bluuebunny/crossref_metadata_2025 huggingface dataset:
A Density‐Based Ramp Metering Model Considering Multilane Context in Urban Expressways
Authors: Tang Li , Luo Xia , Zhai Pengfei , Gao Xunfei
Published: March 2017

As one of the most effective intelligent transportation strategies, ramp metering is regularly discussed and applied all over the world. The classic ramp metering algorithm ALINEA dominates in practical applications due to its advantages in stabilizing traffic flow at a high throughput level. Although ALINEA chooses the traffic occupancy as the optimization parameter, the classic traffic flow variables (density, traffic volume, and travel speed) may be easier obtained and understood by operators in practice. This paper presents a density‐based ramp metering model for multilane context (MDB‐RM) on urban expressways. The field data of traffic flow parameters is collected in Chengdu, China. A dynamic density model for multilane condition is developed. An error function represented by multilane dynamic density is introduced to adjust the different usage between lanes. By minimizing the error function, the density of mainstream traffic can stabilize at the set value, while realizing the maximum decrease of on‐ramp queues. Also, VISSIM Component Object Model of Application Programming Interface is used for comparison of the MDB‐RM model with a noncontrol, ALINEA, and density‐based model, respectively. The simulation results indicate that the MDB‐RM model is capable of achieving a comprehensive optimal result from both sides of the mainstream and on‐ramp.
Statistical Comparison of Cloud and Aerosol Vertical Properties between Two Eastern China Regions Based on CloudSat/CALIPSO Data
Authors: Qiu Yujun , Wang Jing , Yang Keran
Published: March 2017

The relationship between cloud and aerosol properties was investigated over two 4° × 4° adjacent regions in the south (R1) and in the north (R2) in eastern China. The CloudSat/CALIPSO data were used to extract the cloud and aerosol profiles properties. The mean value of cloud occurrence probability (COP) was the highest in the mixed cloud layer (−40°C~0°C) and the lowest in the warm cloud layer (>0°C). The atmospheric humidity was more statistically relevant to COP in the warm cloud layer than aerosol condition. The differences in COP between the two regions in the mixed cloud layer and ice cloud layer (<−40°C) had good correlations with those in the aerosol extinction coefficient. A radar reflectivity factor greater than −10 dBZ occurred mainly in warm cloud layers and mixed cloud layers. A high-COP zone appeared in the above-0°C layer with cloud thicknesses of 2-3 km in both regions and in all the four seasons, but the distribution of the zonal layer in R2 was more continuous than that in R1, which was consistent with the higher aerosol optical thickness in R2 than in R1 in the above-0°C layer, indicating a positive correlation between aerosol and cloud probability.
Effect of Herbal and Fluoride Mouth Rinses onStreptococcus mutansand Dental Caries among 12–15-Year-Old School Children: A Randomized Controlled Trial
Authors: Somaraj Vinej , Shenoy Rekha P. , Shenoy Panchmal Ganesh , Kumar Vijaya , Jodalli Praveen S. , Sonde Laxminarayan
Published: March 2017

To assess and compare the effect of herbal and fluoride mouth rinses onStreptococcus mutanscount and glucan synthesis byStreptococcus mutansand dental caries, a parallel group placebo controlled randomized trial was conducted among 240 schoolchildren (12–15 years old). Participants were randomly divided and allocated into Group I (0.2% fluoride group), Group II (herbal group), and Group III (placebo group). All received 10 ml of respective mouth rinses every fortnight for a period of one year. Intergroup and intragroup comparison were done forStreptococcus mutanscount and glucan synthesis byStreptococcus mutansand dental caries.Streptococcus mutanscount showed a statistically significant difference between Group I and Group III (p=0.035) and also between Group II and Group III (p=0.039). Glucan concentration levels showed a statistically significant difference (p=0.024) between Group II and Group III at 12th month. Mean DMF scores showed no statistical difference between the three groups (p=0.139). No difference in the level of significance was seen in the intention-to-treat and per-protocol analysis. The present study showed that both herbal and fluoride mouth rinses, when used fortnightly, were equally effective and could be recommended for use in school-based health education program to control dental caries. Trial registration number isCTRI/2015/08/006070.
Prevalence and Bacterial Isolates of Mastitis in Dairy Farms in Selected Districts of Eastern Harrarghe Zone, Eastern Ethiopia
Authors: Zeryehun Tesfaheywet , Abera Gerema
Published: March 2017

The study was conducted from November 2015 to April 2016 to estimate the prevalence of clinical and subclinical mastitis in lactating cows, to assess the associated risk factors, and to isolate the major bacterial pathogens in dairy farms in selected district of Eastern Harrarghe Zone, Eastern Ethiopia. The study was carried out in 384 dairy cows based on data collection, farm visit, animal examination, California mastitis test (CMT), and isolation bacterial pathogens using standard techniques. In the present study the overall mastitis at cow level was 247 (64.3%). The prevalence of clinical and subclinical mastitis and quarter level prevalence for clinical and subclinical mastitis were 12.5% and 51.8% at cow level and 10.7% and 46.4% at quarter level, respectively. Clinically, 101 (6.6%) quarters which belong to 75 (19.5%) animals were found to be with blind teat. In the present study prevalence of mastitis was significantly associated with parity and age (p<0.05). Bacteriological examination of milk sample revealed 187 isolates where coagulase negative Staphylococcus species (CNS) (34.2%) was the predominant species while Streptococcus faecalis (2.1%) was identified as the least bacteria. The present study concluded that prevalence of mastitis particularly the subclinical mastitis was major problem of dairy cows in the area and hence warrants serious attention.
Components of Goutengsan in Rat Plasma by Microdialysis Sampling and Its Protection on Aβ1–42‐Induced PC12 Cells Injury
Authors: Huang Hou-Cai , Wang Chun-Fei , Gu Jun-Fei , Chen Juan , Hou Xue-Feng , Zhong Rong-Ling , Xia Zhi , Zhao Di , Yang Nan , Wang Jing , Tan Xiao-Bin , Jia Xiao-Bin , Di Liu-Qing , Dong Zi-Bo , Feng Liang
Published: March 2017

