bluuebunny/crossref_metadata_2025 huggingface dataset:
Performance implications of the fit between suppliers' flexibility and their customers' expected flexibility: A dyadic examination⋆
Authors: Gligor David
Published: May 2018

Although an increase in flexibility for firms usually entails further investments and higher operating overhead for their suppliers (Sheikhzadeh et al., 1998Koste and Malhotra, 1999), most studies have focused exclusively on the benefits derived from additional flexibility enjoyed by the buyer firms neglecting the impact on the financial performance of their suppliers (e.g., Malhotra and Mackelprang, 2012; Gligor, 2014; Mandal, 2015). To explore the complex supplier‐customer interplay, we introduce the concept ofbuyer‐supplier flexibility fit(i.e., the match between the level of flexibility the customer expects from its supplier and the supplier's level of flexibility) and explore its impact on the supplier's financial performance (i.e., ROA). We collected dyadic archival and survey data from 638 firms (319 supplier‐customer dyads) to test these relationships. Our results indicate that buyer‐supplier flexibility fit has a direct and positive impact on the supplier's ROA. Further, the strength of the relationship increases when firms operate in munificent and/or dynamic environments but does not change significantly in complex environments. The relationship also becomes stronger as the exchanged business volume increases between the customer and its supplier, and as the relationship progresses in age. In addition, our findings indicate that firms with perfect buyer‐supplier flexibility fit perform best, followed by firms with negative misfit (i.e., the supplier's level of flexibility is lower than its customer's expected level of flexibility), while firms with positive misfit (i.e., the supplier's level of flexibility is higher than its customer's expected level of flexibility) are the laggards. Interestingly, positive misfit has a stronger negative impact on suppliers' ROA compared to misfit in general and negative misfit. Key corresponding managerial implications are derived.
Investigations of the synergy of Composite Cycle and intercooled recuperation
Authors: Kaiser Sascha , Nickl Markus , Salpingidou Christina , Vlahostergios Zinon , Donnerhack Stefan , Klingels Hermann
Published: May 2018

The synergistic combination of two promising engine architectures for future aero engines is presented. The first is the Composite Cycle Engine, which introduces a piston system in the high pressure part of the core engine, to utilise closed volume combustion and high temperature capability due to instationary operation. The second is the Intercooled Recuperated engine that employs recuperators to utilise waste heat from the core engine exhaust and intercooler to improve temperature levels for recuperation and to reduce compression work. Combinations of both architectures are presented and investigated for improvement potential with respect to specific fuel consumption, engine weight and fuel burn against a turbofan. The Composite Cycle alone provides a 15.6% fuel burn reduction against a turbofan. Options for adding intercooler were screened, and a benefit of up to 1.9% fuel burn could be shown for installation in front of a piston system through a significant, efficiency-neutral weight decrease. Waste heat can be utilised by means of classic recuperation to the entire core mass flow before the combustor, or alternatively on the turbine cooling bleed or a piston engine bypass flow that is mixed again with the main flow before the combustor. As further permutation, waste heat can be recovered either after the low pressure turbine – with or without sequential combustion – or between the high pressure and low pressure turbine. Waste heat recovery after the low pressure turbine was found to be not easily feasible or tied to high fuel burn penalties due to unfavourable temperature levels, even when using sequential combustion or intercooling. Feasible temperature levels could be obtained with inter-turbine waste heat recovery but always resulted in at least 0.3% higher fuel burn compared to the non-recuperated baseline under the given assumptions. Consequently, only the application of an intercooler appears to provide a considerable benefit for the examined thermodynamic conditions in the low fidelity analyses of various engine architecture combinations with the specific heat exchanger design. Since the obtained drawbacks of some waste heat utilisation concepts are small, innovative waste heat management concepts coupled with the further extension of the design space and the inclusion of higher fidelity models may achieve a benefit and motivate future investigations.
Posttraumatic Stress, Depression, and Coping Following the 2015 Nepal Earthquake: A Study on Adolescents
Authors: Sharma Asmita , Kar Nilamadhab
Published: May 2018

Objective

The study aimed to gather data on posttraumatic stress and depression in adolescents following the 2015 Nepal earthquake and explore the adolescents’ coping strategies.

Methods

In a questionnaire-based, cross-sectional study about 1 year after the earthquake, adolescents in two districts with different degrees of impact were evaluated for disaster experience, coping strategies, and symptoms of posttraumatic stress and depression measured with the Child Posttraumatic Stress Scale and the Depression Self Rating Scale.

Results

In the studied sample (N=409), the estimated prevalence of posttraumatic stress disorder (PTSD) (43.3%) and depression (38.1%) was considerable. Prevalence of PTSD was significantly higher in the more affected area (49.0% v 37.9%); however, the prevalence figures were comparable in adolescents who reported a stress. The prevalence of depression was comparable. Female gender, joint family, financial problems, displacement, injury or being trapped in the earthquake, damage to livelihood, and fear of death were significantly associated with a probable PTSD diagnosis. Various coping strategies were used: talking to others, praying, helping others, hoping for the best, and some activities were common. Drug abuse was rare. Most of the coping strategies were comparable among the clinical groups.

