The Nuclear Chaperone Nucleophosmin Escorts an Epstein-Barr Virus Nuclear Antigen to Establish Transcriptional Cascades for Latent Infection in Human B Cells

Epstein-Barr Virus (EBV) is an oncogenic γ-herpesvirus that capably establishes both latent and lytic modes of infection in host cells and causes malignant diseases in humans. Nuclear antigen 2 (EBNA2)-mediated transcription of both cellular and viral genes is essential for the establishment and maintenance of the EBV latency program in B lymphocytes. Here, we employed a protein affinity pull-down and LC-MS/MS analysis to identify nucleophosmin (NPM1) as one of the cellular proteins bound to EBNA2. Additionally, the specific domains that are responsible for protein-protein interactions were characterized as EBNA2 residues 300 to 360 and the oligomerization domain (OD) of NPM1. As in c-MYC, dramatic NPM1 expression was induced in EBV positively infected B cells after three days of viral infection, and both EBNA2 and EBNALP were implicated in the transactivation of the NPM1 promoter. Depletion of NPM1 with the lentivirus-expressed short-hairpin RNAs (shRNAs) effectively abrogated EBNA2-dependent transcription and transformation outgrowth of lymphoblastoid cells. Notably, the ATP-bound state of NPM1 was required to induce assembly of a protein complex containing EBNA2, RBP-Jκ, and NPM1 by stabilizing the interaction of EBNA2 with RBP-Jκ. In a NPM1-knockdown cell line, we demonstrated that an EBNA2-mediated transcription defect was fully restored by the ectopic expression of NPM1. Our findings highlight the essential role of NPM1 in chaperoning EBNA2 onto the latency-associated membrane protein 1 (LMP1) promoters, which is coordinated with the subsequent activation of transcriptional cascades through RBP-Jκ during EBV infection. These data advance our understanding of EBV pathology and further imply that NPM1 can be exploited as a therapeutic target for EBV-associated diseases

Single-crystalline δ-Ni2Si nanowires with excellent physical properties

[[abstract]]In this article, we report the synthesis of single-crystalline nickel silicide nanowires (NWs) via chemical vapor deposition method using NiCl2·6H2O as a single-source precursor. Various morphologies of δ-Ni2Si NWs were successfully acquired by controlling the growth conditions. The growth mechanism of the δ-Ni2Si NWs was thoroughly discussed and identified with microscopy studies. Field emission measurements show a low turn-on field (4.12 V/μm), and magnetic property measurements show a classic ferromagnetic characteristic, which demonstrates promising potential applications for field emitters, magnetic storage, and biological cell separation.[[notice]]補正完畢[[incitationindex]]SCI[[booktype]]電子版[[booktype]]紙

Protein tyrosine phosphatase receptor type O (Ptpro) regulates cerebellar formation during zebrafish development through modulating Fgf signaling

Protein activities controlled by receptor protein tyrosine phosphatases (RPTPs) play comparably important roles in transducing cell surface signals into the cytoplasm by protein tyrosine kinases. Previous studies showed that several RPTPs are involved in neuronal generation, migration, and axon guidance in Drosophila, and the vertebrate hippocampus, retina, and developing limbs. However, whether the protein tyrosine phosphatase type O (ptpro), one kind of RPTP, participates in regulating vertebrate brain development is largely unknown. We isolated the zebrafish ptpro gene and found that its transcripts are primarily expressed in the embryonic and adult central nervous system. Depletion of zebrafish embryonic Ptpro by antisense morpholino oligonucleotide knockdown resulted in prominent defects in the forebrain and cerebellum, and the injected larvae died on the 4th day post-fertilization (dpf). We further investigated the function of ptpro in cerebellar development and found that the expression of ephrin-A5b (efnA5b), a Fgf signaling induced cerebellum patterning factor, was decreased while the expression of dusp6, a negative-feedback gene of Fgf signaling in the midbrain-hindbrain boundary region, was notably induced in ptpro morphants. Further analyses demonstrated that cerebellar defects of ptpro morphants were partially rescued by inhibiting Fgf signaling. Moreover, Ptpro physically interacted with the Fgf receptor 1a (Fgfr1a) and dephosphorylated Fgfr1a in a dose-dependant manner. Therefore, our findings demonstrate that Ptpro activity is required for patterning the zebrafish embryonic brain. Specifically, Ptpro regulates cerebellar formation during zebrafish development through modulating Fgf signaling. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00018-013-1259-7) contains supplementary material, which is available to authorized users