Goutengsan, a Chinese herbal formula, potential protection on Alzheimer’s disease (AD) has been less reported. In current study, we investigated the protection of Goutengsan on Aβ1–42‐induced pheochromocytoma‐derived cells (PC12). Furthermore, the components from Goutengsan in rat plasma were identified by microdialysis (MD) for in vivo sampling. Meanwhile, the protection of components identified was also verified. At last, we found that Goutengsan has a potential protective effect on Aβ1–42‐induced PC12 cells via reducing cells damage and increasing cells vitality as well as six components (pachymic acid, liquiritin, rhynchophylline, isorhynchophylline, corynoxeine, and isocorynoxeine) which may be effective components. This study helps to understand the treatment of Goutengsan for AD and would facilitate the clinical and further studies for this formula.
The Expression of IL-6, TNF-α, and MCP-1 in Respiratory Viral Infection in Acute Exacerbations of Chronic Obstructive Pulmonary Disease
Authors: Zheng Jingtong , Shi Yue , Xiong Lingxin , Zhang Weijie , Li Ying , Gibson Peter G. , Simpson Jodie L. , Zhang Chao , Lu Junying , Sai Jingying , Wang Guoqiang , Wang Fang
Published: March 2017

Viral infection is a common trigger for acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The aim of this study is to investigate the expression of cytokines in AECOPD. Patients with AECOPD requiring hospitalization were recruited. Meanwhile healthy volunteers of similar age that accepted routine check-ups and showed no clinical symptoms of inflammatory diseases were also recruited. Induced sputum and serum were collected. Induced sputum of participants was processed and tested for thirteen viruses and bacteria. Forty cytokines were assayed in serum using the Quantibody Human Inflammation Array 3 (Ray Biotech, Inc.). The most common virus detected in virus positive AECOPD (VP) was influenza A (16%). No virus was found in controls. Circulating levels of IL-6, TNF-α, and MCP-1 were elevated in VP and coinfection subjects (p<0.05), while the levels of 37 other cytokines showed no difference, compared with virus negative groups and controls (p>0.05). Additionally, VP patients were less likely to have received influenza vaccination. VP patients had a systemic inflammation response involving IL-6, TNF-α, and MCP-1 which may be due to virus-induced activation of macrophages. There are important opportunities for further investigating AECOPD mechanisms and for the development of better strategies in the management and prevention of virus-related AECOPD.
A New Calculation Method of Dynamic Kill Fluid Density Variation during Deep Water Drilling
Authors: Fan Honghai , Deng Song , Ren Weiyan , Duan Xili , Cui Cong , Yang Jing
Published: March 2017

There are plenty of uncertainties and enormous challenges in deep water drilling due to complicated shallow flow and deep strata of high temperature and pressure. This paper investigates density of dynamic kill fluid and optimum density during the kill operation process in which dynamic kill process can be divided into two stages, that is, dynamic stable stage and static stable stage. The dynamic kill fluid consists of a single liquid phase and different solid phases. In addition, liquid phase is a mixture of water and oil. Therefore, a new method in calculating the temperature and pressure field of deep water wellbore is proposed. The paper calculates the changing trend of kill fluid density under different temperature and pressure by means of superposition method, nonlinear regression, and segment processing technique. By employing the improved model of kill fluid density, deep water kill operation in a well is investigated. By comparison, the calculated density results are in line with the field data. The model proposed in this paper proves to be satisfactory in optimizing dynamic kill operations to ensure the safety in deep water.
Hypercholesterolemia Increases Colorectal Cancer Incidence by Reducing Production of NKT and γδ T Cells from Hematopoietic Stem Cells
Authors: Tie Guodong , Yan Jinglian , Khair Lyne , Messina Julia A. , Deng April , Kang Joonsoo , Fazzio Thomas , Messina Louis M.
Published: March 2017

Obesity will soon surpass smoking as the most preventable cause of cancer. Hypercholesterolemia, a common comorbidity of obesity, has been shown to increase cancer risk, especially colorectal cancer. However, the mechanism by which hypercholesterolemia or any metabolic disorder increases cancer risk remains unknown. In this study, we show that hypercholesterolemia increases the incidence and pathologic severity of colorectal neoplasia in two independent mouse models. Hypocholesterolemia induced an oxidant stress–dependent increase in miR101c, which downregulated Tet1 in hematopoietic stem cells (HSC), resulting in reduced expression of genes critical to natural killer T cell (NKT) and γδ T-cell differentiation. These effects reduced the number and function of terminally differentiated NKT and γδ T cells in the thymus, the colon submucosa, and during early tumorigenesis. These results suggest a novel mechanism by which a metabolic disorder induces epigenetic changes to reduce lineage priming of HSC toward immune cells, thereby compromising immunosurveillance against cancer. Cancer Res; 77(9); 2351–62. ©2017 AACR.
Individualized Breast Cancer Characterization through Single-Cell Analysis of Tumor and Adjacent Normal Cells
Authors: Anjanappa Manjushree , Cardoso Angelo , Cheng Lijun , Mohamad Safa , Gunawan Andrea , Rice Susan , Dong Yan , Li Lang , Sandusky George E. , Srour Edward F. , Nakshatri Harikrishna
Published: March 2017

