bluuebunny/crossref_metadata_2025 huggingface dataset:
Sounding Out Pharmaceutical Processes
Authors: Smyth Cormac , Kudriashov Evgeny , O'Driscoll Breda , Buckin Vitaly
Published: October 2018

High-resolution ultrasonic spectroscopy is a novel technique with enormous potential for analysis of a wide range of samples and processes. This technique is based on precision measurements of velocity and attenuation of acoustical waves at high frequencies propagating through materials. It allows fast at/on line measurements analysis of formulation consistency (composition, structure) of raw materials, ingredients and intermediates, process impurity analysis, particle sizing, batch to batch variation, stability assessment etc in pharmaceutical industry. The technology can be used for static fingerprint measurements or for dynamic analysis of systems. Optical transparency is not required as ultrasonic waves propagate through opaque samples. The analysis is fast and non-destructive. High-resolution ultrasonic spectrometers were developed, patented and brought to the market by Ultrasonic Scientific Ltd. and recognised with various international awards. These instruments require small sample volumes, down to 0.03 ml, and give excellent resolution. They can be used for the analysis of composition, aggregation, particle sizing, gelation, micellisation, crystallisation, sedimentation, enzymatic activity, conformational transitions in polymers, biopolymer-ligand binding and antigen-antibody interactions, etc. This article describes main features of High-Resolution Ultrasonic Spectroscopy and area of applications of new high-resolution HR-US series of ultrasonic spectrometers.

Several applications are illustrated including the monitoring of denaturation and aggregation of proteins in antibody solution, the measurements of the particle size in emulsions, precipitation in synthetic blood substitutes and crystallisation.
Monitoring Protein-Drug Interactions with Mass Spectrometry and Proteolysis Protein Mass Mapping as a Drug Assay
Authors: Lewis J. Kathleen , Chiang Jay , Siuzdak Gary
Published: October 2018

Presented is a new approach for assaying the effects of drug candidates against protein targets. Human rhinovirus, HRV14, has been analyzed in the presence of both known and potential antiviral drug agents using enzymatically active mass spectrometer sample plates. The combination of automated mass spectrometry with proteolytic digestion provides for the rapid, high-throughput, and sensitive screening of protein-drug interactions. Multiple drug candidates can be assayed from MALDI sample plates containing 100 wells and, to further increase the number of drugs assayed, multiple drugs can be pooled into each solution (10 candidates per well, 1000 candidates per plate). Wells producing spectra indicative of drug activity can be further analyzed to discern the active compound or be tested with alternative assays.
Connecting Social and Natural Ecologies Through a Curriculum of Giving for Student Wellbeing and Engagement
Authors: Nielsen Thomas W. , Ma Jennifer S.
Published: October 2018

Using hermeneutic phenomenology to aid the reader ‘experience’ the data collected, this study reports on 18 college students, 4 staff members and the author's trip to a remote island on the Great Barrier Reef. It is a story of the (re)discovery of the social and natural ecologies that bind us together, and of how explicit teaching and learning about these ecologies can make a difference to young people's abilities to consciously be part of, contribute to, and sustain these ecologies. A grounded theory of five dimensions of giving (to self, others, communities, environment, and the whole) is offered as a beginning framework from which to imbue teaching and learning with meaning and social concern.
Interpersonal Emotion Regulation: A Review of Social and Developmental Components
Authors: Barthel Abigail L. , Hay Aleena , Doan Stacey N. , Hofmann Stefan G.
Published: October 2018

A staple theme in clinical psychology, emotion regulation, or the ability to manage one's emotions, is directly linked with personal wellbeing and the ability to effectively navigate the social world. Until recently, this concept has been limited to a focus on intrapersonal processes, such as suppression. Less emphasis has been placed on developmental, social, and cultural aspects of emotion regulation. We argue here that as social beings, our engagement in emotion regulation may often occur interpersonally, with trusted others helping us to regulate our emotions. This review will highlight recent research on interpersonal emotion regulation processes.
Examination of Hospital Workers’ Emotional Responses to an Infectious Disease Outbreak: Lessons From the 2015 MERS Co-V Outbreak in South Korea
Authors: Son Heejung , Lee Wang Jun , Kim Hyun Soo , Lee Kkot Sil , You Myoungsoon
Published: October 2018

Hospital workers are critical for a successful response to an infectious disease outbreak and for preventing disease transmission to the community. Therefore, hospital crisis management should implement efforts to improve hospital workers’ preparedness in responding to public health emergencies caused by infectious diseases. Traditionally, preparedness and skill of hospital workers have been emphasized, but awareness of the importance of the emotional mindset of hospital workers in dealing with disease outbreaks has only recently increased; therefore, empirical approaches to examining emotional responses of hospital workers has been limited. This study analyzed qualitative data of the 2015 Middle East Respiratory Syndrome outbreak in South Korea. In particular, negative emotions and stress experienced by hospital workers who treated patients were characterized, as were the events that triggered such experiences. These events were categorized into four themes (eg, Mistake, Missing, Delay Due to Communication Failure). Identifying events that trigger negative emotions in hospital workers has important implications for hospitals’ management guidance in relation to an infectious disease outbreak. (Disaster Med Public Health Preparedness. 2019;13:504-510)
PRIME SOLUTIONS TO POLYNOMIAL EQUATIONS IN MANY VARIABLES AND DIFFERING DEGREES
Authors: YAMAGISHI SHUNTARO
Published: October 2018

