bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychological Distress and Weight Gain in Pregnancy: a Population-Based Study
Authors: Vehmeijer Florianne O. L. , Balkaran Sangeeta R. , Santos Susana , Gaillard Romy , Felix Janine F. , Hillegers Manon H. J. , El Marroun Hanan , Jaddoe Vincent W. V.
Published: December 2019

Background

Psychological distress and inappropriate or excessive weight gain are common in pregnancy and are associated with adverse maternal and offspring outcomes. Psychological well-being and weight status of women during pregnancy might be interrelated. We aimed to examine whether psychological distress during pregnancy is associated with gestational weight gain.

Method

In a population-based cohort of 3393 pregnant women, information about psychological distress, depressive and anxiety symptoms was assessed at 20 weeks of gestation using the Brief Symptom Inventory questionnaire. Weight was repeatedly measured during pregnancy and obtained by questionnaire before and after pregnancy. Linear regression and multinomial logistic regression models were used. Weight gain in the second half of pregnancy, total weight gain, and the risks of inadequate and excessive total weight gain were the main outcome measures.

Results

In total, 7.0% of all women experienced psychological distress. Overall psychological distress and anxiety were associated with lower weight gain in the second half of pregnancy (differences − 1.00 kg (95% confidence interval (CI) − 1.62, − 0.37) and − 0.68 kg (95% CI - 1.24, -0.11), respectively). These associations fully attenuated into non-significance after taking account for socio-demographic variables. Similar results were observed for total weight gain. Only women with anxiety symptoms had, independently of potential confounders, a lower risk of excessive weight gain (odds ratio (OR) 0.61 (95% CI 0.48, 0.91)).

Conclusions

In this large prospective cohort study, the observed associations of psychological distress with weight gain during pregnancy seem to be largely explained by common socio-demographic factors.
Introducing the eMCC™: A Validated Taxonomy to Advance Targeted Application of Mindfulness Skills
Authors: Wolever Ruth Q. , Kahn Joel A. , Davis Jennifer , Shields Denise , Schoenberg Poppy L. A.
Published: December 2019

Objective

Describe the two-phase validation process for a taxonomy of skills learned through mindfulness practice.

Methods

Phase I (development) utilized 11 subject matter experts (SMEs) over 5 months. Phase II (judgment) enrolled 60 international SMEs from 116 invited through snowball sampling. They were mostly white (80%) or Asian (15%) women (70%) with longstanding personal mindfulness practices (M = 20 years; SD = 9.6) and extensive mindfulness teaching experience (M = 11 years; SD = 6.7); 59% > 50 years; 88% had graduate degrees. SMEs rated relevance and clarity to calculate Individual Content Validity Indices (I-CVIs) for each category per tier and average CVIs (ave-CVIs) for entire tiers. Participation rate was 52% and 42 SMEs rated secondary tiers.

Results

I-CVIs ranged from 0.57 to 0.97, suggesting the removal of one category from the primary tier, leaving an ave-CVI for relevance of 0.92 (range 0.73–0.97). Clarity ratings for the primary tier (ave-CVI = 0.75; range of I-CVI = 0.52–0.88) necessitated exploration of the subcategories of Awareness (second tier; N = 42) to refine description (ave-CVI = 0.80 for clarity; range 0.64–0.93) while showing excellent content validity for both relevance and fit (ave-CVI = 0.95; range 0.88–1.0 for both).

Conclusions

The eMindful Mindfulness Classification Construct™ (eMCC™) is a validated, atheoretical taxonomy of skills learned through mindfulness practice, created to support development of more precise mindfulness-based interventions (MBIs) that target skill deficits associated with clinical conditions. Further research will validate subcategories, associate specific practices per category, and assess MBIs designed to target specific skills from the eMCC™.
Bolstering Cognitive Resilience via Train-the-Trainer Delivery of Mindfulness Training in Applied High-Demand Settings
Authors: Jha Amishi P. , Zanesco Anthony P. , Denkova Ekaterina , Morrison Alexandra B. , Ramos Nicolas , Chichester Keith , Gaddy John W. , Rogers Scott L.
Published: December 2019

Objectives

Mindfulness training (MT) guidelines recommend that trainers have familiarity and knowledge of the training group as well as extensive MT expertise. Herein, a “train-the-trainer” (TTT) dissemination model was investigated for military service members whose access to MT is threatened by a scarcity of qualified trainers.

Methods

US Army Master Resilience Trainer-Performance Experts (PEs), who had extensive familiarity with soldiers but no prior MT experience, participated in an MT practicum, and then delivered a 4-week MT program (Mindfulness-Based Attention Training, MBAT) contextualized for military personnel. Soldiers (n = 180) undergoing intensive military field training over the study interval were recruited as participants. MBAT was delivered to soldiers by PEs (n = 89) or by a trainer with extensive MT experience (Mindfulness Expert; ME,n = 45) but no military familiarity. The remaining participants served as no-training controls (NTC,n = 46). Soldiers’ performance on sustained attention and working memory (WM) tasks was assessed before (week 0, T1) and after MBAT delivery (week 5, T2), and again 4 weeks later (week 10, T3).

Results

For all participants, sustained attention and WM performance declined over the high-demand field training interval (p < 0.001). Yet, the PE group declined significantly less in attentional (p = 0.040) and WM (p < 0.001) performance relative to the other groups.

