bluuebunny/crossref_metadata_2025 huggingface dataset:
A Method of Stacking AltiKa Repeat Cycle Data that May Reveal 75,000+ Possible Small Seamounts
Authors: Marks K. M. , Smith W. H. F.
Published: November 2018

The SARAL AltiKa radar altimeter measured sea surface height along ground tracks that were regularly revisited by repeating cycles. We devised an automated method of “stacking” the repeat cycles that aligns them to common positions along a model track, selects segments that pass quality criteria, removes the non‐geoidal height and height error from each repeat profile, and calculates the median height profile. This procedure reinforces geoid signals while reducing measurement noise and height signals produced by ocean dynamics. A seamount detection filter applied to the median profiles reveals 75,208 possible small seamounts along AltiKa ground tracks globally. Of these, 4824 are located over multibeam surveys. Seamount heights estimated by subtracting regional depths from the multibeam depths follow a Poisson statistical distribution that suggests at least 84% are less than 2 km tall. A 1 km along‐track sampling of the stacked repeat cycles is available from the National Centers for Environmental Information (NCEI) data repository.
Pinatubo Volcanic Eruption Exacerbated an Abrupt Coral Mortality Event in 1991 Summer
Authors: Wu Chung‐Che , Shen Chuan‐Chou , Lo Li , Hsin Yi‐Chia , Yu Kefu , Chang Ching‐Chih , Lam Doan Dinh , Chou Yu‐Min , Liu Yi , Pallister John , Song Sheng‐Rong , Chiang Hong‐Wei , Burr George S.
Published: November 2018

Widespread coral bleaching and mortality associated with global warming have occurred frequently since the phenomenon was first documented in the early 1980s. One such episode that occurred in 1991 over the tropical Pacific‐Indian Ocean region has been attributed to high summer sea surface temperatures. However, we found that sea surface temperature values from the South China Sea region do not provide a comprehensive explanation for the event. Our results, based on time series records of rare earth elements, trace element Al/Ca ratios, and microdomain images from corals in the South China Sea, suggest that this coral mortality event was exacerbated by heavy ash fallout from the cataclysmic 1991 volcanic eruption of Mount Pinatubo. Our findings highlight the profound impact of a volcanic eruption on the modern vulnerable coral reef ecosystems, already under the stress of global warming.
Indirect Influence of Humidity on Atmospheric Spectra Near 4 μm
Authors: Hartmann J.‐M. , Armante R. , Toon G. C. , Scott N. , Tran H. , Crevoisier C. , Chédin A. , Capelle V.
Published: November 2018

We give the first demonstration that humidity has indirect effects on atmospheric spectra near 4 μm, through the influence of collisions with H2O on both the collision‐induced band of N2 and the wings of the CO2 lines. This is shown by comparing computed and measured values of atmospheric transmissions and outgoing radiances. The usual assumption that collisions with H2O and dry air have equal effect on the N2 and CO2 absorptions leads to significantly underestimated absorptions for humid atmospheres. This bias is considerably reduced when the influences of H2O on the N2 and CO2 contributions to the spectra are taken into account using proper spectroscopic models. This opens perspectives of increased accuracy near 4 μm where the atmosphere is relatively transparent, for astronomical observations of outer objects from ground as well as for retrievals of the Earth land/sea surface temperatures from radiances recorded from space.
Flow Regimes and Adjustment to Wind‐Driven Motions in Lake Pontchartrain Estuary: A Modeling Experiment Using FVCOM
Authors: Li Chunyan , Huang Wei , Chen Changsheng , Lin Huichan
Published: November 2018

Lake Pontchartrain is a brackish estuary and restricted lagoon in the microtidal northern Gulf of Mexico. Using a validated Finite Volume Community Ocean Model (FVCOM), we study the flow regimes and wind‐driven adjustment of circulation in this system. It is found that tidal currents are only significant in the eastern end near the open boundary. Local wind inside the estuary is important in driving the circulation including coastal currents. Numerical experiments confirm that the subtidal wind‐driven flow is in a quasi‐steady balance between wind stress and surface slope. Our results show that the adjustment of surface level inside the system to a sudden change in wind is a transient seiche, which dissipates within two to three cycles, each lasting ~3 hr. After the oscillations, the system reaches a new equilibrium. We show in theory that this is a damped oscillation and as wind changes, an adjustment to a new equilibrium goes much faster than a complete tidal period. This leads to the quasi steady state balance of subtidal wind‐driven flows with essentially no phase lag with wind even though wind changes with time continuously. Wind‐induced circulation behaves differently from the Csanady model with Earth rotation but similar to the prismatic lake model of Engelund without Coriolis: The coastal and shallow regions tend to have flows in the direction of wind, while the interior and deeper waters have return flows against the wind especially in bottom layer. The surface flow may not be in the direction of wind, while the bottom usually has broad and uniform counter wind flows.
Inertia‐Gravity Waves Revealed in Radiosonde Data at Jang Bogo Station, Antarctica (74°37′S, 164°13′E): 1. Characteristics, Energy, and Momentum Flux
Authors: Yoo J.‐H. , Choi T. , Chun H.‐Y. , Kim Y.‐H. , Song I.‐S. , Song B.‐G.
Published: November 2018