Myopia progression after cessation of atropine in children: a systematic review and meta-analysis

Purpose: To comprehensively assess rebound effects by comparing myopia progression during atropine treatment and after discontinuation.Methods: A systematic search of PubMed, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov was conducted up to 20 September 2023, using the keywords “myopia," “rebound,” and “discontinue." Language restrictions were not applied, and reference lists were scrutinized for relevant studies. Our study selection criteria focused on randomized control trials and interventional studies involving children with myopia, specifically those treated with atropine or combination therapies for a minimum of 6 months, followed by a cessation period of at least 1 month. The analysis centered on reporting annual rates of myopia progression, considering changes in spherical equivalent (SE) or axial length (AL). Data extraction was performed by three independent reviewers, and heterogeneity was assessed using I2 statistics. A random-effects model was applied, and effect sizes were determined through weighted mean differences with 95% confidence intervals Our primary outcome was the evaluation of rebound effects on spherical equivalent or axial length. Subgroup analyses were conducted based on cessation and treatment durations, dosage levels, age, and baseline SE to provide a nuanced understanding of the data.Results: The analysis included 13 studies involving 2060 children. Rebound effects on SE were significantly higher at 6 months (WMD, 0.926 D/y; 95%CI, 0.288–1.563 D/y; p = .004) compared to 12 months (WMD, 0.268 D/y; 95%CI, 0.077–0.460 D/y; p = .006) after discontinuation of atropine. AL showed similar trends, with higher rebound effects at 6 months (WMD, 0.328 mm/y; 95%CI, 0.165–0.492 mm/y; p < .001) compared to 12 months (WMD, 0.121 mm/y; 95%CI, 0.02–0.217 mm/y; p = .014). Sensitivity analyses confirmed consistent results. Shorter treatment durations, younger age, and higher baseline SE levels were associated with more pronounced rebound effects. Transitioning or stepwise cessation still caused rebound effects but combining optical therapy with atropine seemed to prevent the rebound effects.Conclusion: Our meta-analysis highlights the temporal and dose-dependent rebound effects after discontinuing atropine. Individuals with shorter treatment durations, younger age, and higher baseline SE tend to experience more significant rebound effects. Further research on the rebound effect is warranted.Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=463093], identifier [registration number

DECOUPLING PROBLEM OF WEAKLY LINEAR COUPLED DOUBLE MINI-BETA-Y LATTICE OF TPS STORAGE RING

Abstract Three double mini-beta-y (3-DMBy) lattice design of the TPS storage ring is in progress to enhance the photon sources at three of the six long straight sections. For the estimation of Touschek beam lifetime, the TRACY code is used to calculate the momentum acceptance of the linear coupled TPS 3-DMBy lattice. The weak linear coupling was generated by adding some random skew quadrupoles at all quadrupole locations in order to create 1% emittance coupling. Using the Teng's symplectic rotation form in program may cause trouble in decoupling the one-turn coupled matrix. This report describes how we solve this decoupling problem and some useful references and comments are also presented

Northern Hemisphere Urban Heat Stress and Associated Labor Hour Hazard from ERA5 Reanalysis

