direct target of LEO. Taken together, we demonstrated that LEO improves oxidative stress and vascular remodeling induced by obesity and targets YTHDF1, raising the possibility of LEO treating other obesity-related metabolic syndromes.

OBJECTIVES: As more families participate expanded newborn screening for metabolic disorders in China, the overall number of false positives increases. Our goal was to assess the potential impact on parental stress, perceptions of the child's health, and family relationships. METHODS: Parents of 49 infants with false-positive screening results for metabolic disorders in the expanded newborn screening panel were compared with parents of 42 children with normal screening results. Parents first completed structured interview using likert scales, closed and open questions. Parents also completed the parenting stress index. RESULTS: A total of 88 mothers and 41 fathers were interviewed. More mothers in the false-positive group reported that their children required extra parental care (21%), compared with 5% of mothers in the normal-screened group (P

One of the most significant evolutionary changes underlying the highly developed cognitive abilities of humans is the greatly enlarged brain volume. In addition to being far greater than in most other species, the volume of the human brain exhibits extensive variation and distinct sexual dimorphism in the general population. However, little is known about the genetic mechanisms underlying normal variation as well as the observed sex difference in human brain volume. Here we show that interleukin-3 (IL3) is strongly associated with brain volume variation in four genetically divergent populations. We identified a sequence polymorphism (rs31480) in the IL3 promoter which alters the expression of IL3 by affecting the binding affinity of transcription factor SP1. Further analysis indicated that IL3 and its receptors are continuously expressed in the developing mouse brain, reaching highest levels at postnatal day 1-4. Furthermore, we found IL3 receptor alpha (IL3RA) was mainly expressed in neural progenitors and neurons, and IL3 could promote proliferation and survival of the neural progenitors. The expression level of IL3 thus played pivotal roles in the expansion and maintenance of the neural progenitor pool and the number of surviving neurons. Moreover, we found that IL3 activated both estrogen receptors, but estrogen didn't directly regulate the expression of IL3. Our results demonstrate that genetic variation in the IL3 promoter regulates human brain volume and reveals novel roles of IL3 in regulating brain development.

Metabolic reprogramming occurs in the clonal evolution of acute myeloid leukemia (AML), which contributes to cell survival under metabolic stress and the development of drug resistance. Leukemic cells exhibit various metabolic profiles, which involve multiple metabolic pathways due to the heterogeneity of AML. However, studies on metabolic targets for AML treatment are mostly focused on glycolysis at present. In this work, we established conditional knock-in AML mouse models harboring Dnmt3aR878H/WT, NrasG12D/WT, and both of the mutations, respectively. Transcriptomic analysis of Gr1+ cells from bone marrow was performed afterward to screen interested metabolic pathways and target genes. Candidate genes were studied using the CRISPR/Cas9 technique, quantitative real-time RT-PCR, and flow cytometric analyses. We revealed that multiple metabolic pathways were affected in AML mice, including lipid metabolism. Endothelial lipase (LIPG) was obviously upregulated in leukemic cells from AML mice with Dnmt3a mutation. We performed knockout of LIPG in OCI-AML3 cells carrying DNMT3A R882C mutation by using the CRISPR/Cas9 technique. Depletion of LIPG led to proliferation inhibition, apoptosis, damage of antioxidant capacity, and myeloid differentiation in OCI-AML3 cells. LIPG might serve as a potential metabolic target for the treatment of AML with abnormal lipid metabolism. [ABSTRACT FROM AUTHOR]

Retinoic acid-inducible gene I (RIG-I) is up-regulated during granulocytic differentiation of acute promyelocytic leukemia (APL) cells induced by all-trans retinoic acid (ATRA). It has been reported that RIG-I recognizes virus-specific 5'-ppp-double-stranded RNA (dsRNA) and activates the type I interferons signaling pathways in innate immunity. However, the functions of RIG-I in hematopoiesis remain unclear, especially regarding its possible interaction with endogenous RNAs and the associated pathways that could contribute to the cellular differentiation and maturation. Herein, we identified a number of RIG-I-binding endogenous RNAs in APL cells following ATRA treatment, including the tripartite motif-containing protein 25 (TRIM2S) messenger RNA (mRNA). TRIM25 encodes the protein known as an E3 ligase for ubiquitin/interferon (IFN)-induced 15-kDa protein (ISG15) that is involved in RIG-I-mediated antiviral signaling. We show that RIG-I could bind TRIM2S mRNA via its helicase domain and C-terminal regulatory domain, enhancing the stability of TRIM2S transcripts. RIG-I could increase the transcriptional expression of TRIM2S by caspase recruitment domain (CARD) domain through an IFN-stimulated response element. In addition, RIG-I activated other key genes in the ISGylation pathway by activating signal transducer and activator of transcription 1 (STAT1), including the modifier ISG15 and several enzymes responsible for the conjugation of ISG15 to protein substrates. RIG-I cooperated with STAT1/2 and interferon regulatory factor 1 (IRF1) to promote the activation of the ISGylation pathway. The integrity of ISGylation in ATRA or RIG-I-induced cell differentiation was essential given that knockdown of TRIM25 or ISG15 resulted in significant inhibition of this process. Our results provide insight into the role of the RIG-I-TRIM25-ISGylation axis in myeloid differentiation. [ABSTRACT FROM AUTHOR]