Characteristics of inertia‐gravity waves (IGWs) at high latitude in Antarctica are investigated using radiosondes launched daily at Jang Bogo Station (74°37′S, 164°13′E), a new Antarctic station that has been operating since 2014, in the troposphere (z = 2–7 km) and lower stratosphere (z = 15–22 km) for 25 months (December 2014 to December 2016). The vertical propagation of IGWs exhibits strong seasonal variations in the stratosphere, with an enhancement (reduction) in downward (upward)‐propagating IGWs from May to mid‐October. In the troposphere, both upward‐ and downward‐propagating IGWs have similar occurrence rates without seasonal variations. The intrinsic phase velocity of IGWs mostly direct to the west (isotropic), while the ground‐relative phase and group velocities are dominant in the east and southeast (northeast), respectively, in the stratosphere (troposphere). The intrinsic frequency, vertical wavelength, and horizontal wavelength of IGWs averaged in the troposphere (stratosphere) are 3.57f (1.93f; where f is the Coriolis parameter), 1.48 (1.48) km, and 63.06 (221.81) km, respectively. The wave energy in the stratosphere has clear seasonal variations with large values in autumn and spring, while that in the troposphere is smaller without obvious seasonal variations. Zonal and meridional momentum fluxes averaged in the stratosphere (troposphere) are −0.008 (−0.0018) and −0.0005 (0.001) m2/s2, respectively. The momentum flux of downward‐propagating IGWs in the stratosphere is mostly positive in both zonal and meridional directions, whereas the directional preference is not obvious in the troposphere. In Part 2, sources of the observed IGWs in the troposphere and stratosphere will be examined.
A Review of Geophysical Methods for Soil Structure Characterization
Authors: Romero‐Ruiz Alejandro , Linde Niklas , Keller Thomas , Or Dani
Published: November 2018

The growing interest in the maintenance of favorable soil structure is largely motivated by its central role in plant growth, soil ecological functioning, and impacts on surface water and energy fluxes. Soil structure pertains to the spatial arrangement of voids and solid constituents, their aggregation, and mechanical state. As a fragile product of soil biological activity that includes invisible ingredients (mechanical and ecological states), soil structure is difficult to define rigorously, and measurements of relevant metrics often rely on core samples or on episodic point measurements. The presence of soil structure has not yet been explicitly incorporated in climate and Earth systems models, partially due to incomplete methodological means to characterize it at relevant scales and to parameterize it in spatially extensive models. We seek to review the potential of harnessing geophysical methods to fill the scale gap in characterization of soil structure directly (via impact of soil pores, transport, and mechanical properties on geophysical signals) or indirectly by measurement of surrogate variables (wetness and rates of drainage). We review basic aspects of soil structure and challenges of characterization across spatial and temporal scales and how geophysical methods could be used for the task. Additionally, we propose the use of geophysical models, inversion techniques, and combination of geophysical methods for extracting soil structure information at previously unexplored spatial and temporal scales.
Crowdsourcing Methods for Data Collection in Geophysics: State of the Art, Issues, and Future Directions
Authors: Zheng Feifei , Tao Ruoling , Maier Holger R. , See Linda , Savic Dragan , Zhang Tuqiao , Chen Qiuwen , Assumpção Thaine H. , Yang Pan , Heidari Bardia , Rieckermann Jörg , Minsker Barbara , Bi Weiwei , Cai Ximing , Solomatine Dimitri , Popescu Ioana
Published: November 2018

Data are essential in all areas of geophysics. They are used to better understand and manage systems, either directly or via models. Given the complexity and spatiotemporal variability of geophysical systems (e.g., precipitation), a lack of sufficient data is a perennial problem, which is exacerbated by various drivers, such as climate change and urbanization. In recent years, crowdsourcing has become increasingly prominent as a means of supplementing data obtained from more traditional sources, particularly due to its relatively low implementation cost and ability to increase the spatial and/or temporal resolution of data significantly. Given the proliferation of different crowdsourcing methods in geophysics and the promise they have shown, it is timely to assess the state of the art in this field, to identify potential issues and map out a way forward. In this paper, crowdsourcing‐based data acquisition methods that have been used in seven domains of geophysics, including weather, precipitation, air pollution, geography, ecology, surface water, and natural hazard management, are discussed based on a review of 162 papers. In addition, a novel framework for categorizing these methods is introduced and applied to the methods used in the seven domains of geophysics considered in this review. This paper also features a review of 93 papers dealing with issues that are common to data acquisition methods in different domains of geophysics, including the management of crowdsourcing projects, data quality, data processing, and data privacy. In each of these areas, the current status is discussed and challenges and future directions are outlined.
A Randomized Controlled Trial of TELEmedicine for Patients with Inflammatory Bowel Disease (TELE-IBD)
Authors: Cross Raymond K. , Langenberg Patricia , Regueiro Miguel , Schwartz David A. , Tracy J. Kathleen , Collins Joseph F. , Katz Jonathan , Ghazi Leyla , Patil Seema A. , Quezada Sandra M. , Beaulieu Dawn , Horst Sara N. , Russman Katharine , Riaz Mahrukh , Jambaulikar Guruprasad , Sivasailam Barathi , Quinn Charlene C.
Published: November 2018

INTRODUCTION:

Telemedicine has shown promise in inflammatory bowel disease (IBD). The objective of this study was to compare disease activity and quality of life (QoL) in a 1-year randomized trial of IBD patients receiving telemedicine vs. standard care.

METHODS:

Patients with worsening symptoms in the prior 2 years were eligible for randomization to telemedicine (monitoring via texts EOW or weekly) or standard care. The primary outcomes were the differences in change in disease activity and QoL between the groups; change in healthcare utilization among groups was a secondary aim.

