Search

This is the working summary of the Accelerator Science working group of theComputing Frontier of the Snowmass meeting 2013. It summarizes the computingrequirements to support accelerator technology in both Energy and IntensityFrontiers.

Long-term potentiation (LTP) of synaptic transmission is thought to be an important cellular mechanism underlying memory formation. A widely accepted model posits that LTP requires the cytoplasmic carboxyl tail (C-tail) of the AMPA (α-amino-3-hydroxy-5-met

Clubfoot is a common birth defect characterized by inward posturing and rigid downward displacement of one or both feet. The etiology of syndromic forms of clubfoot is varied and the causes of isolated clubfoot are not well understood. A microduplication of 2.2 Mb on chromosome 17q23.1q23.2 which includes T-box 4 (TBX4), a hindlimb-specific gene, and 16 other genes was recently identified in 3 of 66 families reported as nonsyndromic clubfoot, but additional non-foot malformations place them in the syndromic clubfoot category. Our study assesses whether variation in or around TBX4 contributes to nonsyndromic clubfoot. To determine whether this microduplication was a common cause of nonsyndromic clubfoot, 605 probands (from 148 multiplex and 457 simplex families) with nonsyndromic clubfoot were evaluated by copy number and oligonucleotide array CGH testing modalities. Only one multiplex family (0.68%) that had 16 with clubfoot and 9 with other foot anomalies, had a 350 kb microduplication, which included the complete duplication of TBX4 and NACA2 and partial duplication of BRIP1. The microduplication was transmitted in an autosomal dominant pattern and all with the microduplication had a range of phenotypes from short wide feet and toes to bilateral clubfoot. Minimal evidence was found for an association between TBX4 and clubfoot and no pathogenic sequence variants were identified in the two known TBX4 hindlimb enhancer elements. Altogether, these results demonstrate that variation in and around the TBX4 gene and the 17q23.1q23.2 microduplication are not a frequent cause of this common orthopedic birth defect and narrows the 17q23.1q23.2 nonsyndromic clubfoot-associated region.

Wenbin Lu,1,* JingJing Ji,1,* Genshan Ma,1 Qiming Dai,1 Lijuan Chen,1 Pengfei Zuo,1 Yuanjin Zhao2 1Department of Cardiology, ZhongDa Hospital Affiliated with Southeast University, Nanjing, China; 2State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China *These authors contributed equally to this work Background: The two-dimensional incubation method is now the most commonly method for mesenchymal stem cell (MSC) production. however, gene expression and secretion of growth factors are relatively low; thus, the transplanted cells cannot be effectively utilized for potential clinical applications after acute myocardial infarction (AMI).Objectives: We aimed to investigate whether our newly made substrates of inverse opal with specific surface microstructures for MSC culturing can increase the viability of the cells and can contributes to decreased myocardial remodeling after transplanted to AMI mice. Methods: The inverse opal structure is fabricated by the convenient bottom-up approach of the self-assembly of colloidal nanoparticles. Mouse-derived MSCs were then cultured on the substrates when expanded at different times to investigate the cell growth status including morphology. Then the inverse opal substrates loaded MSCs were transplanted to AMI mice, cardiomyocyte apoptosis and LV remodeling were further compared. To explore the possible mechanisms of curation, the secretions and viability of MSCs on substrates were determined using mice ELISA kits and JC-1 mitochondrial membrane potential assay kits respectively at normal and hypoxic conditions. Results: 6 times expanded inverse opals allowed greatly the orderly growth of MSCs as compared to four (34% ± 10.6%) and two (20%±7.2%) times expanded as well as unexpanded (13%±4.1%) (P