Conclusions

These results suggest that TTT delivery of short-form MT by context-familiar trainers may be an expeditious route by which to increase access to MT in the service of promoting cognitive resilience in high-demand groups.
Contamination transport model by coupling analytic element and point collocation methods
Authors: Mohammadi A. , Ghaeini-Hessaroeyeh M. , Fadaei-Kermani E.
Published: December 2019

The prediction of contaminant transport in porous media is an important problem in order to prevent the pollution propagation in groundwater. The present model is developed by coupling two mesh-free approaches in order to overcome the restrictions of mesh-dependent methods. In this model, the ground water flow model is developed by analytic-element method and the contaminant transport model is developed by point collocation method in an unconfined aquifer. The model was developed and implemented by Python object-oriented programming language. A particle swarm optimization algorithm has been also utilized to calibrate the model. The model was applied for contamination transport in Astaneh-Kuchesfahan groundwater in north of Iran. Comparison of the model results with the observed data represents a reasonable agreement and capability of the present model in contaminant transport modeling. Moreover, the calculated value for coefficient of determination (R2 = 0.89) indicates that the calibrated parameters are acceptable.
Facile methodology of nanoemulsion preparation using oily polymer for the delivery of poorly soluble drugs
Authors: Wik Johanna , Bansal Kuldeep K. , Assmuth Tatu , Rosling Ari , Rosenholm Jessica M.
Published: December 2019

Aqueous solubility of an active pharmaceutical ingredient (API) is a determining factor that has a direct impact on formulation strategies and overall bioavailability. Fabrication of nanoemulsions of poorly soluble drugs is one of the widely utilized approaches to overcome this problem. However, thermodynamic instability and tedious manufacturing processes of nanoemulsions limit their clinical translation. Therefore, this study was focused on circumventing the abovementioned hurdles by utilizing the polymer as an oil phase, instead of conventional oils. The nanoemulsion was prepared via a facile low-energy nanoprecipitation method using renewable poly(δ-decalactone) (PDL), as an oil phase and Pluronic F-68 as surfactant. The prepared nanoemulsions were characterized in terms of size, drug encapsulation efficiency, stability, and toxicity. Five different hydrophobic drugs were utilized to evaluate the drug delivery capability of the PDL nanoemulsion. The prepared nanoemulsions with sizes less than 200 nm were capable to enhance the aqueous solubility of the drugs by 3 to 10 times compared with the well-established Pluronic F-68 micelles. No phase separation or significant changes in size and drug content was observed with PDL nanoemulsions after high-speed centrifugation and 3 months of storage at two different temperatures (20 °C and 50 °C). PDL nanoemulsions were found to be non-heamolytic up to concentrations of 1 mg/mL, and the cell cytotoxicity studies on MDA-MB-231 and MEF cells suggest a concentration and time-dependent toxicity, where the PDL polymer itself induced no cytotoxicity. The results from this study clearly indicate that the PDL polymer has a tremendous potential to be utilized as an oil phase to prepare stable nanoemulsions via a facile methodology, ultimately favouring clinical translations.
Removal of sulfur contaminants from biogas to enable direct catalytic methanation
Authors: Dannesboe Christian , Hansen John Bøgild , Johannsen Ib
Published: December 2019

In the near future, renewable energy sources will replace fossil energy. To allow full carbon utilization of renewable biomass, we have demonstrated a possible integration between a biogas reactor, an electrolysis unit, and a catalytic methanation reactor. Stringent removal of all sulfur contaminants in raw biogas is required to enable this integration. We demonstrate how existing bulk sulfur removal solutions, like a biotrickling filter loaded with Acidithiobacillus thiooxidans and impregnated activated carbon, are unable to meet this requirement. Only the main sulfur contaminant hydrogen sulfide (H2S) can effectively be removed. Contaminants carbon disulfide (CS2), dimethyl sulfide (DMS), and carbonyl sulfide (COS) will leak through the carbon filter, long before hydrogen sulfide can be detected. Utilization of surplus oxygen from the combined system is proven problem free and allows sulfur removal without introducing contaminants. Provided that a recommended sulfur guard is included, the proposed design is ready for full-scale implementation.
Retrospective Database Analysis of Treatment Patterns Among Patients with Pulmonary Arterial Hypertension
Authors: Studer Sean , Hull Michael , Pruett Janis , Elliott Caitlin , Tsang Yuen , Drake William
Published: December 2019

Introduction

Release of the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines put increased emphasis on using combination therapy, either as upfront or sequential therapy among patients with pulmonary arterial hypertension (PAH). However, with these recommendations and the therapy advances made in the last several years, little is known on the real-world treatment patterns among patients with PAH, particularly before and after publication of the 2015 ESC/ERS guidelines.

Methods

This was a retrospective study of adult commercial and Medicare Advantage with Part D (MAPD) enrollees with at least one claim for a PAH-related medication from January 01, 2012 to March 31, 2017, at least one medical claim with a pulmonary hypertension diagnosis, and continuous health plan enrollment at least 6 months prior to and at least 12 months following the date of the first pharmacy claim for PAH-related therapy (index date). Patients were divided into cohorts based on prescription of monotherapy or combination therapy and index date category (2012–2013, January 2014–July 2015, and August 2015–March 2017).

