bluuebunny/crossref_metadata_2025 huggingface dataset:
Broadband UV-assisted thermal annealing of low-k silicon carbonitride films using a C-rich silazane precursor
Authors: Chang Wei-Yuan , Chung Hau-Ting , Chen Yi-Chang , Leu Jihperng
Published: November 2018

Low-k dielectric silicon carbonitride (SiCxNy) films are deposited by plasma-enhanced chemical vapor deposition using a carbon-rich silazane precursor, N-methyl-aza-2,2,4-trimethylsilacyclopentane (SiC7NH17), at 100 °C. The post-treatments of SiCxNy films are carried out by thermal annealing and a broadband UV-assisted thermal annealing (UV-annealing) at 400 °C for 5 min. Compared to the thermal annealing treatment, UV-annealing can improve both dielectric and mechanical properties of low-k SiCxNy films. Under thermal annealing, SiCxNy films show great thermal stability, but little structural change. In contrast, upon UV-annealing, most of the Si–H and N–H bonds are broken up, which induces more Si–N cross-linking and converts Si–C matrix into Si–N matrix. The ethylene bridges in Si–(CH2)2–Si also remain intact, but the unbridged hydrocarbons in Si–(CH2)2–N and Si–CH2–CH3 bonds decompose completely during the UV-annealing process. These account for the reduced dielectric constant to k = 3.2 from 3.6 and a 21% enhancement of Young's modulus to 7.4 GPa in the SiCxNy films after UV-annealing. Broadband UV-annealing shows promise as a post-treatment method for enhancing the properties of low-k dielectric barrier, SiCxNy films.
The Effect of Projectile Weight on the Optimum Launch Angle and Range
Authors: Herrick David L.
Published: November 2018

A well-known conclusion from elementary ballistic trajectory analysis is that the horizontal range of a projectile is maximized for a launch angle of 45°. The derivation of this result assumes that the launch speed is the same for all possible launch angles, but this neglects the fact that the work done against gravity by the launching mechanism subtracts from the kinetic energy imparted to the projectile. Here we derive a formula for the optimum launch angle for a spring-powered device that takes this angle-dependent factor into account, and examine the resulting consequences for the range of the projectile.
The Color of the Sun – Perception and Spectral Density
Authors: Suits B. H.
Published: November 2018

The peak position of the spectral density for blackbody radiation is given by the Wien displacement law. Within introductory physics materials it is often stated, or implied through example, that the color of the light emitted from a blackbody, such as the Sun, can be ascertained from knowledge of the position of that peak in the spectral density. Such a conclusion is at best incomplete, may be misleading, and in many ways can be considered to be wrong. Here these claims are addressed and a method for introducing and better understanding spectral density is presented. For concreteness, the discussion centers around the solar spectrum, which is often used as an example in physics and astronomy classes.
Improved baking soda vinegar rocket
Authors: Nichols Dan
Published: November 2018

Baking soda and vinegar water bottle rockets provide a fun, cheap way of illustrating Newton’s laws of motion. This article describes safe, reliable improvement over the traditional design of this rocket that will achieve a height of 50 ft.
Project Accelerate: Bringing AP® Physics 1 to Underserved Students
Authors: Greenman Mark D. , Duffy Andrew
Published: November 2018

Economically disadvantaged and underrepresented high school students in many urban, rural, and small suburban communities don’t have access to Advanced Placement® (AP®) courses either because of a lack of trained teachers, limited or no AP program, or a school history of low participation. Physics is often a “gate keeper” course to entry into physical science, technology, engineering and mathematics (STEM) careers and academic programs. Lacking opportunity to access rigorous physics courses in high school, these demographic groups are hard pressed to compete in STEM fields and academic programs with their peers from more affluent communities. Project Accelerate is a partnership program between Boston University (BU) and the nation’s high schools combining the supportive infrastructures from the students’ traditional school with a highly interactive private edX online instructional tool to bring a College Board accredited AP Physics 1 course to schools not offering this opportunity. During the 2015-16 academic year, Boston University piloted this model with four Boston Public School (BPS) high schools and three small suburban high schools. During the first year of the pilot, students enrolled in Project Accelerate outperformed their peer groups enrolled in traditional AP Physics 1 classrooms.
Dispersion of elastic waves in a layer interacting with a Winkler foundation
Authors: Erbaş B. , Kaplunov J. , Nobili A. , Kılıç G.
Published: November 2018

Dispersion of plane harmonic waves in an elastic layer interacting with a one- or two-sided Winkler foundation is analyzed. The long-wave low-frequency polynomial approximations of the full transcendental dispersion relations are derived for a relatively soft foundation. The validity of the conventional engineering formulation of a Kirchhoff plate resting on an elastic foundation is investigated. It is shown that this formulation has to be refined near the cutoff frequency of bending waves. The associated near cutoff expansion is obtained for both cases. A simple explicit formula demonstrating veering of bending and extensional waves is presented for a one-sided foundation.
RAB7A phosphorylation by TBK1 promotes mitophagy via the PINK-PARKIN pathway
Authors: Heo J.-M. , Ordureau A. , Swarup S. , Paulo J. A. , Shen K. , Sabatini D. M. , Harper J. W.
Published: November 2018

TBK1 phosphorylates RAB7A-S72 to support multiple downstream steps in PARKIN-dependent mitophagy.
Nitric Oxide and Iron Signaling Cues Have Opposing Effects on Biofilm Development in Pseudomonas aeruginosa
Authors: Zhu Xinyi , Rice Scott A. , Barraud Nicolas
Published: November 2018