Let $\mathbf{f}=(f_{1},\ldots ,f_{R})$ be a system of polynomials with integer coefficients in which the degrees need not all be the same. We provide sufficient conditions for which the system of equations $f_{j}(x_{1},\ldots ,x_{n})=0~(1\leqslant j\leqslant R)$ satisfies a general local to global type statement, and has a solution where each coordinate is prime. In fact we obtain the asymptotic formula for number of such solutions, counted with a logarithmic weight, under these conditions. We prove the statement via the Hardy–Littlewood circle method. This is a generalization of the work of Cook and Magyar [‘Diophantine equations in the primes’, Invent. Math.198 (2014), 701–737], where they obtained the result when the polynomials of $\mathbf{f}$ all have the same degree. Hitherto, results of this type for systems of polynomial equations involving different degrees have been restricted to the diagonal case.
Spatial modelling of soil organic carbon stocks with combined principal component analysis and geographically weighted regression
Authors: Guo Long , Luo Mei , Zhangyang Chengsi , Zeng Chen , Wang Shanqin , Zhang Haitao
Published: October 2018

With the development of remote sensing and geostatistical technology, complex environmental variables are increasingly easily quantified and applied in modelling soil organic carbon (SOC). However, this emphasizes data redundancy and multicollinearity problems adding to the difficulty in selecting dominant influential auxiliary variables and uncertainty in estimating SOC stocks. The current paper considers the spatial characteristics of SOC density (SOCD) to construct prediction models of SOCD on the basis of reducing the data dimensionality and complexity using the principal component analysis (PCA) method. A total of 260 topsoil samples were collected from Chahe town, China. Eight environmental variables (elevation, aspect, slope, normalized difference vegetation index, normalized difference moisture index, nearest distance to construction area and road, and land use degree comprehensive index) were pre-analysed by PCA and then extracted as the main principal component variables to construct prediction models. Two geostatistical approaches (ordinary kriging and ordinary co-kriging) and two regression approaches (ordinary least squares and geographically weighted regression (GWR)) were used to estimate SOCD. Results showed that PCA played an important role in reducing the redundancy and multicollinearity of the auxiliary variables and GWR achieved the highest prediction accuracy in these four models. GWR considered not only the spatial characteristics of SOCD but also the related valuable information of the auxiliary attributes. In summary, PCA-GWR is a promising spatial method used here to predict SOC stocks.
Périodiser la fin de l'esclavage: Le droit colonial, la Société des Nations et la résistance des esclaves dans le Sahel nigérien, 1920-1930
Authors: Rossi Benedetta
Published: October 2018

Quand, comment et pourquoi l'esclavage a-t-il disparu dans le Sahel nigérien – si tant est qu'il ait complètement disparu ? Quels processus ont favorisé l’émancipation des personnes réduites en esclavage ? Quelles étaient les stratégies des administrateurs coloniaux, des propriétaires d'esclaves, des trafiquants, des esclaves eux-mêmes et de leurs descendants ? Au cours des deux premières décennies de l'occupation française du Sahel central, l'abolition légale n'a pas abouti à l’éradication de l'esclavage car les lois n’étaient pas appliquées. Mais, à partir des années 1920, l'internationalisation de l'abolition qui a suivi la création de la Société des Nations a entraîné la mise en œuvre des lois contre l'esclavage. Cet article entend montrer que l’émancipation a connu une impulsion initiale grâce à la mise en place de mécanismes internationaux de surveillance en mesure de (dé)légitimer le pouvoir colonial à un moment où personne ne cherchait activement à mettre fin à l'esclavage dans cette région. L'article met tout d'abord l'accent sur les ambiguïtés de l'abolitionnisme européen et sur les interconnexions entre la Société des Nations, l’État français et les administrateurs sur le terrain. Il propose ensuite une micro-analyse de la résistance à l'esclavage, en montrant comment des personnes asservies ou victimes de la traite des esclaves, en particulier des jeunes femmes, ont tiré profit des transformations institutionnelles à l’échelle mondiale pour poursuivre leurs propriétaires ou des trafiquants devant les tribunaux. Il examine enfin les souvenirs contemporains d'une femme âgée qui a connu, plus jeune, des situations analogues à celles décrites précédemment dans l'article. Sa perception, ainsi que celle d'autres personnes ayant eu des expériences similaires, s'inscrivent dans un contexte marqué par la tension entre des discours circonscrits en faveur de l'esclavage et la lutte pour l'abolition menée au niveau local.
Überprüfung der Reliabilität und Validität der Kurzform des Physical Self-Description Questionnaire (PSDQ-S) in den Altersgruppen des frühen und späten Erwachsenenalters
Authors: Braun Alexander , Martin Titus , Alfermann Dorothee , Michel Sven
Published: October 2018

