bluuebunny/crossref_metadata_2025 huggingface dataset:
One-carbon metabolites, B vitamins and associations with systemic inflammation and angiogenesis biomarkers among colorectal cancer patients: results from the ColoCare Study
Authors: Kiblawi Rama , Holowatyj Andreana N. , Gigic Biljana , Brezina Stefanie , Geijsen Anne J. M. R. , Ose Jennifer , Lin Tengda , Hardikar Sheetal , Himbert Caroline , Warby Christy A. , Böhm Jürgen , Bours Martijn J. L. , van Duijnhoven Fränzel J. B. , Gumpenberger Tanja , Kok Dieuwertje E. , Koole Janna L. , van Roekel Eline H. , Schrotz-King Petra , Ulvik Arve , Gsur Andrea , Habermann Nina , Weijenberg Matty P. , Ueland Per Magne , Schneider Martin , Ulrich Alexis , Ulrich Cornelia M. , Playdon Mary
Published: February 2020

B vitamins involved in one-carbon metabolism have been implicated in the development of inflammation- and angiogenesis-related chronic diseases, such as colorectal cancer (CRC). Yet, the role of one-carbon metabolism in inflammation and angiogenesis among CRC patients remains unclear. The objective of this study was to investigate associations of components of one-carbon metabolism with inflammation and angiogenesis biomarkers among newly diagnosed CRC patients (n238) in the prospective ColoCare Study, Heidelberg. We cross-sectionally analysed associations between twelve B vitamins and one-carbon metabolites and ten inflammation and angiogenesis biomarkers from pre-surgery serum samples using multivariable linear regression models. We further explored associations among novel biomarkers in these pathways with Spearman partial correlation analyses. We hypothesised that pyridoxal-5’-phosphate (PLP) is inversely associated with inflammatory biomarkers. We observed that PLP was inversely associated with C-reactive protein (CRP) (r–0·33,Plinear< 0·0001), serum amyloid A (SAA) (r–0·23,Plinear= 0·003), IL-6 (r–0·39,Plinear< 0·0001), IL-8 (r–0·20,Plinear= 0·02) and TNFα(r–0·12,Plinear= 0·045). Similar findings were observed for 5-methyl-tetrahydrofolate and CRP (r–0·14), SAA (r–0·14) and TNFα(r–0·15) among CRC patients. Folate catabolite acetyl-para-aminobenzoylglutamic acid (pABG) was positively correlated with IL-6 (r0·27,Plinear< 0·0001), and pABG was positively correlated with IL-8 (r0·21,Plinear< 0·0001), indicating higher folate utilisation during inflammation. Our data support the hypothesis of inverse associations between PLP and inflammatory biomarkers among CRC patients. A better understanding of the role and inter-relation of PLP and other one-carbon metabolites with inflammatory processes among colorectal carcinogenesis and prognosis could identify targets for future dietary guidance for CRC patients.
Dairy producers in the Southeast United States are concerned with cow care and welfare
Authors: Lee Amanda , Schexnayder Susan , Schneider Liesel , Oliver Stephen , Pighetti Gina , Petersson-Wolfe Christina , Bewley Jeffrey , Ward Stephanie , Krawczel Peter
Published: February 2020

This research communication addresses the hypothesis that Southeast dairy producers' self-reported bulk tank somatic cell count (BTSCC) was associated with producers' response to three statements (1) ‘a troublesome thing about mastitis is the worries it causes me,’ (2) ‘a troublesome thing about mastitis is that cows suffer,’ and (3) ‘my broad goals include taking good care of my cows and heifers.’ Surveys were mailed to producers in Georgia, Kentucky, Mississippi, North Carolina, South Carolina, Tennessee, and Virginia (29% response rate, N = 596; final analysis N = 574), as part of a larger survey to assess Southeastern dairy producers' opinions related to BTSCC. Surveys contained 34 binomial (n = 9), Likert scale (n = 7), and descriptive (n = 18) statements targeted at producer self-assessment of herd records, management practices, and BTSCC. Statements 1 and 2 were assessed on a 5-point Likert scale from ‘strongly disagree’ to ‘strongly agree.’ Statement 3 was assessed on a 5-point Likert scale from ‘very unimportant’ to ‘very important.’ Reported mean BTSCC for all participants was 254 500 cells/ml. Separate univariable logistic regressions using generalized linear mixed models (SAS 9.4, Cary, NC, USA) with a random effect of farm, were performed to determine if BTSCC was associated with probability for a producer's response to statements. If BTSCC was significant, forward manual addition was performed until no additional variables were significant (P ≤ 0.05), but included BTSCC, regardless of significance. Bulk tank somatic cell count was associated with ‘a troublesome thing about mastitis is the worries it causes me,’ but not with Statements 2 or 3. This demonstrates that >75% of Southeastern dairy producers are concerned with animal care and cow suffering, regardless of BTSCC. Understanding Southeast producers' emphasis on cow care is necessary to create targeted management tools for herds with elevated BTSCC.
A Systematic Approach for Accuracy Design of Lower-Mobility Parallel Mechanism
Authors: Tian Wenjie , Shen Ziqian , Lv Dongpo , Yin Fuwen
Published: February 2020