Nitric oxide (NO), which induces biofilm dispersal, is a promising strategy for biofilm control in both clinical and industrial contexts. However, competing environmental signals may reduce the efficacy of NO. The results presented here suggest that the presence of iron represents one such environmental cue that antagonizes the activity of NO as a biofilm-dispersing agent. Based on this understanding, we developed a strategy to enhance dispersal by combining NO with an iron-scavenging agent. Overall, this study links two important environmental signals, iron and NO, with their roles in biofilm development and suggests new ways for improving the use of NO in biofilm control strategies.
Early T Follicular Helper Cell Responses and Germinal Center Reactions Are Associated with Viremia Control in Immunized Rhesus Macaques
Authors: Helmold Hait Sabrina , Vargas-Inchaustegui Diego A. , Musich Thomas , Mohanram Venkatramanan , Tuero Iskra , Venzon David J. , Bear Jenifer , Rosati Margherita , Vaccari Monica , Franchini Genoveffa , Felber Barbara K. , Pavlakis George N. , Robert-Guroff Marjorie
Published: November 2018

The modest HIV protection observed in the human RV144 vaccine trial associated antibody responses with vaccine efficacy. T follicular helper (T
FH
) cells are CD4
+
T cells that select antibody secreting cells with high antigenic affinity in germinal centers (GCs) within secondary lymphoid organs. To evaluate the role of T
FH
cells in eliciting prolonged virus-specific humoral responses, we vaccinated rhesus macaques with a combined mucosal prime/systemic boost regimen followed by repeated low-dose intrarectal challenges with SIV, mimicking human exposure to HIV-1. Although the vaccine regimen did not prevent SIV infection, decreased viremia was observed in the immunized macaques. Importantly, vaccine-induced T
FH
responses elicited at day 3 postimmunization and robust GC maturation were strongly associated. Further, early T
FH
-dependent SIV-specific B cell responses were also correlated with decreased viremia. Our findings highlight the contribution of early vaccine-induced GC T
FH
responses to elicitation of SIV-specific humoral immunity and implicate their participation in SIV control.
The Dengue Virus Nonstructural Protein 1 (NS1) Is Secreted from Mosquito Cells in Association with the Intracellular Cholesterol Transporter Chaperone Caveolin Complex
Authors: Rosales Ramirez Romel , Ludert Juan E.
Published: November 2018

The dengue virus protein NS1 is secreted efficiently from both infected vertebrate and mosquito cells. Previously, our group reported that NS1 secretion in mosquito cells follows an unconventional secretion pathway dependent on caveolin-1. In this work, we demonstrate that in mosquito cells, but not in vertebrate cells, NS1 secretion takes place in association with the chaperone caveolin complex, a complex formed by caveolin-1 and the chaperones FKBP52, CyA, and Cy40, which are in charge of cholesterol transport inside the cell. Results obtained with ZIKV-infected mosquito cells suggest that ZIKV NS1 is released following an unconventional secretory route in association with the chaperone caveolin complex. These results uncover important differences in the virus-cell interactions between the vertebrate host and the mosquito vector, as well as novel functions for the chaperone caveolin complex. Moreover, manipulation of the NS1 secretory route may prove a valuable strategy to combat these two mosquito-borne diseases.
Using a 10-step framework to support the implementation of an evidence-based clinical pathways programme
Authors: Flores Emilia J , Mull Nikhil K , Lavenberg Julia G , Mitchell Matthew D , Leas Brian F , Williams Austin , Brennan Patrick J , Umscheid Craig A
Published: November 2018

Background

Integration of evidence into practice is suboptimal. Clinical pathways, defined as multidisciplinary care plans, are a method for translating evidence into local settings and have been shown to improve the value of patient care.

Objective

To describe the development of a clinical pathways programme across a large academic healthcare system.

Methods

We use a 10-step framework (grounded in the Knowledge-to-Action framework and ADAPTE Collaboration methodology for guideline adaptation) to support pathway development and dissemination, including facilitating clinical owner and stakeholder engagement, developing pathway prototypes based on rapid reviews of the existing literature, developing tools for dissemination and impact assessment. We use a cloud-based technology platform (Dorsata, Washington, DC) to assist with development and dissemination across our geographically distributed care settings and providers. Content is viewable through desktop and mobile applications. We measured programme adoption and penetration by examining number of pathways developed as well as mobile application use and pathway views.

Results

From 1 February 2016 to 30 April 2018, a total of 202 pathways were disseminated. The three most common clinical domains represented were oncology (46.5%, n=94), pulmonary/critical care (8.9%, n=18) and cardiovascular medicine (7.4%, n=15). Users opting to register for a personal account totalled 1257; the three largest groups were physicians (45.1%, n=567), advanced practice providers (19.5%, n=245) and nurses (19.1%, n=240). Pathway views reached an average of 2150 monthly views during the last 3 months of the period. The majority of pathways reference at least one evidence-based source (93.6%, n=180).