RESULTS:

348 participants were enrolled (117 control group, 115 TELE-IBD EOW, and 116 TELE-IBD weekly). 259 (74.4%) completed the study. Age was 38.9 ± 12.3 years, 56.6% were women, 91.9% were Caucasian, 67.9% had Crohn’s disease (CD) and 42.5% had active disease at baseline. In CD, all groups experienced a decrease in disease activity (control −5.2 ± 5.0 to 3.7 ± 3.6, TELE-IBD EOW 4.7 ± 4.1 to 4.2 ± 3.9, and TELE-IBD weekly 4.2 ± 4.2 to 3.2 ± 3.4, p < 0.0001 for each of the groups) In UC, only controls had a significant decrease in disease activity (control 2.9 ± 3.1 to 1.4 ± 1.4, p = 0.01, TELE-IBD EOW 2.7 ± 3.1 to 1.7 ± 1.9, p = 0.35, and TELE-IBD Weekly 2.5 ± 2.5 to 2.0 ± 1.8, p = 0.31). QoL increased in all groups; the increase was significant only in TELE-IBD EOW (control 168.1 ± 34.0 to 179.3 ± 28.2, p = 0.06, TELE-IBD EOW 172.3 ± 33.1 to 181.5 ± 28.2, p = 0.03, and TELE-IBD Weekly 172.3 ± 34.5 to 179.2 ± 32.8, p = 0.10). Unadjusted and adjusted changes in disease activity and QoL were not significantly different among groups. Healthcare utilization increased in all groups. TELE-IBD weekly were less likely to have IBD-related hospitalizations and more likely to have non-invasive diagnostic tests and electronic encounters compared to controls; both TELE-IBD groups had decreased non-IBD related hospitalizations and increased telephone calls compared to controls.

DISCUSSION:

Disease activity and QoL, although improved in all participants, were not improved further through use of the TELE-IBD system. TELE-IBD participants experienced a decrease in hospitalizations with an associated increase in non-invasive diagnostic tests, telephone calls and electronic encounters. Research is needed to determine if TELE-IBD can be improved through patient engagement and whether it can decrease healthcare utilization by replacing standard care.
Convergence of independent DISC1 mutations on impaired neurite growth via decreased UNC5D expression
Authors: Srikanth Priya , Lagomarsino Valentina N. , Pearse Richard V. , Liao Meichen , Ghosh Sulagna , Nehme Ralda , Seyfried Nicholas , Eggan Kevin , Young-Pearse Tracy L.
Published: November 2018

The identification of convergent phenotypes in different models of psychiatric illness highlights robust phenotypes that are more likely to be implicated in disease pathophysiology. Here, we utilize human iPSCs harboring distinct mutations in DISC1 that have been found in families with major mental illness. One mutation was engineered to mimic the consequences on DISC1 protein of a balanced translocation linked to mental illness in a Scottish pedigree; the other mutation was identified in an American pedigree with a high incidence of mental illness. Directed differentiation of these iPSCs using NGN2 expression shows rapid conversion to a homogenous population of mature excitatory neurons. Both DISC1 mutations result in reduced DISC1 protein expression, and show subtle effects on certain presynaptic proteins. In addition, RNA sequencing and qPCR showed decreased expression of UNC5D, DPP10, PCDHA6, and ZNF506 in neurons with both DISC1 mutations. Longitudinal analysis of neurite outgrowth revealed decreased neurite outgrowth in neurons with each DISC1 mutation, which was mimicked by UNC5D knockdown and rescued by transient upregulation of endogenous UNC5D. This study shows a narrow range of convergent phenotypes of two mutations found in families with major mental illness, and implicates dysregulated netrin signaling in DISC1 biology.
Bortezomib, lenalidomide, and dexamethasone (VRd) followed by autologous stem cell transplant for multiple myeloma
Authors: Sidiqi M. Hasib , Aljama Mohammed A. , Bin Riaz Irbaz , Dispenzieri Angela , Muchtar Eli , Buadi Francis K. , Warsame Rahma , Lacy Martha Q. , Dingli David , Leung Nelson , Gonsalves Wilson I. , Kapoor Prashant , Kourelis Taxiarchis V. , Hogan William J. , Rajkumar S. Vincent , Kumar Shaji K. , Gertz Morie A.
Published: November 2018