Geometric accuracy is a critical performance factor for parallel robots, and regardless of error compensation, accuracy design or tolerance allocation is another way to ensure the pose accuracy of a robot at design stage. A general method of both geometric error modeling and accuracy design of lower-mobility parallel mechanisms is presented. First, a general approach for error modeling of lower-mobility parallel mechanism is proposed based on screw theory, and then the geometric errors affecting the compensatable and uncompensatable accuracy of the end-effector are separated using the properties of dual vector space. The pose error aroused by compensatable geometric errors can be compensated via kinematic calibration, while the uncompensatable geometric errors should be minimized during the manufacturing and assembly processes. Based on that, the tolerance allocation method is presented, giving each uncompensatable geometric error a proper tolerance by the use of reliability theory. Compared with the traditional tolerance allocation method, the advantages of the proposed method are as follows: the number of geometric errors to be allocated is greatly reduced; the results of serialized tolerance allocation can be obtained according to different reliability indices of pose accuracy of end-effector for designers to choose; on the premise of guaranteeing the same pose accuracy of end-effector, the allocated tolerances are loose and easy to realize. Finally, the proposed methods are successfully applied to an R(2-RPS&RP)&UPS lower-mobility parallel robot, and the effectiveness and practicability of the proposed method are verified.
Filamentary Currents and Alfvénic Vortices in the Inner Magnetosphere
Authors: Chaston C. C. , Bonnell J. W. , Wygant J. R. , Reeves G. D. , Baker D. N.
Published: February 2020

We show that broadband low‐frequency Alfvénic field variations observed in the inner‐magnetosphere from the Van Allen Probes during geomagnetically disturbed intervals are composed of multiscale current sheets, current filaments, flow shears, and vortices. These observations pertain to spacecraft frame frequencies (fsc) over the range 0.1 < fsc < 10 Hz and correspond to structure advected over the spacecraft on scales (λ) over the range 0.1 ≲ λ/ρi ≲ 10. where ρi is the average ion gyroradius. The topology of the current and flow is derived via time domain and spectral approaches adapted for the interpretation of advected structure. The results reveal the action of magnetic and convective nonlinearities in the generation of broadband Alfvénic fluctuations prevalent in the inner magnetosphere during active times. The observed current filamentation and rotational vorticity is suggestive of how broadband Alfvénic field variations on kinetic scales are driven and support geophysically significant particle acceleration in the inner magnetosphere.
Inversion of Dadu River Bedrock Channels for the Late Cenozoic Uplift History of the Eastern Tibetan Plateau
Authors: Ma Zifa , Zhang Huiping , Wang Yizhou , Tao Yaling , Li Xuemei
Published: February 2020

The Dadu River in the eastern Tibetan Plateau has the potential to record transient variations of tectonic uplift since the Late Cenozoic. In this study, we extracted bedrock channels of the Dadu River drainage basin from the 30 m ASTER digital elevation model. The longitudinal river profiles were then analyzed, and three generations of knickpoints were recognized via the slope area method. By solving the analytical solution of the linear transient stream power incision model, we determined a Late Cenozoic history of regional tectonic uplift. The results reveal slow pre–middle Miocene uplift rates (<0.1 mm/a) and then increased gradually to 0.33 ± 0.03 mm/a since 12–15 Ma until present. This increase of uplift rate from bedrock channel inversion is consistent with the regional findings of low‐temperature themochronology, emphasizing the potential and significance to utilize channel profiles to infer the tectonic uplift history.
Shale Anisotropy and Natural Hydraulic Fracture Propagation: An Example from the Jurassic (Toarcian) Posidonienschiefer, Germany
Authors: Hooker John N. , Ruhl Micha , Dickson Alexander J. , Hansen Lars N. , Idiz Erdem , Hesselbo Stephen P. , Cartwright Joe
Published: February 2020

Cores recovered from the Jurassic (Toarcian) Posidonienschiefer (Posidonia Shale) in the Lower Saxony Basin, Germany, contain calcite‐filled fractures (veins) at a low angle to bedding. The veins preferentially form where the shale is both organically rich and thermally mature, supporting previous interpretations that the veins formed as hydraulic fractures in response to volumetric expansion of organic material during catagenesis. Despite the presence of hydrocarbons during fracturing, the calcite fill is fibrous, and so, the veins appear to have contained a mineral‐saturated aqueous solution as they formed. The veins also contain myriad host‐rock inclusions having submillimetric spacing. These inclusions are strands of host rock that were entrained as the veins grew by separating the host rock along bedding planes rather than cutting across planes. The veins therefore produce significantly more surface area – by a factor of roughly 5, for the size of veins observed – compared to an inclusion‐free fracture of the same size. Analysis of vein geometry indicates that, with propagation, a fracture surface area increases with fracture length raised to a power between 1 and 2, assuming linear aperture‐length scaling. As such, this type of fracture efficiently dissipates elastic strain energy as it lengthens, stabilizing propagation and precluding dynamic crack growth. The apparent separation of the host rock along bedding planes suggests that the mechanical weakness of bedding planes is the cause of this inherently stable style of propagation.
The Role of Oceanic Processes in the Initiation of Boreal Winter Intraseasonal Oscillations Over the Indian Ocean
Authors: West B. Jason , Han Weiqing , Zhang Lei , Li Yuanlong
Published: February 2020