There is a need to individualize assays for tumor molecular phenotyping, given variations in the differentiation status of tumor and normal tissues in different patients. To address this, we performed single-cell genomics of breast tumors and adjacent normal cells propagated for a short duration under growth conditions that enable epithelial reprogramming. Cells analyzed were either unselected for a specific subpopulation or phenotypically defined as undifferentiated and highly clonogenic ALDH+/CD49f+/EpCAM+ luminal progenitors, which express both basal cell and luminal cell–enriched genes. We analyzed 420 tumor cells and 284 adjacent normal cells for expression of 93 genes that included a PAM50-intrinsic subtype classifier and stemness-related genes. ALDH+/CD49f+/EpCAM+ tumor and normal cells clustered differently compared with unselected tumor and normal cells. PAM50 gene-set analyses of ALDH+/CD49f+/EpCAM+ populations efficiently identified major and minor clones of tumor cells, with the major clone resembling clinical parameters of the tumor. Similarly, a stemness-associated gene set identified clones with divergent stemness pathway activation within the same tumor. This refined expression profiling technique distinguished genes truly deregulated in cancer from genes that identify cellular precursors of tumors. Collectively, the assays presented here enable more precise identification of cancer-deregulated genes, allow for early identification of therapeutically targetable tumor cell subpopulations, and ultimately provide a refinement of precision therapeutics for cancer treatment. Cancer Res; 77(10); 2759–69. ©2017 AACR.
Long-term Adherence to Colorectal Cancer Screening; 5-Year Results from the Systems of Support to Increase Colorectal Cancer Screening Trial
Authors: Green BB , Anderson ML , Chubak J , Fuller S , Meenan RT , Vernon SW
Published: March 2017

Colorectal cancer (CRC) is the second-leading cause of cancer deaths. Mortality could be rapidly reduced through higher uptake and adherence to CRC screening. Information on long-term screening adherence comes from organized programs that lack a comparison group. Objective: Systems of Support to Increase Colorectal Cancer Screening is an ongoing trial testing a centralized mailed and phone-based program to increase long-term CRC screening adherence. We hypothesized that compared to usual care (UC) intervention-arm patients would have more time in compliance with CRC screening guidelines over 5 years. Methods: The setting was an integrated healthcare organization in Washington State. UC included patient-centered medical home with clinic-based strategies to increase screening. Participants included 4675 individuals initially aged 50–74, not current for CRC screening. Intervention arms combined were compared to UC. The primary outcome was the percent of time covered for CRC screening over 5 years of follow-up. Screening tests contributed covered time based on national guidelines for screening intervals. All participants contributed data, but were censored at disenrollment, death, age 76, or CRC diagnosis. Interventions: Patients were randomly assigned to receive UC, or one of three stepped care interventions: 1. Mailings including mailed fecal tests, a call-in number if colonoscopy or sigmoidoscopy was preferred; 2. Mailings plus brief telephone assistance; 3. Mailings and telephone assistance plus nurse navigation. In year 3, intervention group participants still CRC screening-eligible were randomized to stopped or continued mailed interventions only. Results: Compared to UC, intervention participants had 31% more time not in need of CRC testing (adjusted rate ratio, weighted for exposure time 1.31 [1.25–1.37], 47.2% vs. 62.0% covered time) over 5 years. Fecal testing was responsible for almost all additional covered time. Compared to intervention participants, UC individuals were more likely never to have completed any CRC testing over 5 years (17.4% vs. 10.3%, net difference 7.2%, P < 0.001) Conclusions: An organized mail and phone program led to increased CRC screening adherence over 5 years, mainly because of regular fecal testing uptake.
Perceptions of Cervical Cancer Risk among Ohio Appalachian Women
Authors: Bernardo BM , Reiter PL , Pennell ML , Padamsee TJ , Ruffin MT , Paskett ED
Published: March 2017