Hao Cheng, Yong Zhang, Weiping Lu, Xianzhong Gao, Chenjie Xu, Hongguang Bao Department of Anesthesiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China Background: Management of neuropathic pain is still a clinical challenge. Evidence has accumulated indicating that propolis is effective in attenuating neuropathic pain; however, the mechanism is not fully understood. Our present study investigated the effects and the possible mechanism of caffeic acid phenethyl ester (CAPE), the main ingredient of propolis, in improving neuropathic pain via its inhibition on p38/NF-κB signal pathway in microglia. Materials and methods: Chronic constriction injury (CCI) mice model and the microglial cell line BV-2 were used to investigate the effects and the mechanism of CAPE. Cell signaling was measured by real-time PCR, Western blotting and immunofluorescence assay. Results: CAPE relieved neuropathic pain behaviors induced by CCI in mice. CAPE also inhibited CCI-induced activation of microglia. Furthermore, CAPE suppressed the phosphorylation of p38 mitogen-activated protein kinase, inhibited the translocation of NF-κB and decreased the expression of proinflammatory cytokines tumor necrosis factor-α, IL-1β and IL-6. Conclusion: CAPE was found to be an effective and safe drug candidate for alleviating neuropathic pain by its powerful inhibition on the P38/NF-κB signal pathway. Keywords: caffeic acid phenethyl ester, NF-κB, neuropathic pain, microglia

Zhenyu Dai,1,* Yue Li,2,* Yonggang Yan,3 Ruijie Wan,1 Qiang Ran,1 Weizhong Lu,1 Bo Qiao,4 Hong Li3 1Department of Orthopedics, Chongqing Traditional Chinese Medicine Hospital, Chongqing, People’s Republic of China; 2Department of Clinical Laboratory, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, People’s Republic of China; 3College of Physical Science and Technology, Sichuan University, Chengdu, People’s Republic of China; 4Department of Orthopedics, the First Affiliated Hospital, Chongqing Medical University, Chongqing, People’s Republic of China *These authors contributed equally to this work Objective: To evaluate the internal fixation effect of nano-calcium-deficient hydroxyapatite/poly-amino acid (n-CDHA/PAA) composite screws in the intraarticular fracture model. Materials and methods: A total of 35 New Zealand White rabbits were used in a bilateral femoral intercondylar fracture model and randomly divided into two groups. n-CDHA/PAA screws were used in the experimental group, and medical metal screws were used in the control group. The fracture condition, range of motion, and the screw push-out strength were assessed, and an arthroscopic examination of knee joint was performed at 4, 8, and 12 weeks after surgery. The biodegradation of the n-CDHA/PAA screws in vivo was tested through weighing, and changes in screw structure were assessed by X-ray diffraction at 12 weeks after surgery. Results: The general situation of all animals was good and showed no incision infection and dehiscence after surgery. X-ray scanning showed that significant callus growth was present in both groups at 4 weeks after surgery, and there was no significant difference (P>0.05) in the Lane-Sandhu score between the experimental and control groups at all time points after surgery. There were no statistically significant differences (P>0.05) in the range of motion and Oswestry Arthroscopy Score of arthroscopic examination of the knee joints between the two groups. The screw push-out strength of the control group was stronger than that of the experimental group at 4 weeks after surgery (P0.05). The degradation tests showed that the n-CDHA/PAA screws degraded gradually after implantation, and the weight loss rate was approximately 16% at 12 weeks after surgery. The X-ray diffraction results showed that the crystal structure of the outer surface of the n-CDHA/PAA screw has changed at 12 weeks after surgery. Conclusion: The n-CDHA/PAA screw is an effective and safe implant as a potential internal fixation device for an intercondylar fracture of the femur, and its internal fixation effect was similar to that of medical metal screw. Keywords: n-CDHA/PAA screw, internal fixation, intraarticular fracture, biocompatibility, bioactivity