Conclusions

A considerable proportion of adolescents had posttraumatic stress and depression 1 year after the earthquake. There is a need for clinical interventions and follow-up studies regarding the outcome. Disaster Med Public Health Preparedness. 2019;13:236–242)
Strategies for screening cord blood for a public cord blood bank in high HIV prevalence regions
Authors: Meissner-Roloff M. , Gaggia L. , Vermeulen M. , Mazanderani A. F. H. , du Plessis N. M. , Steel H. C. , Pepper M. S.
Published: May 2018

The probability of a Black African finding a matched unrelated donor for a hematopoietic stem cell transplant is minimal due to the high degree of genetic diversity amongst individuals of African origin. This problem could be resolved in part by the establishment of a public cord blood (CB) stem cell bank. The high prevalence of human immunodeficiency virus (HIV) amongst women attending antenatal clinics in sub-Saharan Africa together with the risk of mother-to-child transmission increases the risk of transplant transmissible infection. In addition to screening the mother in a period inclusive of 7 days prior to the following delivery, we propose that all CB units considered for storage undergo rigorous and reliable screening for HIV. The Ultrio-plus® assay is a highly specific and sensitive test for detecting HIV, hepatitis-B and hepatitis-C viruses in peripheral blood. We validated the Ultrio-plus® assay for analytical sensitivity in detecting HIV in CB at the level of detection of the assay. Until more comprehensive and sensitive methods are developed, the sensitivity and reliability of the Ultrio-plus® assay suggest that it could be used for the routine screening of CB units in conjunction with currently recommended maternal screening to reduce the risk of transplant transmissible infection.
Simulating Duration Data for the Cox Model
Authors: Harden Jeffrey J. , Kropko Jonathan
Published: May 2018

The Cox proportional hazards model is a popular method for duration analysis that is frequently the subject of simulation studies. However, no standard method exists for simulating durations directly from its data generating process because it does not assume a distributional form for the baseline hazard function. Instead, simulation studies typically rely on parametric survival distributions, which contradicts the primary motivation for employing the Cox model. We propose a method that generates a baseline hazard function at random by fitting a cubic spline to randomly drawn points. Durations drawn from this function match the Cox model’s inherent flexibility and improve the simulation’s generalizability. The method can be extended to include time-varying covariates and non-proportional hazards.
Radiocarbon-dated peat development: anthropogenic and climatic signals in a Holocene raised bog and lake profile from the Eastern part of the Carpathian Basin
Authors: Tapody Réka Orsolya , Gulyás Sándor , Törőcsik Tünde , Sümegi Pál , Molnár Dávid , Sümegi Balázs P , Molnár Mihály
Published: May 2018

The peat bog at Homoródszentpál Kerek-tó (Round Lake), situated in Homoród Hills of the Eastern Carpathians in Romania, provides a continuous record of paleoclimatic and paleoenvironmental changes from the Early Holocene. In this study, we present a 7500-year-long high-resolution record of past climatic changes and signs of human impact recorded in a peat bog via integrating sedimentological, paleoecological and geochemical proxies. The basin of Round Lake formed around the Pleistocene–Holocene border when the permafrost thawed. Ponded water accumulated in the catchment basin from the beginning of the Holocene but ca. 7500 cal BP years ago lacustrine sedimentation was exchanged for peat accumulation. The 570-cm-long core was subsampled at 2–4 cm intervals and subjected to grain-size, loss-on-ignition (LOI), pollen, and radiocarbon (14C) analyses. Our findings were correlated with and interpreted in the light of paleobotanical records deriving from archaeological sites and the newest bioclimatological models of the nearby areas. Sedimentological analysis document erosion and accumulation events which were influenced by more complex processes like climate change. Based on environmental historical and climatic data we aimed to reconstruct the environmental changes of forested areas in the Homoródi Hills.
Dietaryl-threonine supplementation attenuates lipopolysaccharide-induced inflammatory responses and intestinal barrier damage of broiler chickens at an early age
Authors: Chen Yueping , Zhang Hao , Cheng Yefei , Li Yue , Wen Chao , Zhou Yanmin
Published: May 2018

This study was conducted to investigate the protective effects ofl-threonine (l-Thr) supplementation on growth performance, inflammatory responses and intestinal barrier function of young broilers challenged with lipopolysaccharide (LPS). A total of 144 1-d-old male chicks were allocated to one of three treatments: non-challenged broilers fed a basal diet (control group), LPS-challenged broilers fed a basal diet withoutl-Thr supplementation and LPS-challenged broilers fed a basal diet supplemented with 3·0 g/kgl-Thr. LPS challenge was performed intraperitoneally at 17, 19 and 21 d of age, whereas the control group received physiological saline injection. Compared with the control group, LPS challenge impaired growth performance of broilers, andl-Thr administration reversed LPS-induced increase in feed/gain ratio. LPS challenge elevated blood cell counts related to inflammation, and pro-inflammatory cytokine concentrations in serum (IL-1βand TNF-α), spleen (IL-1βand TNF-α) and intestinal mucosa (jejunal interferon-γ(IFN-γ) and ileal IL-1β). The concentrations of intestinal cytokines in LPS-challenged broilers were reduced byl-Thr supplementation. LPS administration increased circulatingd-lactic acid concentration, whereas it reduced villus height, the ratio between villus height and crypt depth and goblet density in both jejunum and ileum. LPS-induced decreases in jejunal villus height, intestinal villus height:crypt depth ratio and ileal goblet cell density were reversed withl-Thr supplementation. Similarly, LPS-induced alterations in the intestinal mRNA abundances of genes related to intestinal inflammation and barrier function (jejunal toll-like receptor 4,IFN-γand claudin-3, and ilealIL-1βand zonula occludens-1) were normalised withl-Thr administration. It can be concluded thatl-Thr supplementation could attenuate LPS-induced inflammatory responses and intestinal barrier damage of young broilers.
The difference between the scope of a norm and its apparent source
Authors: Birch Jonathan
Published: May 2018