Conclusions

A healthcare system can successfully use a framework and technology platform to support the development and dissemination of pathways across a multisite institution.
Modeling the influence of chemical composition on compressive strength behavior of alkali-activated phosphorus slag cement using statistical design
Authors: Mehdizadeh Hamideh , Kani Ebrahim Najafi
Published: November 2018

In this study, a statistical experimental design based on response surface methodology (RSM) has been applied to predict and optimize the compressive strength of alkali-activated phosphorus slag in different ages (3, 7, and 28 days). For this purpose, the binder samples were prepared with different molar ratios of SiO2/Na2O (S/N), Na2O/Al2O3(Na/Al), and H2O/Al2O3(H/Al) as alkali activator. Results showed that S/N molar ratio plays its role in early ages of curing and Na/Al molar ratio, and showed its significant effect on 7 and 28 days of compressive strength. H/Al molar ratio had the most significant effect on compressive strength compared to the other parameters. The derived RSM models were statistically adequate and could be used to predict the compressive strength. The optimum chemical composition of activator to obtain the highest compressive strength was achieved as 0.39, 1.34, and 30 for S/N, Na/Al, and H/Al molar ratios, respectively, with compressive strength of 30, 65, and 100 MPa at 3, 7, and 28 days of curing.
Decadal changes in the productivity of New England fish populations
Authors: Tableau Adrien , Collie Jeremy S. , Bell Richard J. , Minto Cóilín
Published: November 2018

The Northwest Atlantic continental shelf is a large ecosystem undergoing rapid environmental changes, which are expected to modify the productivity of natural marine resources. Current management of most fished species assumes stationary production relationships or time-invariant recruitment rates. With linear state-space models, we examined the evidence of dynamic productivity for 25 stocks of the Northeast US shelf. We expanded the suite of options available within the state-space approach to produce robust estimates. Fifteen of the stocks exhibited time-varying productivity or changes in their maximum reproductive rate. Few productivity time series are related across the whole region, though adjacent stocks of the same species exhibited similar trends. Some links to region-wide environmental variables were observed. We demonstrate that fish recruitment can often be better predicted over a short-term horizon by accounting for dynamic productivity, which could be valuable for fisheries management. Improving predictions by incorporating environmental covariates or covariance among the stocks must be considered case by case and with caution, as their relationships may change over time.
Recalibrating the molecular clock for Arctic marine invertebrates based on DNA barcodes
Authors: Loeza-Quintana Tzitziki , Carr Christina M. , Khan Tooba , Bhatt Yash A. , Lyon Samantha P. , Hebert Paul D.N. , Adamowicz Sarah J.
Published: November 2018

Divergence times for species assemblages of Arctic marine invertebrates have often been estimated using a standard rate (1.4%/MY) of molecular evolution calibrated using a single sister pair of tropical crustaceans. Because rates of molecular evolution vary among taxa and environments, it is essential to obtain clock calibrations from northern lineages. The recurrent opening and closure of the Bering Strait provide an exceptional opportunity for clock calibration. Here, we apply the iterative calibration approach to investigate patterns of molecular divergence among lineages of northern marine molluscs and arthropods using publicly available sequences of the cytochrome c oxidase subunit I (COI) gene and compare these results with previous estimates of trans-Bering divergences for echinoderms and polychaetes. The wide range of Kimura two-parameter (K2P) divergences among 73 trans-Bering sister pairs (0.12%–16.89%) supports multiple pulses of migration through the Strait. Overall, the results indicate a rate of K2P divergence of 3.2%/MY in molluscs, 5%–5.2%/MY in arthropods, and 3.5%–4.7%/MY in polychaetes. While these rates are considerably higher than the often-adopted 1.4%/MY rate, they are similar to calibrations (3%–5%/MY) in several other studies of marine invertebrates. This upward revision in rates means there is a need both to reevaluate the evolutionary history of marine lineages and to reexamine the impact of prior climatic changes upon the diversification of marine life.
INTERACTION EFFECT BETWEEN BEAM DIAMETER AND ENERGY DENSITY IN LASER-INDUCED TACTILE PERCEPTION
Authors: CHOI MI-HYUN , KIM HYUNG-SIK , JO JI-HUN , KIM JI-SUN , JUN JAE-HOON , PARK JONG-RAK , CHUNG SOON-CHEOL
Published: November 2018

This study aims to investigate the interaction effect between the beam diameter and energy density, which are perceived as laser-induced tactile perception by humans, by diversely varying the laser parameters, beam diameter, and energy. Eight healthy male college students of 23.5[Formula: see text][Formula: see text][Formula: see text]1.7 years participated in the study. The range of the beam diameter of the displayed laser stimulation was between 0.03[Formula: see text]mm and 8[Formula: see text]mm, and a total of 21 sizes were displayed. The laser energy was sequentially displayed from the minimum energy that can be displayed by one beam diameter to the maximum energy range that does not exceed the maximum permissible exposure (MPE) level since the energy varies according to the beam diameter. The laser energy was controlled by an optical density ([Formula: see text]) filter and was measured by an optical power meter (energy meter). Furthermore, the beam diameter was adjusted by moving the lens, which was confirmed with the beam profiler. The experimental test consists of the control phase (19[Formula: see text]s), stimulus phase (7[Formula: see text]s), and response phase (4[Formula: see text]s); the total duration of the test was 30[Formula: see text]s. The stimulus phase is the period in which stimulation was displayed on the skin through laser irradiation, and the stimulation was displayed by changing the beam diameter and the energy from the laser. The total number of beam diameter and energy pairs displayed to the subjects was 113 and 5 trials of irradiation were conducted for each pair. Stimulation perception response was recorded by pressing the response buttons during the response phase, and the responses were predefined as “no feeling,” “tactile sensation”, and “pain.” Through the extracted response data from the response phase, the beam diameter and energy density pair in which more than 50% of the subjects responded as having perceived tactile sensation were selected from the possible laser energy that could be displayed from one beam diameter. The simulation results showed that increasing the beam diameter increased the penetration depth, indicating an effective energy transfer to the skin. Therefore, increasing the beam diameter results in increased scattering, and hence increased penetration depth, and ultimately a more effective energy transfer. Therefore, increased beam diameter results in higher energy transfer efficiency, indicating that the required energy density by more than 50% of the subjects to perceive tactile sensation decreased.
EFFECT OF SHORT-TERM SLING EXERCISE WITH WHOLE BODY VIBRATION RECOVERY METHOD ON HEART RATE, BLOOD PRESSURE AND LACTIC ACID LEVEL VARIABILITY
Authors: OH JU-HWAN , KWON TAE-KYU , HONG CHUL-UN , LEE YOUNG-CHUN
Published: November 2018