Mingze Su,1 Lingjie Liao,2 Hui Xing,2 Shuai Wang,1,3 Yutang Li,4 Wei Lu,1,5 Lingyuan He,1 Juan Deng,1 Yiming Shao,2 Tong Li,1 Hui Zhuang1 1Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; 2State Key Laboratory of Infectious Disease Prevention and Control, National Centre for AIDS/STD Control and Prevention, Chinese Centre for Disease Control and Prevention, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, Beijing 102206, China; 3Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing 100191, China; 4Key Laboratory of Medical Molecular Virology of Ministries of Health and Education, Shanghai Medical College, Fudan University, Shanghai 200032, China; 5Department of Laboratory, The Second Affiliated Hospital of Medical College of Xi’an Jiaotong University, Xi’an, Shaanxi 710004, China Purpose: This study aimed to investigate the HIV and hepatitis B virus (HBV) co-infection in three HIV high endemic areas with different modes of HIV transmission and explore the HBV nucleos(t)ide analogue resistance (NUCr) substitutions in this cohort receiving antiretroviral therapy (ART). Patients and methods: The enrolled 705 HIV-infected patients were from three different regions in China and received lamivudine-based ART for at least 1 year. After screening for hepatitis B surface antigen (HBsAg), the hepatitis B e antigen (HBeAg), and antibody against hepatitis B core antigen (anti-HBc and anti-HBc IgM), HBV DNA in plasma of patients positive for HBsAg was tested. The reverse transcriptase (RT) sequences of HBV were analyzed by direct sequencing. Results: The overall HBsAg-positive rate was 7.1% (50/705) (Guangxi [25/170, 14.7%], ­Xinjiang [13/257, 5.1%], and Henan [12/278, 4.3%]). The age, transmission route, and ethnic status were found to be associated with HIV/HBV co-infection. We obtained 23 HBV RT sequences belonging to genotypes B (9/23, 39.1%), C (13/23, 56.5%), and D (1/23, 4.4%). About 65.2% (15/23) of RT sequences harbored NUCr substitutions, all of which had combination substitution patterns. Patients with HBV NUCr had significantly higher HBV DNA level and ratio of HBeAg-positive than those without NUCr. None of the patients was found to have both lamivudine-resistant HBV and HIV. Conclusion: Our results suggested that HBsAg-positive rate in the studied patients was similar to that of the general population in each of the studied regions, where the age, transmission route, and ethnic status might also play roles in HIV/HBV co-infection. The HBV combination NUCr substitutions were common in co-infected patients under ART. Monitoring of HBV infection and NUCr substitutions in HIV-infected patients would help in providing better clinical decisions and management, thus lowering patients’ risks to develop end-stage liver diseases. Keywords: human immunodeficiency virus, hepatitis B virus, co-infection, nucleos(t)ide analogue resistance, hepatitis B surface antigen

Yongyu Rui,* Wengting Lu,* Si Li, Cancan Cheng, Jingjing Sun, Qiu Yang Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Background: Integron, ISCR1 and complex class 1 integrons lead bacteria to become resistant to antibiotic regimens. The aim of this study was to detect common mobile genetic elements of multidrug-resistant Gram-negative bacilli and evaluate the genotyping of these bacilli in blood specimens from septicemia patients in southern China. Methods: A total of 837 Gram-negative bacilli including 578 strains containing Enterobacteriaceae and 259 strains containing non-fermentative bacilli were investigated in blood samples collected from septicemia patients between 2011 and 2014 in southern China. Mobile genetic elements, such as class 1 integrons, the insertion sequence common region 1 (ISCR1), and complex class 1 integrons, were detected from the 837 strains. Results: Twenty-seven types of gene cassette arrays were found among 837 strains in which 492 (58.8%) class 1 integron-positive isolates and 254 (51.6%) gene cassette-positive isolates were found, including the first description of two types, aacA4-blaIMP-1-blaOXA-30-catB3 and aac(6′)-II-aadA13-cmlA8-blaOXA-10, in the corresponding species and two gene cassettes, putative helicase and aadA-like, originally detected in integrons. Twelve types of ISCR1-linked resistance gene regions in 196 ISCR1-positive bacilli and seven different types of complex class 1 integron-positive strains were obtained including four distinct complex class 1 integrons that have never been described in any species. Enterobacterial repetitive intergenic consensus (ERIC)-PCR fngerprinting showed that isolates with identical gene profles were clonally unrelated. Conclusion: Our results indicated that we should pay more attention to enhance the quality of infection control measures and prevent hospital infection, so as to avoid the outbreak of multidrug-resistant Gram-negative bacilli. Keywords: septicemia, multidrug-resistant, integron, ISCR1, complex class 1 integrons