We should distinguish between the apparent source of a norm and the scope of the norm's satisfaction conditions. Wide-scope social norms need not be externalised, and externalised social norms need not be wide in scope. Attending to this distinction leads to a problem for Stanford: The adaptive advantages he attributes to externalised norms are actually advantages of wide-scope norms.
Externalization is common to all value judgments, and norms are motivating because of their intersubjective grounding
Authors: Isern-Mas Carme , Gomila Antoni
Published: May 2018

We show that externalization is a feature not only of moral judgment, but also of value judgment in general. It follows that the evolution of externalization was not specific to moral judgment. Second, we argue that value judgments cannot be decoupled from the level of motivations and preferences, which, in the moral case, rely on intersubjective bonds and claims.
INTERGENERATIONAL MOBILITY IN EDUCATION AND OCCUPATION
Authors: Alonso-Carrera Jaime , Caballé Jordi , Raurich Xavier
Published: May 2018

We build a model that, according to the empirical evidence, gives rise to oscillations in wealth within a dynasty while keeping intergenerational persistence in education attainment. We propose a mechanism based on the interaction between wealth and effort as suggested by the Carnegie conjecture, according to which wealthier individuals devote less effort in their job occupations than poorer. Oscillations in wealth arise from changes in the occupation chosen by different generations of the same dynasty as a response to both inherited wealth and college premium. Our mechanism generates a rich social stratification with several classes in the long run due to the combination of different levels of education and occupation types. Furthermore, we generate a large mobility in wealth among classes even in the long run. Our model highlights the role played by the minimum cost on education investment, the borrowing constraints, and the complementarity between education and occupational effort.
The Excitation of Secondary Gravity Waves From Local Body Forces: Theory and Observation
Authors: Vadas Sharon L. , Zhao Jian , Chu Xinzhao , Becker Erich
Published: May 2018

We examine the characteristics of secondary gravity waves (GWs) excited by a localized (in space) and intermittent (in time) body force in the atmosphere. This force is a horizontal acceleration of the background flow created when primary GWs dissipate and deposit their momentum on spatial and temporal scales of the wave packet. A broad spectrum of secondary GWs is excited with horizontal scales much larger than that of the primary GW. The polarization relations cause the temperature spectrum of the secondary GWs generally to peak at larger intrinsic periods τIr and horizontal wavelengths λH than the vertical velocity spectrum. We find that the one‐dimensional spectra (with regard to frequency or wave number) follow lognormal distributions. We show that secondary GWs can be identified by a horizontally displaced observer as “fishbone” or “>” structures in z − t plots whereby the positive and negative GW phase lines meet at the “knee,” zknee, which is the altitude of the force center. We present two wintertime cases of lidar temperature measurements at McMurdo, Antarctica (166.69°E, 77.84°S) whereby fishbone structures are seen with zknee=43 and 52 km. We determine the GW parameters and density‐weighted amplitudes for each. We show that these parameters are similar below and above zknee. We verify that the GWs with upward (downward) phase progression are downward (upward) propagating via use of model background winds. We conclude that these GWs are likely secondary GWs having ground‐based periods τr=6–10 hr and vertical wavelengths λz=6–14 km, and that they likely propagate primarily southward.
Six Decades of Glacial Mass Loss in the Canadian Arctic Archipelago
Authors: Noël Brice , van de Berg Willem Jan , Lhermitte Stef , Wouters Bert , Schaffer Nicole , van den Broeke Michiel R.
Published: May 2018

The Canadian Arctic Archipelago comprises multiple small glaciers and ice caps, mostly concentrated on Ellesmere and Baffin Islands in the northern (NCAA, Northern Canadian Arctic Archipelago) and southern parts (SCAA, Southern Canadian Arctic Archipelago) of the archipelago, respectively. Because these glaciers are small and show complex geometries, current regional climate models, using 5‐ to 20‐km horizontal resolution, do not properly resolve surface mass balance patterns. Here we present a 58‐year (1958–2015) reconstruction of daily surface mass balance of the Canadian Arctic Archipelago, statistically downscaled to 1 km from the output of the regional climate model RACMO2.3 at 11 km. By correcting for biases in elevation and ice albedo, the downscaling method significantly improves runoff estimates over narrow outlet glaciers and isolated ice fields. Since the last two decades, NCAA and SCAA glaciers have experienced warmer conditions (+1.1°C) resulting in continued mass loss of 28.2 ± 11.5 and 22.0 ± 4.5 Gt/year, respectively, more than doubling (11.9 Gt/year) and doubling (11.9 Gt/year) the pre‐1996 average. While the interior of NCAA ice caps can still buffer most of the additional melt, the lack of a perennial firn area over low‐lying SCAA glaciers has caused uninterrupted mass loss since the 1980s. In the absence of significant refreezing capacity, this indicates inevitable disappearance of these highly sensitive glaciers.
Acoustic and Microseismic Characterization in Steep Bedrock Permafrost on Matterhorn (CH)
Authors: Weber Samuel , Faillettaz Jérome , Meyer Matthias , Beutel Jan , Vieli Andreas
Published: May 2018