We retrospectively reviewed all patients (n = 243) receiving bortezomib, lenalidomide, and dexamethasone (VRd) induction followed by autologous stem cell transplantation (ASCT) for multiple myeloma at the Mayo Clinic between January 2010 and April of 2017. Median age was 61 (interquartile range, 55–67) with 62% of patients being male. High-risk cytogenetic abnormalities (HRA) were present in 34% of patients. A total of 166 (68%) patients received some form of maintenance/other therapy post transplant (no maintenance (NM, n = 77), lenalidomide maintenance (LM, n = 108), bortezomib maintenance (BM, n = 39), and other therapy (OT, n = 19)). Overall response rate at day 100 post ASCT was 99% (CR 42%) with CR rate increasing to 62% at time of best response post transplant. Two year and 5 year overall survival rates were 90% and 67%, respectively, with an estimated median overall survival (OS) and progression-free survival (PFS) of 96 and 28 months, respectively. HRA was associated with a worse OS but not PFS (median OS: not reached for standard risk vs 60 months for HRA, P = 0.0006; median PFS: 27 months for standard risk vs 22 months for HRA, P = 0.70). The combination of VRd followed by ASCT is a highly effective regimen producing deep and durable responses in many patients.
Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways
Authors: Duffy David L. , Zhu Gu , Li Xin , Sanna Marianna , Iles Mark M. , Jacobs Leonie C. , Evans David M. , Yazar Seyhan , Beesley Jonathan , Law Matthew H. , Kraft Peter , Visconti Alessia , Taylor John C. , Liu Fan , Wright Margaret J. , Henders Anjali K. , Bowdler Lisa , Glass Dan , Ikram M. Arfan , Uitterlinden André G. , Madden Pamela A. , Heath Andrew C. , Nelson Elliot C. , Green Adele C. , Chanock Stephen , Barrett Jennifer H. , Brown Matthew A. , Hayward Nicholas K. , MacGregor Stuart , Sturm Richard A. , Hewitt Alex W. ,   Melanoma GWAS Consortium, Lee Jeffrey E. , Brossard Myriam , Moses Eric K. , Song Fengju , Kumar Rajiv , Easton Douglas F. , Pharoah Paul D. P. , Swerdlow Anthony J. , Kypreou Katerina P. , Harland Mark , Randerson-Moor Juliette , Akslen Lars A. , Andresen Per A. , Avril Marie-Françoise , Azizi Esther , Scarrà Giovanna Bianchi , Brown Kevin M. , Dębniak Tadeusz , Elder David E. , Fang Shenying , Friedman Eitan , Galan Pilar , Ghiorzo Paola , Gillanders Elizabeth M. , Goldstein Alisa M. , Gruis Nelleke A. , Hansson Johan , Helsing Per , Hočevar Marko , Höiom Veronica , Ingvar Christian , Kanetsky Peter A. , Chen Wei V. , Landi Maria Teresa , Lang Julie , Lathrop G. Mark , Lubiński Jan , Mackie Rona M. , Mann Graham J. , Molven Anders , Novaković Srdjan , Olsson Håkan , Puig Susana , Puig-Butille Joan Anton , Radford-Smith Graham L. , van der Stoep Nienke , van Doorn Remco , Whiteman David C. , Craig Jamie E. , Schadendorf Dirk , Simms Lisa A. , Burdon Kathryn P. , Nyholt Dale R. , Pooley Karen A. , Orr Nicholas , Stratigos Alexander J. , Cust Anne E. , Ward Sarah V. , Schulze Hans-Joachim , Dunning Alison M. , Demenais Florence , Amos Christopher I. , Kayser Manfred , Hunter David J. , Newton Bishop Julia A. , Spector Timothy D. , Montgomery Grant W. , Mackey David A. , Smith George Davey , Nijsten Tamar E. , Bishop D. Timothy , Bataille Veronique , Falchi Mario , Han Jiali , Martin Nicholas G.
Published: November 2018

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.
Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma
Authors: Corre Sébastien , Tardif Nina , Mouchet Nicolas , Leclair Héloïse M. , Boussemart Lise , Gautron Arthur , Bachelot Laura , Perrot Anthony , Soshilov Anatoly , Rogiers Aljosja , Rambow Florian , Dumontet Erwan , Tarte Karin , Bessede Alban , Guillemin Gilles J. , Marine Jean-Christophe , Denison Michael S. , Gilot David , Galibert Marie-Dominique
Published: November 2018

BRAF inhibitors target the BRAF-V600E/K mutated kinase, the driver mutation found in 50% of cutaneous melanoma. They give unprecedented anti-tumor responses but acquisition of resistance ultimately limits their clinical benefit. The master regulators driving the expression of resistance-genes remain poorly understood. Here, we demonstrate that the Aryl hydrocarbon Receptor (AhR) transcription factor is constitutively activated in a subset of melanoma cells, promoting the dedifferentiation of melanoma cells and the expression of BRAFi-resistance genes. Typically, under BRAFi pressure, death of BRAFi-sensitive cells leads to an enrichment of a small subpopulation of AhR-activated and BRAFi-persister cells, responsible for relapse. Also, differentiated and BRAFi-sensitive cells can be redirected towards an AhR-dependent resistant program using AhR agonists. We thus identify Resveratrol, a clinically compatible AhR-antagonist that abrogates deleterious AhR sustained-activation. Combined with BRAFi, Resveratrol reduces the number of BRAFi-resistant cells and delays tumor growth. We thus propose AhR-impairment as a strategy to overcome melanoma resistance.
Sound identity is represented robustly in auditory cortex during perceptual constancy
Authors: Town Stephen M. , Wood Katherine C. , Bizley Jennifer K.
Published: November 2018

Perceptual constancy requires neural representations that are selective for object identity, but also tolerant across identity-preserving transformations. How such representations arise in the brain and support perception remains unclear. Here, we study tolerant representation of sound identity in the auditory system by recording neural activity in auditory cortex of ferrets during perceptual constancy. Ferrets generalize vowel identity across variations in fundamental frequency, sound level and location, while neurons represent sound identity robustly across acoustic variations. Stimulus features are encoded with distinct time-courses in all conditions, however encoding of sound identity is delayed when animals fail to generalize and during passive listening. Neurons also encode information about task-irrelevant sound features, as well as animals’ choices and accuracy, while population decoding out-performs animals’ behavior. Our results show that during perceptual constancy, sound identity is represented robustly in auditory cortex across widely varying conditions, and behavioral generalization requires conserved timing of identity information.
MR imaging tracking of inflammation-activatable engineered neutrophils for targeted therapy of surgically treated glioma
Authors: Wu Meiying , Zhang Haixian , Tie Changjun , Yan Chunhong , Deng Zhiting , Wan Qian , Liu Xin , Yan Fei , Zheng Hairong
Published: November 2018