Zusammenfassung. Mit dem Physical Self-Description Questionnaire Short (PSDQ-S) von Marsh, Martin und Jackson (2010) liegt eine auf 40 Items gekürzte validierte Version des Physical Self-Description Questionnaire von Marsh, Richards, Johnson, Roche und Tremayne (1994) vor, die bereits in mehrere Sprachen übersetzt ist. Die vorliegende Studie evaluierte den deutschsprachigen PSDQ-S anhand von 402 Probanden im frühen und späten Erwachsenenalter. Im Ergebnis lassen die Analyse der Reliabilität und Validität sowie der Vergleich mit den Befunden von Marsh et al. (2010) , Stiller und Alfermann (2007) sowie weiterer übersetzter und validierter PSDQ-S-Versionen die Verwendung der deutschsprachigen Kurzform empfehlen. Ebenso wie die Originalversion ist sie für männliche und weibliche Personen, sowie für die Altersgruppen des frühen und späten Erwachsenenalters geeignet. Für alle vier Gruppen besteht eine äquivalente Faktorstruktur.
Quantifying the Sources of Ionosphere Day‐To‐Day Variability
Authors: Fang Tzu‐Wei , Fuller‐Rowell Tim , Yudin Valery , Matsuo Tomoko , Viereck Rodney
Published: October 2018

Simulations from the coupled Whole Atmosphere Model and Global Ionosphere Plasmasphere show significant day‐to‐day variations in total electron content (TEC) and theFregion peak density (NmF2). The Whole Atmosphere Model‐Global Ionosphere Plasmasphere was driven by the auroral precipitation patterns inferred from TIROS/NOAA, daily solar irradiance measurements derived from the satellite observations, and 5‐min interplanetary magnetic field/solar wind parameters during June and July 2012. Overall, the combination of solar, magnetosphere, and lower atmosphere drivers produced similar magnitude of variability consistent with that seen in observations. Results also show that the relative variability is much larger at night than in the daytime, due to much lower background density, and depended strongly on latitude and local time. Additional simulations were also performed to distinguish the contributions to the variability from solar activity, geomagnetic activity, and lower atmospheric perturbations. Results show that globally, geomagnetic activity is the main contributor to theNmF2variability, followed by lower atmosphere perturbation, and then solar activity. For TEC variability, again, geomagnetic activity is the main contributor, followed by solar activity, and then lower atmosphere perturbation. In terms of absolute variability, at low latitudes solar activity dominates the TEC variability, most likely due to the importance of solar EUV driving the changes in ionosphere density through photoionization, while the contributions from the lower atmosphere and geomagnetic activity are almost equally. For the middle‐ and high‐latitude regions, the solar activity and geomagnetic activity are the most important sources for the TEC variability.
Unusual Generation of Localized EPB in the Dawn Sector Triggered by a Moderate Geomagnetic Storm
Authors: Sripathi S. , Abdu M. A. , Patra A. K. , Ghodpage R. N.
Published: October 2018

An interesting piece of observation related to the equatorial plasma bubble (EPB) that is triggered by a geomagnetic storm at dawn sector on 4–5 February 2011 is presented. The storm activity was initiated at 17 UT when interplanetary magnetic field (IMF) Bz turned southward and the Dst index started decreasing (accompanied by AE intensifications) attaining its minimum at −70 nT. The IMF Bz presented large fluctuations marked by southward/northward transitions at slow and rapid rates and eventually returning to normal in the morning of 5 February. Observations from the very high frequency radar located at Gadanki, an off‐equatorial station; an all‐sky imager located at Kolhapur, a low‐latitude station; and an ionosonde at Tirunelveli, an equatorial station, are analyzed to study the impact of this storm on the postmidnight to presunrise equatorial spread F. The results demonstrate that EPB irregularities can be generated by penetration electric field during what can be characterized as a moderate storm event. In contrast to prevailing belief, the present results show that EPB/equatorial spread F can be generated by undershielding electric field in the dawn sector, caused by an unusually delayed polarity reversal of the penetration electric field. The results further reveal oscillatory behavior in the height of F layer topside irregularities in association with IMF Bz oscillations. Observation of radar echoes from nighttime E layer irregularity structures and their Doppler velocities representing the penetration electric field polarity and intensity are also a notable finding of this paper.
Small‐Scale and Mesoscale Variabilities in the Electric Field and Particle Precipitation and Their Impacts on Joule Heating
Authors: Zhu Qingyu , Deng Yue , Richmond Arthur , Maute Astrid
Published: October 2018

In this study, the electric field and the particle precipitation at different spatial scale sizes have been investigated by utilizing the Dynamic Explorer 2 satellite data set, focusing on conditions of moderately strong southward interplanetary magnetic field. Dynamic Explorer 2 data from the period between 1981 and 1983, from all universal times, seasons, and both hemispheres, have been processed and binned over geomagnetic latitude and local time. It is found that, as compared with the large‐scale (>500 km) average electric field and particle precipitation, the variabilities (i.e., departures from the large‐scale average) of electric field and particle precipitation are not negligible. Moreover, the electric field variability tends to be anticorrelated with the particle precipitation variability in the auroral regions on small scale and mesoscale (<500 km). The impacts associated with the small‐scale and mesoscale electric field and particle precipitation variabilities on Joule heating have also been addressed in this study by using the Global Ionosphere and Thermosphere Model. It is found that although Joule heating can be significantly enhanced by the small‐scale and mesoscale electric field variabilities (~27% globally), the corresponding change in the particle precipitation tends to depress such enhancement (−5% globally), which is not negligible on the dusk side (up to −17.5% locally). It is the first time that the correlation between electric field and particle precipitation variabilities on small scale and mesoscale has been quantified. Furthermore, the impact on Joule heating associated with the correlation between the small‐scale and mesoscale electric field and particle precipitation variabilities has been evaluated unprecedentedly in a general circulation model.
Melt Pond Conditions on Declining Arctic Sea Ice Over 1979–2016: Model Development, Validation, and Results
Authors: Zhang Jinlun , Schweiger Axel , Webster Melinda , Light Bonnie , Steele Michael , Ashjian Carin , Campbell Robert , Spitz Yvette
Published: October 2018