Observational analyses and ocean general circulation model experiments were performed to understand the influence of oceanic processes on warm sea surface temperature anomalies (SSTAs) prior to convection initiation of boreal winter intraseasonal oscillations (ISOs), including the Madden‐Julian Oscillation (MJO), in the tropical Indian Ocean. We found 39 strong ISOs that passed over the Indian Ocean Warm Pool (WP) region during the November–April season of the 2001–2012 period. Seventeen of them (44%) initiated over the Seychelles‐Chagos Thermocline Ridge (SCTR) before propagating eastward to the WP and Maritime Continent. Including only global‐scale MJOs, 71% (24%) of the remaining MJO events initiated from the SCTR (WP). Four (seven) SCTR (WP) ISO events were preceded by SSTAs that were strongly influenced by wind stress‐driven oceanic processes; all four (2/7) SCTR (WP) events were MJOs. Composite analyses of the four oceanic process influenced SCTR MJO events showed that wind stress‐driven oceanic processes contributed about 30% (between 0.1 and 0.2 °C) of the preconvection warming in the SCTR, which coincides with the Intertropical Convergence Zone with mean SST > 28 °C. Reduced upwelling and entrainment played a more important role than horizontal advection in elevating the +SSTAs. Case studies revealed that the two ocean process‐influenced primary MJO SCTR events were also associated with oceanic equatorial Rossby waves. Furthermore, results of a linear atmospheric mixed layer model indicated that boundary layer processes related to SSTAs contributed approximately half of the total convergence during MJO initiation, relative to the effect of the free troposphere, for the Rossby wave‐influenced events.
Estimating Wind Speed and Direction Using Wave Spectra
Authors: Voermans J. J. , Smit P. B. , Janssen T. T. , Babanin A. V.
Published: February 2020

Compact wave buoys are increasingly used to provide monitoring of coastal and oceanic conditions by measuring surface waves in real time. Due to their relatively compact size, they are generally not suited to measure wind directly. However, since the wave field is intrinsically coupled to the wind field, wave measurements can serve as a proxy observation of ocean surface winds. In this study, we use spectral wave observations to estimate wind speed and direction based on the assumption of a universal
shape of the wave energy spectrum in the equilibrium range and the presence of a logarithmic wind speed profile above the ocean surface. The wind speed and direction were estimated between 2014 and 2017 at more than a 100 coastal sites with colocated wave and wind observations. Estimates of wind speed and direction based on wave measurements have a root‐mean‐square error of 2 m/s for wind speeds between 3 and 12 m/s (and a relative error of 17% for wind speeds between 10 and 20 m/s) and up to 20° for wind speeds between 10 and 20 m/s. The accuracy of proxy measurements of wind depends on fetch, wave steepness, wave age, directional alignment between wind and dominant waves, and temporal variability of the wind. Further, we show that estimates of wind speed and direction improve considerably as the size of the buoy is reduced.
Simulation of Atmospheric Microbursts Using a Numerical Mesoscale Model at High Spatiotemporal Resolution
Authors: Bolgiani Pedro , Fernández‐González Sergio , Valero Francisco , Merino Andrés , García‐Ortega Eduardo , Sánchez José Luis , Martín María Luisa
Published: February 2020

Atmospheric microbursts are low‐level meteorological events that can produce significant damage on the surface and pose a major risk to aircraft flying close to the ground. Studies and ad hoc numerical models have been developed to understand the origin and dynamics of the microburst; nevertheless, there are few researches of the phenomenon using global and mesoscale models. This is mainly due to the limitations in resolution, as microbursts normally span for less than 4 km and 20 min. In this paper, the Weather Research and Forecasting model is used at resolutions of 400 m and 3 min to test if it can properly capture the variables and dynamics of high‐reflectivity microbursts. Several microphysics and planetary boundary layer parametrizations are tested to find the best model configuration for the simulation of this kind of episodes. General conditions are evaluated by using thermodynamic diagrams. Surface and vertical wind speed, reflectivity, precipitation, and other variables for each simulated event are compared with observations, and the model's sensitivity to the variables is assessed. The dynamics and evolution of the microburst is evaluated using different plots of a chosen event. The results show that the model is able to reproduce high‐reflectivity microbursts in accordance with observations, although there is a tendency to underestimate the intensity of variables, most markedly on the wind vertical velocity. Regarding the microphysics schemes, the Morrison parametrization performs better than the WRF single‐moment 6‐class scheme. No major differences are found between the Mellor‐Yamada‐Janjic and the Mellor‐Yamada‐Nakanishi‐Niino planetary boundary layer parametrizations.
Impact of Abrupt Late Holocene Monsoon Climate Change on the Status of an Alpine Lake in North China
Authors: Cheng Bei , Liu Jianbao , Chen Shengqian , Zhang Zhiping , Shen Zhongwei , Yan Xinwei , Li Fanyi , Chen Guangjie , Zhang Xiaosen , Wang Xin , Chen Jianhui
Published: February 2020

The late Holocene is generally regarded as an interval of monsoon recession and decreased precipitation in North China. However, the extent to which this affected the status of lakes in North China is unclear. In the study, we analyzed multiple proxies (δ13C, magnetic susceptibility [χlf], and exogenous element concentrations) from Lake Mayinghai, an undisturbed alpine lake in North China. We also compared the results with previously published paleoenvironmental records from the Chinese Loess Plateau. We aimed to determine the extent of the influence of variations in the East Asian summer monsoon (EASM) on the status of Lake Mayinghai during the late Holocene. The results demonstrate that negative δ13C values at Lake Mayinghai correspond to high sedimentary tree pollen content and high reconstructed precipitation, indicating that variations in δ13C likely reflect variations in vegetation and the EASM in North China. A comparison of the δ13C record with other proxies from the same core reveals an abrupt change in the EASM at ~3 kyr before present (BP), which is also evident in other regional climate records from the Chinese Loess Plateau. The rapid decline in EASM intensity at ~3 kyr BP is also consistent with changes in the status of Lake Mayinghai, Lake Gonghai, Lake Ganhai, and Lake Daihai, in that these lakes underwent an abrupt retreat after 3 kyr BP, demonstrating that the rapid decline in EASM intensity at ~3 kyr BP had a large impact on lake evolution in North China.
Using Metabolic Energy Density Metrics to Understand Differences in Ecosystem Function During Drought
Authors: Wiesner Susanne , Stoy Paul C. , Staudhammer Christina L. , Starr Gregory
Published: February 2020