Results

Out of 1878 patients, 90.8% initiated with monotherapy and 9.2% initiated with combination therapy. The percentage of patients with index combination therapy increased from 5.7% in 2012–2013 to 13.0% in August 2015–March 2017. Patients with index combination therapy had better persistence (11.6 months versus 10.3 months) and adherence (0.95 versus 0.85). Overall, the discontinuation rate was 40% and was higher in monotherapy versus combination therapy patients (42.8% versus 12.2%). Approximately 30.2% of patients had a second regimen, of which 50% were combination regimens. The time to combination therapy initiation decreased from 10.5 months in 2012–2013 to 3.4 months in August 2015–March 2017.

Conclusions

The majority of patients initiated monotherapy treatment for PAH, most often a phosphodiesterase 5 inhibitor (PDE5i). Patients with upfront combination therapy increased following publication of the 2015 ESC/ERS guidelines, indicating that physicians responded to the guideline’s option of prescribing upfront combination therapy.
When Less Is More: On the Use of Historical Yield Data with Application to Rating Area Crop Insurance Contracts
Authors: Liu Yong , Ker Alan P.
Published: December 2019

Crop insurance is the cornerstone program of domestic farm policy in most developed countries. Although most countries’ rating methodology corrects for time-varying movements in the first two moments, it is unclear whether using the entire yield series remains appropriate.  We use distributional tests and an out-of-sample retain-cede rating game to answer whether governments/insurers should historically trim yields in estimating their premium rates. Despite small sample sizes and the need to estimate tail probabilities, the historical data appear to be sufficiently different such that trimming is justified.
Gastroenteric parasite of wild Galliformes in the Italian Alps: implication for conservation management
Authors: Fanelli A. , Menardi G. , Chiodo M. , Giordano O. , Ficetto G. , Bessone M. , Lasagna A. , Carpignano M.G. , Molinar Min A. , Gugiatti A. , Meneguz P.G. , Tizzani P.
Published: December 2019

This study provides insights about the diversity, prevalence and distribution of alpine wild galliformes gastrointestinal parasite community, trying to fill a gap in the scientific information currently available in scientific literature. The analysis included three host species: 77 rock partridge (Alectoris graeca saxatilis), 83 black grouse (Tetrao tetrix tetrix) and 26 rock ptarmigan (Lagopus muta helveticus) shot during the hunting seasons 2008–2015. Parasites isolated wereAscaridia compar, Capillaria caudinflataand cestodes. The rock ptarmigan was free from gastrointestinal parasites, whereas the most prevalent helminth (37%) wasA. comparin both black grouse and rock partridge.C. caudinflataoccurrence was significantly higher in black grouse (prevalence = 10%, mean abundance = 0.6 parasites/sampled animal) than in rock partridge (prevalence = 1.20%, mean abundance = 0.01 parasites/sampled animal). Significant differences were detected among hunting districts.A. comparwas found with a significant higher degree of infestation in the hunting districts in the northern part of the study area whereas cestodes abundance was higher in Lanzo Valley. Quantitative analysis of risk factors was carried out using a generalized linear model (GLM) only on the most common parasite (A. compar). Latitude was the only factors associated with infestation risk (OR = 52.4). This study provides information on the composition and variability of the parasite community in the alpine Galliformes species.
Diagnostik von ICT Literacy: Messen Multiple-Choice-Aufgaben und simulationsbasierte Aufgaben vergleichbare Konstrukte?
Authors: Senkbeil Martin , Ihme Jan Marten
Published: December 2019

Zusammenfassung. ICT Literacy legt eine performanzbasierte Erfassung mit simulierten und interaktiven Testaufgaben nahe. Der vorliegende Beitrag untersucht, ob mit Multiple-Choice (MC)-Aufgaben ein vergleichbares Konstrukt wie mit Simulationsaufgaben erfasst wird. Hierfür wurden die Testergebnisse zweier Instrumente aus aktuellen Large-Scale-Studien gegenübergestellt, die an N = 2 075 Jugendlichen erhoben wurden: der auf MC-Aufgaben basierende ICT Literacy-Test für Klasse 9 des Nationalen Bildungspanels (National Educational Panel Study, NEPS) und der simulationsbasierte Kompetenztest der internationalen Schulleistungsstudie ICILS 2013 (International Computer and Information Literacy Study). Die Analysen unterstützen die Gültigkeit der Konstruktinterpretation des MC-basierten Tests in NEPS. Im Sinne der konvergenten Evidenz korrelieren die MC-Aufgaben substanziell mit den computer- und simulationsbasierten Aufgaben in ICILS 2013 (.68 ≤  r ≤ .90). Weiterhin ergeben sich positive und für beide Tests vergleichbar hohe Korrelationen mit ICT-bezogenen Schülermerkmalen (z. B. Selbstwirksamkeit). Weiterführende Analysen zum Zusammenhang mit allgemeinen kognitiven Fähigkeiten zeigen zudem, dass ICT Literacy und kognitive Grundfähigkeiten distinkte Faktoren repräsentieren.
Sources, Transport, and Transformation of Dissolved Organic Matter in a Large River System: Illustrated by the Changjiang River, China
Authors: Wang Xiaona , Wu Ying , Bao Hongyan , Gan Shuchai , Zhang Jing
Published: December 2019