Astemizole has gained attention as an antineoplastic drug that targets important ion channels. The present study aimed to investigate the protective effects of astemizole against hydrogen peroxide (H2O2)‑induced oxidative damage to human umbilical vein endothelial cells (HUVECs). HUVECs were pretreated with astemizole (0.5 and 1 μM) for 12 h, then exposed to H2O2 (200 μM) for 12 h. Cell viability was measured using the MTT assay. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH‑Px), reactive oxygen species (ROS) and apoptotic percentage were determined. Additionally, the protein expression of p53, p21Cip1/Waf1and p16INK4a was measured by western blot analysis The results demonstrated that astemizole (0.5‑1 μM) was able to significantly restore the viability of HUVECs under oxidative stress and scavenge intracellular ROS induced by H2O2. Astemizole also suppressed the production of lipid peroxides, such as MDA, and restored the activities of endogenous antioxidants, including SOD and GSH‑Px, indicating that cell apoptosis may be inhibited. In addition, astemizole significantly increased p53, P21Cip1/Waf1 and p16INK4a protein expression. In conclusion, astemizole effectively protected endothelial cells against oxidative stress induced by H2O2, a function that may involve ROS/p53/p21Cip1/Waf1/ p16INK4a signaling pathways. The present study therefore served as a preliminary investigation into the ROS‑protective effects of astemizole, and may pave the way for future studies into the development of this compound as a novel therapy for atherosclerosis. [ABSTRACT FROM AUTHOR]

DNMT3A is frequently mutated in acute myeloid leukemia (AML). To explore the features of human AML with the hotspot DNMT3A R882H mutation, we generated Dnmt3a R878H conditional knockin mice, which developed AML with enlarged Lin-Sca1+cKit+ cell compartments. The transcriptome and DNA methylation profiling of bulk leukemic cells and the single-cell RNA sequencing of leukemic stem/progenitor cells revealed significant changes in gene expression and epigenetic regulatory patterns that cause differentiation arrest and growth advantage. Consistent with leukemic cell accumulation in G2/M phase, CDK1 was up-regulated due to mTOR activation associated with DNA hypomethylation. Overexpressed CDK1-mediated EZH2 phosphorylation resulted in an abnormal trimethylation of H3K27 profile. The mTOR inhibitor rapamycin elicited a significant therapeutic response in Dnmt3aR878H/WT mice. [ABSTRACT FROM AUTHOR]

Soluble amyloid-β (Aβ) oligomers, also known as Aβ-derived diffusible ligands (ADDLs), are thought to be the key pathogenic factor in Alzheimer's disease (AD), but there is still no effective treatment for preventing or reversing the progression of the disease. Targeting NMDA receptor trafficking and regulation is a new strategy for early treatment of AD. Aβ oligomers have been found to bind to the fibronectin (FN) type III repeat domain of EphB2 to trigger EphB2 degradation, thereby impairing the normal functioning of NMDA receptors and resulting in cognitive deficits. Here, we identified for the first time the interaction sites of the EphB2 FN domain with ADDLs by applying the peptide array method to design and synthesize four candidate peptides (Pep21, Pep25, Pep32, and Pep63) that might be able to block the EphB2-ADDL interaction. Among them, Pep63 was found to be the most effective at inhibiting the binding between EphB2 and ADDLs. We found that Pep63 not only rescued the ADDL-induced depletion of EphB2- and GluN2B-containing NMDA receptors from the neuronal surface in cultured hippocampal neurons, but also improved impaired memory deficits in APPswe/PS1dE9 (APP/PS1) transgenic mice and the phosphorylation and surface expression of GluN2B-containing NMDA receptors in cultures. Together, these results suggest that blocking the EphB2-ADDL interaction by small interfering peptides may be a promising strategy for AD treatment. [ABSTRACT FROM AUTHOR]

Objective: To study the prevalence rate of tuberous sclerosis complex in autistic disorder. Methods: We studied one cohort of children followed up since 2005 until 2009, with autistic disorder, to determine the incidence of tuberous sclerosis complex. We established an autistic disorder registry in 2005 at China Rehabilitation Research Center. During the 4-year period (2005-2009), we collected a database of 429 children (390 boys and 39 girls; male to female ratio 10:1) with autistic disorder and pervasive developmental disorders. We routinely examined all children with autistic disorder for any features of tuberous sclerosis complex by looking for neurocutaneous markers such as depigmented spots. In those with infantile spasm or epilepsy, the clinical features of tuberous sclerosis complex were monitored regularly during follow-up. Findings: Of these, five had tuberous sclerosis complex. Thus, the prevalence rate of tuberous sclerosis complex in autistic disorder is 1.17%. All of these children were mentally retarded with moderate to severe grades. Their IQ or developmental quotient was less than 70. Conclusion: The prevalence rate of tuberous sclerosis complex in autistic disorder was 1.17% in our region; autism spectrum disorder is a condition that might be associated with development of tuberous sclerosis complex. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article published in the previous issue regarding the newborn screening programs for identifying the babies at risk of having uncommon but serious medical conditions that can affect their normal development.