OBJECTIVE: To describe how Ohio Appalachian women are over- or under-estimating risk for cervical cancer by comparing an objective measure of cervical cancer risk to subjective interpretations of risk. METHODS: A cervical cancer risk index was computed for 530 female participants recruited from clinics in Ohio Appalachia (2006–2008). Risk factors for cervical cancer, including human papillomavirus infection, number of sexual partners, parity, age at first intercourse, age at first pregnancy, oral contraceptive use and cigarette smoking were used to create a cervical cancer risk index. This index was used to categorize participants into low, average or high risk for cervical cancer. Subjective risk was assessed by asking women to indicate whether they believe their risk of cervical cancer to be below, about average, or higher than other women. Objective risk categories were compared to subjective risk to determine if women were accurately perceiving risk, or over- or under-estimating risk. A multinomial logistic regression model was used to determine correlates of risk perception accuracy. The outcome was a categorical variable consisting of over-estimating risk, underestimating risk and accurate risk perception, with accurate risk perception serving as the reference level in the model. RESULTS: Out of 530 women, 33.6% (n = 178) over-estimated risk and 24.9% (n = 132) under-estimated risk. Women with household incomes of <$25 k were more likely to under-estimate cervical cancer risk, as opposed to being accurate in their risk perception, than women in households earning over $50 k [OR = 2.06, 95% CI (1.04–4.07)] as were women with less than a high-school education [OR = 2.52, 95% CI (1.06–5.96)] compared to women with a college education. Also, women who reported recent alcohol use were more likely to under-estimate risk [OR = 1.94, 95% CI (1.18–3.19)] compared to women with no self-reported recent alcohol use. No variables were found to be associated with risk over-estimation. CONCLUSIONS: Many women in Ohio Appalachia do not accurately perceive their cervical cancer risk. Low income and education are associated with under-estimating risk. Future studies should determine if risk misperceptions are associated with cervical cancer screening and other preventive behaviors.
Targeting CD38 Suppresses Induction and Function of T Regulatory Cells to Mitigate Immunosuppression in Multiple Myeloma
Authors: Feng Xiaoyan , Zhang Li , Acharya Chirag , An Gang , Wen Kenneth , Qiu Lugui , Munshi Nikhil C. , Tai Yu-Tzu , Anderson Kenneth C.
Published: March 2017

Purpose: We study CD38 levels in immunosuppressive CD4+CD25highFoxp3+ regulatory T cells (Treg) and further define immunomodulating effects of a therapeutic CD38 mAb isatuximab/SAR650984 in multiple myeloma.

Experimental Design: We evaluated percentages of CD38-expressing subsets in Tregs from normal donors and multiple myeloma patients. Peripheral blood mononuclear cells (PBMC) were then treated with isatuximab with or without lenalidomide or pomalidomide to identify their impact on the percentage and immunosuppressive activity of Tregs on CD4+CD25− T cells (Tcons). We investigated the mechanism of increased Tregs in multiple myeloma patients in ex vivo cocultures of multiple myeloma cells with PBMCs or Tcons.

Results: CD38 expression is higher on Tregs than Tcons from multiple myeloma patients versus normal donors. CD38 levels and the percentages of CD38high Tregs are increased by lenalidomide and pomalidomide. Isatuximab preferentially decreases Treg and increases Tcon frequencies, which is enhanced by pomalidomide/lenalidomide. Isatuximab reduces Foxp3 and IL10 in Tregs and restores proliferation and function of Tcons. It augments multiple myeloma cell lysis by CD8+ T and natural killer cells. Coculture of multiple myeloma cells with Tcons significantly induces Tregs (iTregs), which express even higher CD38, CD25, and FoxP3 than natural Tregs. This is associated with elevated circulating CD38+ Tregs in multiple myeloma patients versus normal donors. Conversely, isatuximab decreases multiple myeloma cell- and bone marrow stromal cell–induced iTreg by inhibiting both cell–cell contact and TGFβ/IL10. Finally, CD38 levels correlate with differential inhibition by isatuximab of Tregs from multiple myeloma versus normal donors.

Conclusions: Targeting CD38 by isatuximab can preferentially block immunosuppressive Tregs and thereby restore immune effector function against multiple myeloma. Clin Cancer Res; 23(15); 4290–300. ©2017 AACR.
White Matter Disruption and Connected Speech in Non-Fluent and Semantic Variants of Primary Progressive Aphasia
Authors: Marcotte Karine , Graham Naida L. , Fraser Kathleen C. , Meltzer Jed A. , Tang-Wai David F. , Chow Tiffany W. , Freedman Morris , Leonard Carol , Black Sandra E. , Rochon Elizabeth
Published: March 2017

Differential patterns of white matter disruption have recently been reported in the non-fluent (nfvPPA) and semantic (svPPA) variants of primary progressive aphasia (PPA). No single measure is sufficient to distinguish between the PPA variants, but connected speech allows for the quantification of multiple measures. The aim of the present study was to further investigate the white matter correlates associated with connected speech features in PPA. We examined the relationship between white matter metrics and connected speech deficits using an automated analysis of transcriptions of connected speech and diffusion tensor imaging in language-related tracts. Syntactic, lexical, and semantic features were automatically extracted from transcriptions of topic-directed interviews conducted with groups of individuals with nfvPPA or svPPA as well as with a group of healthy controls. A principal component analysis was performed in order to reduce the number of language measures and yielded a five-factor solution. The results indicated that nfvPPA patients differed from healthy controls on a syntactic factor, and svPPA patients differed from controls on two semantic factors. However, the patient groups did not differ on any factor. Moreover, a correlational analysis revealed that the lexical richness factor was significantly correlated with radial diffusivity in the left inferior longitudinal fasciculus, which suggests that semantic deficits in connected speech reflect a disruption of this ventral pathway, and which is largely consistent with the results of previous studies. Using an automated approach for the analysis of connected speech combined with probabilistic tractography, the present findings demonstrate that nfvPPA patients are impaired relative to healthy controls on syntactic measures and have increased radial diffusivity in the left superior longitudinal fasciculus, whereas the svPPA group was impaired on lexico-semantic measures relative to controls and showed increased radial diffusivity in the uncinate and inferior longitudinal fasciculus bilaterally.
Identification of a Cryptic Insertion ins(11;X)(q23;q28q12) Resulting in a KMT2A-FLNA Fusion in a 13-Month-Old Child with Acute Myelomonocytic Leukemia
Authors: Lentes Jana , Thomay Kathrin , Schneider Dominik T. , Bernbeck Benedikt , Reinhardt Dirk , Marschalek Rolf , Meyer Claus , Schlegelberger Brigitte , Göhring Gudrun
Published: March 2017