Cell-based drug delivery systems have shown promising capability for tumor-targeted therapy owing to the intrinsic tumor-homing and drug-carrying property of some living cells. However, imaging tracking of their migration and bio-effects is urgently needed for clinical application, especially for glioma. Here, we report the inflammation-activatable engineered neutrophils by internalizing doxorubicin-loaded magnetic mesoporous silica nanoparticles (ND-MMSNs) which can provide the potential for magnetic resonance (MR) imaging tracking of the drug-loaded cells to actively target inflamed brain tumor after surgical resection of primary tumor. The phagocytized D-MMSNs possess high drug loading efficiency and do not affect the host neutrophils’ viability, thus remarkably improving intratumoral drug concentration and delaying relapse of surgically treated glioma. Our study offers a new strategy in targeted cancer theranostics through combining the merits of living cells and nanoparticle carriers.
An E2-ubiquitin thioester-driven approach to identify substrates modified with ubiquitin and ubiquitin-like molecules
Authors: Bakos Gábor , Yu Lu , Gak Igor A. , Roumeliotis Theodoros I. , Liakopoulos Dimitris , Choudhary Jyoti S. , Mansfeld Jörg
Published: November 2018

Covalent modifications of proteins with ubiquitin and ubiquitin-like molecules are instrumental to many biological processes. However, identifying the E3 ligase responsible for these modifications remains a major bottleneck in ubiquitin research. Here, we present an E2-thioester-driven identification (E2~dID) method for the targeted identification of substrates of specific E2 and E3 enzyme pairs. E2~dID exploits the central position of E2-conjugating enzymes in the ubiquitination cascade and provides in vitro generated biotinylated E2~ubiquitin thioester conjugates as the sole source for ubiquitination in extracts. This enables purification and mass spectrometry-based identification of modified proteins under stringent conditions independently of the biological source of the extract. We demonstrate the sensitivity and specificity of E2-dID by identifying and validating substrates of APC/C in human cells. Finally, we perform E2~dID with SUMO in S. cerevisiae, showing that this approach can be easily adapted to other ubiquitin-like modifiers and experimental models.
21-Gene assay as predictor of chemotherapy benefit in HER2-negative breast cancer
Authors: Geyer Charles E. , Tang Gong , Mamounas Eleftherios P. , Rastogi Priya , Paik Soonmyung , Shak Steven , Baehner Frederick L. , Crager Michael , Wickerham D. Lawrence , Costantino Joseph P. , Wolmark Norman
Published: November 2018

The NSABP B-20 prospective-retrospective study of the 21-gene Oncotype DX Breast Cancer Recurrence Score® test predicted benefit from addition of chemotherapy to tamoxifen in node-negative, estrogen-receptor positive breast cancer when recurrence score (RS) was ≥31. HER2 is a component of the RS algorithm with a positive coefficient and contributes to higher RS values. Accrual to B-20 occurred prior to routine testing for HER2, so questions have arisen regarding assay performance if HER2-positive patients were identified and excluded. We report an exploratory reanalysis of the B-20, 21-gene study following exclusion of such patients. Patients were considered HER2 positive if quantitative RT-PCR for HER2 was ≥11.5 units, and excluded from re-analyses performed using the original cutoffs: <18, 18–30, ≥31, and the TAILORx cutoffs: <11, 11–25, >25. The endpoint remained distant recurrence-free interval (DRFI) as in the original study. Distribution was estimated via the Kaplan–Meier method and compared via log-rank test. Multivariate Cox proportional hazards models estimated chemotherapy benefit in each group. In the RS < 18 and 18–30 groups, 1.7 and 6.7% were HER2 positive. In the RS ≥ 31 group, 41% were HER2 positive. Exclusion resulted in fewer events, with loss of significance for benefit from chemotherapy in the overall HER2-negative cohort (log-rankP = 0.06), but substantial benefit from chemotherapy remained in the RS ≥ 31 cohort (HR = 0.18; 95% CI: 0.07–0.47) and the RS > 25 cohort (HR = 0.28; 95% CI: 0.12–0.64). No benefit from chemotherapy was evident in the other RS groups. Following exclusion of HER2-positive patients based on RT-PCR expression, substantial benefit of chemotherapy remained for RS ≥ 31 as originally employed, and with RS > 25 employed in TAILORx.
The 2.1 Å structure of protein F9 and its comparison to L1, two components of the conserved poxvirus entry-fusion complex
Authors: Diesterbeck Ulrike S. , Gittis Apostolos G. , Garboczi David N. , Moss Bernard
Published: November 2018

The poxvirus F9 protein is a component of the vaccinia virus entry fusion complex (EFC) which consists of 11 proteins. The EFC forms a unique apparatus among viral fusion proteins and complexes. We solved the atomic structure of the F9 ectodomain at 2.10 Å. A structural comparison to the ectodomain of the EFC protein L1 indicated a similar fold and organization, in which a bundle of five α-helices is packed against two pairs of β-strands. However, instead of the L1 myristoylation site and hydrophobic cavity, F9 possesses a protruding loop between α-helices α3 and α4 starting at Gly90. Gly90 is conserved in all poxviruses except Salmon gill poxvirus (SGPV) and Diachasmimorpha longicaudata entomopoxvirus. Phylogenetic sequence analysis of all Poxviridae F9 and L1 orthologs revealed the SGPV genome to contain the most distantly related F9 and L1 sequences compared to the vaccinia proteins studied here. The structural differences between F9 and L1 suggest functional adaptations during evolution from a common precursor that underlie the present requirement for each protein.
Spatial pattern of plutonium and radiocaesium contamination released during the Fukushima Daiichi nuclear power plant disaster
Authors: Dunne James A. , Martin Peter G. , Yamashiki Yosuke , Ang Ian X. Y. , Scott Tom B. , Richards David A.
Published: November 2018