Understanding of processes and factors influencing slope stability is essential for assessing the stability of potentially hazardous slopes. Passive monitoring of acoustic emissions and microseismology provides subsurface information on fracturing (timing and identification of the mechanism) and therefore complement surface displacement data. This study investigates for the first time acoustic and microseismic signals generated in steep, fractured bedrock permafrost, covering the broad frequency range of 1 − 105 Hz. The analysis of artificial forcing experiments using a rebound hammer in a controlled setting led to two major findings: First, statistically insignificant cross correlation between signals indicates that waveforms change strongly with propagation distance. Second, a significant amplification is found in the frequency band 33–67 Hz. This finding is strongly supported by evidence from artificial rockfall events and more importantly by naturally occurring fracture events identified in fracture displacement data. Thus, filtering this frequency band enables enhanced detection of microseismic events relevant for slope stability assessment. The analysis of 2‐year time series in this frequency band further suggests that the detected energy rate baseline of all automatically triggered events using the STA/LTA algorithm is not sensitive to temperature forcing, an observation of primary importance for long‐term data collection, analysis, and interpretation. The event detection in the established frequency band is not only improved but also not affected by the short‐ and long‐term temperature changes in such a rapidly changing environment.
Spatial‐Temporal Patterns of Evapotranspiration Along an Elevation Gradient on Mount Gongga, Southwest China
Authors: Hu Zhaoyong , Wang Genxu , Sun Xiangyang , Zhu Meizhuang , Song Chunlin , Huang Kewei , Chen Xiaopeng
Published: May 2018

Evapotranspiration (ET) is a crucial component of the hydrological cycle in terrestrial ecosystems, but estimating ET in mountainous regions is challenging. In this study, the performance of a generalized nonlinear formulation of the complementary principle while estimating daily ET was evaluated, and the spatial‐temporal variation of ET was analyzed across four vegetation types along an elevation gradient on Mount Gongga, Southwest China. The values of the calibrated Priestley and Taylor coefficients for each of the four sites ranged from 0.98 to 1.13. The correlation coefficients between the estimated and observed daily actual evapotranspiration for each of the four sites ranged from 0.71 to 0.92. A markedly asymmetrical complementary relationship existed among the four studied sites, and the values showed less scattered during the wet season. The annual ET rates were 779.12, 781.63, 701.77, and 625.17 mm/yr in the broadleaf forest (BLF), broadleaf and coniferous mixed forest (BCF), coniferous forest (CF), and shrub land (SL), respectively, and showed a decreasing trend of 9.72 mm per 100 m along the elevation gradient. After recalibration of the seasonal αe values, the estimated annual ET rates increased and were closer to the observed values in BLF and BCF. The results indicate that daily ET in mountainous areas can be estimated using the generalized nonlinear formulation of the complementary relationship together with routine meteorological data alone, but seasonal changes in αe values should be taken into consideration in forests with deciduous trees.
The Sleep Checkup: Sleep Screening, Guidance, and Management in Pediatric Primary Care
Authors: Honaker Sarah Morsbach , Saunders Taylor
Published: May 2018

Few studies have examined strategies to address sleep difficulties and promote sleep health in pediatric primary care. The aims of the current study are to (a) describe the content, acceptability, and preliminary feasibility of the Sleep Checkup delivered by behavioral health providers in two urban primary care clinics and (b) report child sleep outcomes from the implementation of the Sleep Checkup. Participants were 83 children ages birth to 18 years, presenting to their primary care provider (PCP) for a sick- or well-child visit. Thirteen faculty PCPs responded to an anonymous survey about their perception of the service. The percentage of parents with concerns about their child’s sleep ranged from 0% for newborns to 41.6% for preschoolers. Of those reporting no concern, more than half subsequently reported sleep symptoms or practices suggesting a sleep problem or disorder. Providers reported overall high satisfaction. They rated the service as beneficial to providers ( M = 4.85; 5 = strongly agree), to patients ( M = 4.77), and to trainee learning ( M = 4.77). Providers did not find the Sleep Checkup disruptive to patient flow ( M = 1.08; 1 = strongly disagree). High rates of problematic sleep habits and symptoms of sleep disorders were found in an urban primary care sample, including in children whose parents denied any sleep concerns.

Implications for Impact Statement

This study introduces the Sleep Checkup, a novel clinical tool designed to prevent, identify, and manage pediatric sleep disturbances in primary care settings. Data from its implementation support preliminary acceptability and feasibility of the Sleep Checkup. Further, sleep outcomes suggest high rates of sleep disturbance and highlight the need for systematic sleep screening and guidance.
Integrating impedance-based growth-rate monitoring into a microfluidic cell culture platform for live-cell microscopy
Authors: Chawla Ketki , Bürgel Sebastian C. , Schmidt Gregor W. , Kaltenbach Hans-Michael , Rudolf Fabian , Frey Olivier , Hierlemann Andreas
Published: May 2018

