bluuebunny/crossref_metadata_2025 huggingface dataset:
Correction to: Risk of dementia among postmenopausal breast cancer survivors treated with aromatase inhibitors versus tamoxifen: a cohort study using primary care data from the UK
Authors: Bromley Susan E. , Matthews Anthony , Smeeth Liam , Stanway Susannah , Bhaskaran Krishnan
Published: October 2019

The article Risk of dementia among postmenopausal breast cancer survivors treated with aromatase inhibitors versus tamoxifen: a cohort study using primary care data from the UK, written by Susan E. Bromley, was originally published electronically on the publisher’s internet portal.
Pränataldiagnostik – klassische Analytik mittels Chorionzottenbiopsie und Amniocentese
Authors: Duba Hans-Christoph , Arzt Wolfgang
Published: October 2019

In diesem Artikel werden die Methoden der klassischen invasiven Pränataldiagnostik und die häufigsten, mittels konventioneller Zytogenetik diagnostizierten Chromosomenaberrationen beschrieben, um ihren, trotz der in anderen Beiträgen abgehandelten neuen Methoden, nach wie vor wichtigen Stellenwert herauszuheben.
Compatibility evaluation of modified seawater for EOR in carbonate reservoirs through the introduction of polyphosphate compound
Authors: Ghosh Bisweswar , Sun Liying , Thomas Nithin Chacko
Published: October 2019

Waterflood-assisted oil recovery with sulfate-spiked seawater would cause incompatibility scaling in carbonate reservoirs and reduce economic benefits. This research investigated the benefits of polyphosphate compounds in reducing scaling potential as well as its effect on oil recovery when mixed in high sulfate flood water. Severity of scaling potential of sulfate-spiked water in a carbonate reservoir environment was measured, followed by systematic screening of a polyphosphate compound, which successfully inhibited the sulfate scale precipitation at concentration as low as 100 ppm. The new formulation (seawater with four times sulfate and phosphate, SW4SP) was evaluated and compared with benchmark formulation (modified seawater with four times sulfate, SW4S). Contact angle, ζ-potential and drainage studies show that SW4SP changed the rock wettability from oil wet to water wet to a larger degree compared to SW4S. Improved recovery efficiency of SW4SP was confirmed through a set of core flooding studies in the tertiary and quaternary flood modes. Whereas SW4S recovered 7.7% of original oil in place (OOIP), SW4SP recovered about 8% of OOIP in the tertiary mode under approximately identical flow conditions. Flooding with SW4SP in the quaternary mode following a tertiary flood with SW4S on the same core resulted in 1.7% additional oil recovery, showing improved efficiency of the new flood water formulation.
Retrospective Analysis of Cancer-Associated Myositis Patients over the Past 3 Decades in a Hungarian Myositis Cohort
Authors: András Csilla , Bodoki Levente , Nagy-Vincze Melinda , Griger Zoltán , Csiki Emese , Dankó Katalin
Published: October 2019

Association between cancer and myositis has been extensively reported and malignancy is a potentially life-threating complication in myositis. In this retrospective study authors give an overview of Hungarian cancer-associated myositis (CAM) patients treated at a single centre managing 450 myositis patients. All patients were diagnosed according to Bohan and Peter. Statistical analysis of disease onset, age, sex, muscle, skin and extramuscular symptoms, muscle enzymes, presence of antibodies, treatment and prognosis was performed. 43 patients could be considered as having CAM. 83.72% had cancer within one year of diagnosis of myositis. Most common localizations were ductal carcinoma of breast and adenocarcinoma of lung. Significant differences were observed between CAM and the non-CAM control patients: DM:PM ratio was 2.31:1 vs. 0.87:1, respectively (p = 0.029), age at diagnosis was 56.60 ± 12.79 vs. 38.88 ± 10.88 years, respectively (p < 0.001). Tumour-treatment was the following: surgical removal in 55.81%, chemotherapy in 51.1%, radiotherapy in 39.53%, hormone treatment in 18.6%, combination therapy in 51.16% of patients. Muscle enzyme levels of patients undergoing surgery were significantly reduced after intervention. 36 patients died (83.72%); 25 DM (83.33%) and 11 PM patients (84.62%); 5 years survival was 15.4% for PM and 27.5% for DM. This study demonstrates that DM, distal muscle weakness, asymmetric Raynaud’s phenomenon, older age, ANA-negativity are risk factors for developing malignancy and polymyositis patients have less chance of long-lasting survival. It is very important to think about cancer and follow every single myositis patient in the clinical routine because survival rate of CAM is very poor.
Corrosion Behaviour of Type 316L Stainless Steel in Hot Caustic Aqueous Environments
Authors: Davalos Monteiro Raul , van de Wetering Jan , Krawczyk Benjamin , Engelberg Dirk L.
Published: October 2019

The corrosion behaviour of type 316L stainless steel in aqueous 30–50 wt%. NaOH at temperatures up to 90 °C has been elucidated. Exposure to room temperature environment showed parabolic weight loss behaviour, with corrosion rates of up to 0.4 mm/year. Higher NaOH concentrations and exposure temperatures resulted in a reduced stability of the electrochemical passivity domain, associated with higher corrosion rates. Exposure to de-aerated 50 wt%. NaOH presented corrosion rates of up to 0.5 mm/year at open circuit potential, with maximum corrosion rates under polarisation of up to ≈ 18 mm/year. The formation of a dark iron-oxy-hydroxide and nickel-oxide was observed, with exposure to temperatures in excess of 50 °C. The behaviour of type 316L stainless steel in hot caustic environment is compared to types 204, 304, 2205 stainless steel, and nickel alloy 200.