Terrestrial ecosystems obtain energy in the form of carbon‐containing molecules. Quantifying energy acquisition and dissipation throughout an ecosystem may be useful for describing their resistance and resilience to disturbances. Three longleaf pine savannas with different vegetation composition—a result of variation in soil moisture and land use legacy—were used as a case study to test energy‐based metrics of ecosystem metabolic function. Available energy from gross ecosystem exchange of CO2 and its dissipation into metabolic energy density (EM) and energy storage were used to identify differences in drought recovery over an 8‐year period. Sites with higher plant functional diversity in the understory stored more energy and lowered their EM by ~20% when adapting to drought. In contrast, the site with greater abundance of woody understory and overstory species relied on stored energy twice as often as the more diverse sites. The absence of native understory species, due to anthropogenic legacy, prolonged ecosystem‐scale drought recovery by 1 year. This study provides the tools to understand differences in site metabolic energy dynamics and has the potential to identify site characteristics that indicate greater vulnerability to disturbances. Metabolic energy density can be applied to any global ecosystem and provides a first step to describe coupled carbon and energy allocation in ecosystems, which may be used to further refine ecological theory and its management implications.
Increasing Rates of Carbon Burial in Southwest Florida Coastal Wetlands
Authors: Breithaupt Joshua L. , Smoak Joseph M. , Bianchi Thomas S. , Vaughn Derrick R. , Sanders Christian J. , Radabaugh Kara R. , Osland Michael J. , Feher Laura C. , Lynch James C. , Cahoon Donald R. , Anderson Gordon H. , Whelan Kevin R.T. , Rosenheim Brad E. , Moyer Ryan P. , Chambers Lisa G.
Published: February 2020

Rates of organic carbon (OC) burial in some coastal wetlands appear to be greater in recent years than they were in the past. Possible explanations include ongoing mineralization of older OC or the influence of an unaccounted‐for artifact of the methods used to measure burial rates. Alternatively, the trend may represent real acceleration in OC burial. We quantified OC burial rates of mangrove and coastal freshwater marshes in southwest Florida through a comparison of rates derived from 210Pb, 137Cs, and surface marker horizons. Age/depth profiles of lignin: OC were used to assess whether down‐core remineralization had depleted the OC pool relative to lignin, and lignin phenols were used to quantify the variability of lignin degradation. Over the past 120 years, OC burial rates at seven sites increased by factors ranging from 1.4 to 6.2. We propose that these increases represent net acceleration. Change in relative sea‐level rise is the most likely large‐scale driver of acceleration, and sediment deposition from large storms can contribute to periodic increases. Mangrove sites had higher OC and lignin burial rates than marsh sites, indicating inherent differences in OC burial factors between the two habitat types. The higher OC burial rates in mangrove soils mean that their encroachment into coastal freshwater marshes has the potential to increase burial rates in those locations even more than might be expected from the acceleration trends. Regionally, these findings suggest that burial represents a substantially growing proportion of the coastal wetland carbon budget.
Sensing System for Remote Areas in Antarctica
Authors: Porte Joaquim , Maso Josep M. , Pijoan Joan Lluis , Badia David
Published: February 2020

Every year, the number of Internet of Things devices is growing exponentially. The current Internet of Things technology to support the connectivity of such a huge number of devices is limited by the coverage of the base stations deployed. In case of remote areas without coverage of any operator, the use of a satellite connection is such a high‐cost option. The only alternative option for very remote sensor is high frequency (HF) communications with ionospheric reflection. The HF band (3–30 MHz) with Near Vertical Incidence Skywave allows a large coverage area (up to 250 km) without the need of line of sight. The HF radio links usually need higher power transmissions with larger antennas supported by a mast. In this paper, we explore a new transmission scheme for low‐power transmissions, which is equivalent to use small and low gain HF antennas. We study the performance of several digital modulations using different bandwidths and transmission power. The field tests have been done around the Spanish Antarctic Base at Livingston Island to ensure the availability of the system even in polar areas where the behavior of the ionosphere is quite different from lower latitudes. However, the proposed physical layer fits well with any other remote location that requires low power data communication.
Active Radar Cross Section Reduction of an Object Using Microstrip Antennas
Authors: Sengupta Sohini , Council Henry , Jackson David R. , Onofrei Daniel
Published: February 2020

The research performed in this paper suggests that the radar cross section of an arbitrarily shaped object can be reduced by canceling the scattering from the object with the radiation from an antenna (implemented here as a microstrip antenna) placed on the surface of the object. Assuming that the direction of arrival of the incident signal is known, the radiation from the defending antenna can be adjusted in real‐time to cancel the scattering from the object in order to produce a negligible total field at the distant receiver so that the object becomes invisible to a monostatic radar working in a given known frequency band. This is implemented using an analog sensor on the object to measure the time domain field on the object, which is then connected to the antenna through an amplifier and phase shifter to control the radiation from the patch antenna. The system is implemented in real time and does not require any digitization or signal processing. The radar cross section reduction can thus be achieved with a wide variety of incident signals in the prescribed frequency band.
When Plasma Streams Tie up Equatorial Plasma Irregularities with Auroral Ones
Authors: Zakharenkova Irina , Cherniak Iurii
Published: February 2020