Yelong Shen,1,2 Lirong Yan,1 Xingfeng Shao,1 Bin Zhao,2 Jinlun Bai,3 Wange Lu,3 Danny JJ Wang1 1Laboratory of FMRI Technology (LOFT), Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California (USC), Los Angeles, CA, USA; 2Shandong Medical Imaging Research Institute, School of Medicine, Shandong University, Jinan, Shangdong, China; 3Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California (USC), Los Angeles, CA, USA Purpose: The purpose of this study was to investigate the feasibility and sensitivity of cellular magnetic resonance imaging (MRI) with ferumoxytol nanocomplex-labeled macrophages at ultrahigh magnetic field of 7 T.Materials and methods: THP-1-induced macrophages were labeled using self-assembling heparin + protamine + ferumoxytol nanocomplexes which were injected into a gelatin phantom visible on both microscope and MRI. Susceptibility-weighted imaging (SWI) and balanced steady-state free precession (bSSFP) pulse sequences were applied at 3 and 7 T. The average, maximum intensity projection, and root mean square combined images were generated for phase-cycled bSSFP images. The signal-to-noise ratio and contrast-to-noise ratio (CNR) efficiencies were calculated. Ex vivo experiments were then performed using a formalin-fixed pig brain injected with ~100 and ~1,000 labeled cells, respectively, at both 3 and 7 T.Results: A high cell labeling efficiency (>90%) was achieved with heparin + protamine + ferumoxytol nanocomplexes. Less than 100 cells were detectable in the gelatin phantom at both 3 and 7 T. The 7 T data showed more than double CNR efficiency compared to the corresponding sequences at 3 T. The CNR efficiencies of phase-cycled bSSFP images were higher compared to those of SWI, and the root mean square combined bSSFP showed the highest CNR efficiency with minimal banding. Following co-registration of microscope and MR images, more cells (51/63) were detected by bSSFP at 7 T than at 3 T (36/63). On pig brain, both ~100 and ~1,000 cells were detected at 3 and 7 T. While the cell size appeared larger due to blooming effects on SWI, bSSFP allowed better contrast to precisely identify the location of the cells with higher signal-to-noise ratio efficiency.Conclusion: The proposed cellular MRI with ferumoxytol nanocomplex-labeled macrophages at 7 T has a high sensitivity to detect

Jian Qiu,1 Yunfeng Fu,2 Xiaohong Huang,1 Longwen Shu,1 Jiewei Xu,3 Weiguo Lu2,4 1Department of Obstetrics and Gynecology, Huzhou Central Hospital, Huzhou, Zhejiang, 2Department of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 3Department of General Surgery, Huzhou Central Hospital, Huzhou, Zhejiang, 4Women’s Reproductive Health Laboratory of Zhejiang Province, Hangzhou, Zhejiang, People’s Republic of China Abstract: Uterine artery embolization (UAE) is considered to be an effective treatment for patients with cesarean scar pregnancy, especially for those presenting uncontrollable hemorrhage. However, it can also cause some potential complications. Pulmonary embolism is a rare but fatal complication in patients treated with UAE. Here, we report a case of a woman who was diagnosed with cesarean scar pregnancy presenting with pulmonary embolism during the operation of dilation and curettage after UAE treatment. Prompt resuscitation was carried out and the patient received anticoagulant treatment immediately. During the follow-up, she recovered well without any complications. We present the clinical details and imaging findings, followed by discussions of the etiology, treatments, and prevention strategies. Keywords: pulmonary embolism, cesarean scar pregnancy, uterine artery embolization

Flow-acoustic feedback is one of the main types of noise in a cavity, is caused by the instability of the cavity shear layer and is enhanced through an acousticwave feedback mechanism. The flow characteristics of the cavity boundary/shear layer and the characteristic frequencies of the flow-acoustic feedback in the cavities are studied numerically, with aspect ratios ranging from 1/2 to 4/3. The freestream Mach number is equal to 0.11, corresponding to an Re-based cavity length of 2.1×105. Improved Delayed Detached Eddy Simulations combined with Ffowcs Williams-Hawkings acoustic analogy are used to simulate the flow and noise characteristics of the cavities. Autocorrelation analysis of flow field fluctuations is used to establish a link between the boundary/shear layer pressure fluctuations and flow-acoustic feedback noise. For the low aspect ratio cavities investigated in this paper, convection velocities along the shear layer development direction are obtained using wavenumberfrequency analysis. The deeper the cavity, the lower the shear layer flow velocity. Correspondingly, the characteristic frequencies of the narrowband noise generated by the flow-acoustic feedback shift linearly toward the low frequency band as the cavity depth increases. The results of the predicted noise characteristic frequencies obtained using wavenumber-frequency analysis and Rossiter's empirical formula are in agreement with the calculated results. [ABSTRACT FROM AUTHOR]