Graphic Abstract
Short-term deflection of RC beams using a discrete rotation approach
Authors: El-Zeadani Mohamed , Rashid Raizal Saifulnaz Muhammad , Amran Mugahed Yahya Hussein , Hejazi Farzad , Jaafar Mohd Saleh
Published: October 2019

Quantifying the deflection of RC beams has been performed traditionally using full-interaction moment–curvature methods without considering the slip that takes place between the reinforcement and the surrounding concrete. This was commonly carried out by deriving empirically based flexural rigidities and using elastic deflection equations to predict the deformation of RC structures. However, as flexural and flexural/shear cracks form in RC beams with increase in applied load, the reinforcement steel begins to slip against the surrounding concrete surface causing the cracks to widen and ultimately increasing the deflection at mid-span. Current design rules cannot cope directly with the deformation induced by the widening of cracks. Because of that, this study focused on predicting the non-time dependent deflection of RC beams at both service and ultimate limit states using a mechanics-based discrete rotation approach. The mechanics-based solution was compared with experimental test results and well-established code methods to which a good agreement between the results was observed. The method presented accounts for the non-linear behavior of the concrete in compression, the partial-interaction behavior of the reinforcement, and the deflection was computed while considering the rotation of discrete cracks. Due to its generic nature, the method presented does not require any calibration with experimental findings on the member level, which makes it appropriate to quantify the deflection or RC structures with different types of concrete and novel reinforcement material.
Porous SiC/melamine-derived carbon foam frameworks with excellent electromagnetic wave absorbing capacity
Authors: Ye Xinli , Chen Zhaofeng , Ai Sufen , Hou Bin , Zhang Junxiong , Liang Xiaohui , Zhou Qianbo , Liu Hezhou , Cui Sheng
Published: October 2019

Porous three-dimensional SiC/melamine-derived carbon foam (3D-SiC/MDCF) composite with an original open pore structure was fabricated by the heat treatment of the commercial melamine foam (MF), carbonization of the stable MF, and chemical vapor deposition of the ultra-thin SiC coating. Scanning electron microscopy (SEM) and X-ray diffraction (XRD) were employed to detect the microstructure and morphology of the as-prepared composites. The results indicated that the 3D-SiC/MDCF composites with the coating structure were prepared successfully. The obtained minimum reflection loss was -29.50 dB when the frequency and absorption thickness were 11.36 GHz and 1.75 mm, respectively. Further, a novel strategy was put forward to state that the best microwave absorption property with a thin thickness of 1.65 mm was gained, where the minimum reflection loss was -24.51 dB and the frequency bandwidth was 3.08 GHz. The excellent electromagnetic wave absorption ability resulted from the specific cladding structure, which could change the raw dielectric property to acquire excellent impedance matching. This present work had a certain extend reference meaning for the potential applications of the lightweight wave absorption materials with target functionalities.
SURREAL: Subgraph Robust Representation Learning
Authors: Al-Sayouri Saba A. , Koutra Danai , Papalexakis Evangelos E. , Lam Sarah S.
Published: October 2019

The success of graph embeddings or nodrepresentation learning in a variety of downstream tasks, such as node classification, link prediction, and recommendation systems, has led to their popularity in recent years. Representation learning algorithms aim to preserve local and global network structure by identifying node neighborhoods. However, many existing network representation learning methods generate embeddings that are still not effective enough, or lead to unstable representations due to random processes (e.g., random walks to generate context) and thus, cannot generalize to multi-graph problems. In this paper, we propose SURREAL, a novel, stable graph embedding algorithmic framework that leverages “spatio-electric” (SE) subgraphs: it learns graph representations using the analogy of graphs with electrical circuits. It preserves both local and global connectivity patterns, and addresses the issue of high-degree nodes that may incidentally connect a pair of nodes in a graph. Further, it exploits the strength of weak ties and meta-data that have been neglected by baselines. The experiments show that SURREAL outperforms state-of-the-art techniques by up to 37% (6% on average) on different multi-label classification problems. Further, in contrast to baseline methods, SURREAL, being deterministic, is stable and thus can generalize to single and multi-graph tasks.
DEGREE OF THE -OPERATOR AND NONCROSSING PARTITIONS
Authors: SUN HAO
Published: October 2019

The $W$-operator, $W([n])$, generalises the cut-and-join operator. We prove that $W([n])$ can be written as the sum of $n!$ terms, each term corresponding uniquely to a permutation in $S_{\!n}$. We also prove that there is a correspondence between the terms of $W([n])$ with maximal degree and noncrossing partitions.
Medical Students Can be Trained to be Life-Saving First Aid Instructors for Laypeople: A Feasibility Study from Gaza, Occupied Palestinian Territory
Authors: Ismail Anas , AlRayyes Maisara , Shatat Mohammed , Al Hafi Rajai , Heszlein-Lossius Hanne , Veronese Guido , Gilbert Mads
Published: October 2019

Introduction:

Bystanders can improve the outcome in emergencies by activating the “chain of survival.” Gaza’s (Palestine) population has little, if any, access to training in Basic Life Support (BLS) and cardiopulmonary resuscitation (CPR). The goal was to recruit local medical students to be life-saving first aid instructors, and have them train 3,000 laypeople in BLS and CPR.