We present a new pattern of storm‐induced ionospheric irregularities behavior at midlatitudes—poleward‐streaming plasma density depletions. Under disturbed conditions, they appear at North America low latitudes as a part of extended postsunset equatorial plasma bubbles, and further, they are streaming from low latitudes in a northwestward, poleward direction toward the main ionospheric trough and auroral irregularities zone. The poleward‐streaming plasma depletions represent a new phenomenon with the similar northwestward transportation path across the continental United States as storm‐enhanced density (SED) plumes. The channels of poleward‐streaming plasma depletions were stretched from low‐latitude base toward higher latitudes—they are found to occur for geomagnetic storms under specific combination of steady southward interplanetary magnetic field, subauroral polarization streams (SAPS) electric fields, and enhanced westward drifts at midlatitudes, resulting in northwestward plasma transportation equatorward of the SAPS region. The poleward‐streaming plasma depletions form an illusion of traveling ionospheric disturbances (TIDs) moving in a poleward, northwestward direction—this propagation direction is opposite to typical equatorward propagation of storm‐induced large‐scale TIDs generated in the auroral zone and propagated toward the equator. This phenomenon is accompanied by strong ionospheric irregularities that occurred over both edges of plasma depletion channel at midlatitudes. For two comparable geomagnetic storms, these poleward‐streaming plasma depletions persisted for several hours, posing a localized threat for GPS‐based positioning applications. Even moderate‐to‐intense storms (Dst minimum−145 nT) can promote such effects at midlatitudes.
Rupture Process of the 26 May 2019 Mw 8.0 Northern Peru Intermediate‐Depth Earthquake and Insights Into Its Mechanism
Authors: Liu Wei , Yao Huajian
Published: February 2020

In the Nazca‐South American subduction zone, the subducted slab is flattened beneath northern Andes, called the Peruvian flat slab. The 2019 Mw 8.0 northern Peru intermediate‐depth normal‐faulting earthquake occurred at the leading edge of the Peruvian flat slab, where the slab rebends and sinks into greater depths. Here we investigate this earthquake by back projection analysis and finite fault inversion using seismic waveforms at teleseismic distances. The rupture process indicates that this earthquake ruptured mainly along strike (353°) ~150 km north‐northwestward within ~55 s (average rupture velocity ~2.7 km/s), resulting in two major slip areas with three high slip rate areas, which are consistent with three high‐frequency energy radiation subevents. Our study suggests that such a heterogeneous rupture may be caused by slab bending forces and dehydration embrittlement associated with morphology of the slab.
Daratumumab monotherapy for patients with intermediate-risk or high-risk smoldering multiple myeloma: a randomized, open-label, multicenter, phase 2 study (CENTAURUS)
Authors: Landgren C. Ola , Chari Ajai , Cohen Yael C. , Spencer Andrew , Voorhees Peter , Estell Jane A. , Sandhu Irwindeep , Jenner Matthew W. , Williams Catherine , Cavo Michele , van de Donk Niels W. C. J. , Beksac Meral , Moreau Philippe , Goldschmidt Hartmut , Kuppens Steven , Bandekar Rajesh , Clemens Pamela L. , Neff Tobias , Heuck Christoph , Qi Ming , Hofmeister Craig C.
Published: February 2020

Current guidelines for smoldering multiple myeloma (SMM) recommend active monitoring until the onset of multiple myeloma (MM) before initiating treatment or enrollment in a clinical trial. Earlier intervention may delay progression to MM. In CENTAURUS, 123 patients with intermediate-risk or high-risk SMM were randomly assigned to daratumumab 16 mg/kg intravenously on extended intense (intense), extended intermediate (intermediate), or short dosing schedules. At the prespecified primary analysis (15.8-month median follow-up), the complete response (CR) rates (co-primary endpoint) were 2.4%, 4.9%, and 0% for intense, intermediate, and short dosing, respectively; the co-primary endpoint of CR rate >15% was not met. Progressive disease (PD)/death rates (number of patients who progressed or died divided by total duration of progression-free survival [PFS] in patient-years; co-primary endpoint) for intense, intermediate, and short dosing were 0.055 (80% confidence interval [CI], 0.014–0.096), 0.102 (80% CI, 0.044–0.160), and 0.206 (80% CI, 0.118–0.295), respectively, translating to a median PFS ≥24 months in all arms (P < 0.0001, <0.0001, and =0.0213, respectively). With longer follow-up (median follow-up, 25.9 months), CR rates were 4.9%, 9.8%, and 0% for intense, intermediate, and short dosing, respectively. PD/death rates for intense, intermediate, and short dosing were 0.059 (80% CI, 0.025–0.092), 0.107 (80% CI, 0.058–0.155), and 0.150 (80% CI, 0.089–0.211), respectively, again translating to a median PFS ≥ 24 months in all arms (P < 0.0001 for all arms). Twenty-four–month PFS rates were 89.9% (90% CI, 78.5–95.4%), 82.0% (90% CI, 69.0–89.9%), and 75.3% (90% CI, 61.1–85.0%) for intense, intermediate, and short dosing, respectively. Pharmacokinetic analyses indicated that intense dosing maintained target-saturating trough concentrations in most patients throughout weekly, every-2-week, and every-4-week dosing periods. No new safety signals were observed. These data provide the basis for an ongoing phase 3 study of daratumumab in SMM.
mPTP opening caused by Cdk5 loss is due to increased mitochondrial Ca2+ uptake
Authors: NavaneethaKrishnan Saranya , Rosales Jesusa L. , Lee Ki-Young
Published: February 2020