The objective of this study was to compare heart rate, blood pressure, and lactic acid level with different recovery methods after having maximal exercise to provide reliable data regarding efficient recovery methods. Heart rate, blood pressure, and lactic acid level were continuously recorded for 30[Formula: see text]min at 5-min intervals during a recovery period after performing a maximal exercise test based on the Bruce-protocol. Study subjects were 36 healthy men in the 20[Formula: see text]s. They were randomly assigned to a passive recovery group ([Formula: see text] people), a sling exercise group ([Formula: see text] people), and a sling exercise with whole-body vibration group ([Formula: see text] people). One-way ANOVA was conducted to compare the recovery effects by using SPSS 18.0 Korea. The statistical significance was accepted at [Formula: see text]. Our results revealed that SWRG showed significantly faster heart rate recovery than SRG. Systolic and diastolic blood pressure tended to decrease more in the combined group than the PRG. Thirdly, the lactic acid level decreased to a lower level in the combined group than the PRG.
THE NPD SPEED-MARKET SUCCESS RELATIONSHIP: A META-ANALYSIS
Authors: MILLSON MURRAY R. , WILEMON DAVE
Published: November 2018

This study explores the relationship between new product development (NPD) process speed, as an independent variable, and the perceived market success of products resulting from these NPD processes, as a dependent variable. This is the first meta-analysis that examines the impact of NPD speed on NPD success/performance. This study extends existing research by analysing NPD speed and NPD success correlations found in papers published between 1980 and 2017. The primary research question examined in this study is “Is there a consistent, linear relationship between NPD speed and NPD success/performance across studies?”. To address this question, correlation coefficients related to the relationship between NPD speed and NPD success/performance were gathered from published journal papers. The meta-analytic data gathered during this study resulted in a total of 2,840 individual, correlational relationships. Based on a meta-analytical examination of this data, it was found that the sample data for this study did not represent a single population of correlational relationships. Research implications, limitations, and research directions are provided in this study.
Water inflow into tunnels: assessment of the Gerede water transmission tunnel (Turkey) with complex hydrogeology
Authors: Apaydin Ahmet , Korkmaz Nur , Ciftci Donmez
Published: November 2018

The Gerede is the longest and most problematic water transmission tunnel in Turkey, at 31.6 km long with an overburden of 600 m. The tunnel will transmit water from the Ulusu river to the Camlidere reservoir. High-pressure water ingress and collapses have resulted in many delays. Although construction began in 2012, and was intended to be completed in 2014, completion is now estimated to be in 2019. The tunnel passes through permeable Tertiary sedimentary and volcano-sedimentary rocks, and Jurassic–Cretaceous limestone. Water ingress has occurred on 45 occasions along the 26 km excavated. The initial total discharge was 1.7 m
3
 s
−1
and decreased to 0.5 m
3
 s
−1
over time. The recharge conditions, tectonic structure, progress of the excavation and sealing by grouting affect the quantity, locations and temporal changes of the inflow of water. The major faults and formation contacts are the most problematic sites to be considered.

With the many delays in the tunnel, the driving plan and tunnel boring machine (TBM) were changed while the construction continued. The tunnel shows that hydrogeological conditions, in particular, should be taken into consideration when choosing the TBM and driving course. However, the problems we encountered provided valuable experience for future projects.
Reconstructing the Himalayan margin prior to collision with Asia: Proterozoic and lower Paleozoic geology and its implications for Cenozoic tectonics
Authors: Myrow P. M. , Hughes N. C. , McKenzie N. R.
Published: November 2018

Reconstructing the stratigraphic architecture of deposits prior to Cenozoic Himalayan uplift is critical for unravelling the structural, metamorphic, depositional and erosional history of the orogen. The nature and distribution of Proterozoic and lower Paleozoic strata have helped elucidate the relationship between lithotectonic zones, as well as the geometries of major bounding faults. Stratigraphic and geochronological work has revealed a uniform and widespread pattern of Paleoproterozoic strata >1.6 Ga that are unconformably overlain by <1.1 Ga rocks. The overlying Neoproterozoic strata record marine sedimentation, including a Cryogenian diamictite, a well-developed carbonate platform succession and condensed fossiliferous Precambrian–Cambrian boundary strata. Palaeontological study of Cambrian units permits correlation from the Indian craton through three Himalayan lithotectonic zones to a precision of within a few million years. Detailed sedimentological and stratigraphic analysis shows the differentiation of a proximal realm of relatively condensed, nearshore, evaporite-rich units to the south and a distal realm of thick, deltaic deposits to the north. Thus, Neoproterozoic and Cambrian strata blanketed the northern Indian craton with an extensive, northward-deepening, succession. Today, these rocks are absent from parts of the inner Lesser Himalaya, and the uplift and erosion of these proximal facies explains a marked change in global seawater isotopic chemistry at 16 Ma.
Designing emotionally sentient agents
Authors: McDuff Daniel , Czerwinski Mary
Published: November 2018