In pediatric acute myeloid leukemia (AML), chromosomal abnormalities leading to a disruption of the lysine methyltransferase 2A (KMT2A) gene in 11q23 are the most frequent rearrangements. Here, we report on the identification of a novel cryptic insertion, ins(11;X)(q23;q28q12), resulting in a translocation of the KMT2A gene in 11q23, leading to a KMT2A-FLNA fusion in a 13-month-old boy with de novo acute myelomonocytic leukemia, who died 38 days after diagnosis. The patient presented a complex karyotype 48∼49,Y,del(X)(q12),+del(X)(q12),+8,ins(11;X)(q23; q28q12),+19. The identified fusion gene was predicted to be out-of-frame (fusion of portions of KMT2A exon 11 with FLNA exon 11). However, RT-PCR experiments demonstrated that a potentially functional transcript was generated by alternative splicing where KMT2A exon 10 was spliced in-frame to the truncated FLNA exon 11. This case report helps to better understand the rare but potentially severe impact of KMT2A- FLNA fusions in infants with AML to improve prognostic stratification of therapy and clinical management.
Repeated Cold Stress Reduces Cyclophosphamide-Induced Cystitis/Bladder Pain and Macrophage Activity in Mice
Authors: Tsubota Maho , Miyamoto Tomoyoshi , Hiruma Saki , Saeki Haruka , Miyazaki Takaya , Sekiguchi Fumiko , Funakami Yoshinori , Kawabata Atsufumi
Published: March 2017

We examined the effect of repeated cold (RC) stress on cyclophosphamide (CPA)-induced cystitis/bladder pain in mice, in relation to macrophage activity. CPA, given i.p. at 400 mg/kg, caused bladder pain symptoms accompanying cystitis in both unstressed and RC-stressed mice, which were prevented by the macrophage inhibitor minocycline. A low dose, that is, 200 mg/kg, of CPA still produced bladder pain symptoms in unstressed but not RC-stressed mice. Lipopolysaccharide-induced cytokine production in peritoneal macrophages from RC-stressed mice was less than that from unstressed mice. Thus, RC stress appears to reduce CPA-induced bladder pain in mice, which may be associated with the decreased macrophage activity.
The Clinical Characteristics of Acute Cerebrovascular Accidents Resulting from Ovarian Hyperstimulation Syndrome
Authors: Yang Shuna , Yuan Junliang , Qin Wei , Li Yue , Yang Lei , Hu Wenli
Published: March 2017

Background and Purpose: Ovarian hyperstimulation syndrome (OHSS) is a serious complication that occurs after the ovarian-induction treatment. Acute cerebrovascular accident is one of the most dangerous manifestations of the syndrome. However, the characteristics of stroke resulting from OHSS have so far not been well summarised in any study. Methods: We reported 2 cases of acute cerebrovascular accidents secondary to OHSS. And then we performed a literature search for reports on this type of stroke, and summarised their characteristics. Results: Thirty-six published cases of this type of stroke were reviewed. Thirty two out of 36 (88.9%) of the women were 35 years old or younger. Stroke in 28 out of 36 (77.8%) of these cases was caused by arterial thrombosis. In 17 out of 28 cases, the involved cerebral vascular branches were mainly middle cerebral artery (MCA) and internal carotid artery (ICA). The acute cerebrovascular accidents happened 7 and 9.25 days after embryo transplantation or 8 and 8.33 days after last human chorionic gonadotropin treatment respectively. The prognosis of patients was relatively good after anticoagulation and some supportive treatments. Conclusion: The MCA and ICA are easily involved in stroke resulting from OHSS. The young age may be a risk factor for developing stroke secondary to OHSS. Once thromboembolism develops, administering appropriate therapy is crucial.
Gene Editing With CRISPR/Cas9 RNA-Directed Nuclease
Authors: Doetschman Thomas , Georgieva Teodora
Published: March 2017

Genetic engineering of model organisms and cultured cells has for decades provided important insights into the mechanisms underlying cardiovascular development and disease. In the past few years the development of several nuclease systems has broadened the range of model/cell systems that can be engineered. Of these, the CRISPR (clustered regularly interspersed short palindromic repeats)/Cas9 (CRISPR-associated protein 9) system has become the favorite for its ease of application. Here we will review this RNA-guided nuclease system for gene editing with respect to its usefulness for cardiovascular studies and with an eye toward potential therapy. Studies on its off-target activity, along with approaches to minimize this activity will be given. The advantages of gene editing versus gene targeting in embryonic stem cells, including the breadth of species and cell types to which it is applicable, will be discussed. We will also cover its use in iPSC for research and possible therapeutic purposes; and we will review its use in muscular dystrophy studies where considerable progress has been made toward dystrophin correction in mice. The CRISPR/Ca9s system is also being used for high-throughput screening of genes, gene regulatory regions, and long noncoding RNAs. In addition, the CRISPR system is being used for nongene-editing purposes such as activation and inhibition of gene expression, as well as for fluorescence tagging of chromosomal regions and individual mRNAs to track their cellular location. Finally, an approach to circumvent the inability of post-mitotic cells to support homologous recombination-based gene editing will be presented. In conclusion, applications of the CRISPR/Cas system are expanding at a breath-taking pace and are revolutionizing approaches to gain a better understanding of human diseases.
Cardiovascular Disease and Patterns of Change in Functional Status Over 15 Years: Findings From the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Kucharska‐Newton Anna , Griswold Michael , Yao Zhihao Howard , Foraker Randi , Rose Kathryn , Rosamond Wayne , Wagenknecht Lynne , Koton Silvia , Pompeii Lisa , Windham B. Gwen
Published: March 2017