A melt pond (MP) distribution equation has been developed and incorporated into the Marginal Ice‐Zone Modeling and Assimilation System to simulate Arctic MPs and sea ice over 1979–2016. The equation differs from previous MP models and yet benefits from previous studies for MP parameterizations as well as a range of observations for model calibration. Model results show higher magnitude of MP volume per unit ice area and area fraction in most of the Canada Basin and the East Siberian Sea and lower magnitude in the central Arctic. This is consistent with Moderate Resolution Imaging Spectroradiometer observations, evaluated with Measurements of Earth Data for Environmental Analysis (MEDEA) data, and closely related to top ice melt per unit ice area. The model simulates a decrease in the total Arctic sea ice volume and area, owing to a strong increase in bottom and lateral ice melt. The sea ice decline leads to a strong decrease in the total MP volume and area. However, the Arctic‐averaged MP volume per unit ice area and area fraction show weak, statistically insignificant downward trends, which is linked to the fact that MP water drainage per unit ice area is increasing. It is also linked to the fact that MP volume and area decrease relatively faster than ice area. This suggests that overall the actual MP conditions on ice have changed little in the past decades as the ice cover is retreating in response to Arctic warming, thus consistent with the Moderate Resolution Imaging Spectroradiometer observations that show no clear trend in MP area fraction over 2000–2011.
Atlantic Water Heat Transport Variability in the 20th Century Arctic Ocean From a Global Ocean Model and Observations
Authors: Muilwijk Morven , Smedsrud Lars H. , Ilicak Mehmet , Drange Helge
Published: October 2018

Northward ocean heat transport and its variability influence the Arctic sea ice cover, contribute to surface warming or cooling, or simply warm or cool the Arctic Ocean interior. A simulation with the forced global ocean model NorESM20CR, aided by hydrographic observations since 1900, show large decadal fluctuations in the ocean heat transport, with the largest variations in the Atlantic sector. The simulated net poleward ocean heat transport over the last century is about 68 TW, and 88% of this occurs in the Barents Sea Opening (45 TW) and the Fram Strait (15 TW). Typical variations are 40 TW over time scales between 5 and 10 years, related to thermohaline and wind stress forcings. The mean heat transport in the Davis Strait is about 10 TW, and less than 5 TW flows north in the Bering Strait. The core temperature of the Atlantic Water (AW) entering the Arctic Ocean has increased in recent decades, consistent with an ongoing expansion of the Atlantic domain (Atlantification), but earlier warm events are also documented. The temperature of the northward‐flowing AW thus plays a vital role, with decadal variations of around 0.5 ∘C. The Nordic Seas atmosphere contributes with thermodynamic forcing, dampening the advected heat anomalies. In the Barents Sea, variations in the inflow volume flux dominate, while variations in temperature dominate the heat transport in the Fram Strait. There are significant trends over recent decades, also dominated by the Barents Sea that presently has 1 Sv higher volume transport and +1.0 ∘C warmer AW than the long‐term mean.
Terrain‐Enhanced Precipitation Processes Above the Melting Layer: Results From OLYMPEX
Authors: McMurdie L. A. , Rowe A. K. , Houze R. A. , Brodzik S. R. , Zagrodnik J. P. , Schuldt T. M.
Published: October 2018

Enhancement of precipitation processes aloft over complex terrain is documented using reflectivity data from an S‐band scanning radar (NPOL) that was deployed on the west coast of Washington State during the Olympic Mountains Experiment (OLYMPEX). From November 2015 through mid‐January 2016, NPOL obtained high‐resolution data within sectors over the ocean and over the windward slopes of the Olympic Mountains. Contoured Frequency by Altitude Diagrams of radar reflectivity highlight a higher frequency of occurrence of larger reflectivities for all heights between 2 and 8 km over land compared to ocean, with the largest difference in the 4‐ to 6‐km range indicating a robust signature of enhancement aloft over the windward slopes. This enhancement pattern is found to some degree under all environmental conditions considered but is especially pronounced during periods of high vapor transport, high melting level height, southwest low‐level winds, and neutral stability. These conditions are generally associated with warm sectors of midlatitude cyclones and atmospheric rivers. Past studies have postulated that a secondary enhancement in reflectivity aloft was an intrinsic part of atmospheric river type systems. However, these results show that further significant enhancement of this signature occurs as deep moist‐neutral, high water vapor content flow is lifted when it encounters a mountain range. Reflectivity data from the dual‐precipitation radar aboard the Global Precipitation Measurement satellite also documents this reflectivity increase aloft over the Olympic Mountains compared to the adjacent ocean, showing the potential for Global Precipitation Measurement to provide reliable estimates of precipitation structure over remote mountainous regions.
Near-resonance enhanced label-free stimulated Raman scattering microscopy with spatial resolution near 130 nm
Authors: Bi Yali , Yang Chi , Chen Yage , Yan Shuai , Yang Guang , Wu Yaozu , Zhang Guoping , Wang Ping
Published: October 2018