The sources, transport, and transformation of terrestrial dissolved organic matter (DOM) in large river systems are of great interest due to their importance in the regional and global carbon cycles. However, knowledge of these factors is limited, especially for different DOM compositions coupling with hydrodynamics at the basin scale. To investigate the dynamics of different DOM compositions in a large river system, we characterized the dissolved organic carbon (DOC), chromophoric DOM (CDOM), and dissolved lignin at both moderate (September–October 2009) and high (August 2012) discharges in the Changjiang River basin. We found that extensive soil erosion resulted in the increased DOC concentration in the middle to lower reaches in 2012. In 2009, the transformation of DOM was dominated by flocculation and photo degradation due to the low flow velocity and depressed particle suspension. In 2012, the degradation of CDOM and dissolved lignin was coupled and dominated by microbial degradation and photo degradation. In 2012, CDOM (absorbance and fluorescence) and dissolved lignin concentrations were positively correlated, demonstrating the potential of using CDOM to quantitatively estimate dissolved lignin. Mass balance estimations of the DOM fluxes further confirmed that 17.0% (6.1%) of DOC, 24.2% (32.3%) of dissolved lignin, and 14.5% (0.8%) of CDOM were degraded at high (moderate) discharge. This study reveals contrasting transformation processes of DOM compositions with different sources and reactivities along the Changjiang River under different hydrological conditions, and it provides new insights into the linkage between the chemical and optical properties of DOM in large river systems.
Global Carbon Sequestration Is Highly Sensitive to Model‐Based Formulations of Nitrogen Fixation
Authors: Peng Jing , Wang Ying‐Ping , Houlton Benjamin Z. , Dan Li , Pak Bernard , Tang Xiba
Published: December 2019

Biological nitrogen fixation (BNF) is the largest nitrogen (N) input pathway in natural terrestrial ecosystems at present, fueling the drawdown of atmospheric CO2 in vegetation and soil on decadal to century time scales. Here, we use a global land‐surface model (CABLE) with three different approaches for estimating the responses of BNF to CO2, climate, and N deposition through Year 2100, particularly the linear versus nonlinear dependence of BNF on C investment and the temperature dependence of BNF. From 1900 to 2100, the cumulative rise in BNF varied from 1.6 to 3.0 Pg N, translating to an increase in terrestrial carbon (C) storage between 33 and 68 Pg C. This range reflects the different approaches used to model BNF (i.e., C‐limited vs. resource optimization approaches), indicating major uncertainties in C‐climate‐N interactions in Earth system model forecasts. The differences among different approaches were most significant at high or low latitudes. At high latitudes, accounting for temperature dependence of BNF resulted in 53% and 79% additional BNF increases and 14% and 21% additional land C accumulation in evergreen needle leaf forest and tundra, respectively, from 1901 to 2100. At low latitudes, resource optimization approaches using linear dependence of BNF on C investment estimated more rapid increase in BNF and therefore greater C accumulation than the C‐limited approach using nonlinear dependence. The difference in the estimated additional C accumulation due to varying BNF was as much as 24% for deciduous broadleaf forest. Our findings highlight the need for more field measurements of BNF, particularly at high latitudes to better constrain the projected BNF under future conditions, and also the fundamental importance of BNF in determining the pattern, response, and magnitude of terrestrial C accumulation through 2100.
Snowpack‐ and Soil Water Content‐Related Hydrologic Indices and Their Association With Radial Growth of Conifers in the Sierra Nevada, California
Authors: Shamir Eylon , Meko Dave , Touchan Ramzi , Lepley Kai S. , Campbell Rochelle , Kaliff Rebecca N. , Georgakakos Konstantine P.
Published: December 2019

The utility of a high‐resolution snow‐hydrologic model to derive climatological indices that describe the variability in radial growth of four conifer species in two Sierra Nevada sites is presented herein. Nine annual indices associated with radial growth were developed to represent the winter dormancy, characteristics of the snowpack and soil water content, and the duration of the seasons. Site chronologies of earlywood (EW) and latewood (LW) ring widths were developed for mountain hemlock (Tsuga mertensiana), red fir (Abies magnifica), white fir (Abies concolor), and ponderosa pine (Pinus ponderosa) at two sites on leeward and windward slopes. The signal strength for annual climatological indices derived from model output was tested with correlation and regression, in combination with principal components analysis. Results show significant snow‐related climate signal in the tree‐ring data, with substantial differences between species and between EW and LW. Dependence on previous year's snow and soil moisture (a lagged response) were found for EW of hemlock and red fir. The primary EW‐LW signal contrast for those species is a shift toward dependence on current‐year moisture conditions for LW, especially for red fir. Lagged climate response was less evident for white fir and ponderosa pine. Regression of tree‐ring series on principal components of climatological indices showed a stronger average signal in EW (R2 = 0.48) than in LW (R2 = 0.35). Differences in tree‐ring hydrologic signal at the two sites are attributed to microclimate and contrasts in snow regime. Results attest to the hydrologic model usefulness for investigating temporal relationships between tree rings and local climate.
So What Is in an Earth System Model?
Authors: Jones C. D.
Published: December 2019

Use of numerical models is at the heart of climate science. Models underpin process understanding; our ability to explain observed past changes and subsequently making predictions/projections of the coming decades to help guide climate policy. Roland Séférian and colleagues (2019, https://doi.org/10.1029/2019MS001791) have written an excellent paper documenting CNRM‐CERFACS's latest complex model, “CNRM‐ESM2‐1,” which will be used for CMIP6 simulations and will produce data to be analyzed by the research community for many years to come. Here I explain the importance of Seferian et al. and why it showcases a new degree of comprehensiveness needed for model documentation activity.
Evidence From High‐Resolution Topography for Multiple Earthquakes on High Slip‐to‐Length Fault Scarps: The Bilila‐Mtakataka Fault, Malawi
Authors: Hodge M. , Biggs J. , Fagereng Å. , Mdala H. , Wedmore L. N. J. , Williams J. N.
Published: December 2019