Plutonium and radiocaesium are hazardous contaminants released by the Fukushima Daiichi nuclear power plant (FDNPP) disaster and their distribution in the environment requires careful characterisation using isotopic information. Comprehensive spatial survey of 134Cs and 137Cs has been conducted on a regular basis since the accident, but the dataset for 135Cs/137Cs atom ratios and trace isotopic analysis of Pu remains limited because of analytical challenges. We have developed a combined chemical procedure to separate Pu and Cs for isotopic analysis of environmental samples from contaminated catchments. Ultra-trace analyses reveal a FDNPP Pu signature in environmental samples, some from further afield than previously reported. For two samples, we attribute the dominant source of Pu to Reactor Unit 3. We review the mechanisms responsible for an emergent spatial pattern in 134,135Cs/137Cs in areas northwest (high 134Cs/137Cs, low 135Cs/137Cs) and southwest (low 134Cs/137Cs, high 135Cs/137Cs) of FDNPP. Several samples exhibit consistent 134,135Cs/137Cs values that are significantly different from those deposited on plant specimens collected in previous works. A complex spatial pattern of Pu and Cs isotopic signature is apparent. To confidently attribute the sources of mixed fallout material, future studies must focus on analysis of individual FDNPP-derived particles.
Indentation of a surface-stiffened elastic substrate
Authors: Selvadurai A. P. S.
Published: November 2018

The paper deals with the problem of the indentation of a substrate in the form of an isotropic elastic halfspace that is reinforced at the surface by a bonded layer, which has flexibility characteristic of a Poisson-Kirchhoff-Germain thin plate. The presence of the reinforcing layer changes the characteristics of the indentation problem, in that the techniques that are applicable for the solution of the direct indentation of the halfspace cannot be applied to develop a load-displacement relationship for the indenter. The integro-differential equation governing the indentation of the surface reinforced halfspace is solved using a discretization approach and numerical results are presented to demonstrate the influence of the stiffness of the reinforcing layer on the Boussinesq indention problem.
Transcriptomic changes with increasing algal symbiont reveal the detailed process underlying establishment of coral-algal symbiosis
Authors: Yuyama Ikuko , Ishikawa Masakazu , Nozawa Masafumi , Yoshida Masa-aki , Ikeo Kazuho
Published: November 2018

To clarify the establishment process of coral-algal symbiotic relationships, coral transcriptome changes during increasing algal symbiont densities were examined in juvenile corals following inoculation with the algae Symbiodinium goreaui (clade C) and S. trenchii (clade D), and comparison of their transcriptomes with aposymbiotic corals by RNA-sequencing. Since Symbiodinium clades C and D showed very different rates of density increase, comparisons were made of early onsets of both symbionts, revealing that the host behaved differently for each. RNA-sequencing showed that the number of differentially-expressed genes in corals colonized by clade D increased ca. two-fold from 10 to 20 days, whereas corals with clade C showed unremarkable changes consistent with a slow rate of density increase. The data revealed dynamic metabolic changes in symbiotic corals. In addition, the endocytosis pathway was also upregulated, while lysosomal digestive enzymes and the immune system tended to be downregulated as the density of clade D algae increased. The present dataset provides an enormous number of candidate symbiosis-related molecules that exhibit the detailed process by which coral-algal endosymbiosis is established.
The development of a new parameter for tracking post-transcriptional regulation allows the detailed map of the Pseudomonas aeruginosa Crc regulon
Authors: Corona Fernando , Reales-Calderón Jose Antonio , Gil Concha , Martínez José Luis
Published: November 2018

Bacterial physiology is regulated at different levels, from mRNA synthesis to translational regulation and protein modification. Herein, we propose a parameter, dubbed post-transcriptional variation (PTV), that allows extracting information on post-transcriptional regulation from the combined analysis of transcriptomic and proteomic data. We have applied this parameter for getting a deeper insight in the regulon of the Pseudomonas aeruginosa post-transcriptional regulator Crc. P. aeruginosa is a free-living microorganism, and part of its ecological success relies on its capability of using a large number of carbon sources. The hierarchical assimilation of these sources when present in combination is regulated by Crc that, together with Hfq (the RNA-binding chaperon in the complex), impedes their translation when catabolite repression is triggered. Most studies on Crc regulation are based either in transcriptomics or in proteomics data, which cannot provide information on post-transcriptional regulation when analysed independently. Using the PTV parameter, we present a comprehensive map of the Crc post-transcriptional regulon. In addition of controlling the use of primary and secondary carbon sources, Crc regulates as well cell respiration, c-di-GMP mediated signalling, and iron utilization. Thus, besides controlling the hyerarchical assimilation of carbon sources, Crc is an important element for keeping bacterial homeostasis and, consequently, metabolic robustness.
Electron waiting times in hybrid junctions with topological superconductors
Authors: Mi Shuo , Burset Pablo , Flindt Christian
Published: November 2018