High-resolution optical microscopes that can break 180 nm in spatial resolution set to conventional microscopies are much-needed tools. However, current optical microscopes have to rely on exogenous fluorescent labels to achieve high resolution in biological imaging. Herein, we report near-resonance enhanced label-free stimulated Raman scattering (SRS) microscopy with a lateral resolution near 130 nm, in which the high-resolution image contrast originates directly from a low concentration of endogenous biomolecules, with sensitivity gains of approximately 23 times. Moreover, by using a 0.3-m-long optical fiber, we developed hyperspectral SRS microscopy based on spectral focusing technology. Attributed to enhancements in spatial resolution and sensitivity, we demonstrated high-resolution imaging of three-dimensional structures in single cells and high-resolution mapping of large-scale intact mouse brain tissues in situ. By using enhanced high-resolution hyperspectral SRS, we chemically observed sphingomyelin distributed in the myelin sheath that insulates single axons. Our concept opens the door to biomedical imaging with ~130 nm resolution.
YLT-11, a novel PLK4 inhibitor, inhibits human breast cancer growth via inducing maladjusted centriole duplication and mitotic defect
Authors: Lei Qian , Xiong Lu , Xia Yong , Feng Zhanzhan , Gao Tiantao , Wei Wei , Song Xuejiao , Ye Tinghong , Wang Ningyu , Peng Cuiting , Li Zhongping , Liu Zhihao , Yu Luoting
Published: October 2018

Polo-like kinase 4 (PLK4) is indispensable for precise control of centriole duplication. Abnormal expression of PLK4 has been reported in many human cancers, and inhibition of PLK4 activity results in their mitotic arrest and apoptosis. Therefore, PLK4 may be a valid therapeutic target for antitumor therapy. However, clinically available small-molecule inhibitors targeting PLK4 are deficient and their underlying mechanisms still remain not fully clear. Herein, the effects of YLT-11 on breast cancer cells and the associated mechanism were investigated. In vitro, YLT-11 exhibited significant antiproliferation activities against breast cancer cells. Meanwhile, cells treated with YLT-11 exhibited effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication and mitotic defects, sequentially making tumor cells more vulnerable to chemotherapy. Furthermore, YLT-11 could strongly regulate downstream factors of PLK4, which was involved in cell cycle regulation, ultimately inducing apoptosis of breast cancer cell. In vivo, oral administration of YLT-11 significantly suppressed the tumor growth in human breast cancer xenograft models at doses that are well tolerated. In summary, the preclinical data show that YLT-11 could be a promising candidate drug for breast tumor therapy.
Cancer-associated fibroblasts promote progression and gemcitabine resistance via the SDF-1/SATB-1 pathway in pancreatic cancer
Authors: Wei Lusheng , Ye Huilin , Li Guolin , Lu Yuanting , Zhou Quanbo , Zheng Shangyou , Lin Qing , Liu Yimin , Li Zhihua , Chen Rufu
Published: October 2018

Cancer-associated fibroblasts (CAFs), a dominant component of the pancreatic tumor microenvironment, are mainly considered as promotors of malignant progression, but the underlying molecular mechanism remains unclear. Here, we show that SDF-1 secreted by CAFs stimulates malignant progression and gemcitabine resistance in pancreatic cancer, partially owing to paracrine induction of SATB-1 in pancreatic cancer cells. CAF-secreted SDF-1 upregulated the expression of SATB-1 in pancreatic cancer cells, which contributed to the maintenance of CAF properties, forming a reciprocal feedback loop. SATB-1 was verified to be overexpressed in human pancreatic cancer tissues and cell lines by quantitative real-time PCR, western blot, and immunohistochemical staining, which correlated with tumor progression and clinical prognosis in pancreatic cancer patients. We found that SATB-1 knockdown inhibited proliferation, migration, and invasion in SW1990 and PANC-1 cells in vitro, whereas overexpression of SATB-1 in Capan-2 and BxPC-3 cells had the opposite effect. Immunofluorescence staining showed that conditioned medium from SW1990 cells expressing SATB-1 maintained the local supportive function of CAFs. Furthermore, downregulation of SATB-1 inhibited tumor growth in mouse xenograft models. In addition, we found that overexpression of SATB-1 in pancreatic cancer cells participated in the process of gemcitabine resistance. Finally, we investigated the clinical correlations between SDF-1 and SATB-1 in human pancreatic cancer specimens. In summary, these findings demonstrated that the SDF-1/CXCR4/SATB-1 axis may be a potential new target of clinical interventions for pancreatic cancer patients.
Expression-based drug screening of neural progenitor cells from individuals with schizophrenia
Authors: Readhead Benjamin , Hartley Brigham J. , Eastwood Brian J. , Collier David A. , Evans David , Farias Richard , He Ching , Hoffman Gabriel , Sklar Pamela , Dudley Joel T. , Schadt Eric E. , Savić Radoslav , Brennand Kristen J.
Published: October 2018