Geomorphological features such as fault scarps and stream knickpoints are indicators of recent fault activity. Determining whether these features formed during a single earthquake or over multiple earthquakes cycles has important implications for the interpretation of the size and frequency of past events. Here, we focus on the Bilila‐Mtakataka fault, Malawi, where the 20 m high fault scarps exceed the height expected from a single earthquake rupture. We use a high‐resolution digital elevation model (1 m) to identify complexity in the fault scarp and knickpoints in river profiles. Of 39 selected scarp profiles, 20 showed evidence of either multiscarps or composite scarps, and of the seven selected river and stream profiles, five showed evidence for multiple knickpoints. A near‐uniform distribution of vertical offsets on the subscarps suggests they were formed by separate earthquakes. These independent methods agree that at least two earthquakes have occurred with an average vertical offset per event of 10 and 12 m. This contrasts earlier studies which proposed that this scarp formed during a single event and demonstrates the importance of high‐resolution topographic data for understanding tectonic geomorphology. We use a one‐dimensional diffusion model of scarp degradation to demonstrate how fault splays form multiscarps and estimate the diffusion ageof the Bilila‐Mtakataka fault scarp to be m, corresponding to years since formation. We calculate that a continuous rupture would equate to a Mearthquake, greater than the largest seismic event previously recorded in East Africa.
Integrated Drought Index (IDI) for Drought Monitoring and Assessment in India
Authors: Shah Deep , Mishra Vimal
Published: December 2019

Drought monitoring and declaration in India are challenging due to the requirement of multiple drought indices representing meteorological, hydrological, and agricultural droughts that are often not available in near real‐time. In addition, the current drought monitoring efforts do not consider groundwater storage variability. To overcome this, we develop an Integrated Drought Index (IDI) that combines the response of meteorological, hydrological, and agricultural droughts and accounts for groundwater storage. We use the Gaussian copula to integrate the 12‐month Standardized Precipitation Index (SPI), 4‐month Standardized Runoff Index (SRI), 1‐month Standardized Soil moisture Index (SSI), and 1‐month Standardized Groundwater Index (SGI) to develop IDI. Hydrologic variables (total runoff, soil moisture, and groundwater) required in IDI were simulated using the Variable Infiltration Capacity (VIC) with SIMple Groundwater Model (VIC‐SIMGM). We evaluated IDI against the Drought Severity Index (DSI), terrestrial and groundwater storage anomalies from the Gravity Recovery and Climate Experiment (GRACE) satellites, groundwater well, and streamflow anomalies. Moreover, we identify the three major droughts with the highest severity (based on IDI) that occurred in 1965, 1987, and 2002 in the Sabarmati river basin. The three most severe droughts occurred in 1966, 1979, and 2010 in the Brahmani basin. Notwithstanding the large intermodel uncertainty, which arises primarily from precipitation projections, the drought frequency based on IDI is projected to decline in Sabarmati while it increases in Brahmani basin under the warming climate. Our results show that IDI can be effectively used for drought monitoring and assessment under retrospective and future climate in India.
Optical frequency synthesizer with an integrated erbium tunable laser
Authors: Xin Ming , Li Nanxi , Singh Neetesh , Ruocco Alfonso , Su Zhan , Magden Emir Salih , Notaros Jelena , Vermeulen Diedrik , Ippen Erich P. , Watts Michael R. , Kärtner Franz X.
Published: December 2019

Optical frequency synthesizers have widespread applications in optical spectroscopy, frequency metrology, and many other fields. However, their applicability is currently limited by size, cost, and power consumption. Silicon photonics technology, which is compatible with complementary-metal-oxide-semiconductor fabrication processes, provides a low-cost, compact size, lightweight, and low-power-consumption solution. In this work, we demonstrate an optical frequency synthesizer using a fully integrated silicon-based tunable laser. The synthesizer can be self-calibrated by tuning the repetition rate of the internal mode-locked laser. A 20 nm tuning range from 1544 to 1564 nm is achieved with ~10−13 frequency instability at 10 s averaging time. Its flexibility and fast reconfigurability are also demonstrated by fine tuning the synthesizer and generating arbitrary specified patterns over time-frequency coordinates. This work promotes the frequency stability of silicon-based integrated tunable lasers and paves the way toward chip-scale low-cost optical frequency synthesizers.
Therapeutically targeting head and neck squamous cell carcinoma through synergistic inhibition of LSD1 and JMJD3 by TCP and GSK-J1
Authors: Zhang Wei , Cheng Jie , Diao Pengfei , Wang Dongmiao , Zhang Wei , Jiang Hongbing , Wang Yanling
Published: December 2019

Background

The histone demethylase LSD1 is a key mediator driving tumorigenesis, which holds potential as a promising therapeutic target. However, treatment with LSD1 inhibitors alone failed to result in complete cancer regression.

Methods

The synergistic effects of TCP (a LSD1 inhibitor) and GSK-J1 (a JMJD3 inhibitor) against HNSCC were determined in vitro and in preclinical animal models. Genes modulated by chemical agents or siRNAs in HNSCC cells were identified by RNA-seq and further functionally interrogated by bioinformatics approach. Integrative siRNA-mediated gene knockdown, rescue experiment and ChIP-qPCR assays were utilised to characterise the mediators underlying the therapeutic effects conferred by TCP and GSK-J1.