Emotionally sentient systems will enable computers to perform complex tasks more effectively, making better decisions and offering more productive services.
Point: Should AI technology be regulated?
Authors: Etzioni Oren
Published: November 2018

Considering the difficult technical and sociological issues affecting the regulation of artificial intelligence research and applications.
Counterpoint: Regulators should allow the greatest space for AI innovation
Authors: O'Sullivan Andrea , Thierer Adam
Published: November 2018

Permissionless innovation should be the governing policy for AI technologies.
Why SRE documents matter
Authors: Nukala Shylaja , Rau Vivek
Published: November 2018

How documentation enables SRE teams to manage new and existing services.
Securing agent 111, and the job of software architect
Authors: Arquilla John , Bugayenko Yegor
Published: November 2018

The
Communications
Web site, http://cacm.acm.org, features more than a dozen bloggers in the BLOG@CACM community. In each issue of
Communications
, we'll publish selected posts or excerpts.

twitter

Follow us on Twitter at http://twitter.com/blogCACM

http://cacm.acm.org/blogs/blog-cacm

John Arquilla describes the new state of cyberspying, while Yegor Bugayenko considers the importance of a software architect to development projects.
AI judges and juries
Authors: Kugler Logan
Published: November 2018

Artificial intelligence is changing the legal industry.
Technology for the deaf
Authors: Kirkpatrick Keith
Published: November 2018

Why aren't better assistive technologies available for those communicating using ASL?
Early growth response protein-1 upregulates long noncoding RNA Arid2-IR to promote extracellular matrix production in diabetic kidney disease
Authors: Yang Yan-Lin , Hu Fang , Xue Meng , Jia Yi-Jie , Zheng Zong-Ji , Li Yang , Xue Yao-Ming
Published: November 2018

Diabetic kidney disease (DKD) has surpassed chronic glomerulonephritis as the leading cause of end-stage renal disease. Previously, we showed that early growth response protein-1 (Egr1) plays a key role in DKD by enhancing mesangial cell proliferation and extracellular matrix (ECM) production. The long noncoding RNA (lncRNA) AT-rich interactive domain 2-IR (Arid2-IR) has been identified as a mothers against decapentaplegic homolog 3 (Smad3)-associated lncRNA in unilateral ureteral obstructive kidney disease. However, the effect of Egr1 on Arid2-IR in the development of DKD is still unknown. In this study, we found that Arid2-IR was increased in mice with high-fat diet and streptozotocin-induced type 2 diabetes and in mouse mesangial cells cultured with high glucose to mimic diabetes. Knockdown of Arid2-IR in mouse mesangial cells reduced the high expression levels of collagen-α1(I) (Col1a1) and α-smooth muscle actin (α-SMA) induced by high glucose. Furthermore, Arid2-IR expression changed the increased expression of Col1a1 and α-SMA caused by overexpression of Egr1. Overall, these data suggest that increased Arid2-IR likely contributes to ECM production in DKD and that Egr1 promotes ECM production in DKD partly by upregulating Arid2-IR. Thus, Arid2-IR may be a new target in the treatment of DKD.
MicroRNA-146a-5p enhances radiosensitivity in hepatocellular carcinoma through replication protein A3-induced activation of the DNA repair pathway
Authors: Luo Jing , Si Zhong-Zhou , Li Ting , Li Jie-Qun , Zhang Zhong-Qiang , Chen Guang-Shun , Qi Hai-Zhi , Yao Hong-Liang
Published: November 2018

Hepatocellular carcinoma (HCC) is known for its high mortality rate worldwide. Based on intensive studies, microRNA (miRNA) expression functions in tumor suppression. Therefore, we aimed to evaluate the contribution of miR-146a-5p to radiosensitivity in HCC through the activation of the DNA damage repair pathway by binding to replication protein A3 (RPA3). First, the limma package of R was performed to differentially analyze HCC expression chip, and regulative miRNA of RPA3 was predicted. Expression of miR-146a-5p, RPA3, and DNA damage repair pathway-related factors in tissues and cells was determined. The effects of radiotherapy on the expression of miR-146a-5p and RPA3 as well as on cell radiosensitivity, proliferation, cell cycle, and apoptosis were also assessed. The results showed that there exists a close correlation between miR-146a and the radiotherapy effect on HCC progression through regulation of RPA3 and the DNA repair pathway. The positive rate of ATM, pCHK2, and Rad51 in HCC tissues was higher when compared with that of the paracancerous tissues. SMMC-7721 and HepG2 cell proliferation were significantly inhibited following 8 Gy 6Mv dose. MiR-146a-5p restrained the expression of RPA3 and promoted the expression of relative genes associated with the DNA repair pathway. In addition, miR-146a-5p overexpression suppresses cell proliferation and enhances radiosensitivity and cell apoptosis in HCC cells. In conclusion, the present study revealed that miR-146a-5p could lead to the restriction of proliferation and the promotion of radiosensitivity and apoptosis in HCC cells through activation of DNA repair pathway and inhibition of RPA3.
GDE5 inhibition accumulates intracellular glycerophosphocholine and suppresses adipogenesis at a mitotic clonal expansion stage
Authors: Okazaki Yuri , Nakamura Keishi , Takeda Shuto , Yoshizawa Ikumi , Yoshida Fumiyo , Ohshima Noriyasu , Izumi Takashi , Klein Janet D. , Kumrungsee Thanutchaporn , Sands Jeff M. , Yanaka Noriyuki
Published: November 2018