N-methyl-D-aspartate receptors (NMDARs) are crucial for neuronal development and synaptic plasticity. Dysfunction of NMDARs is associated with multiple neurodevelopmental disorders, including epilepsy, autism spectrum disorder, and intellectual disability. Understanding the impact of genetic variants of NMDAR subunits can shed light on the mechanisms of disease. Here, we characterized the functional implications of a de novo mutation of the GluN2A subunit (P1199Rfs*32) resulting in the truncation of the C-terminal domain. The variant was identified in a male patient with epileptic encephalopathy, multiple seizure types, severe aphasia, and neurobehavioral changes. Given the known role of the CTD in NMDAR trafficking, we examined changes in receptor localization and abundance at the postsynaptic membrane using a combination of molecular assays in heterologous cells and rat primary neuronal cultures. We observed that the GluN2A P1199Rfs*32-containing receptors traffic efficiently to the postsynaptic membrane but have increased extra-synaptic expression relative to WT GluN2A-containing NMDARs. Using in silico predictions, we hypothesized that the mutant would lose all PDZ interactions, except for the recycling protein Scribble1. Indeed, we observed impaired binding to the scaffolding protein postsynaptic protein-95 (PSD-95); however, we found the mutant interacts with Scribble1, which facilitates the recycling of both the mutant and the WT GluN2A. Finally, we found that neurons expressing GluN2A P1199Rfs*32 have fewer synapses and decreased spine density, indicating compromised synaptic transmission in these neurons. Overall, our data show that GluN2A P1199Rfs*32 is a loss-of-function variant with altered membrane localization in neurons and provide mechanistic insight into disease etiology. [ABSTRACT FROM AUTHOR]

Personalized decision-making, aiming to derive optimal treatment regimes based on individual characteristics, has recently attracted increasing attention in many fields, such as medicine, social services and economics. Current literature mainly focuses on estimating treatment regimes from a single source population. In real-world applications, the distribution of a target population can be different from that of the source population. Therefore, treatment regimes learned by existing methods may not generalize well to the target popu- lation. Because of privacy concerns and other practical issues, individual-level data from the target population are often not available, which makes treatment regime learning more challenging. We consider the problem of treatment regime estimation when the source and target populations may be heterogeneous, individual-level data are available from the source population and only the summary information of covariates, such as moments, is accessible from the target population. We develop a weighting framework that tailors a treatment regime for a given target population by leveraging the available summary statistics. Specifically, we propose a calibrated augmented inverse probability weighted estimator of the value function for the target population and estimate an optimal treatment regime by maximizing this estimator within a class of prespecified regimes. We show that the proposed calibrated estimator is consistent and asymptotically normal even with flexible semi/nonparametric models for nuisance function approximation, and that the variance of the value estimator can be consistently estimated. We demonstrate the empirical performance of the proposed method using simulation studies and a real application using two datasets on sepsis. [ABSTRACT FROM AUTHOR]

Here, two field-grown grape species including Vitis amurensis Rupr. ‘Shuangfeng’ and V. riparia × V. labrusca ‘Beta’ showed different survival capabilities after overwintering. Their shoots’ cold hardiness and associated physiological changes were analyzed during seasonal cold acclimation and deaaclimation to illuminate response mechanisms on low temperature. The fluctuations of cold hardiness were synchronized in the two species, but ‘Shuangfeng’ had a higher tolerance than ‘Beta’ to cold stress, which was consistent with the field performance. Leaves and shoots of ‘Shuangfeng’ reddened, responds quickly to the natural low temperature, while those of ‘Beta’ remained green during the same period. Perhaps owing to variations in the carbohydrate accumulations in different colored leaves, so the freezing tolerance of ‘Shuangfeng’ correlated with total soluble sugars in the phloem, while the starch in the xylem and phloem determined the ‘Beta’s tolerance. The timing and types of the accumulated carbohydrates may be responsible for the difference in the water status, energy accumulation and cold hardiness between the two grape species. [ABSTRACT FROM AUTHOR]