Results

Treatment with TCP and GSK-J1 impaired cell proliferation, induced apoptosis and senescence in vitro, which were largely recapitulated by simultaneous LSD1 and JMJD3 knockdown. Combinational treatment inhibited tumour growth and progression in vivo. Differentially expressed genes modulated by TCP and GSK-J1 were significantly enriched in cell proliferation, apoptosis and cancer-related pathways. SPP1 was identified as the mediator of synergy underlying the pro-apoptosis effects conferred by TCP and GSK-J1. Co-upregulation of LSD1 and JMJD3 associated with worse prognosis in patients with HNSCC.

Conclusions

Our findings revealed a novel therapeutic strategy of simultaneous LSD1 and JMJD3 inhibition against HNSCC.
Plasmacytoid dendritic cell deficiency in neonates enhances allergic airway inflammation via reduced production of IFN-α
Authors: Wu Min , Gao Liuchuang , He Miao , Liu Hangyu , Jiang Han , Shi Ketai , Shang Runshi , Liu Bing , Gao Shan , Chen Hebin , Gong Feili , Gelfand Erwin W. , Huang Yafei , Han Junyan
Published: December 2019

Allergic asthma, a chronic inflammatory airway disease associated with type 2 cytokines, often originates in early life. Immune responses at an early age exhibit a Th2 cell bias, but the precise mechanisms remain elusive. Plasmacytoid dendritic cells (pDCs), which play a regulatory role in allergic asthma, were shown to be deficient in neonatal mice. We report here that this pDC deficiency renders neonatal mice more susceptible to severe allergic airway inflammation than adult mice in an OVA-induced experimental asthma model. Adoptive transfer of pDCs or administration of IFN-α to neonatal mice prevented the development of allergic inflammation in wild type but not in IFNAR1−/− mice. Similarly, adult mice developed more severe allergic inflammation when pDCs were depleted. The protective effects of pDCs were mediated by the pDC-/IFN-α-mediated negative regulation of the secretion of epithelial cell-derived CCL20, GM-CSF, and IL-33, which in turn impaired the recruitment of cDC2 and ILC2 cells to the airway. In asthmatic patients, the percentage of pDCs and the level of IFN-α were lower in children than in adults. These results indicate that impairment of pDC-epithelial cell crosstalk in neonates is a susceptibility factor for the development of allergen-induced allergic airway inflammation.
The valley Nernst effect in WSe2
Authors: Dau Minh Tuan , Vergnaud Céline , Marty Alain , Beigné Cyrille , Gambarelli Serge , Maurel Vincent , Journot Timotée , Hyot Bérangère , Guillet Thomas , Grévin Benjamin , Okuno Hanako , Jamet Matthieu
Published: December 2019

The Hall effect can be extended by inducing a temperature gradient in lieu of electric field that is known as the Nernst (-Ettingshausen) effect. The recently discovered spin Nernst effect in heavy metals continues to enrich the picture of Nernst effect-related phenomena. However, the collection would not be complete without mentioning the valley degree of freedom benchmarked by the valley Hall effect. Here we show the experimental evidence of its missing counterpart, the valley Nernst effect. Using millimeter-sized WSe$${}_{2}$$2 mono-multi-layers and the ferromagnetic resonance-spin pumping technique, we are able to apply a temperature gradient by off-centering the sample in the radio frequency cavity and address a single valley through spin-valley coupling. The combination of a temperature gradient and the valley polarization leads to the valley Nernst effect in WSe$${}_{2}$$2 that we detect electrically at room temperature. The valley Nernst coefficient is in good agreement with the predicted value.
Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer
Authors: O’Connell James , Porter John , Kroeplien Boris , Norman Tim , Rapecki Stephen , Davis Rachel , McMillan David , Arakaki Tracy , Burgin Alex , Fox III David , Ceska Tom , Lecomte Fabien , Maloney Alison , Vugler Alex , Carrington Bruce , Cossins Benjamin P , Bourne Tim , Lawson Alastair
Published: December 2019

Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein–protein interactions.
Multi-functional genome-wide CRISPR system for high throughput genotype–phenotype mapping
Authors: Lian Jiazhang , Schultz Carl , Cao Mingfeng , HamediRad Mohammad , Zhao Huimin
Published: December 2019

Genome-scale engineering is an indispensable tool to understand genome functions due to our limited knowledge of cellular networks. Unfortunately, most existing methods for genome-wide genotype–phenotype mapping are limited to a single mode of genomic alteration, i.e. overexpression, repression, or deletion. Here we report a multi-functional genome-wide CRISPR (MAGIC) system to precisely control the expression level of defined genes to desired levels throughout the whole genome. By combining the tri-functional CRISPR system and array-synthesized oligo pools, MAGIC is used to create, to the best of our knowledge, one of the most comprehensive and diversified genomic libraries in yeast ever reported. The power of MAGIC is demonstrated by the identification of previously uncharacterized genetic determinants of complex phenotypes, particularly those having synergistic interactions when perturbed to different expression levels. MAGIC represents a powerful synthetic biology tool to investigate fundamental biological questions as well as engineer complex phenotypes for biotechnological applications.
Stress sensitization among severely neglected children and protection by social enrichment
Authors: Wade Mark , Zeanah Charles H. , Fox Nathan A. , Tibu Florin , Ciolan Laura E. , Nelson Charles A.
Published: December 2019