We investigate the waiting time distributions (WTDs) of superconducting hybrid junctions, considering both conventional and topologically nontrivial superconductors hosting Majorana bound states at their edges. To this end, we employ a scattering matrix formalism that allows us to evaluate the waiting times between the transmissions and reflections of electrons or holes. Specifically, we analyze normal-metal–superconductor (NIS) junctions and NISIN junctions, where Cooper pairs are spatially split into different leads. The distribution of waiting times is sensitive to the simultaneous reflection of electrons and holes, which is enhanced by the zero-energy state in topological superconductors. For the NISIN junctions, the WTDs of trivial superconductors feature a sharp dependence on the applied voltage, while for topological ones they are mostly independent of it. This particular voltage dependence is again connected to the presence of topological edge states, showing that WTDs are a promising tool for identifying topological superconductivity.
Macrophages mediate corticotomy-accelerated orthodontic tooth movement
Authors: Wang Yan , Zhang Hanwen , Sun Wen , Wang Siyu , Zhang Shuting , Zhu Linlin , Chen Yali , Xie Lizhe , Sun Zongyang , Yan Bin
Published: November 2018

Clinical evidence has suggested that surgical corticotomy of the alveolar bone can accelerate local orthodontic tooth movement (OTM), but the underlying cell and molecular mechanisms remain largely unclear. The present study examined the role of macrophages played in corticotomy-assisted OTM. Orthodontic nickel-titanium springs were applied to the left maxillary first molars of rats or mice to induce OTM with or without corticotomy. Corticotomy enhanced OTM distance by accelerating movement through induction of local osteoclastogenesis and macrophage infiltration during OTM. Further analysis showed that macrophages were polarized toward an M1-like phenotype immediately after corticotomy and then switched to an M2-like phenotype during OTM. The microenvironment of corticotomy induced macrophage infiltration and polarization through the production of TNF-α. More importantly, the amount of OTM induced by corticotomy was significantly decreased after mice were depleted of monocyte/macrophages by injection of liposome-encapsulated clodronate. Further experiments by incubating cultured macrophages with fresh tissue suspension obtained from post-corticotomy gingiva switched the cells to an M1 phenotype through activation of the nuclear factor-κB (NF-κB) signaling pathway, and to an M2 phenotype through activation of the JAK/STAT3 signaling pathway. Our results suggest that corticotomy induces macrophage polarization first by activating the NF-κB signaling pathway and later by activating the JAK/STAT3 signaling pathway, and that these processes contribute to OTM by triggering production of inflammatory cytokines and osteoclastogenesis.
Automatic Detection of Prostate Tumor Habitats using Diffusion MRI
Authors: Tschudi Yohann , Pollack Alan , Punnen Sanoj , Ford John C. , Chang Yu-Cherng , Soodana-Prakash Nachiketh , Breto Adrian L. , Kwon Deukwoo , Munera Felipe , Abramowitz Matthew C. , Kryvenko Oleksandr N. , Stoyanova Radka
Published: November 2018

A procedure for identification of optimal Apparent Diffusion Coefficient (ADC) thresholds for automatic delineation of prostatic lesions with restricted diffusion at differing risk for cancer was developed. The relationship between the size of the identified Volumes of Interest (VOIs) and Gleason Score (GS) was evaluated. Patients with multiparametric (mp)MRI, acquired prior to radical prostatectomy (RP) (n = 18), mpMRI-ultrasound fused (MRI-US) (n = 21) or template biopsies (n = 139) were analyzed. A search algorithm, spanning ADC thresholds in 50 µm2/s increments, determined VOIs that were matched to RP tumor nodules. Three ADC thresholds for both peripheral zone (PZ) and transition zone (TZ) were identified for estimation of VOIs at low, intermediate, and high risk of prostate cancer. The determined ADC thresholds for low, intermediate and high risk in PZ/TZ were: 900/800; 1100/850; and 1300/1050 µm2/s. The correlation coefficients between the size of the high/intermediate/low risk VOIs and GS in the three cohorts were 0.771/0.778/0.369, 0.561/0.457/0.355 and 0.423/0.441/0.36 (p < 0.05). Low risk VOIs mapped all RP lesions; area under the curve (AUC) for intermediate risk VOIs to discriminate GS6 vs GS ≥ 7 was 0.852; for high risk VOIs to discriminate GS6,7 vs GS ≥ 8 was 0.952. In conclusion, the automatically delineated volumes in the prostate with restricted diffusion were found to strongly correlate with cancer aggressiveness.
Diet-dependent gene expression highlights the importance of Cytochrome P450 in detoxification of algal secondary metabolites in a marine isopod
Authors: De Wit Pierre , Yamada Keith , Panova Marina , André Carl , Johannesson Kerstin
Published: November 2018

Isopods of the genus Idotea have an unusual ability to feed on algae containing high amounts of chemical defense molecules, such as species of the genera Fucus and Ulva. In this study, we compared gene expression patterns of Idotea balthica individuals fed with Fucus vesiculosus to individuals fed with Ulva lactuca. We generated the first-ever transcriptome assembly for this species, and found 3,233 differentially expressed genes across feeding regimes. However, only a handful of biological functions were enriched with regard to differentially expressed genes, the most notable being “alkaloid metabolic process”. Within this category, we found eight differentially expressed cytochrome P450 (CYP) unigenes, all of which had a higher expression in the U. lactuca diet treatment. A phylogenetic analysis showed that the differentially expressed CYP genes are closely related to a CYP gene described from the hepatopancreas of the spiny lobster Panulirus argus, and we hypothesize that these transcripts are involved in metabolite detoxification. This is a first step in the understanding of this algae-grazer interaction, and will form a basis for future work to characterize cytochrome P450 functioning in marine crustaceans.
Correlative Light-Electron Microscopy detects lipopolysaccharide and its association with fibrin fibres in Parkinson’s Disease, Alzheimer’s Disease and Type 2 Diabetes Mellitus
Authors: de Waal Greta M. , Engelbrecht Lize , Davis Tanja , de Villiers Willem J. S. , Kell Douglas B. , Pretorius Etheresia
Published: November 2018