A lack of biologically relevant screening models hinders the discovery of better treatments for schizophrenia (SZ) and other neuropsychiatric disorders. Here we compare the transcriptional responses of 8 commonly used cancer cell lines (CCLs) directly with that of human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells (NPCs) from 12 individuals with SZ and 12 controls across 135 drugs, generating 4320 unique drug-response transcriptional signatures. We identify those drugs that reverse post-mortem SZ-associated transcriptomic signatures, several of which also differentially regulate neuropsychiatric disease-associated genes in a cell type (hiPSC NPC vs. CCL) and/or a diagnosis (SZ vs. control)-dependent manner. Overall, we describe a proof-of-concept application of transcriptomic drug screening to hiPSC-based models, demonstrating that the drug-induced gene expression differences observed with patient-derived hiPSC NPCs are enriched for SZ biology, thereby revealing a major advantage of incorporating cell type and patient-specific platforms in drug discovery.
The signalling conformation of the insulin receptor ectodomain
Authors: Weis Felix , Menting John G. , Margetts Mai B. , Chan Shu Jin , Xu Yibin , Tennagels Norbert , Wohlfart Paulus , Langer Thomas , Müller Christoph W. , Dreyer Matthias K. , Lawrence Michael C.
Published: October 2018

Understanding the structural biology of the insulin receptor and how it signals is of key importance in the development of insulin analogs to treat diabetes. We report here a cryo-electron microscopy structure of a single insulin bound to a physiologically relevant, high-affinity version of the receptor ectodomain, the latter generated through attachment of C-terminal leucine zipper elements to overcome the conformational flexibility associated with ectodomain truncation. The resolution of the cryo-electron microscopy maps is 3.2 Å in the insulin-binding region and 4.2 Å in the membrane-proximal region. The structure reveals how the membrane proximal domains of the receptor come together to effect signalling and how insulin’s negative cooperativity of binding likely arises. Our structure further provides insight into the high affinity of certain super-mitogenic insulins. Together, these findings provide a new platform for insulin analog investigation and design.
Sleep-like cortical OFF-periods disrupt causality and complexity in the brain of unresponsive wakefulness syndrome patients
Authors: Rosanova M. , Fecchio M. , Casarotto S. , Sarasso S. , Casali A. G. , Pigorini A. , Comanducci A. , Seregni F. , Devalle G. , Citerio G. , Bodart O. , Boly M. , Gosseries O. , Laureys S. , Massimini M.
Published: October 2018

Unresponsive wakefulness syndrome (UWS) patients may retain intact portions of the thalamocortical system that are spontaneously active and reactive to sensory stimuli but fail to engage in complex causal interactions, resulting in loss of consciousness. Here, we show that loss of brain complexity after severe injuries is due to a pathological tendency of cortical circuits to fall into silence (OFF-period) upon receiving an input, a behavior typically observed during sleep. Spectral and phase domain analysis of EEG responses to transcranial magnetic stimulation reveals the occurrence of OFF-periods in the cortex of UWS patients (N = 16); these events never occur in healthy awake individuals (N = 20) but are similar to those detected in healthy sleeping subjects (N = 8). Crucially, OFF-periods impair local causal interactions, and prevent the build-up of global complexity in UWS. Our findings link potentially reversible local events to global brain dynamics that are relevant for pathological loss and recovery of consciousness.
Design and self-assembly of hexahedral coordination cages for cascade reactions
Authors: Jiao Jingjing , Li Zijian , Qiao Zhiwei , Li Xu , Liu Yan , Dong Jinqiao , Jiang Jianwen , Cui Yong
Published: October 2018

The search for supramolecular reactors that contain no catalytically active sites but can promote chemical transformations has received significant attention, but it remains a synthetic challenge. Here we demonstrate a strategy of incorporating bulky and electro-rich aromatic linkers into metallocages to induce cascade reactions. Two hexahedral cages with a framework formula [(Zn8L6)(OTf)16] are assembled from six tetrakis-bidentate ligands derived from tetraphenylethylene and eight zinc(II)tris(pyridylimine) centers. The cage cavities can accommodate different molecules such as anthranilamide and aromatic aldehyde through supramolecular interactions, allowing for a cascade condensation and cyclization to produce nonplanar 2,3-dihyroquinazolinones. The reaction is highly efficient with high rate enhancements (up to kcat/kuncat = 38,000) and multiple turnovers compared to the bulk reaction mixture. Control experiments and molecular simulations suggest that the acceleration is attributed to inherent strength of binding affinity for reactants and the release of products to establish catalytic turnover is due to the host−guest geometry discrepancy.
Ballistic tracks in graphene nanoribbons
Authors: Aprojanz Johannes , Power Stephen R. , Bampoulis Pantelis , Roche Stephan , Jauho Antti-Pekka , Zandvliet Harold J. W. , Zakharov Alexei A. , Tegenkamp Christoph
Published: October 2018

High quality graphene nanoribbons epitaxially grown on the sidewalls of silicon carbide (SiC) mesa structures stand as key building blocks for graphene-based nanoelectronics. Such ribbons display 1D single-channel ballistic transport at room temperature with exceptionally long mean free paths. Here, using spatially-resolved two-point probe (2PP) measurements, we selectively access and directly image a range of individual transport modes in sidewall ribbons. The signature of the independently contacted channels is a sequence of quantised conductance plateaus for different probe positions. These result from an interplay between edge magnetism and asymmetric terminations at opposite ribbon edges due to the underlying SiC structure morphology. Our findings demonstrate a precise control of transport through multiple, independent, ballistic tracks in graphene-based devices, opening intriguing pathways for quantum information device concepts.
Prospective observational cohort study of symptom control prediction in paediatric asthma by using the Royal College of Physicians three questions
Authors: Andrews Glen , Lo David K. H. , Richardson Matthew , Wilson Andrew , Gaillard Erol A.
Published: October 2018