Background

Cardiovascular disease (
CVD
) is the leading cause of premature disability, yet few prospective studies have examined functional status (
FS
) among persons with
CVD
. Our aim was to examine patterns of change in
FS
prior to and after hospitalization for nonfatal myocardial infarction, stroke, and heart failure among members of the Atherosclerosis Risk in Communities (ARIC) study cohort.

Methods and Results

FS
was assessed using a modified Rosow‐Breslau questionnaire administered during routine annual telephone interviews conducted from 1993 through 2007 among 15 277
ARIC
study participants. An
FS
score was constructed as a summary measure of responses to questions about participants' ability to perform selected tasks of daily living (eg, walking half a mile, climbing stairs). Incidence of
CVD
was assessed through
ARIC
surveillance of hospitalized events. Rate of change in
FS
over time prior to and following a
CVD
event was examined using generalized estimating equations. A decline in
FS
was observed on average 2 years prior to a myocardial infarction hospitalization and on average 3 years prior to a stroke or heart failure hospitalization.
FS
post–myocardial infarction declined relative to pre‐event levels but improved to close to pre–myocardial infarction levels within 3 years. Decline in
FS
following incident heart failure and stroke remained over time. Observed patterns of change in
FS
did not differ appreciably by race or sex.

Conclusions

This study documents that a decline in
FS
precedes incidence of
CVD
‐related hospitalization by at least 2 years, providing a strong argument for routine preventative assessment of
FS
among older adults.
Efficacy of Prophylactic Dexmedetomidine in Preventing Postoperative Junctional Ectopic Tachycardia After Pediatric Cardiac Surgery
Authors: El Amrousy Doaa Mohamed , Elshmaa Nagat S. , El‐Kashlan Mohamed , Hassan Samir , Elsanosy Mohamed , Hablas Nahed , Elrifaey Shimaa , El‐Feky Wael
Published: March 2017

Background

Postoperative junctional ectopic tachycardia is one of the most serious arrhythmias that occur after pediatric cardiac surgery, difficult to treat and better to be prevented. Our aim was to assess the efficacy of prophylactic dexmedetomidine in preventing junctional ectopic tachycardia after pediatric cardiac surgery.

Methods and Results

A prospective controlled study was carried out on 90 children who underwent elective cardiac surgery for congenital heart diseases. Patients were randomized into 2 groups. Group I (dexmedetomidine group): 60 patients received dexmedetomidine; Group
II
(Placebo group): 30 patients received the same amount of normal saline intravenously. The primary outcome was the incidence of postoperative junctional ectopic tachycardia. Secondary outcomes included bradycardia, hypotension, vasoactive inotropic score, ventilation time, pediatric cardiac care unit stay, length of hospital stay, and perioperative mortality. The incidence of junctional ectopic tachycardia was significantly reduced in the dexmedetomidine group (3.3%) compared with the placebo group (16.7%) with
P
<0.005. Heart rate while coming off cardiopulmonary bypass was significantly lower in the dexmedetomidine group (130.6±9) than the placebo group (144±7.1) with
P
<0.001. Mean ventilation time, and mean duration of intensive care unit and hospital stay (days) were significantly shorter in the dexmedetomidine group than the placebo group (
P
<0.001). However, there was no significant difference between the 2 groups as regards mortality, bradycardia, or hypotension (
P
>0.005).

Conclusion

Prophylactic use of dexmedetomidine is associated with significantly decreased incidence of postoperative junctional ectopic tachycardia in children after congenital heart surgery without significant side effects.
Natural History of Ruptured but Untreated Intracranial Aneurysms
Authors: Korja Miikka , Kivisaari Riku , Rezai Jahromi Behnam , Lehto Hanna
Published: March 2017

Background and Purpose—

Knowledge on a natural history of untreated ruptured intracranial aneurysms is based on a small historical cohort from 1960s. We calculated mortality rates for patients with untreated ruptured intracranial aneurysms using a more recent and relatively large hospital cohort.

Methods—

Patients admitted to the study hospital between 1968 and 2007 with saccular but untreated ruptured intracranial aneurysms were identified from the hospital aneurysm registry of 6850 patients. The study cohort included only patients who were followed up until death and for whom the date of symptom onset and the date of hospital admission were available.

Results—

For 510 patients identified, the median survival time from symptom onset to death was 20 days. The 1-year mortality rate was 65%, but varied substantially by admission delays and clinical status on admission, being lowest (13%) for patients admitted later than a month after symptom onset and highest (89%) for poor-grade patients. The 1-year mortality rate was 75% for good-grade patients admitted within a week.