Growth rate is a widely studied parameter for various cell-based biological studies. Growth rates of cell populations can be monitored in chemostats and micro-chemostats, where nutrients are continuously replenished. Here, we present an integrated microfluidic platform that enables long-term culturing of non-adherent cells as well as parallel and mutually independent continuous monitoring of (i) growth rates of cells by means of impedance measurements and of (ii) specific other cellular events by means of high-resolution optical or fluorescence microscopy. Yeast colonies were grown in a monolayer under culturing pads, which enabled high-resolution microscopy, as all cells were in the same focal plane. Upon cell growth and division, cells leaving the culturing area passed over a pair of electrodes and were counted through impedance measurements. The impedance data could then be used to directly determine the growth rates of the cells in the culturing area. The integration of multiple culturing chambers with sensing electrodes enabled multiplexed long-term monitoring of growth rates of different yeast strains in parallel. As a demonstration, we modulated the growth rates of engineered yeast strains using calcium. The results indicated that impedance measurements provide a label-free readout method to continuously monitor the changes in the growth rates of the cells without compromising high-resolution optical imaging of single cells.
Burkholderia bacteria use chemotaxis to find social amoeba Dictyostelium discoideum hosts
Authors: Shu Longfei , Zhang Bojie , Queller David C , Strassmann Joan E
Published: May 2018

A key question in cooperation is how to find the right partners and maintain cooperative relationships. This is especially challenging for horizontally transferred bacterial symbionts where relationships must be repeatedly established anew. In the social amoeba Dictyostelium discoideum farming symbiosis, two species of inedible Burkholderia bacteria (Burkholderia agricolaris and Burkholderia hayleyella) initiate stable associations with naive D. discoideum hosts and cause carriage of additional bacterial species. However, it is not clear how the association between D. discoideum and its carried Burkholderia is formed and maintained. Here, we look at precisely how Burkholderia finds its hosts. We found that both species of Burkholderia clones isolated from D. discoideum, but not other tested Burkholderia species, are attracted to D. discoideum supernatant, showing that the association is not simply the result of haphazard engulfment by the amoebas. The chemotactic responses are affected by both partners. We find evidence that B. hayleyella prefers D. discoideum clones that currently or previously carried Burkholderia, while B. agricolaris does not show this preference. However, we find no evidence of Burkholderia preference for their own host clone or for other hosts of their own species. We further investigate the chemical differences of D. discoideum supernatants that might explain the patterns shown above using a mass spectrometry based metabolomics approach. These results show that these bacterial symbionts are able to preferentially find and to some extent choose their unicellular partners. In addition, this study also suggests that bacteria can actively search for and target phagocytic cells, which may help us better understand how bacteria interact with immune systems.
Uncovering the hidden impacts of inequality on mental health: a global study
Authors: Yu Shoukai
Published: May 2018

Women are nearly twice as likely as men to suffer from mental illness. This gender disparity in depressive disorders may relate to social inequalities and living standards across nations. Currently, these disparities were not reflected at the level of health policies. This study utilized global data for depressive disorders and socioeconomic data from the United Nations’ World Bank databases and Global Burden of Disease database to demonstrate the correlation between social inequality and gender disparities in mental health. This study investigated the association among the ratio of female to male depressive disorder rates, gross domestic product, the GINI Index, and the gender inequality index for 122 countries. The research yielded some major findings. First, there exists a significant correlation between gender inequality and gender disparities in mental health. Second, the GINI index is significantly associated with male—but not female—depressive disorder rates. Third, gender disparities in depressive disorders are associated with a country’s wealth. These findings can help to inform society, policy-makers, and clinicians to improve the overall health level globally.
Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy
Authors: Madan Babita , McDonald Mitchell J. , Foxa Gabrielle E. , Diegel Cassandra R. , Williams Bart O. , Virshup David M.
Published: May 2018

Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. One of the key challenges in developing targeted anti-cancer drugs is to balance efficacy with on-target toxicity. Given the crucial role Wnts play in the differentiation of osteoblasts and osteoclasts, acute inhibition of Wnt signaling is likely to affect bone homeostasis. In this study, we evaluated the skeletal effect of small molecule inhibitor of an o-acyl transferase porcupine (PORCN) that prevents Wnt signaling by blocking the secretion of all Wnts. Micro-computed tomography and histomorphometric evaluation revealed that the bones of mice treated with two structurally distinct PORCN inhibitors LGK974 and ETC-1922159 (ETC-159) had loss-of-bone volume and density within 4 weeks of exposure. This decreased bone mass was associated with a significant increase in adipocytes within the bone marrow. Notably, simultaneous administration of a clinically approved anti-resorptive, alendronate, a member of the bisphosphonate family, mitigated loss-of-bone mass seen upon ETC-159 treatment by regulating activity of osteoclasts and blocking accumulation of bone marrow adipocytes. Our results support the addition of bone protective agents when treating patients with PORCN inhibitors. Mitigation of bone toxicity can extend the therapeutic utility of Wnt pathway inhibitors.
Alpha-fetoprotein kinetics in patients with hepatocellular carcinoma receiving ramucirumab or placebo: an analysis of the phase 3 REACH study
Authors: Chau Ian , Park Joon Oh , Ryoo Baek-Yeol , Yen Chia-Jui , Poon Ronnie , Pastorelli Davide , Blanc Jean-Frédéric , Kudo Masatoshi , Pfiffer Tulio , Hatano Etsuro , Chung Hyun Cheol , Kopeckova Katerina , Phelip Jean-Marc , Brandi Giovanni , Ohkawa Shinichi , Li Chung-Pin , Okusaka Takuji , Hsu Yanzhi , Abada Paolo B. , Zhu Andrew X.
Published: May 2018

Background

Post-hoc analyses of AFP response and progression and their relationship with objective measures of response and survival were performed in patients from REACH.