The Royal College of Physicians three questions (RCP3Q) is widely used for assessing asthma control within primary care in the UK, despite limited evidence in children. This study compared the RCP3Q as a tool for assessing asthma control in children (5–16 years) against the validated Asthma Control Test (ACT), Childhood Asthma Control Test (C-ACT), and Mini-Paediatric Quality of Life Questionnaire (MiniPAQLQ). We conducted a prospective observational cohort study involving children from eight primary care practices in Leicestershire. Children with doctor diagnosed asthma, or receiving regular asthma medication, were invited to participate. A total of 319 participants completed the MiniPAQLQ and the C-ACT/ACT questionnaires, before RCP3Q responses were collected as part of their routine asthma review conducted immediately afterwards. RCP3Q sensitivity for detecting uncontrolled asthma ranged from 43–60% and specificity from 80–82%. Using an RCP3Q score ≥2 to predict uncontrolled asthma and an RCP3Q score of zero to predict well-controlled asthma resulted in 10% of participants misclassified as uncontrolled and 8% as well-controlled, respectively. Using an RCP3Q threshold score of ≥1 resulted in 25% of participants being misclassified as uncontrolled. Our data suggests limited utility of the RCP3Q to assess asthma control in children. Alternative indicators of asthma control, such as the validated Asthma Control Test and the Children’s Asthma Control Test should be considered instead.
Interspecies cross-feeding orchestrates carbon degradation in the rumen ecosystem
Authors: Solden Lindsey M. , Naas Adrian E. , Roux Simon , Daly Rebecca A. , Collins William B. , Nicora Carrie D. , Purvine Sam O. , Hoyt David W. , Schückel Julia , Jørgensen Bodil , Willats William , Spalinger Donald E. , Firkins Jeffrey L. , Lipton Mary S. , Sullivan Matthew B. , Pope Phillip B. , Wrighton Kelly C.
Published: October 2018

Because of their agricultural value, there is a great body of research dedicated to understanding the microorganisms responsible for rumen carbon degradation. However, we lack a holistic view of the microbial food web responsible for carbon processing in this ecosystem. Here, we sampled rumen-fistulated moose, allowing access to rumen microbial communities actively degrading woody plant biomass in real time. We resolved 1,193 viral contigs and 77 unique, near-complete microbial metagenome-assembled genomes, many of which lacked previous metabolic insights. Plant-derived metabolites were measured with NMR and carbohydrate microarrays to quantify the carbon nutrient landscape. Network analyses directly linked measured metabolites to expressed proteins from these unique metagenome-assembled genomes, revealing a genome-resolved three-tiered carbohydrate-fuelled trophic system. This provided a glimpse into microbial specialization into functional guilds defined by specific metabolites. To validate our proteomic inferences, the catalytic activity of a polysaccharide utilization locus from a highly connected metabolic hub genome was confirmed using heterologous gene expression. Viral detected proteins and linkages to microbial hosts demonstrated that phage are active controllers of rumen ecosystem function. Our findings elucidate the microbial and viral members, as well as their metabolic interdependencies, that support in situ carbon degradation in the rumen ecosystem.
Two alternatively-spliced human nebulin isoforms with either exon 143 or exon 144 and their developmental regulation
Authors: Lam Le Thanh , Holt Ian , Laitila Jenni , Hanif Mubashir , Pelin Katarina , Wallgren-Pettersson Carina , Sewry Caroline A. , Morris Glenn E.
Published: October 2018

Nebulin is a very large protein required for assembly of the contractile machinery in muscle. Mutations in the nebulin gene NEB are a common cause of nemaline myopathy. Nebulin mRNA is alternatively-spliced so that each mRNA contains either exon 143 or exon 144. We have produced monoclonal antibodies specific for the regions of nebulin encoded by these two exons, enabling analysis of expression of isoforms at the protein level for the first time. All antibodies recognized a protein of the expected size (600–900 kD) and stained cross-striations of sarcomeres in muscle sections. Expression of exon 143 is developmentally-regulated since newly-formed myotubes in cell culture expressed nebulin with exon 144 only; this was confirmed at the mRNA level by qPCR. In fetal muscle, nebulin with exon 143 was expressed in some myotubes by 12-weeks of gestation and strongly-expressed in most myotubes by 17-weeks. In mature human muscle, the exon 144 antibody stained all fibres, but the exon 143 antibody staining varied from very strong in some fibres to almost-undetectable in other fibres. The results show that nebulin containing exon 144 is the default isoform early in myogenesis, while regulated expression of nebulin containing exon 143 occurs at later stages of muscle development.
Acoustophoretic Orientation of Red Blood Cells for Diagnosis of Red Cell Health and Pathology
Authors: Rico Laura G. , Juncà Jordi , Ward Mike D. , Bradford Jolene A. , Bardina Jorge , Petriz Jordi
Published: October 2018