Mammalian glycerophosphodiesterases (GDEs) were recently shown to be involved in multiple cellular signaling pathways. This study showed that decreased GDE5 expression results in accumulation of intracellular glycerophosphocholine (GPC), showing that GDE5 is actively involved in GPC/choline metabolism in 3T3-L1 adipocytes. Using 3T3-L1 adipocytes, we further studied the biological significance of GPC/choline metabolism during adipocyte differentiation. Inhibition of GDE5 suppressed the formation of lipid droplets, which is accompanied by the decreased expression of adipocyte differentiation markers. We further showed that the decreased GDE5 expression suppressed mitotic clonal expansion (MCE) of preadipocytes. Decreased expression of CTP: phosphocholine cytidylyltransferase (CCTβ), a rate-limiting enzyme for phosphatidylcholine (PC) synthesis, is similarly able to inhibit MCE and PC synthesis; however, the decreased GDE5 expression resulted in accumulation of intracellular GPC but did not affect PC synthesis. Furthermore, we showed that mRNAs of proteoglycans and transporters for organic osmolytes are significantly upregulated and that intracellular amino acids and urea levels are altered in response to GDE5 inhibition. Finally, we showed that reduction of GDE5 expression increased lactate dehydrogenase release from preadipocytes. These observations indicate that decreased GDE5 expression can suppress adipocyte differentiation not through the PC pathway but possibly by intracellular GPC accumulation. These results provide insight into the roles of mammalian GDEs and their dependence upon osmotic regulation by altering intracellular GPC levels.
Na+/Ca2+ exchanger overexpression in smooth muscle augments cytosolic Ca2+ in femoral arteries of living mice
Authors: Zhang Jin , Wang Youhua , Chen Ling , Wier W. Gil , Blaustein Mordecai P.
Published: November 2018

Plasma membrane Na+/Ca2+ exchanger-1 (NCX1) helps regulate the cytosolic Ca2+ concentration ([Ca2+]CYT) in arterial myocytes. NCX1 mediates both Ca2+ entry and exit and tends to promote net Ca2+ entry in partially constricted arteries. Mean blood pressure (telemetry) is elevated by ≈10 mmHg in transgenic (TG) mice that overexpress NCX1 specifically in smooth muscle. We tested the hypothesis that NCX1 overexpression mediates Ca2+ gain and elevated [Ca2+]CYT in exposed femoral arteries that also express the Ca2+ biosensor exogenous myosin light chain kinase. [Ca2+]CYT and the NCX1-dependent (SEA0400-sensitive) component, ≈15% of total basal constriction in controls, were increased in TG arteries, but constrictions to phenylephrine and ANG II were comparable in TG and control arteries. Normalized phenylephrine dose-response curves and constriction to 30 and 300 ng/kg iv ANG II were virtually identical in control and TG arteries. ANG II-evoked constrictions, superimposed on elevated basal tone, accounted for the larger blood pressure responses to ANG II in TG arteries. TG and control mouse arteries fit the same pCa-constriction relationship over a wide range of pCa (≈125–500 nM). Vasodilation to acetylcholine, normalized to passive diameter, was also comparable in TG and control arteries, implying normal endothelial function. TG artery Na+ nitroprusside (nitric oxide donor)-induced dilations were, however, shifted to lower Na+ nitroprusside concentrations, indicating that TG myocyte vasodilator mechanisms were augmented. Maximum arterial dilation was comparable in TG and control mice, although passive diameter was ≈6–7% smaller in TG mice. The changes in TG arteries were apparently largely functional rather than structural, despite the congenital hypertension.

NEW & NOTEWORTHY Smooth muscle Na+/Ca2+ exchanger-1 transgene overexpression (TG mice) increases femoral artery basal cytosolic Ca2+ concentration ([Ca2+]CYT) and tone in vivo and raises blood pressure. Arterial constriction to phenylephrine and angiotensin II are normal but superimposed on the augmented basal [Ca2+]CYT and tone (constriction) in TG mouse arteries. Similar effects in resistance arteries would explain the elevated blood pressure. Acetylcholine-induced vasodilation is unimpaired, implying a normal endothelium, but TG arteries are hypersensitive to sodium nitroprusside.
Disruption of cardiac Med1 inhibits RNA polymerase II promoter occupancy and promotes chromatin remodeling
Authors: Hall Duane D. , Spitler Kathryn M. , Grueter Chad E.
Published: November 2018