Conclusions—

Mortality rates for patients with untreated ruptured intracranial aneurysms are even worse than presented in the historical study. When discussing with subarachnoid hemorrhage patients and their relatives about treatment options, the presented natural history figures are of use.
Effectiveness of an Intervention to Improve Risk Factor Knowledge in Patients With Stroke
Authors: Olaiya Muideen T. , Cadilhac Dominique A. , Kim Joosup , Ung David , Nelson Mark R. , Srikanth Velandai K. , Bladin Christopher F. , Gerraty Richard P. , Fitzgerald Sharyn M. , Phan Thanh , Frayne Judith , Thrift Amanda G.
Published: March 2017

Background and Purpose—

Despite the benefit of risk awareness in secondary prevention, survivors of stroke are often unaware of their risk factors. We determined whether a nurse-led intervention improved knowledge of risk factors in people with stroke or transient ischemic attack.

Methods—

Prospective study nested within a randomized controlled trial of risk factor management in survivors of stroke or transient ischemic attack. Intervention: 3 nurse education visits and specialist review of care plans. Outcome: unprompted knowledge of risk factors of stroke or transient ischemic attack at 24 months. Effect of intervention on knowledge and factors associated with knowledge were determined using multivariable regression models.

Results—

Knowledge was assessed in 268 consecutive participants from the main trial, 128 in usual care and 140 in the intervention. Overall, 34% of participants were unable to name any risk factor. In adjusted analyses, the intervention group had better overall knowledge than controls (incidence risk ratio, 1.26; 95% confidence interval, 1.00–1.58). Greater functional ability and polypharmacy were associated with better knowledge and older age and having more comorbidities associated with poorer knowledge.

Conclusions—

Overall knowledge of risk factors of stroke or transient ischemic attack was better in the intervention group than controls. However, knowledge was generally poor. New and more effective strategies are required, especially in subgroups identified as having poor knowledge.

Clinical Trial Registration—

URL:
http://www.anzctr.org.au
. Unique identifier: ACTRN12608000166370.
Major Thought Restructuring: The Roles of Different Prefrontal Cortical Regions
Authors: Seyed-Allaei Shima , Avanaki Zahra Nasiri , Bahrami Bahador , Shallice Tim
Published: March 2017

An important question for understanding the neural basis of problem solving is whether the regions of human prefrontal cortices play qualitatively different roles in the major cognitive restructuring required to solve difficult problems. However, investigating this question using neuroimaging faces a major dilemma: either the problems do not require major cognitive restructuring, or if they do, the restructuring typically happens once, rendering repeated measurements of the critical mental process impossible. To circumvent these problems, young adult participants were challenged with a one-dimensional Subtraction (or Nim) problem [Bouton, C. L. Nim, a game with a complete mathematical theory. The Annals of Mathematics, 3, 35–39, 1901] that can be tackled using two possible strategies. One, often used initially, is effortful, slow, and error-prone, whereas the abstract solution, once achieved, is easier, quicker, and more accurate. Behaviorally, success was strongly correlated with sex. Using voxel-based morphometry analysis controlling for sex, we found that participants who found the more abstract strategy (i.e., Solvers) had more gray matter volume in the anterior medial, ventrolateral prefrontal, and parietal cortices compared with those who never switched from the initial effortful strategy (i.e., Explorers). Removing the sex covariate showed higher gray matter volume in Solvers (vs. Explorers) in the right ventrolateral prefrontal and left parietal cortex.
A Double Dissociation between Anterior and Posterior Superior Temporal Gyrus for Processing Audiovisual Speech Demonstrated by Electrocorticography
Authors: Ozker Muge , Schepers Inga M. , Magnotti John F. , Yoshor Daniel , Beauchamp Michael S.
Published: March 2017

Human speech can be comprehended using only auditory information from the talker's voice. However, comprehension is improved if the talker's face is visible, especially if the auditory information is degraded as occurs in noisy environments or with hearing loss. We explored the neural substrates of audiovisual speech perception using electrocorticography, direct recording of neural activity using electrodes implanted on the cortical surface. We observed a double dissociation in the responses to audiovisual speech with clear and noisy auditory component within the superior temporal gyrus (STG), a region long known to be important for speech perception. Anterior STG showed greater neural activity to audiovisual speech with clear auditory component, whereas posterior STG showed similar or greater neural activity to audiovisual speech in which the speech was replaced with speech-like noise. A distinct border between the two response patterns was observed, demarcated by a landmark corresponding to the posterior margin of Heschl's gyrus. To further investigate the computational roles of both regions, we considered Bayesian models of multisensory integration, which predict that combining the independent sources of information available from different modalities should reduce variability in the neural responses. We tested this prediction by measuring the variability of the neural responses to single audiovisual words. Posterior STG showed smaller variability than anterior STG during presentation of audiovisual speech with noisy auditory component. Taken together, these results suggest that posterior STG but not anterior STG is important for multisensory integration of noisy auditory and visual speech.
Temporal Proximity Promotes Integration of Overlapping Events
Authors: Zeithamova Dagmar , Preston Alison R.
Published: March 2017