We previously demonstrated that loss of Cdk5 in breast cancer cells promotes ROS-mediated cell death by inducing mitochondrial permeability transition pore (mPTP) opening (Oncogene 37, 1788–1804). However, the molecular mechanism by which Cdk5 loss causes mPTP opening remains to be investigated. Using primary mouse embryonic fibroblasts (MEFs) isolated from Cdk5−/− mouse embryos, we show that absence of Cdk5 causes a significant increase in both mPTP opening and mitochondrial Ca2+ level. Analysis of subcellular fractions of MEFs demonstrates that Cdk5 localizes in the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) and Cdk5 loss in MAMs causes increased ER-mitochondria tethering, a process required for Ca2+ transfer from the ER to the mitochondria. Loss of Cdk5 also causes increased ATP-mediated mitochondrial Ca2+ uptake from the ER. Inhibition of ER Ca2+ release or mitochondrial Ca2+ uptake in Cdk5−/− MEFs prevents mPTP opening, indicating that mPTP opening in Cdk5−/− MEFs is due to increased Ca2+ transfer from the ER to the mitochondria. Altogether, our findings suggest that Cdk5 in MAMs regulates mitochondrial Ca2+ homeostasis that is disturbed upon Cdk5 loss, which leads to mPTP opening.
Lipidome-based rapid diagnosis with machine learning for detection of TGF-β signalling activated area in head and neck cancer
Authors: Ishii Hiroki , Saitoh Masao , Sakamoto Kaname , Sakamoto Kei , Saigusa Daisuke , Kasai Hirotake , Ashizawa Kei , Miyazawa Keiji , Takeda Sen , Masuyama Keisuke , Yoshimura Kentaro
Published: February 2020

Background

Several pro-oncogenic signals, including transforming growth factor beta (TGF-β) signalling from tumour microenvironment, generate intratumoural phenotypic heterogeneity and result in tumour progression and treatment failure. However, the precise diagnosis for tumour areas containing subclones with cytokine-induced malignant properties remains clinically challenging.

Methods

We established a rapid diagnostic system based on the combination of probe electrospray ionisation-mass spectrometry (PESI-MS) and machine learning without the aid of immunohistological and biochemical procedures to identify tumour areas with heterogeneous TGF-β signalling status in head and neck squamous cell carcinoma (HNSCC). A total of 240 and 90 mass spectra were obtained from TGF-β-unstimulated and -stimulated HNSCC cells, respectively, by PESI-MS and were used for the construction of a diagnostic system based on lipidome.

Results

This discriminant algorithm achieved 98.79% accuracy in discrimination of TGF-β1-stimulated cells from untreated cells. In clinical human HNSCC tissues, this approach achieved determination of tumour areas with activated TGF-β signalling as efficiently as a conventional histopathological assessment using phosphorylated-SMAD2 staining. Furthermore, several altered peaks on mass spectra were identified as phosphatidylcholine species in TGF-β-stimulated HNSCC cells.

Conclusions

This diagnostic system combined with PESI-MS and machine learning encourages us to clinically diagnose intratumoural phenotypic heterogeneity induced by TGF-β.
Long non-coding RNA dysregulation is a frequent event in non-small cell lung carcinoma pathogenesis
Authors: Acha-Sagredo Amelia , Uko Bubaraye , Pantazi Paschalia , Bediaga Naiara G. , Moschandrea Chryssanthi , Rainbow Lucille , Marcus Michael W. , Davies Michael P. A. , Field John K. , Liloglou Triantafillos
Published: February 2020

Background

Long non-coding RNAs compose an important level of epigenetic regulation in normal physiology and disease. Despite the plethora of publications of lncRNAs in human cancer, the landscape is still unclear.

Methods

Microarray analysis in 44 NSCLC paired specimens was followed by qPCR-based validation in 29 (technical) and 38 (independent) tissue pairs. Cross-validation of the selected targets was achieved in 850 NSCLC tumours from TCGA datasets.

Results

Twelve targets were successfully validated by qPCR (upregulated: FEZF1-AS1, LINC01214, LINC00673, PCAT6, NUTM2A-AS1, LINC01929; downregulated: PCAT19, FENDRR, SVIL-AS1, LANCL1-AS1, ADAMTS9-AS2 and LINC00968). All of them were successfully cross validated in the TCGA datasets. Abnormal DNA methylation was observed in the promoters of FENDRR, FEZF1-AS1 and SVIL-AS1. FEZF1-AS1 and LINC01929 were associated with survival in the TCGA set.