The Mediator coactivator complex directs gene-specific expression by binding distal enhancer-bound transcription factors through its Med1 subunit while bridging to RNA polymerase II (Pol II) at gene promoters. In addition, Mediator scaffolds epigenetic modifying enzymes that determine local DNA accessibility. Previously, we found that deletion of Med1 in cardiomyocytes deregulates more than 5,000 genes and promotes acute heart failure. Therefore, we hypothesized that Med1 deficiency disrupts enhancer-promoter coupling. Using chromatin immunoprecipitation-coupled deep sequencing (ChIP-seq; n = 3/ChIP assay), we found that the Pol II pausing index is increased in Med1 knockout versus floxed control mouse hearts primarily due to a decrease in Pol II occupancy at the majority of transcriptional start sites without a corresponding increase in elongating species. Parallel ChIP-seq assays reveal that Med1-dependent gene expression correlates strongly with histone H3 K27 acetylation, which is indicative of open and active chromatin at transcriptional start sites, whereas H3 K27 trimethylated levels, representing condensed and repressed DNA, are broadly increased and inversely correlate with absolute expression levels. Furthermore, Med1 deletion leads to dynamic changes in acetyl-K27 associated superenhancer regions and their enriched transcription factor-binding motifs that are consistent with altered gene expression. Our findings suggest that Med1 is important in establishing enhancer-promoter coupling in the heart and supports the proposed role of Mediator in establishing preinitiation complex formation. We also found that Med1 determines chromatin accessibility within genes and enhancer regions and propose that the composition of transcription factors associated with superenhancer changes to direct gene-specific expression.

NEW & NOTEWORTHY Based on our previous findings that transcriptional homeostasis and cardiac function are disturbed by cardiomyocyte deletion of the Mediator coactivator Med1 subunit, we investigated potential underlying changes in RNA polymerase II localization and global chromatin accessibility. Using chromatin immunoprecipitation sequencing, we found that disrupted transcription arises from a deficit in RNA polymerase II recruitment to gene promoters. Furthermore, active versus repressive chromatin marks are redistributed within gene loci and at enhancer regions correlated with gene expression changes.
BPIFA1 regulates lung neutrophil recruitment and interferon signaling during acute inflammation
Authors: Britto Clemente J. , Niu Naiqian , Khanal Sara , Huleihel Luai , Herazo-Maya Jose D. , Thompson Alison , Sauler Maor , Slade Martin D. , Sharma Lokesh , Dela Cruz Charles S. , Kaminski Naftali , Cohn Lauren E.
Published: November 2018

Bpifa1 (BPI fold-containing group A member 1) is an airway host-protective protein with immunomodulatory properties that binds to LPS and is regulated by infectious and inflammatory signals. Differential expression of Bpifa1 has been widely reported in lung disease, yet the biological significance of this observation is unclear. We sought to understand the role of Bpifa1 fluctuations in modulating lung inflammation. We treated wild-type (WT) and Bpifa1−/− mice with intranasal LPS and performed immunological and transcriptomic analyses of lung tissue to determine the immune effects of Bpifa1 deficiency. We show that neutrophil (polymorphonuclear cells, PMNs) lung recruitment and transmigration to the airways in response to LPS is impaired in Bpifa1−/− mice. Transcriptomic analysis revealed a signature of 379 genes that differentiated Bpifa1−/− from WT mice. During acute lung inflammation, the most downregulated genes in Bpifa1−/− mice were Cxcl9 and Cxcl10. Bpifa1−/− mice had lower bronchoalveolar lavage concentrations of C-X-C motif chemokine ligand 10 (Cxcl10) and Cxcl9, interferon-inducible PMN chemokines. This was consistent with lower expression of IFNγ, IFNλ, downstream IFN-stimulated genes, and IFN-regulatory factors, which are important for the innate immune response. Administration of Cxcl10 before LPS treatment restored the inflammatory response in Bpifa1−/− mice. Our results identify a novel role for Bpifa1 in the regulation of Cxcl10-mediated PMN recruitment to the lungs via IFNγ and -λ signaling during acute inflammation.
Interaction between TRPV1-expressing neurons in the hypothalamus
Authors: Molinas Adrien J. R. , Desmoulins Lucie D. , Hamling Brooke V. , Butcher Sierra M. , Anwar Imran J. , Miyata Kayoko , Enix Courtney L. , Dugas Courtney M. , Satou Ryousuke , Derbenev Andrei V. , Zsombok Andrea
Published: November 2018

Transient receptor potential vanilloid type 1 (TRPV1) is a ligand-gated ion channel expressed in the peripheral and central nervous systems. TRPV1-dependent mechanisms take part in a wide range of physiological and pathophysiological pathways including the regulation of homeostatic functions. TRPV1 expression in the hypothalamus has been described as well as evidence that TRPV1-dependent excitatory inputs to hypothalamic preautonomic neurons are diminished in diabetic conditions. Here we aimed to determine the functional expression of TRPV1 in two hypothalamic nuclei known to be involved in the central control of metabolism and to test the hypothesis that TRPV1-expressing neurons receive TRPV1-expressing inputs. A mouse model (TRPV1Cre/tdTom) was generated to identify TRPV1-expressing cells and determine the cellular properties of TRPV1-expressing neurons in adult mice. Our study demonstrated the functional expression of TRPV1 in the dorsomedial hypothalamic nucleus and paraventricular nucleus in adult mice. Our findings revealed that a subset of TRPV1Cre/tdTom neurons receive TRPV1-expressing excitatory inputs, indicating direct interaction between TRPV1-expressing neurons. In addition, astrocytes likely play a role in the modulation of TRPV1-expressing neurons. In summary, this study identified specific hypothalamic regions where TRPV1 is expressed and functional in adult mice and the existence of direct connections between TRPV1Cre/tdTom neurons.