Many chronic diseases, including those classified as cardiovascular, neurodegenerative, or autoimmune, are characterized by persistent inflammation. The origin of this inflammation is mostly unclear, but it is typically mediated by inflammatory biomarkers, such as cytokines, and affected by both environmental and genetic factors. Recently circulating bacterial inflammagens such as lipopolysaccharide (LPS) have been implicated. We used a highly selective mouse monoclonal antibody to detect bacterial LPS in whole blood and/or platelet poor plasma of individuals with Parkinson’s Disease, Alzheimer’s type dementia, or Type 2 Diabetes Mellitus. Our results showed that staining is significantly enhanced (P < 0.0001) compared to healthy controls. Aberrant blood clots in these patient groups are characterized by amyloid formation as shown by the amyloid-selective stains thioflavin T and Amytracker™ 480 or 680. Correlative Light-Electron Microscopy (CLEM) illustrated that the LPS antibody staining is located in the same places as where amyloid fibrils may be observed. These data are consistent with the Iron Dysregulation and Dormant Microbes (IDDM) hypothesis in which bacterial inflammagens such as LPS are responsible for anomalous blood clotting as part of the aetiology of these chronic inflammatory diseases.
The beneficial effects of Lactobacillus reuteri ADR-1 or ADR-3 consumption on type 2 diabetes mellitus: a randomized, double-blinded, placebo-controlled trial
Authors: Hsieh Ming-Chia , Tsai Wan-Hua , Jheng Yu-Pang , Su Shih-Li , Wang Shu-Yi , Lin Chi-Chen , Chen Yi-Hsing , Chang Wen-Wei
Published: November 2018

Probiotics have been reported to ameliorate symptoms of type 2 diabetes mellitus (T2DM) in animal models and human studies. We previously demonstrated that oral administration of Lactobacillus reuteri ADR-3 reduced insulin resistance in high-fructose-fed (HFD) rats. In the present study, we first identified another L. reuteri strain, ADR-1, which displayed anti-diabetes activity that reduced the levels of serum HbA1c and cholesterol and that increased antioxidant proteins in HFD rats. We further performed a randomized, double-blinded, placebo-controlled trial with a total of 68 T2DM patients to examine the beneficial effects of oral consumption of L. reuteri strains ADR-1 and ADR-3 and to investigate the associated changes in intestinal flora using a quantitative PCR method to analyze 16 S rRNA in fecal specimens. Significant reductions in HbA1c and serum cholesterol were observed in participants in the live ADR-1 consumption group (n = 22) after 3 months of intake when compared with those in the placebo group (n = 22). Although there was no significant difference in the HbA1c serum level among participants who consumed heat-killed ADR-3 (n = 24), the systolic blood pressure and mean blood pressure were significantly decreased after 6 months of intake. There was no obvious change in serum inflammatory cytokines or antioxidant proteins in participants after intaking ADR-1 or ADR-3, except for a reduction in IL-1β in the ADR-3 consumption group after 6 months of intake. With the analysis of fecal microflora, we found that L. reuteri or Bifidobacterium spp. were significantly increased in the ADR-1 and ADR-3 consumption groups, respectively, after 6 months of intake. Interestingly, a significant reduction in HbA1c was observed in the ADR-1 and ADR-3 consumption participants who displayed at least an 8-fold increase in fecal L. reuteri. We also observed that there was a significantly positive correlation between Bifidobacterium spp. and Lactobacillus spp. in participants with increased levels of fecal L. reuteri. In the ADR-1 intake group, the fecal Lactobacillus spp. level displayed a positive correlation with Bifidobacterium spp. but was negatively correlated with Bacteroidetes. The total level of fecal L. reuteri in participants in the ADR-3 consumption group was positively correlated with Firmicutes. In conclusion, L. reuteri strains ADR-1 and ADR-3 have beneficial effects on T2DM patients, and the consumption of different strains of L. reuteri may influence changes in intestinal flora, which may lead to different outcomes after probiotic intake.
Genome-wide discovery of DNA polymorphisms among chickpea cultivars with contrasting seed size/weight and their functional relevance
Authors: Rajkumar Mohan Singh , Garg Rohini , Jain Mukesh
Published: November 2018

Seed size/weight is a major agronomic trait which determine crop productivity in legumes. To understand the genetic basis of seed size determination, we sought to identify DNA polymorphisms between two small (Himchana 1 and Pusa 362) and two large-seeded (JGK 3 and PG 0515) chickpea cultivars via whole genome resequencing. We identified a total of 75535 single nucleotide polymorphisms (SNPs), 6486 insertions and deletions (InDels), 1938 multi-nucleotide polymorphisms (MNPs) and 5025 complex variants between the two small and two large-seeded chickpea cultivars. Our analysis revealed 814, 244 and 72 seed-specific genes harboring DNA polymorphisms in promoter or non-synonymous and large-effect DNA polymorphisms, respectively. Gene ontology analysis revealed enrichment of cell growth and division related terms in these genes. Among them, at least 22 genes associated with quantitative trait loci, and those involved in cell growth and division and encoding transcription factors harbored promoter and/or large-effect/non-synonymous DNA polymorphisms. These also showed higher expression at late-embryogenesis and/or mid-maturation stages of seed development in the large-seeded cultivar, suggesting their role in seed size/weight determination in chickpea. Altogether, this study provided a valuable resource for large-scale genotyping applications and a few putative candidate genes that might play crucial role in governing seed size/weight in chickpea.