Childhood adversity may sensitize certain individuals to later stress which triggers or amplifies psychopathology. The current study uses data from a longitudinal randomized controlled trial to examine whether severe early neglect among children reared in institutions increases vulnerability to the effects of later stressful life events on externalizing problems in adolescence, and whether social enrichment in the form of high-quality foster care buffers this risk. Children abandoned to Romanian institutions were randomly assigned to a foster care intervention or care-as-usual during early childhood. A sample of never-institutionalized children served as a comparison group. Here we report that, among those with prolonged institutional rearing, more stressful life events in preadolescence predicted higher externalizing problems in adolescence. This effect was not observed for never-institutionalized children or those in foster care, thus providing experimental evidence that positive caregiving experiences protect against the stress-sensitizing effects of childhood neglect on externalizing problems in adolescence.
Human muscle-derived CLEC14A-positive cells regenerate muscle independent of PAX7
Authors: Marg Andreas , Escobar Helena , Karaiskos Nikos , Grunwald Stefanie A. , Metzler Eric , Kieshauer Janine , Sauer Sascha , Pasemann Diana , Malfatti Edoardo , Mompoint Dominique , Quijano-Roy Susanna , Boltengagen Anastasiya , Schneider Joanna , Schülke Markus , Kunz Séverine , Carlier Robert , Birchmeier Carmen , Amthor Helge , Spuler Andreas , Kocks Christine , Rajewsky Nikolaus , Spuler Simone
Published: December 2019

Skeletal muscle stem cells, called satellite cells and defined by the transcription factor PAX7, are responsible for postnatal muscle growth, homeostasis and regeneration. Attempts to utilize the regenerative potential of muscle stem cells for therapeutic purposes so far failed. We previously established the existence of human PAX7-positive cell colonies with high regenerative potential. We now identified PAX7-negative human muscle-derived cell colonies also positive for the myogenic markers desmin and MYF5. These include cells from a patient with a homozygous PAX7 c.86-1G > A mutation (PAX7null). Single cell and bulk transcriptome analysis show high intra- and inter-donor heterogeneity and reveal the endothelial cell marker CLEC14A to be highly expressed in PAX7null cells. All PAX7-negative cell populations, including PAX7null, form myofibers after transplantation into mice, and regenerate muscle after reinjury. Transplanted PAX7neg cells repopulate the satellite cell niche where they re-express PAX7, or, strikingly, CLEC14A. In conclusion, transplanted human cells do not depend on PAX7 for muscle regeneration.
Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations
Authors: Inoue Satoshi , Hirota Yasushi , Ueno Toshihide , Fukui Yamato , Yoshida Emiko , Hayashi Takuo , Kojima Shinya , Takeyama Reina , Hashimoto Taiki , Kiyono Tohru , Ikemura Masako , Taguchi Ayumi , Tanaka Tomoki , Tanaka Yosuke , Sakata Seiji , Takeuchi Kengo , Muraoka Ayako , Osuka Satoko , Saito Tsuyoshi , Oda Katsutoshi , Osuga Yutaka , Terao Yasuhisa , Kawazu Masahito , Mano Hiroyuki
Published: December 2019

Uterine adenomyosis is a benign disorder that often co-occurs with endometriosis and/or leiomyoma, and impairs quality of life. The genomic features of adenomyosis are unknown. Here we apply next-generation sequencing to adenomyosis (70 individuals and 192 multi-regional samples), as well as co-occurring leiomyoma and endometriosis, and find recurring KRAS mutations in 26/70 (37.1%) of adenomyosis cases. Multi-regional sequencing reveals oligoclonality in adenomyosis, with some mutations also detected in normal endometrium and/or co-occurring endometriosis. KRAS mutations are more frequent in cases of adenomyosis with co-occurring endometriosis, low progesterone receptor (PR) expression, or progestin (dienogest; DNG) pretreatment. DNG’s anti-proliferative effect is diminished via epigenetic silencing of PR in immortalized cells with mutant KRAS. Our genomic analyses suggest that adenomyotic lesions frequently contain KRAS mutations that may reduce DNG efficacy, and that adenomyosis and endometriosis may share molecular etiology, explaining their co-occurrence. These findings could lead to genetically guided therapy and/or relapse risk assessment after uterine-sparing surgery.
Requirement for p62 acetylation in the aggregation of ubiquitylated proteins under nutrient stress
Authors: You Zhiyuan , Jiang Wen-Xue , Qin Ling-Yun , Gong Zhou , Wan Wei , Li Jin , Wang Yusha , Zhang Hongtao , Peng Chao , Zhou Tianhua , Tang Chun , Liu Wei
Published: December 2019

Autophagy receptor p62/SQSTM1 promotes the assembly and removal of ubiquitylated proteins by forming p62 bodies and mediating their encapsulation in autophagosomes. Here we show that under nutrient-deficient conditions, cellular p62 specifically undergoes acetylation, which is required for the formation and subsequent autophagic clearance of p62 bodies. We identify K420 and K435 in the UBA domain as the main acetylation sites, and TIP60 and HDAC6 as the acetyltransferase and deacetylase. Mechanically, acetylation at both K420 and K435 sites enhances p62 binding to ubiquitin by disrupting UBA dimerization, while K435 acetylation also directly increases the UBA-ubiquitin affinity. Furthermore, we show that acetylation of p62 facilitates polyubiquitin chain-induced p62 phase separation. Our results suggest an essential role of p62 acetylation in the selective degradation of ubiquitylated proteins in cells under nutrient stress, by specifically regulating the assembly of p62 bodies.
Machine learning for the detection of early immunological markers as predictors of multi-organ dysfunction
Authors: Bravo-Merodio Laura , Acharjee Animesh , Hazeldine Jon , Bentley Conor , Foster Mark , Gkoutos Georgios V. , Lord Janet M.
Published: December 2019