Events with overlapping elements can be encoded as two separate representations or linked into an integrated representation, yet we know little about the conditions that promote one form of representation over the other. Here, we tested the hypothesis that the proximity of overlapping events would increase the probability of integration. Participants first established memories for house–object and face–object pairs; half of the pairs were learned 24 hr before an fMRI session, and the other half 30 min before the session. During scanning, participants encoded object–object pairs that overlapped with the initial pairs acquired on the same or prior day. Participants were also scanned as they made inference judgments about the relationships among overlapping pairs learned on the same or different day. Participants were more accurate and faster when inferring relationships among memories learned on the same day relative to those acquired across days, suggesting that temporal proximity promotes integration. Evidence for reactivation of existing memories—as measured by a visual content classifier—was equivalent during encoding of overlapping pairs from the two temporal conditions. In contrast, evidence for integration—as measured by a mnemonic strategy classifier from an independent study [Richter, F. R., Chanales, A. J. H., & Kuhl, B. A. Predicting the integration of overlapping memories by decoding mnemonic processing states during learning. Neuroimage, 124, 323–335, 2016]—was greater for same-day overlapping events, paralleling the behavioral results. During inference itself, activation patterns further differentiated when participants were making inferences about events acquired on the same day versus across days. These findings indicate that temporal proximity of events promotes integration and further influences the neural mechanisms engaged during inference.
Binding by Random Bursts: A Computational Model of Cognitive Control
Authors: Verguts Tom
Published: March 2017

A neural synchrony model of cognitive control is proposed. It construes cognitive control as a higher-level action to synchronize lower-level brain areas. Here, a controller prefrontal area (medial frontal cortex) can synchronize two cortical processing areas. The synchrony is achieved by a random theta frequency-locked neural burst sent to both areas. The choice of areas that receive this burst is determined by lateral frontal cortex. As a result of this synchrony, communication between the two areas becomes more efficient. The model is tested on the classical Stroop cognitive control task, and its operation is explored in several simulations. Both reactive and proactive controls are implemented via theta power modulation. Increasing theta power improves behavioral performance; furthermore, via theta–gamma phase–amplitude coupling, theta also increases gamma frequency power and synchrony in posterior processing areas. Thus, the model solves a central computational problem for cognitive control (how to allow rapid communication between arbitrary brain areas), while making rich contact with behavioral and neurophysiological data.
Noradrenergic Stimulation Impairs Memory Generalization in Women
Authors: Kluen Lisa Marieke , Agorastos Agorastos , Wiedemann Klaus , Schwabe Lars
Published: March 2017

Memory generalization is essential for adaptive decision-making and action. Our ability to generalize across past experiences relies on medial-temporal lobe structures, known to be highly sensitive to stress. Recent evidence suggests that stressful events may indeed interfere with memory generalization. Yet, the mechanisms involved in this generalization impairment are unknown. We tested here whether a pharmacological elevation of major stress mediators—noradrenaline and glucocorticoids—is sufficient to disrupt memory generalization. In a double-blind, placebo-controlled design, healthy men and women received orally a placebo, hydrocortisone, the α2-adrenoceptor antagonist yohimbine that leads to increased noradrenergic stimulation, or both drugs, before they completed an associative learning task probing memory generalization. Drugs left learning performance intact. Yohimbine, however, led to a striking generalization impairment in women, but not in men. Hydrocortisone, in turn, had no effect on memory generalization, neither in men nor in women. The present findings indicate that increased noradrenergic activity, but not cortisol, is sufficient to disrupt memory generalization in a sex-specific manner, with relevant implications for stress-related mental disorders characterized by generalization deficits.
Broadband Mid-Infrared Stand-Off Reflection–Absorption Spectroscopy Using a Pulsed External Cavity Quantum Cascade Laser
Authors: Liu Xunchen , Chae Inseok , Miriyala Naresh , Lee Dongkyu , Thundat Thomas , Kim Seonghwan
Published: March 2017

Broadband mid-infrared molecular spectroscopy is essential for detection and identification of many chemicals and materials. In this report, we present stand-off mid-infrared spectra of 1,3,5-trinitro-1,3,5-triazine or cyclotrimethylene trinitramine (RDX) residues on a stainless-steel surface measured by a broadband external cavity quantum cascade laser (QCL) system. The pulsed QCL is continuously scanned over 800 cm−1 in the molecular fingerprint region and the amplitude of the reflection signal is measured by either a boxcar-averager-based scheme or a lock-in-amplifier-based scheme with 1 MHz and 100 kHz quartz crystal oscillators. The main background noise is due to the laser source instability and is around 0.1% of normalized intensity. The direct absorption spectra have linewidth resolution around 0.1 cm−1 and peak height sensitivity around 10−2 due to baseline interference fringes. Stand-off detection of 5–50 µg/cm2 of RDX trace adsorbed on a stainless steel surface at the distance of 5 m is presented.
Discrete Spectrum Reconstruction Using Integral Approximation Algorithm
Authors: Sizikov Valery , Sidorov Denis
Published: March 2017

An inverse problem in spectroscopy is considered. The objective is to restore the discrete spectrum from observed spectrum data, taking into account the spectrometer’s line spread function. The problem is reduced to solution of a system of linear–nonlinear equations (SLNE) with respect to intensities and frequencies of the discrete spectral lines. The SLNE is linear with respect to lines’ intensities and nonlinear with respect to the lines’ frequencies. The integral approximation algorithm is proposed for the solution of this SLNE. The algorithm combines solution of linear integral equations with solution of a system of linear algebraic equations and avoids nonlinear equations. Numerical examples of the application of the technique, both to synthetic and experimental spectra, demonstrate the efficacy of the proposed approach in enabling an effective enhancement of the spectrometer’s resolution.