Methods:

One hundred and seventeen medical students from Al Azhar University-Gaza (Gaza City, Palestine) were trained as BLS and CPR instructors. Twelve training hours were delivered in practical BLS and CPR skills, plus four in communication and didactical skills, to enable training of laypeople. Students answered a questionnaire exploring demographics, prior training experience, expectations, and motivation to join the training. Teaching material were developed after the European Resuscitation Council (ERC; Niel, Belgium) guidelines and similar training at The Arctic University of Norway (Tromsø, Norway).

Results:

A total of 117 medical students (52.1% female; 47.9% male), from third through sixth year, completed training, and all were in their early twenties. Ninety-five (81.2%) agreed to answer the questionnaire. Of those, five students lost family members during Israeli military operations. Eighty-two (70.1%) never had hands-on first aid training. Seventy-six (80.0%) hoped the training would improve their community’s response to emergencies. With 58 training sessions completed, 1,312 laypeople (596 males; 716 females) were trained: 5.52 lay trainees per student instructor. The majority (n = 1,012; 77.1%) were school students aged 13–20 years.

Conclusion:

It is feasible to recruit local medical students for practical BLS and CPR trainings targeting laypeople in communities under stress. The training impact on local resilience and patients’ outcomes need further studies.
Understanding the use and impact of allied health services for people with chronic health conditions in Central and Eastern Sydney, Australia: a five-year longitudinal analysis
Authors: Barr Margo Linn , Welberry Heidi , Comino Elizabeth J. , Harris-Roxas Ben F. , Harris Elizabeth , Lloyd Jane , Whitney Sarah , O’Connor Claire , Hall John , Harris Mark Fort
Published: October 2019

Aim:

To describe the characteristics of people in Central and Eastern Sydney (CES), NSW, who had a General Practice Management Plan (GPMP) and claimed for at least one private allied health service item; and to examine if allied health service use results in less hospitalisations over a five-year period.

Background:

The number of people living with chronic health conditions is increasing in Australia. The Chronic Disease Management programme was introduced to the Medicare Benefits Schedule (MBS) to provide a more structured approach to managing patients with chronic conditions and complex care needs. The programme supports general practitioners claiming up to one GPMP and one Team Care Arrangement every year, and the patient additionally claiming for up to five private allied health services visits.

Methods:

A prospective longitudinal study was conducted. The sample consisted of 5771 participants in CES who had a GPMP within a two-year health service utilisation baseline period (2007–2009). The analysis used the 45 and Up Study questionnaire data linked to the MBS, hospitalisation, death and emergency department data for the period 2006–2014.

Findings:

Of the eligible participants, 43% (2460) had at least one allied health service item claim in the subsequent 12 months. Allied health services were reported as physiotherapy, podiatry and other allied health services. The highest rates of allied health service use were among participants aged 85 years and over (49%). After controlling for confounding factors, a significant difference was found between having claimed for five or more physiotherapy services and emergency admissions (HR: 0.83; 95% CI: 0.72–0.95) and potentially preventable hospitalisations (HR: 0.79; 95% CI: 0.64–0.96) in the subsequent five years. Use of allied health service items was well targeted towards those with chronic and complex care needs, and use of physiotherapy services was associated with less avoidable hospitalisations.
Enforcers beyond Borders: Transnational NGOs and the Enforcement of International Law
Authors: Eilstrup-Sangiovanni Mette , Sharman J.C.
Published: October 2019

Scholars have studied international NGOs as advocates and service providers, but have neglected their importance in autonomously enforcing international law. We have two basic aims: first to establish the nature and significance of transnational NGO enforcement, and second to explore the factors behind its rise. NGO enforcement comprises a spectrum of practices, from indirect (e.g., monitoring and investigation), to direct enforcement (e.g., prosecution and interdiction). We explain NGO enforcement by an increased demand for the enforcement of international law, and factors that have lowered the cost of supply for non-state enforcement. Increased demand for enforcement reflects the growing gap between the increased legalization of international politics and states’ limited enforcement capacity. On the supply side, the diffusion of new technologies and greater access to new legal remedies facilitate increased non-state enforcement. We evidence these claims via case studies from the environmental and anti-corruption sectors.
Observational Evidence of Irrigation Influence on Vegetation Health and Land Surface Temperature in India
Authors: Ambika Anukesh Krishnankutty , Mishra Vimal
Published: October 2019

Irrigated area in India has significantly increased after the green revolution. However, quantification of irrigation influence on vegetation health and land surface temperature (LST) remains limited. Here, we develop a high‐resolution (250 m) remotely sensed data of enhanced vegetation index (EVI) and LST from Moderate Resolution Imaging Spectroradiometer for 2000–2017 at the 8‐day temporal resolution for India to quantify the role of irrigation in the modulation of EVI, LST, and vegetation health. We show that irrigation‐dominated regions have significantly (p value < 0.05) higher EVI and cooler (1–2 K) LST during the crop‐growing season in the Indo‐Gangetic Plain. Vegetation health in highly irrigated areas is poorly correlated with meteorological drought primarily due to irrigation. Moreover, vegetation health is negatively correlated with groundwater storage anomalies in the highly irrigated Indo‐Gangetic Plain. Irrigation in Indo‐Gangetic Plain modulated EVI, LST, and vegetation health and resulted in groundwater depletion during 2002–2016.
Cold Plasmaspheric Electrons Affected by ULF Waves in the Inner Magnetosphere: A Van Allen Probes Statistical Study
Authors: Ren Jie , Zong Q. G. , Zhou X. Z. , Spence H. E. , Funsten H. O. , Wygant J. R. , Rankin R.
Published: October 2019