Conclusions

Our study provides through multiple levels of internal and external validation, a comprehensive list of dysregulated lncRNAs in NSCLC. We therefore envisage this dataset to serve as an important source for the lung cancer research community assisting future investigations on the involvement of lncRNAs in the pathogenesis of the disease and providing novel biomarkers for diagnosis, prognosis and therapeutic stratification.
Regulation of heterotopic ossification by monocytes in a mouse model of aberrant wound healing
Authors: Sorkin Michael , Huber Amanda K. , Hwang Charles , Carson William F. , Menon Rajasree , Li John , Vasquez Kaetlin , Pagani Chase , Patel Nicole , Li Shuli , Visser Noelle D. , Niknafs Yashar , Loder Shawn , Scola Melissa , Nycz Dylan , Gallagher Katherine , McCauley Laurie K. , Xu Jiajia , James Aaron W. , Agarwal Shailesh , Kunkel Stephen , Mishina Yuji , Levi Benjamin
Published: February 2020

Heterotopic ossification (HO) is an aberrant regenerative process with ectopic bone induction in response to musculoskeletal trauma, in which mesenchymal stem cells (MSC) differentiate into osteochondrogenic cells instead of myocytes or tenocytes. Despite frequent cases of hospitalized musculoskeletal trauma, the inflammatory responses and cell population dynamics that regulate subsequent wound healing and tissue regeneration are still unclear. Here we examine, using a mouse model of trauma-induced HO, the local microenvironment of the initial post-injury inflammatory response. Single cell transcriptome analyses identify distinct monocyte/macrophage populations at the injury site, with their dynamic changes over time elucidated using trajectory analyses. Mechanistically, transforming growth factor beta-1 (TGFβ1)-producing monocytes/macrophages are associated with HO and aberrant chondrogenic progenitor cell differentiation, while CD47-activating peptides that reduce systemic macrophage TGFβ levels and help ameliorate HO. Our data thus implicate CD47 activation as a therapeutic approach for modulating monocyte/macrophage phenotypes, MSC differentiation and HO formation during wound healing.
Neo-functionalization of a Teosinte branched 1 homologue mediates adaptations of upland rice
Authors: Lyu Jun , Huang Liyu , Zhang Shilai , Zhang Yesheng , He Weiming , Zeng Peng , Zeng Yan , Huang Guangfu , Zhang Jing , Ning Min , Bao Yachong , Zhao Shilei , Fu Qi , Wade Len J. , Chen Hua , Wang Wen , Hu Fengyi
Published: February 2020

The rice orthologue of maize domestication geneTeosinte branched 1(Tb1) affects tillering. But, unlike maizeTb1gene, it was not selected during domestication. Here, we report that anOsTb1duplicate gene (OsTb2) has been artificially selected during upland rice adaptation and that natural variation inOsTb2is associated with tiller number. Interestingly, transgenic rice overexpressing this gene shows increased rather than decreased tillering, suggesting thatOsTb2gains a regulatory effect opposite to that ofOsTb1following duplication. Functional analyses suggest that the OsTb2 protein positively regulates tillering by interacting with the homologous OsTb1 protein and counteracts the inhibitory effect of OsTb1 on tillering. We further characterize two functional variations withinOsTb2that regulate protein function and gene expression, respectively. These results not only present an example of neo-functionalization that generates an opposite function following duplication but also suggest that theTb1homologue has been selected in upland rice.
Polarized resonant emission of monolayer WS2 coupled with plasmonic sawtooth nanoslit array
Authors: Han Chunrui , Ye Jianting
Published: February 2020

Transition metal dichalcogenide (TMDC) monolayers have enabled important applications in light emitting devices and integrated nanophotonics because of the direct bandgap, spin-valley locking and highly tunable excitonic properties. Nevertheless, the photoluminescence polarization is almost random at room temperature due to the valley decoherence. Here, we show the room temperature control of the polarization states of the excitonic emission by integrating WS2 monolayers with a delicately designed metasurface, i.e. a silver sawtooth nanoslit array. The random polarization is transformed to linear when WS2 excitons couple with the anisotropic resonant transmission modes that arise from the surface plasmon resonance in the metallic nanostructure. The coupling is found to enhance the valley coherence that contributes to ~30% of the total linear dichroism. Further modulating the transmission modes by optimizing metasurfaces, the total linear dichroism of the plasmon-exciton hybrid system can approach 80%, which prompts the development of photonic devices based on TMDCs.
Novel mucosal adjuvant, mastoparan-7, improves cocaine vaccine efficacy
Authors: St. John Ashley L. , Choi Hae Woong , Walker Q. David , Blough Bruce , Kuhn Cynthia M. , Abraham Soman N. , Staats Herman F.
Published: February 2020

Cocaine is one of the most potent and addictive psychostimulants known and there are no available pharmacotherapies to treat cocaine addiction. Here we describe a novel cocaine vaccine employing the mucosal adjuvant and mast cell-activating oligopeptide, mastoparan-7 (M7), to achieve optimal IgA antibody responses in mucosal secretions and effective induction of humoral immunity using a short immunization protocol. This formulation, using a hapten-carrier system to deliver cocaine as antigen, also reduced cocaine penetration of the blood brain barrier and protected mice from its psychoactive effects by reducing cocaine-induced locomotion. Surprisingly, the magnitude of cocaine-specific antibody titers induced by each adjuvant was not the major determinant of functional protection from cocaine challenge. A side-by-side comparison of the two haptens, cocaine and its analog GNC demonstrated that cocaine haptenation resulted in superior functional protection when used in combination with the novel mucosal adjuvant, M7. These results provide a new potential strategy for combatting cocaine addiction through mucosal vaccination.
Influence of Severity of Type and Timing of Retrospectively Reported Childhood Maltreatment on Female Amygdala and Hippocampal Volume
Authors: Herzog Julia I. , Thome Janine , Demirakca Traute , Koppe Georgia , Ende Gabriele , Lis Stefanie , Rausch Sophie , Priebe Kathlen , Müller-Engelmann Meike , Steil Regina , Bohus Martin , Schmahl Christian
Published: February 2020