Distortions of the normal bi-concave disc shape for red blood cells (RBCs) appear in a number of pathologies resulting from defects in cell membrane skeletal architecture, erythrocyte ageing, and mechanical damage. We present here the potential of acoustic cytometry for developing new approaches to light-scattering based evaluation of red blood cell disorders and of the effects of storage and ageing on changes or damage to RBCs membranes. These approaches could be used to immediately evaluate the quality of erythrocytes prior to blood donation and following transfusion. They could also be applied to studying RBC health in diseases and other pathologies, such as artificial heart valve hemolysis, thermal damage or osmotic fragility. Abnormal distributions of erythrocytes can typically be detected after just 30 to 45 seconds of acquisition time using 1–2 µL starting blood volumes.
The first set of universal nuclear protein-coding loci markers for avian phylogenetic and population genetic studies
Authors: Liu Yang , Liu Simin , Yeh Chia-Fen , Zhang Nan , Chen Guoling , Que Pinjia , Dong Lu , Li Shou-hsien
Published: October 2018

Multiple nuclear markers provide genetic polymorphism data for molecular systematics and population genetic studies. They are especially required for the coalescent-based analyses that can be used to accurately estimate species trees and infer population demographic histories. However, in avian evolutionary studies, these powerful coalescent-based methods are hindered by the lack of a sufficient number of markers. In this study, we designed PCR primers to amplify 136 nuclear protein-coding loci (NPCLs) by scanning the published Red Junglefowl (Gallus gallus) and Zebra Finch (Taeniopygia guttata) genomes. To test their utility, we amplified these loci in 41 bird species representing 23 Aves orders. The sixty-three best-performing NPCLs, based on high PCR success rates, were selected which had various mutation rates and were evenly distributed across 17 avian autosomal chromosomes and the Z chromosome. To test phylogenetic resolving power of these markers, we conducted a Neoavian phylogenies analysis using 63 concatenated NPCL markers derived from 48 whole genomes of birds. The resulting phylogenetic topology, to a large extent, is congruence with results resolved by previous whole genome data. To test the level of intraspecific polymorphism in these makers, we examined the genetic diversity in four populations of the Kentish Plover (Charadrius alexandrinus) at 17 of NPCL markers chosen at random. Our results showed that these NPCL markers exhibited a level of polymorphism comparable with mitochondrial loci. Therefore, this set of pan-avian nuclear protein-coding loci has great potential to facilitate studies in avian phylogenetics and population genetics.
SMTracker: a tool for quantitative analysis, exploration and visualization of single-molecule tracking data reveals highly dynamic binding of B. subtilis global repressor AbrB throughout the genome
Authors: Rösch Thomas C. , Oviedo-Bocanegra Luis M. , Fritz Georg , Graumann Peter L.
Published: October 2018

Single-particle (molecule) tracking (SPT/SMT) is a powerful method to study dynamic processes in living cells at high spatial and temporal resolution. Even though SMT is becoming a widely used method in bacterial cell biology, there is no program employing different analytical tools for the quantitative evaluation of tracking data. We developed SMTracker, a MATLAB-based graphical user interface (GUI) for automatically quantifying, visualizing and managing SMT data via five interactive panels, allowing the user to interactively explore tracking data from several conditions, movies and cells on a track-by-track basis. Diffusion constants are calculated a) by a Gaussian mixture model (GMM) panel, analyzing the distribution of positional displacements in x- and y-direction using a multi-state diffusion model (e.g. DNA-bound vs. freely diffusing molecules), and inferring the diffusion constants and relative fraction of molecules in each state, or b) by square displacement analysis (SQD), using the cumulative probability distribution of square displacements to estimate the diffusion constants and relative fractions of up to three diffusive states, or c) through mean-squared displacement (MSD) analyses, allowing the discrimination between Brownian, sub- or superdiffusive behavior. A spatial distribution analysis (SDA) panel analyzes the subcellular localization of molecules, summarizing the localization of trajectories in 2D- heat maps. Using SMTracker, we show that the global transcriptional repressor AbrB performs highly dynamic binding throughout the Bacillus subtilis genome, with short dwell times that indicate high on/off rates in vivo. While about a third of AbrB molecules are in a DNA-bound state, 40% diffuse through the chromosome, and the remaining molecules freely diffuse through the cells. AbrB also forms one or two regions of high intensity binding on the nucleoids, similar to the global gene silencer H-NS in Escherichia coli, indicating that AbrB may also confer a structural function in genome organization.
Metabolic fingerprints of Serratia liquefaciens under simulated Martian conditions using Biolog GN2 microarrays
Authors: Schwendner Petra , Schuerger Andrew C.
Published: October 2018

Microorganisms growing at atmospheric pressures of 0.7 kPa may have a significant impact on the search for life on Mars. Data on their nutrient requirements in a simulated Martian environment are required to ascertain both the potential risk of forward contamination and the potential of past or present habitability of Mars. Serratia liquefaciens can grow at concomitant conditions of low pressure, low temperature, and anoxic atmosphere. Changes in the metabolic fingerprint of S. liquefaciens grown under varying physical conditions including diverse atmospheric pressures (0.7 kPa to 101.3 kPa), temperatures (30 °C or 0 °C), and atmospheric gas compositions (Earth or CO2) were investigated using Biolog GN2 assays. Distinct patterns for each condition were observed. Above 10 kPa S. liquefaciens performed similar to Earth-normal pressure conditions (101.3 kPa) whereas below 10 kPa shifts in metabolic patterns were observed. The differences indicated a physiological alteration in which S. liquefaciens lost its ability to metabolize the majority of the provided carbon sources at 0.7 kPa with a significant decrease in the oxidation of amino acids. By measuring the physiological responses to different carbon sources we were able to identify nutritional constraints that support cellular replication under simulated shallow Mars subsurface conditions.