Methods

Serum AFP was measured at baseline and every 3 cycles (2 weeks/cycle). Associations between AFP and radiographic progression and efficacy end points were analysed.

Results

Median percent AFP increase from baseline was smaller in the ramucirumab than in the placebo arm throughout treatment. Time to AFP progression (HR 0.621; P < 0.0001) and to radiographic progression (HR 0.613; P < 0.0001) favoured ramucirumab. Association between AFP and radiographic progression was shown at 6 (OR 6.44, 95% CI 4.03, 10.29; P < 0.0001) and 12 weeks (OR 2.28, 95% CI 1.47, 3.53; P = 0.0002). AFP response was higher with ramucirumab compared with placebo (P < 0.0001). More patients in the ramucirumab arm experienced tumour shrinkage and AFP response compared with placebo. Survival was longer in patients with AFP response (13.6 months) than in patients without (6.2 months), irrespective of treatment (HR 0.457, P < 0.0001).

Conclusions

Treatment with ramucirumab prolonged time to AFP progression, slowed AFP increase and was more likely to induce AFP response. Similar benefits in radiographic progression and response correlated with AFP changes.
REGγ deficiency suppresses tumor progression via stabilizing CK1ε in renal cell carcinoma
Authors: Chen Shaojun , Wang Qingwei , Wang Longsheng , Chen Hui , Gao Xiao , Gong Dongkui , Ma Junjie , Kubra Syeda , Yao Xudong , Li Xiaotao , Li Lei , Zhai Wei , Zheng Junhua
Published: May 2018

Renal cell carcinoma (RCC) is the most common malignant disease of kidney in adults. The proteasome activator REGγ was previously reported to promote the degradation of multiple important regulatory proteins and involved in the progression and development of numerous human cancers. Here, we first reported that REGγ was upregulated in RCC and its upregulation was correlated with a poor prognosis in RCC patients. REGγ depletion obviously suppressed RCC cells proliferation in vitro and in vivo. Notably, casein kinase 1ε (CK1ε) was identified as a novel target of REGγ and knockdown of CK1ε effectively abolished the effect of REGγ depletion on RCC cells growth. Importantly, we also observed that REGγ depletion activated Hippo signaling pathway via stabilizing CK1ε in RCC, indicating the cross-talk between REGγ/CK1ε axis and Hippo pathway during RCC development. In conclusion, our findings suggested that REGγ played a pivotal role in the development of RCC and maybe helpful to identify new therapeutic strategies in the treatment of RCC.
Gamma synuclein is a novel Twist1 target that promotes TGF-β-induced cancer cell migration and invasion
Authors: Shao Ting , Song Peiying , Hua Hui , Zhang Hongying , Sun Xiangmin , Kong Qingbin , Wang Jiao , Luo Ting , Jiang Yangfu
Published: May 2018

Transforming growth factor β (TGF-β) is critical for embryonic development, adult tissue homeostasis, and tumor progression. TGF-β suppresses tumors at early stage, but promotes metastasis at later stage through oncogenes such as Twist1. Gamma-synuclein (SNCG) is overexpressed in a variety of invasive and metastatic cancer. Here, we show that TGF-β induces SNCG expression by Smad-Twist1 axis, thus promoting TGF-β- and Twist1-induced cancer cell migration and invasion. We identify multiple Twist1-binding sites (E-boxes) in SNCG promoter. Chromatin immunoprecipitation and luciferase assays confirm the binding of Twist1 to the E-boxes of SNCG promoter sequence (−129/−1026 bp). Importantly, the Twist1-binding site close to the transcription initiation site is critical for the upregulation of SNCG expression by TGF-β and Twist1. Mutations of Twist1 motif on the SNCG promoter constructs markedly reduces the promoter activity. We further show that TGF-β induces Twist1 expression through Smad thereby enhancing the binding of Twist1 to SNCG promoter, upregulating SNCG promoter activity and increasing SNCG expression. SNCG knockdown abrogates TGF-β- or Twist1-induced cancer cell migration and invasion. Finally, SNCG knockdown inhibits the promotion of cancer metastasis by Twist1. Together, our data demonstrate that SNCG is a novel target of TGF-β-Smad-Twist1 axis and a mediator of Twist1-induced cancer metastasis.
Distinct roles of XPF-ERCC1 and Rad1-Rad10-Saw1 in replication-coupled and uncoupled inter-strand crosslink repair
Authors: Seol Ja-Hwan , Holland Cory , Li Xiaolei , Kim Christopher , Li Fuyang , Medina-Rivera Melisa , Eichmiller Robin , Gallardo Ignacio F. , Finkelstein Ilya J. , Hasty Paul , Shim Eun Yong , Surtees Jennifer A. , Lee Sang Eun
Published: May 2018