Increasing surface air temperature is a fundamental characteristic of a warming world. Rising temperatures have potential impacts on human health through heat stress. One heat stress metric is the wet-bulb globe temperature, which takes into consideration the effects of radiation, humidity, and wind speed. It also has broad health and environmental implications. This study presents wet-bulb globe temperatures calculated from the fifth-generation European Centre for Medium-Range Weather Forecasts atmospheric reanalysis and combines it with health guidelines to assess heat stress variability and the potential for reduction in labor hours over the past decade on both the continental and urban scale. Compared to 2010–2014, there was a general increase in heat stress during the period from 2015 to 2019 throughout the northern hemisphere, with the largest warming found in tropical regions, especially in the northern part of the Indian Peninsula. On the urban scale, our results suggest that heat stress might have led to a reduction in labor hours by up to ~20% in some Asian cities subject to work–rest regulations. Extremes in heat stress can be explained by changes in radiation and circulation. The resultant threat is highest in developing countries in tropical areas where workers often have limited legal protection and healthcare. The effect of heat stress exposure is therefore a collective challenge with environmental, economic, and social implications.publishedVersio

The influence of over-distraction on biomechanical response of cervical spine post anterior interbody fusion: a comprehensive finite element study

Introduction: Anterior cervical discectomy and fusion (ACDF) has been considered as the gold standard surgical treatment for cervical degenerative pathologies. Some surgeons tend to use larger-sized interbody cages during ACDF to restore the index intervertebral disc height, hence, this study evaluated the effect of larger-sized interbody cages on the cervical spine with ACDF under both static and cyclic loading.Method: Twenty pre-operative personalized poro-hyperelastic finite element (FE) models were developed. ACDF post-operative models were then constructed and four clinical scenarios (i.e., 1) No-distraction; 2) 1 mm distraction; 3) 2 mm distraction; and 4) 3 mm distraction) were predicted for each patient. The biomechanical responses at adjacent spinal levels were studied subject to static and cyclic loading. Non-parametric Friedman statistical comparative tests were performed and the p values less than 0.05 were reflected as significant.Results: The calculated intersegmental range of motion (ROM) and intradiscal pressure (IDP) from 20 pre-operative FE models were within the overall ranges compared to the available data from literature. Under static loading, greater ROM, IDP, facet joint force (FJF) values were detected post ACDF, as compared with pre-op. Over-distraction induced significantly higher IDP and FJF in both upper and lower adjacent levels in extension. Higher annulus fibrosus stress and strain values, and increased disc height and fluid loss at the adjacent levels were observed in ACDF group which significantly increased for over-distraction groups.Discussion: it was concluded that using larger-sized interbody cages (the height of ≥2 mm of the index disc height) can result in remarkable variations in biomechanical responses of adjacent levels, which may indicate as risk factor for adjacent segment disease. The results of this comprehensive FE investigation using personalized modeling technique highlight the importance of selecting the appropriate height of interbody cage in ACDF surgery

Dimethyl Sulfoxide (DMSO) Exacerbates Cisplatin-induced Sensory Hair Cell Death in Zebrafish (Danio rerio)

Inner ear sensory hair cells die following exposure to aminoglycoside antibiotics or chemotherapeutics like cisplatin, leading to permanent auditory and/or balance deficits in humans. Zebrafish (Danio rerio) are used to study drug-induced sensory hair cell death since their hair cells are similar in structure and function to those found in humans. We developed a cisplatin dose-response curve using a transgenic line of zebrafish that expresses membrane-targeted green fluorescent protein under the control of the Brn3c promoter/enhancer. Recently, several small molecule screens have been conducted using zebrafish to identify potential pharmacological agents that could be used to protect sensory hair cells in the presence of ototoxic drugs. Dimethyl sulfoxide (DMSO) is typically used as a solvent for many pharmacological agents in sensory hair cell cytotoxicity assays. Serendipitously, we found that DMSO potentiated the effects of cisplatin and killed more sensory hair cells than treatment with cisplatin alone. Yet, DMSO alone did not kill hair cells. We did not observe the synergistic effects of DMSO with the ototoxic aminoglycoside antibiotic neomycin. Cisplatin treatment with other commonly used organic solvents (i.e. ethanol, methanol, and polyethylene glycol 400) also did not result in increased cell death compared to cisplatin treatment alone. Thus, caution should be exercised when interpreting data generated from small molecule screens since many compounds are dissolved in DMSO.National Institutes of Health (U.S.) (DC010998)National Institutes of Health (U.S.) (NIH DC010231)Harvard College (1780- )Sarah Fuller Foundation for Little Deaf Childre