Six years of Van Allen Probes data are used to investigate cold plasmaspheric electrons affected by ultralow‐frequency (ULF) waves in the inner magnetosphere (L<7) including spatial distributions, occurrence conditions, and resonant energy range. Events exhibit a global distribution within L= 4–7 but preferentially occur at L∼5.5–7 in the dayside, while there is higher occurrence rate in the duskside than dawnside. They can occur under different geomagnetic activities and solar wind velocities (VS), but the occurrence rates are increasing with larger AE, |SYMH|, and VS. These features are closely associated with the generation and propagation of ULF waves in Pc4 (45–150 s) and Pc5 (150–600 s) bands. Combined with electron observations from HOPE instrument, the resonant energies inferred from wave power indicate that cold electrons at ones to hundreds of electron volts can be affected by ULF waves. This study may shed new light on further investigations on the acceleration and transportation of cold plasmaspheric particles that would affect plasmaspheric material release to the Earth's magnetosphere and instabilities for exciting various waves.
Subseasonal to Seasonal Prediction of Wintertime Northern Hemisphere Extratropical Cyclone Activity by S2S and NMME Models
Authors: Zheng Cheng , Chang Edmund Kar‐Man , Kim Hyemi , Zhang Minghua , Wang Wanqiu
Published: October 2019

In this study, the prediction of wintertime extratropical cyclone activity from subseasonal to seasonal timescale in current dynamical models' reforecasts is investigated. On seasonal time scales, the North American Multi‐Model Ensemble (NMME) models show skillful predictions over the eastern North Pacific, North America and the western North Atlantic with at least 5 months lead. The prediction skill is highly related to El Nino‐Southern Oscillation (ENSO), as using the ENSO‐related SST pattern gives rise to prediction skill with very similar spatial pattern and amplitude. On subseasonal time scales, models in the Seasonal to Sub‐seasonal Prediction (S2S) dataset have skillful predictions up to 4 weeks lead over regions from the eastern North Pacific to the western Atlantic, as well as northern Europe, the eastern Atlantic and East Asia. Generally, forecast skill improves with a larger ensemble size. The subseasonal prediction skill from the Pacific to the western Atlantic is related to ENSO, and that over eastern Atlantic, Europe and East Asia are associated with stratospheric polar vortex anomalies. Current models do not show much skill from the Madden‐Julian Oscillation (MJO), as the MJO impact on extratropical cyclone activity is not well captured by the models. European Centre for Medium‐Range Weather Forecasts (ECMWF) model has the highest single model subseasonal prediction skill. The prediction skill in the ECMWF model is higher than its estimated potential predictability, likely because the signal‐to‐noise ratio is too low in the model hindcasts.
Correction to: Bone morphogenetic protein 2 is a depot-specific regulator of human adipogenesis
Authors: Denton Nathan F. , Eghleilib Mohamed , Al-Sharifi Sama , Todorčević Marijana , Neville Matt J. , Loh Nellie , Drakesmith Alexander , Karpe Fredrik , Pinnick Katherine E.
Published: October 2019

We erroneously published the original Article with an incorrect Copyright line. This has been updated in the XML, PDF and HTML versions of this Article.
The protein kinase CK2 contributes to the malignant phenotype of cholangiocarcinoma cells
Authors: Di Maira Giovanni , Gentilini Alessandra , Pastore Mirella , Caligiuri Alessandra , Piombanti Benedetta , Raggi Chiara , Rovida Elisabetta , Lewinska Monika , Andersen Jesper B. , Borgo Christian , Salvi Mauro , Ottaviani Daniele , Ruzzene Maria , Marra Fabio
Published: October 2019

Cholangiocarcinoma (CCA) is a particularly aggressive hepatobiliary malignancy, for which the molecular mechanisms underlying the malignant phenotype are still poorly understood, and novel and effective therapeutic strategies are limited. The pro-survival protein kinase CK2 is frequently overexpressed in cancer and is receiving increasing interest as an anti-tumor drug target. Its precise role in CCA biology is still largely unknown. Here we show that expression of the CK2α and α’ catalytic subunits and of the β regulatory subunit is increased in human CCA samples. Increased expression of CK2 subunits was shown in CCA cell lines compared to non-transformed cholangiocytes. We used chemical inhibition of CK2 and genetic modification by CRISPR/Cas9 to explore the contribution of CK2 to the malignant phenotype of CCA cells. Disruption of CK2 activity results in cell death through apoptosis, reduced invasion and migration potential, and G0/G1 cell cycle arrest. Importantly, CCA cells with a reduced CK2 activity are more sensitive to chemotherapy. Altogether, our results demonstrate that CK2 significantly contributes to increased proliferative potential and augmented growth of CCA cells and indicate the rationale for its targeting as a promising pharmacologic strategy for cholangiocarcinoma.
Corticotropin releasing factor-binding protein (CRF-BP) as a potential new therapeutic target in Alzheimer’s disease and stress disorders
Authors: Vandael Dorien , Gounko Natalia V.
Published: October 2019