Yeast Rad1–Rad10 (XPF–ERCC1 in mammals) incises UV, oxidation, and cross-linking agent-induced DNA lesions, and contributes to multiple DNA repair pathways. To determine how Rad1–Rad10 catalyzes inter-strand crosslink repair (ICLR), we examined sensitivity to ICLs from yeast deleted forSAW1andSLX4, which encode proteins that interact physically with Rad1–Rad10 and bind stalled replication forks. Saw1, Slx1, and Slx4 are critical for replication-coupled ICLR inmus81deficient cells. Two rad1 mutations that disrupt interactions between Rpa1 and Rad1–Rad10 selectively disable non-nucleotide excision repair (NER) function, but retain UV lesion repair. Mutations in the analogous region of XPF also compromised XPF interactions with Rpa1 and Slx4, and are proficient in NER but deficient in ICLR and direct repeat recombination. We propose that Rad1–Rad10 makes distinct contributions to ICLR depending on cell cycle phase: in G1, Rad1–Rad10 removes ICL via NER, whereas in S/G2, Rad1–Rad10 facilitates NER-independent replication-coupled ICLR.
Extremely stable graphene electrodes doped with macromolecular acid
Authors: Kwon Sung-Joo , Han Tae-Hee , Ko Taeg Yeoung , Li Nannan , Kim Youngsoo , Kim Dong Jin , Bae Sang-Hoon , Yang Yang , Hong Byung Hee , Kim Kwang S. , Ryu Sunmin , Lee Tae-Woo
Published: May 2018

Although conventional p-type doping using small molecules on graphene decreases its sheet resistance (Rsh), it increases after exposure to ambient conditions, and this problem has been considered as the biggest impediment to practical application of graphene electrodes. Here, we report an extremely stable graphene electrode doped with macromolecular acid (perfluorinated polymeric sulfonic acid (PFSA)) as a p-type dopant. The PFSA doping on graphene provides not only ultra-high ambient stability for a very long time (> 64 days) but also high chemical/thermal stability, which have been unattainable by doping with conventional small-molecules. PFSA doping also greatly increases the surface potential (~0.8 eV) of graphene, and reduces its Rsh by ~56%, which is very important for practical applications. High-efficiency phosphorescent organic light-emitting diodes are fabricated with the PFSA-doped graphene anode (~98.5 cd A−1 without out-coupling structures). This work lays a solid platform for practical application of thermally-/chemically-/air-stable graphene electrodes in various optoelectronic devices.
Protein polarization driven by nucleoid exclusion of DnaK(HSP70)–substrate complexes
Authors: Collet Clémence , Thomassin Jenny-Lee , Francetic Olivera , Genevaux Pierre , Tran Van Nhieu Guy
Published: May 2018

Many bacterial proteins require specific subcellular localization for function. How Escherichia coli proteins localize at one pole, however, is still not understood. Here, we show that the DnaK (HSP70) chaperone controls unipolar localization of the Shigella IpaC type III secretion substrate. While preventing the formation of lethal IpaC aggregates, DnaK promoted the incorporation of IpaC into large and dynamic complexes (LDCs) restricted at the bacterial pole through nucleoid occlusion. Unlike stable polymers and aggregates, LDCs show dynamic behavior indicating that nucleoid occlusion also applies to complexes formed through transient interactions. Fluorescence recovery after photobleaching analysis shows DnaK-IpaC exchanges between opposite poles and DnaKJE-mediated incorporation of immature substrates in LDCs. These findings reveal a key role for LDCs as reservoirs of functional DnaK-substrates that can be rapidly mobilized for secretion triggered upon bacterial contact with host cells.
Tuning the interplay between nematicity and spin fluctuations in Na1−xLi
x
FeAs superconductors
Authors: Baek S.-H. , Bhoi Dilip , Nam Woohyun , Lee Bumsung , Efremov D. V. , Büchner B. , Kim Kee Hoon
Published: May 2018

Strong interplay of spin and charge/orbital degrees of freedom is the fundamental characteristic of the iron-based superconductors (FeSCs), which leads to the emergence of a nematic state as a rule in the vicinity of the antiferromagnetic state. Despite intense debate for many years, however, whether nematicity is driven by spin or orbital fluctuations remains unsettled. Here, by use of transport, magnetization, and 75As nuclear magnetic resonance (NMR) measurements, we show a striking transformation of the relationship between nematicity and spin fluctuations (SFs) in Na1−xLi
x
FeAs; For x ≤ 0.02, the nematic transition promotes SFs. In contrast, for x ≥ 0.03, the system undergoes a non-magnetic phase transition at a temperature T0 into a distinct nematic state that suppresses SFs. Such a drastic change of the spin fluctuation spectrum associated with nematicity by small doping is highly unusual, and provides insights into the origin and nature of nematicity in FeSCs.
Introduced species that overcome life history tradeoffs can cause native extinctions
Authors: Catford Jane A. , Bode Michael , Tilman David
Published: May 2018

Introduced species threaten native biodiversity, but whether exotic species can competitively displace native species remains contested. Building on theory that predicts multi-species coexistence based on a competition-colonisation tradeoff, we derive a mechanistic basis by which human-mediated species invasions could cause extinctions through competitive displacement. In contrast to past invasions, humans principally introduce modern invaders, repeatedly and in large quantities, and in ways that can facilitate release from enemies and competitors. Associated increases in exotic species’ propagule rain, survival and competitive ability could enable some introduced species to overcome the tradeoffs that constrain all other species. Using evidence from metacommunity models, we show how species introductions could disrupt species coexistence, generating extinction debts, especially when combined with other forms of anthropogenic environmental change. Even though competing species have typically coexisted following past biogeographic migrations, the multiplicity and interactive impacts of today’s threats could change some exotic species into agents of extinction.
Distinct epigenomic patterns are associated with haploinsufficiency and predict risk genes of developmental disorders
Authors: Han Xinwei , Chen Siying , Flynn Elise , Wu Shuang , Wintner Dana , Shen Yufeng
Published: May 2018