Deleterious effects of adverse childhood experiences (ACE) on human brain volume are widely reported. First evidence points to differential effects of ACE on brain volume in terms of timing of ACE. Upcoming studies additionally point towards the impact of different types (i.e., neglect and abuse) of ACE in terms of timing. The current study aimed to investigate the correlation between retrospectively reported severity of type (i.e., the extent to which subjects were exposed to abuse and/or neglect, respectively) and timing of ACE on female brain volume in a sample of prolonged traumatized subjects. A female sample with ACE (N = 68) underwent structural magnetic resonance imaging and a structured interview exploring the severity of ACE from age 3 up to 17 using the “Maltreatment and Abuse Chronology of Exposure” (MACE). Random forest regression with conditional interference trees was applied to assess the impact of ACE severity as well as the severity of ACE type, (i.e. to what extent individuals were exposed to neglect and/or abuse) at certain ages on pre-defined regions of interest such as the amygdala, hippocampus, and anterior cingulate (ACC) volume. Analyses revealed differential type and timing-specific effects of ACE on stress sensitive brain structures: Amygdala and hippocampal volume were affected by ACE severity during a period covering preadolescence and early adolescence. Crucially, this effect was driven by the severity of neglect.
The gender dependent influence of sodium bicarbonate supplementation on anaerobic power and specific performance in female and male wrestlers
Authors: Durkalec–Michalski Krzysztof , Zawieja Emilia E. , Zawieja Bogna E. , Michałowska Patrycja , Podgórski Tomasz
Published: February 2020

The aim of this study was the assessment of progressive low-dose sodium bicarbonate (NaHCO3) supplementation on the anaerobic indices in two bouts of Wingate tests (WT) separated by wrestling-specific performance test and assessing the gender differences in response. Fifty-one (18 F) wrestlers completed a randomized trial of either a NaHCO3 (up to 100 mg·kg−1) or a placebo for 10 days. Before and after treatment, athletes completed an exercise protocol that comprised, in sequence, the first WT1, dummy throw test (DT), and second WT2. The number of completed throws increased significantly in males from 19.3 ± 2.6 NaHCO3pre to 21.7 ± 2.9 NaHCO3post. ΔWT2-WT1 improved particularly in the midsection of 30-s WT on NaHCO3. However, no significant differences were found in peak power (PP), power drop (PD) and average power (AP) (analyzed separately for each WT), and ΔWT2-WT1 in PP and PD. Interaction with gender was significant for AP, PP and PD, every second of WT1 and WT2, as well as DT test. In conclusion, our study suggests that the response to NaHCO3 may be gender-specific and progressive low-dose NaHCO3 supplementation allows the advantageous strengthening of wrestling-specific performance in males. It can also lead to maintenance of high anaerobic power mainly in the midsection of the 30-s Wingate test.
Graphlets in Multiplex Networks
Authors: Dimitrova Tamarа , Petrovski Kristijan , Kocarev Ljupcho
Published: February 2020

We develop graphlet analysis for multiplex networks and discuss how this analysis can be extended to multilayer and multilevel networks as well as to graphs with node and/or link categorical attributes. The analysis has been adapted for two typical examples of multiplexes: economic trade data represented as a 957-plex network and 75 social networks each represented as a 12-plex network. We show that wedges (open triads) occur more often in economic trade networks than in social networks, indicating the tendency of a country to produce/trade of a product in local structure of triads which are not closed. Moreover, our analysis provides evidence that the countries with small diversity tend to form correlated triangles. Wedges also appear in the social networks, however the dominant graphlets in social networks are triangles (closed triads). If a multiplex structure indicates a strong tie, the graphlet analysis provides another evidence for the concepts of strong/weak ties and structural holes. In contrast to Granovetter’s seminal work on the strength of weak ties, in which it has been documented that the wedges with only strong ties are absent, here we show that for the analyzed 75 social networks, the wedges with only strong ties are not only present but also significantly correlated.
GloBody Technology: Detecting Anti-Drug Antibody against VH/VL domains
Authors: Saxena Gauri K. , Theocharopoulos Ioannis , Aziz Nisha Thaslima , Jones Meleri , Gnanapavan Sharmilee , Giovannoni Gavin , Schmierer Klaus , Garnett James A. , Baker David , Kang Angray S.
Published: February 2020

The occurrence of anti-drug antibodies following administration of therapeutic monoclonal antibody to patients is a growing problem that is attracting attention from frontline clinicians. Ideally, an initial indicative point of care test would provide guidance to seek testing approved by the regulatory authorities. Here we describe a platform for the detection of IgG anti-drug antibodies that may provide an initial screen for all therapeutic monoclonal antibodies. Synthetic genes encoding Nanoluciferase polypeptides were inserted between the variable heavy and light domain encoding region of known antibody drugs (alemtuzumab and adalimumab) to generate recombinant single chain GloBodies, which retain the drug antibody paratopes and Nanoluciferase activity. In the presence of anti-drug antibodies, the GloBody is bound by specific IgG in the sample. These complexes are captured on immobilised Protein G and the luciferase activity determined. The amount of light generated being indicative of the anti-drug IgG antibody levels in serum. It should be possible to assemble GloBody reagents for all therapeutic monoclonal antibodies and adapt the capture phase to include additional specific isotypes. The assay has the potential to be developed for use with a drop of blood allowing initial pre-screening in a point of care setting.
Publisher Correction: Study on the Visualization of Pigment in Haematococcus pluvialis by Raman Spectroscopy Technique
Authors: Shao Yongni , Gu Weimin , Jiang Linjun , Zhu Yiming , Gong Aiping
Published: February 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.