Alzheimer’s disease is the most common cause of dementia and one of the most complex human neurodegenerative diseases. Numerous studies have demonstrated a critical role of the environment in the pathogenesis and pathophysiology of the disease, where daily life stress plays an important role. A lot of epigenetic studies have led to the conclusion that chronic stress and stress-related disorders play an important part in the onset of neurodegenerative disorders, and an enormous amount of research yielded valuable discoveries but has so far not led to the development of effective treatment strategies for Alzheimer’s disease. Corticotropin-releasing factor (CRF) is one of the major hormones and at the same time a neuropeptide acting in stress response. Deregulation of protein levels of CRF is involved in the pathogenesis of Alzheimer’s disease, but little is known about the precise roles of CRF and its binding protein, CRF-BP, in neurodegenerative diseases. In this review, we summarize the key evidence for and against the involvement of stress-associated modulation of the CRF system in the pathogenesis of Alzheimer’s disease and discuss how recent findings could lead to new potential treatment possibilities in Alzheimer’s disease by using CRF-BP as a therapeutic target.
Examining the association between genetic liability for schizophrenia and psychotic symptoms in Alzheimer’s disease
Authors: Creese Byron , Vassos Evangelos , Bergh Sverre , Athanasiu Lavinia , Johar Iskandar , Rongve Arvid , Medbøen Ingrid Tøndel , Vasconcelos Da Silva Miguel , Aakhus Eivind , Andersen Fred , Bettella Francesco , Braekhus Anne , Djurovic Srdjan , Paroni Giulia , Proitsi Petroula , Saltvedt Ingvild , Seripa Davide , Stordal Eystein , Fladby Tormod , Aarsland Dag , Andreassen Ole A. , Ballard Clive , Selbaek Geir ,   on behalf of the AddNeuroMed consortium and the Alzheimer’s Disease Neuroimaging Initiative
Published: October 2019

Psychosis (delusions or hallucinations) in Alzheimer’s disease (AD + P) occurs in up to 50% of individuals and is associated with significantly worse clinical outcomes. Atypical antipsychotics, first developed for schizophrenia, are commonly used in AD + P, suggesting shared mechanisms. Despite this implication, little empirical research has been conducted to examine whether there are mechanistic similarities between AD + P and schizophrenia. In this study, we tested whether polygenic risk score (PRS) for schizophrenia was associated with AD + P. Schizophrenia PRS was calculated using Psychiatric Genomics Consortium data at ten GWAS p value thresholds (PT) in 3111 AD cases from 11 cohort studies characterized for psychosis using validated, standardized tools. Association between PRS and AD + P status was tested by logistic regression in each cohort individually and the results meta-analyzed. The schizophrenia PRS was associated with AD + P at an optimum PT of 0.01. The strongest association was for delusions where a one standard deviation increase in PRS was associated with a 1.18-fold increased risk (95% CI: 1.06–1.3; p = 0.001). These new findings point towards psychosis in AD—and particularly delusions—sharing some genetic liability with schizophrenia and support a transdiagnostic view of psychotic symptoms across the lifespan.
Coffee intake and decreased amyloid pathology in human brain
Authors: Kim Jee Wook , Byun Min Soo , Yi Dahyun , Lee Jun Ho , Jeon So Yeon , Jung Gijung , Lee Han Na , Sohn Bo Kyung , Lee Jun-Young , Kim Yu Kyeong , Shin Seong A , Sohn Chul-Ho , Lee Dong Young ,   for the KBASE Research Group
Published: October 2019

Several epidemiological and preclinical studies supported the protective effect of coffee on Alzheimer’s disease (AD). However, it is still unknown whether coffee is specifically related with reduced brain AD pathologies in human. Hence, this study aims to investigate relationships between coffee intake and in vivo AD pathologies, including cerebral beta-amyloid (Aβ) deposition, the neurodegeneration of AD-signature regions, and cerebral white matter hyperintensities (WMH). A total of 411 non-demented older adults were included. Participants underwent comprehensive clinical assessment and multimodal neuroimaging including [11C] Pittsburgh compound B-positron emission tomography (PET), [18F] fluorodeoxyglucose PET, and magnetic resonance imaging scans. Lifetime and current coffee intake were categorized as follows: no coffee or <2 cups/day (reference category) and ≥2 cups/day (higher coffee intake). Lifetime coffee intake of ≥2 cups/day was significantly associated with a lower Aβ positivity compared to coffee intake of <2 cups/day, even after controlling for potential confounders. In contrast, neither lifetime nor current coffee intake was not related to hypometabolism, atrophy of AD-signature region, and WMH volume. The findings suggest that higher lifetime coffee intake may contribute to lowering the risk of AD or related cognitive decline by reducing pathological cerebral amyloid deposition.
Recommendations and future directions for supervised machine learning in psychiatry
Authors: Cearns Micah , Hahn Tim , Baune Bernhard T.
Published: October 2019

Machine learning methods hold promise for personalized care in psychiatry, demonstrating the potential to tailor treatment decisions and stratify patients into clinically meaningful taxonomies. Subsequently, publication counts applying machine learning methods have risen, with different data modalities, mathematically distinct models, and samples of varying size being used to train and test models with the promise of clinical translation. Consequently, and in part due to the preliminary nature of such works, many studies have reported largely varying degrees of accuracy, raising concerns over systematic overestimation and methodological inconsistencies. Furthermore, a lack of procedural evaluation guidelines for non-expert medical professionals and funding bodies leaves many in the field with no means to systematically evaluate the claims, maturity, and clinical readiness of a project. Given the potential of machine learning methods to transform patient care, albeit, contingent on the rigor of employed methods and their dissemination, we deem it necessary to provide a review of current methods, recommendations, and future directions for applied machine learning in psychiatry. In this review we will cover issues of best practice for model training and evaluation, sources of systematic error and overestimation, model explainability vs. trust, the clinical implementation of AI systems, and finally, future directions for our field.
Correction: SOCS5 inhibition induces autophagy to impair metastasis in hepatocellular carcinoma cells via the PI3K/Akt/mTOR pathway
Authors: Zhang Mao , Liu Shihai , Chua Mei-Sze , Li Haoran , Luo Dingan , Wang Sheng , Zhang Shun , Sun Chuandong , Han Bing
Published: October 2019