The immune response to major trauma has been analysed mainly within post-hospital admission settings where the inflammatory response is already underway and the early drivers of clinical outcome cannot be readily determined. Thus, there is a need to better understand the immediate immune response to injury and how this might influence important patient outcomes such as multi-organ dysfunction syndrome (MODS). In this study, we have assessed the immune response to trauma in 61 patients at three different post-injury time points (ultra-early (<=1 h), 4–12 h, 48–72 h) and analysed relationships with the development of MODS. We developed a pipeline using Absolute Shrinkage and Selection Operator and Elastic Net feature selection methods that were able to identify 3 physiological features (decrease in neutrophil CD62L and CD63 expression and monocyte CD63 expression and frequency) as possible biomarkers for MODS development. After univariate and multivariate analysis for each feature alongside a stability analysis, the addition of these 3 markers to standard clinical trauma injury severity scores yields a Generalized Liner Model (GLM) with an average Area Under the Curve value of 0.92 ± 0.06. This performance provides an 8% improvement over the Probability of Survival (PS14) outcome measure and a 13% improvement over the New Injury Severity Score (NISS) for identifying patients at risk of MODS.
Repeated Porphyromonas gingivalis W83 exposure leads to release pro-inflammatory cytokynes and angiotensin II in coronary artery endothelial cells
Authors: Viafara-García Sergio M. , Morantes Sandra Johanna , Chacon-Quintero Yersson , Castillo Diana Marcela , Lafaurie Gloria Inés , Buitrago Diana Marcela
Published: December 2019

The role of Porphyromonas gingivalis (P. gingivalis) or its virulence factors, including lipopolysaccharide (LPS) not only has been related with periodontitis but also with endothelial dysfunction, a key mechanism involved in the genesis of atherosclerosis and hypertension that involving systemic inflammatory markers as angiotensin II (Ang II) and cytokines. This study compares the effect of repeated and unique exposures of P. gingivalis W83 LPS and live bacteria on the production and expression of inflammatory mediators and vasoconstrictor molecules with Ang II. Human coronary artery endothelial cells (HCAEC) were stimulated with purified LPS of P. gingivalis (1.0, 3.5 or 7.0 μg/mL) or serial dilutions of live bacteria (MOI 1: 100 - 1:0,1) at a single or repeated exposure for a time of 24 h. mRNA expression levels of AGTR1, AGTR2, IL-8, IL-1β and MCP-1 were determined by RT-qPCR, and IL-6, MCP-1, IL-8, IL-1β and GM-CSF levels were measured by flow cytometry, ELISA determined Ang II levels. Live bacteria in a single dose increased mRNA levels of AGTR1, and repeated doses increased mRNA levels of IL-8 and IL-1β (p < 0.05). Repeated exposure of live-P. gingivalis induced significant production IL-6, MCP-1 and GM-CSF (p < 0.05). Moreover, these MCP-1, IL-6 and GM-CSF levels were greater than in cells treated with single exposure (p < 0.05), The expression of AGTR1 and production of Ang II induced by live-P. gingivalis W83 showed a vasomotor effect of whole bacteria in HCAEC more than LPS. In conclusion, the findings of this study suggest that repeated exposure of P. gingivalis in HCAEC induces the activation of proinflammatory and vasoconstrictor molecules that lead to endothelial dysfunction being a key mechanism of the onset and progression of arterial hypertension and atherosclerosis.
CETSA-based target engagement of taxanes as biomarkers for efficacy and resistance
Authors: Langebäck Anette , Bacanu Smaranda , Laursen Henriette , Mout Lisanne , Seki Takahiro , Erkens-Schulze Sigrun , Ramos Anderson Daniel , Berggren Anna , Cao Yihai , Hartman Johan , van Weerden Wytske , Bergh Jonas , Nordlund Pär , Lööf Sara
Published: December 2019

The use of taxanes has for decades been crucial for treatment of several cancers. A major limitation of these therapies is inherent or acquired drug resistance. A key to improved outcome of taxane-based therapies is to develop tools to predict and monitor drug efficacy and resistance in the clinical setting allowing for treatment and dose stratification for individual patients. To assess treatment efficacy up to the level of drug target engagement, we have established several formats of tubulin-specific Cellular Thermal Shift Assays (CETSAs). This technique was evaluated in breast and prostate cancer models and in a cohort of breast cancer patients. Here we show that taxanes induce significant CETSA shifts in cell lines as well as in animal models including patient-derived xenograft (PDX) models. Furthermore, isothermal dose response CETSA measurements allowed for drugs to be rapidly ranked according to their reported potency. Using multidrug resistant cancer cell lines and taxane-resistant PDX models we demonstrate that CETSA can identify taxane resistance up to the level of target engagement. An imaging-based CETSA format was also established, which in principle allows for taxane target engagement to be accessed in specific cell types in complex cell mixtures. Using a highly sensitive implementation of CETSA, we measured target engagement in fine needle aspirates from breast cancer patients, revealing a range of different sensitivities. Together, our data support that CETSA is a robust tool for assessing taxane target engagement in preclinical models and clinical material and therefore should be evaluated as a prognostic tool during taxane-based therapies.