NEW & NOTEWORTHY Transient receptor potential vanilloid type 1 (TRPV1) is expressed in the hypothalamus, and TRPV1-dependent regulation of preautonomic neurons is decreased in hyperglycemic conditions. Our study demonstrated functional expression of TRPV1 in two hypothalamic nuclei involved in the control of energy homeostasis. Our results also revealed that a subset of TRPV1-expressing neurons receive TRPV1-expressing excitatory inputs. These findings suggest direct interaction between TRPV1-expressing neurons.
Causal inference for spatial constancy across whole body motion
Authors: Perdreau Florian , Cooke James R. H. , Koppen Mathieu , Medendorp W. Pieter
Published: November 2018

The brain uses self-motion information to internally update egocentric representations of locations of remembered world-fixed visual objects. If a discrepancy is observed between this internal update and reafferent visual feedback, this could be either due to an inaccurate update or because the object has moved during the motion. To optimally infer the object’s location it is therefore critical for the brain to estimate the probabilities of these two causal structures and accordingly integrate and/or segregate the internal and sensory estimates. To test this hypothesis, we designed a spatial updating task involving passive whole body translation. Participants, seated on a vestibular sled, had to remember the world-fixed position of a visual target. Immediately after the translation, the reafferent visual feedback was provided by flashing a second target around the estimated “updated” target location, and participants had to report the initial target location. We found that the participants’ responses were systematically biased toward the position of the second target position for relatively small but not for large differences between the “updated” and the second target location. This pattern was better captured by a Bayesian causal inference model than by alternative models that would always either integrate or segregate the internally updated target location and the visual feedback. Our results suggest that the brain implicitly represents the posterior probability that the internally updated estimate and the visual feedback come from a common cause and uses this probability to weigh the two sources of information in mediating spatial constancy across whole body motion.

NEW & NOTEWORTHY When we move, egocentric representations of object locations require internal updating to keep them in register with their true world-fixed locations. How does this mechanism interact with reafferent visual input, given that objects typically do not disappear from view? Here we show that the brain implicitly represents the probability that both types of information derive from the same object and uses this probability to weigh their contribution for achieving spatial constancy across whole body motion.
Functional brain stem circuits for control of nose motion
Authors: Kurnikova Anastasia , Deschênes Martin , Kleinfeld David
Published: November 2018

Rodents shift their nose from side to side when they actively explore and lateralize odors in the space. This motor action is driven by a pair of muscles, the deflector nasi. We studied the premotor control of this motion. We used replication-competent rabies virus to transsynaptically label inputs to the deflector nasi muscle and find putative premotor labeling throughout the parvocellular, intermediate, and gigantocellular reticular formations, as well as the trigeminal nuclei, pontine reticular formation, midbrain reticular formation, red nucleus, and superior colliculus. Two areas with extensive labeling were analyzed for their impact on nose movement. One area is in the reticular formation caudal to the facial motor nucleus and is denoted the nose retrofacial area. The second is in the caudal part of the intermediate reticular region near the oscillator for whisking (the nose IRt). Functionally, we find that optogenetic activation of glutamatergic cells in both areas drives deflection of the nose. Ablation of cells in the nose retrofacial area, but not the nose IRt, impairs movement of the nose in response to the presentation of odorants but otherwise leaves movement unaffected. These data suggest that the nose retrofacial area is a conduit for a sensory-driven orofacial motor action. Furthermore, we find labeling of neurons that are immediately upstream of premotor neurons in the preBötzinger complex that presumably synchronizes a small, rhythmic component of nose motion to breathing.

NEW & NOTEWORTHY We identify two previously undescribed premotor areas in the medulla that control deflection of the nose. This includes a pathway for directed motion of the nose in response to an odorant.
Dentate spikes and learning: disrupting hippocampal function during memory consolidation can improve pattern separation
Authors: Lensu Sanna , Waselius Tomi , Penttonen Markku , Nokia Miriam S.
Published: November 2018

Hippocampal dentate spikes (DSs) are short-duration, large-amplitude fluctuations in hilar local field potentials and take place while resting and sleeping. During DSs, dentate gyrus granule cells increase firing while CA1 pyramidal cells decrease firing. Recent findings suggest DSs play a significant role in memory consolidation after training on a hippocampus-dependent, nonspatial associative learning task. Here, we aimed to find out whether DSs are important in other types of hippocampus-dependent learning tasks as well. To this end, we trained adult male Sprague-Dawley rats in a spatial reference memory task, a fixed interval task, and a pattern separation task. During a rest period immediately after each training session, we either let neural activity to take place as usual, timed electrical stimulation of the ventral hippocampal commissure (vHC) to immediately follow DSs, or applied the vHC stimulation during a random neural state. We found no effect of vHC stimulation on performance in the spatial reference memory task or in the fixed interval task. Surprisingly, vHC stimulation, especially contingent on DSs, improved performance in the pattern separation task. In conclusion, the behavioral relevance of hippocampal processing and DSs seems to depend on the task at hand. It could be that in an intact brain, offline memory consolidation by default involves associating neural representations of temporally separate but related events. In some cases this might be beneficial for adaptive behavior in the future (associative learning), while in other cases it might not (pattern separation).

NEW & NOTEWORTHY The behavioral relevance of dentate spikes seems to depend on the learning task at hand. We suggest that dentate spikes are related to associating neural representations of temporally separate but related events within the dentate gyrus. In some cases this might be beneficial for adaptive behavior in the future (associative learning), while in other cases it might not (pattern separation).