Following publication of this article [1], it was realized that an error was made in typesetting which resulted in a change in the ordering of the last two authors. The correct ordering of the authors for the paper is as follows:

Mao Zhang, Shihai Liu, Mei-Sze Chua, Haoran Li, Dingan Luo, Sheng Wang, Shun Zhang, Chuandong Sun (*) & Bing Han (*)

[(*) indicates corresponding author]

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
MLH1 deficiency leads to deregulated mitochondrial metabolism
Authors: Rashid Sukaina , Freitas Marta O. , Cucchi Danilo , Bridge Gemma , Yao Zhi , Gay Laura , Williams Marc , Wang Jun , Suraweera Nirosha , Silver Andrew , McDonald Stuart A. C. , Chelala Claude , Szabadkai Gyorgy , Martin Sarah A.
Published: October 2019

The DNA mismatch repair (MMR) pathway is responsible for the repair of base–base mismatches and insertion/deletion loops that arise during DNA replication. MMR deficiency is currently estimated to be present in 15–17% of colorectal cancer cases and 30% of endometrial cancers. MLH1 is one of the key proteins involved in the MMR pathway. Inhibition of a number of mitochondrial genes, including POLG and PINK1 can induce synthetic lethality in MLH1-deficient cells. Here we demonstrate for the first time that loss of MLH1 is associated with a deregulated mitochondrial metabolism, with reduced basal oxygen consumption rate and reduced spare respiratory capacity. Furthermore, MLH1-deficient cells display a significant reduction in activity of the respiratory chain Complex I. As a functional consequence of this perturbed mitochondrial metabolism, MLH1-deficient cells have a reduced anti-oxidant response and show increased sensitivity to reactive oxidative species (ROS)-inducing drugs. Taken together, our results provide evidence for an intrinsic mitochondrial dysfunction in MLH1-deficient cells and a requirement for MLH1 in the regulation of mitochondrial function.
EPHB4 inhibition activates ER stress to promote immunogenic cell death of prostate cancer cells
Authors: Sagar Vinay , Vatapalli Rajita , Lysy Barbara , Pamarthy Sahithi , Anker Jonathan F. , Rodriguez Yara , Han Huiying , Unno Kenji , Stadler Walter M. , Catalona William J. , Hussain Maha , Gill Parkash S. , Abdulkadir Sarki A.
Published: October 2019

The EPHB4 receptor is implicated in the development of several epithelial tumors and is a promising therapeutic target, including in prostate tumors in which EPHB4 is overexpressed and promotes tumorigenicity. Here, we show that high expression of EPHB4 correlated with poor survival in prostate cancer patients and EPHB4 inhibition induced cell death in both hormone sensitive and castration-resistant prostate cancer cells. EPHB4 inhibition reduced expression of the glucose transporter, GLUT3, impaired glucose uptake, and reduced cellular ATP levels. This was associated with the activation of endoplasmic reticulum stress and tumor cell death with features of immunogenic cell death (ICD), including phosphorylation of eIF2α, increased cell surface calreticulin levels, and release of HMGB1 and ATP. The changes in tumor cell metabolism after EPHB4 inhibition were associated with MYC downregulation, likely mediated by the SRC/p38 MAPK/4EBP1 signaling cascade, known to impair cap-dependent translation. Together, our study indicates a role for EPHB4 inhibition in the induction of immunogenic cell death with implication for prostate cancer therapy.
Multi-trait single-step genomic prediction accounting for heterogeneous (co)variances over the genome
Authors: Karaman Emre , Lund Mogens S. , Su Guosheng
Published: October 2019

Widely used genomic prediction models may not properly account for heterogeneous (co)variance structure across the genome. Models such as BayesA and BayesB assume locus-specific variance, which are highly influenced by the prior for (co)variance of single nucleotide polymorphism (SNP) effect, regardless of the size of data. Models such as BayesC or GBLUP assume a common (co)variance for a proportion (BayesC) or all (GBLUP) of the SNP effects. In this study, we propose a multi-trait Bayesian whole genome regression method (BayesN0), which is based on grouping a number of predefined SNPs to account for heterogeneous (co)variance structure across the genome. This model was also implemented in single-step Bayesian regression (ssBayesN0). For practical implementation, we considered multi-trait single-step SNPBLUP models, using (co)variance estimates from BayesN0 or ssBayesN0. Genotype data were simulated using haplotypes on first five chromosomes of 2200 Danish Holstein cattle, and phenotypes were simulated for two traits with heritabilities 0.1 or 0.4, assuming 200 quantitative trait loci (QTL). We compared prediction accuracy from different prediction models and different region sizes (one SNP, 100 SNPs, one chromosome or whole genome). In general, highest accuracies were obtained when 100 adjacent SNPs were grouped together. The ssBayesN0 improved accuracies over BayesN0, and using (co)variance estimates from ssBayesN0 generally yielded higher accuracies than using (co)variance estimates from BayesN0, for the 100 SNPs region size. Our results suggest that it could be a good strategy to estimate (co)variance components from ssBayesN0, and then to use those estimates in genomic prediction using multi-trait single-step SNPBLUP, in routine genomic evaluations.
Context-dependent limb movement encoding in neuronal populations of motor cortex
Authors: Omlor Wolfgang , Wahl Anna-Sophia , Sipilä Pia , Lütcke Henry , Laurenczy Balazs , Chen I-Wen , Sumanovski Lazar T. , van ’t Hoff Marcel , Bethge Philipp , Voigt Fabian F. , Schwab Martin E. , Helmchen Fritjof
Published: October 2019