Haploinsufficiency is a major mechanism of genetic risk in developmental disorders. Accurate prediction of haploinsufficient genes is essential for prioritizing and interpreting deleterious variants in genetic studies. Current methods based on mutation intolerance in population data suffer from inadequate power for genes with short transcripts. Here we show haploinsufficiency is strongly associated with epigenomic patterns, and develop a computational method (Episcore) to predict haploinsufficiency leveraging epigenomic data from a broad range of tissue and cell types by machine learning methods. Based on data from recent exome sequencing studies on developmental disorders, Episcore achieves better performance in prioritizing likely-gene-disrupting (LGD) de novo variants than current methods. We further show that Episcore is less-biased by gene size, and complementary to mutation intolerance metrics for prioritizing LGD variants. Our approach enables new applications of epigenomic data and facilitates discovery and interpretation of novel risk variants implicated in developmental disorders.
Author Correction: Oxidative rearrangement of (+)-sesamin by CYP92B14 co-generates twin dietary lignans in sesame
Authors: Murata Jun , Ono Eiichiro , Yoroizuka Seigo , Toyonaga Hiromi , Shiraishi Akira , Mori Shoko , Tera Masayuki , Azuma Toshiaki , Nagano Atsushi J. , Nakayasu Masaru , Mizutani Masaharu , Wakasugi Tatsuya , Yamamoto Masayuki P. , Horikawa Manabu
Published: May 2018

The original version of of the Supplementary Information associated with this Article inadvertently omitted oligonucleotide primer sequences from Supplementary Table 3 and Supplementary Methods describing the molecular cloning of CYP92B14, CPR1 and CYP81Q cDNA fragments. The HTML has been updated to include a corrected version of the Supplementary Information.
Author Correction: Highly (001)-textured p-type WSe2 Thin Films as Efficient Large-Area Photocathodes for Solar Hydrogen Evolution
Authors: Bozheyev Farabi , Harbauer Karsten , Zahn Clark , Friedrich Dennis , Ellmer Klaus
Published: May 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
The Relationship between Robot’s Nonverbal Behaviour and Human’s Likability Based on Human’s Personality
Authors: Thepsoonthorn Chidchanok , Ogawa Ken-ichiro , Miyake Yoshihiro
Published: May 2018

At current state, although robotics technology has been immensely developed, the uncertainty to completely engage in human-robot interaction is still growing among people. Many current studies then started to concern about human factors that might influence human’s likability like human’s personality, and found that compatibility between human’s and robot’s personality (expressions of personality characteristics) can enhance human’s likability. However, it is still unclear whether specific means and strategy of robot’s nonverbal behaviours enhances likability from human with different personality traits and whether there is a relationship between robot’s nonverbal behaviours and human’s likability based on human’s personality. In this study, we investigated and focused on the interaction via gaze and head nodding behaviours (mutual gaze convergence and head nodding synchrony) between introvert/extravert participants and robot in two communication strategies (Backchanneling and Turn-taking). Our findings reveal that the introvert participants are positively affected by backchanneling in robot’s head nodding behaviour, which results in substantial head nodding synchrony whereas the extravert participants are positively influenced by turn-taking in gaze behaviour, which leads to significant mutual gaze convergence. This study demonstrates that there is a relationship between robot’s nonverbal behaviour and human’s likability based on human’s personality.
Concentration-dependent protein loading of extracellular vesicles released by Histoplasma capsulatum after antibody treatment and its modulatory action upon macrophages
Authors: Baltazar Ludmila Matos , Zamith-Miranda Daniel , Burnet Meagan C. , Choi Hyungwon , Nimrichter Leonardo , Nakayasu Ernesto S. , Nosanchuk Joshua D.
Published: May 2018

Diverse pathogenic fungi secrete extracellular vesicles (EV) that contain macromolecules, including virulence factors that can modulate the host immune response. We recently demonstrated that the binding of monoclonal antibodies (mAb) modulates howHistoplasma capsulatumload and releases its extracellular vesicles (EV). In the present paper, we addressed a concentration-dependent impact on the fungus’ EV loading and release with different mAb, as well as the pathophysiological role of these EV during the host-pathogen interaction. We found that the mAbs differentially regulate EV content in concentration-dependent and independent manners. Enzymatic assays demonstrated that laccase activity in EV fromH.capsulatumopsonized with 6B7 was reduced, but urease activity was not altered. The uptake ofH.capsulatumby macrophages pre-treated with EV, presented an antibody concentration-dependent phenotype. The intracellular killing of yeast cells was potently inhibited in macrophages pre-treated with EV from 7B6 (non-protective) mAb-opsonizedH.capsulatumand this inhibition was associated with a decrease in the reactive-oxygen species generated by these macrophages. In summary, our findings show that opsonization quantitatively and qualitatively modifiesH.capsulatumEV load and secretion leading to distinct effects on the host’s immune effector mechanisms, supporting the hypothesis that EV sorting and secretion are dynamic mechanisms for a fine-tuned response by fungal cells.