Neuronal networks of the mammalian motor cortex (M1) are important for dexterous control of limb joints. Yet it remains unclear how encoding of joint movement in M1 depends on varying environmental contexts. Using calcium imaging we measured neuronal activity in layer 2/3 of the M1 forelimb region while mice grasped regularly or irregularly spaced ladder rungs during locomotion. We found that population coding of forelimb joint movements is sparse and varies according to the flexibility demanded from individual joints in the regular and irregular context, even for equivalent grasping actions across conditions. This context-dependence of M1 encoding emerged during task learning, fostering higher precision of grasping actions, but broke apart upon silencing of projections from secondary motor cortex (M2). These findings suggest that M1 exploits information from M2 to adapt encoding of joint movements to the flexibility demands of distinct familiar contexts, thereby increasing the accuracy of motor output.
The global diversity of Haemonchus contortus is shaped by human intervention and climate
Authors: Sallé G. , Doyle S. R. , Cortet J. , Cabaret J. , Berriman M. , Holroyd N. , Cotton J. A.
Published: October 2019

Haemonchus contortus is a haematophagous parasitic nematode of veterinary interest. We have performed a survey of its genome-wide diversity using single-worm whole genome sequencing of 223 individuals sampled from 19 isolates spanning five continents. We find an African origin for the species, together with evidence for parasites spreading during the transatlantic slave trade and colonisation of Australia. Strong selective sweeps surrounding the β-tubulin locus, a target of benzimidazole anthelmintic drug, are identified in independent populations. These sweeps are further supported by signals of diversifying selection enriched in genes involved in response to drugs and other anthelmintic-associated biological functions. We also identify some candidate genes that may play a role in ivermectin resistance. Finally, genetic signatures of climate-driven adaptation are described, revealing a gene acting as an epigenetic regulator and components of the dauer pathway. These results begin to define genetic adaptation to climate in a parasitic nematode.
Nanoscale deformation mechanics reveal resilience in nacre of Pinna nobilis shell
Authors: Gim Jiseok , Schnitzer Noah , Otter Laura M. , Cui Yuchi , Motreuil Sébastien , Marin Frédéric , Wolf Stephan E. , Jacob Dorrit E. , Misra Amit , Hovden Robert
Published: October 2019

The combination of soft nanoscale organic components with inorganic nanograins hierarchically designed by natural organisms results in highly ductile structural materials that can withstand mechanical impact and exhibit high resilience on the macro- and nano-scale. Our investigation of nacre deformation reveals the underlying nanomechanics that govern the structural resilience and absorption of mechanical energy. Using high-resolution scanning/transmission electron microscopy (S/TEM) combined with in situ indentation, we observe nanoscale recovery of heavily deformed nacre that restores its mechanical strength on external stimuli up to 80% of its yield strength. Under compression, nacre undergoes deformation of nanograins and non-destructive locking across organic interfaces such that adjacent inorganic tablets structurally join. The locked tablets respond to strain as a continuous material, yet the organic boundaries between them still restrict crack propagation. Remarkably, the completely locked interface recovers its original morphology without any noticeable deformation after compressive contact stresses as large as 1.2 GPa.
Sub-nanomolar sensitive GZnP3 reveals TRPML1-mediated neuronal Zn2+ signals
Authors: Minckley Taylor F. , Zhang Chen , Fudge Dylan H. , Dischler Anna M. , LeJeune Kate D. , Xu Haoxing , Qin Yan
Published: October 2019

Although numerous fluorescent Zn2+ sensors have been reported, it is unclear whether and how Zn2+ can be released from the intracellular compartments into the cytosol due to a lack of probes that can detect physiological dynamics of cytosolic Zn2+. Here, we create a genetically encoded sensor, GZnP3, which demonstrates unprecedented sensitivity for Zn2+ at sub-nanomolar concentrations. Using GZnP3 as well as GZnP3-derived vesicular targeted probes, we provide the first direct evidence that Zn2+ can be released from endolysosomal vesicles to the cytosol in primary hippocampal neurons through the TRPML1 channel. Such TRPML1-mediated Zn2+ signals are distinct from Ca2+ in that they are selectively present in neurons, sustain longer, and are significantly higher in neurites as compared to the soma. Together, our work not only creates highly sensitive probes for investigating sub-nanomolar Zn2+ dynamics, but also reveals new pools of Zn2+ signals that can play critical roles in neuronal function.
Large scale and integrated platform for digital mass culture of anchorage dependent cells
Authors: Cho Kyoung Won , Kim Seok Joo , Kim Jaemin , Song Seuk Young , Lee Wang Hee , Wang Liu , Soh Min , Lu Nanshu , Hyeon Taeghwan , Kim Byung-Soo , Kim Dae-Hyeong
Published: October 2019

Industrial applications of anchorage-dependent cells require large-scale cell culture with multifunctional monitoring of culture conditions and control of cell behaviour. Here, we introduce a large-scale, integrated, and smart cell-culture platform (LISCCP) that facilitates digital mass culture of anchorage-dependent cells. LISCCP is devised through large-scale integration of ultrathin sensors and stimulator arrays in multiple layers. LISCCP provides real-time, 3D, and multimodal monitoring and localized control of the cultured cells, which thereby allows minimizing operation labour and maximizing cell culture performance. Wireless integration of multiple LISCCPs across multiple incubators further amplifies the culture scale and enables digital monitoring and local control of numerous culture layers, making the large-scale culture more efficient. Thus, LISCCP can transform conventional labour-intensive and high-cost cell cultures into efficient digital mass cell cultures. This platform could be useful for industrial applications of cell cultures such as in vitro toxicity testing of drugs and cosmetics and clinical scale production of cells for cell therapy.
Extracellular pyridine nucleotides trigger plant systemic immunity through a lectin receptor kinase/BAK1 complex
Authors: Wang Chenggang , Huang Xiaoen , Li Qi , Zhang Yanping , Li Jian-Liang , Mou Zhonglin
Published: October 2019

Systemic acquired resistance (SAR) is a long-lasting broad-spectrum plant immunity induced by mobile signals produced in the local leaves where the initial infection occurs. Although multiple structurally unrelated signals have been proposed, the mechanisms responsible for perception of these signals in the systemic leaves are unknown. Here, we show that exogenously applied nicotinamide adenine dinucleotide (NAD+) moves systemically and induces systemic immunity. We demonstrate that the lectin receptor kinase (LecRK), LecRK-VI.2, is a potential receptor for extracellular NAD+(eNAD+) and NAD+phosphate (eNADP+) and plays a central role in biological induction of SAR. LecRK-VI.2 constitutively associates with BRASSINOSTEROID INSENSITIVE1-ASSOCIATED KINASE1 (BAK1) in vivo. Furthermore, BAK1 and its homolog BAK1-LIKE1 are required for eNAD(P)+signaling and SAR, and the kinase activities of LecR-VI.2 and BAK1 are indispensable to their function in SAR. Our results indicate that eNAD+is a putative mobile signal, which triggers SAR through its receptor complex LecRK-VI.2/BAK1 inArabidopsis thaliana.
Oncolytic adenovirus programmed by synthetic gene circuit for cancer immunotherapy
Authors: Huang Huiya , Liu Yiqi , Liao Weixi , Cao Yubing , Liu Qiang , Guo Yakun , Lu Yinying , Xie Zhen
Published: October 2019

Improving efficacy of oncolytic virotherapy remains challenging due to difficulty increasing specificity and immune responses against cancer and limited understanding of its population dynamics. Here, we construct programmable and modular synthetic gene circuits to control adenoviral replication and release of immune effectors selectively in hepatocellular carcinoma cells in response to multiple promoter and microRNA inputs. By performing mouse model experiments and computational simulations, we find that replicable adenovirus has a superior tumor-killing efficacy than non-replicable adenovirus. We observe a synergistic effect on promoting local lymphocyte cytotoxicity and systematic vaccination in immunocompetent mouse models by combining tumor lysis and secretion of immunomodulators. Furthermore, our computational simulations show that oncolytic virus which encodes immunomodulators can exert a more robust therapeutic efficacy than combinatorial treatment with oncolytic virus and immune effector. Our results provide an effective strategy to engineer oncolytic adenovirus, which may lead to innovative immunotherapies for a variety of cancers.
Self-sensing, tunable monolayer MoS2 nanoelectromechanical resonators
Authors: Manzeli Sajedeh , Dumcenco Dumitru , Migliato Marega Guilherme , Kis Andras
Published: October 2019

Excellent mechanical properties and the presence of piezoresistivity make single layers of transition metal dichalcogenides (TMDCs) viable candidates for integration in nanoelectromechanical systems (NEMS). We report on the realization of electromechanical resonators based on single-layer MoS2with both piezoresistive and capacitive transduction schemes. Operating in the ultimate limit of membrane thickness, the resonant frequency of MoS2resonators is primarily defined by the built-in mechanical tension and is in the very high frequency range. Using electrostatic interaction with a gate electrode, we tune the resonant frequency, allowing for the extraction of resonator parameters such as mass density and built-in strain. Furthermore, we study the origins of nonlinear dynamic response at high driving force. The results shed light on the potential of TMDC-based NEMS for the investigation of nanoscale mechanical effects at the limits of vertical downscaling and applications such as resonators for RF-communications, force and mass sensors.
Deciphering nanoconfinement effects on molecular orientation and reaction intermediate by single molecule imaging
Authors: Dong Bin , Pei Yuchen , Mansour Nourhan , Lu Xuemei , Yang Kai , Huang Wenyu , Fang Ning
Published: October 2019

Nanoconfinement could dramatically change molecular transport and reaction kinetics in heterogeneous catalysis. Here we specifically design a core-shell nanocatalyst with aligned linear nanopores for single-molecule studies of the nanoconfinement effects. The quantitative single-molecule measurements reveal unusual lower adsorption strength and higher catalytic activity on the confined metal reaction centres within the nanoporous structure. More surprisingly, the nanoconfinement effects on enhanced catalytic activity are larger for catalysts with longer and narrower nanopores. Experimental evidences, including molecular orientation, activation energy, and intermediate reactive species, have been gathered to provide a molecular level explanation on how the nanoconfinement effects enhance the catalyst activity, which is essential for the rational design of highly-efficient catalysts.