bluuebunny/crossref_metadata_2025 huggingface dataset:
Building the health workforce: Saudi Arabia's challenges in achieving Vision 2030
Authors: Albejaidi Fahad , Nair Kesavan S.
Published: August 2019

Background

Saudi Arabia's Vision 2030 represents a major structural shift in all economic sectors. Health care is one of the largest sectors significantly contributing to achievement of the vision

Objectives

To provide an overview of health workforce in Saudi Arabia and identify various critical issues and challenges that need to be addressed in achieving health system goals envisaged in the Vision.

Methods

This paper is based on extensive review of literature conducted to stimulate pertinent descriptive information on health workforce in Saudi Arabia.

Findings

Saudi nationals constitute 44% of all health workforce and 29.5% of all physicians employed by the health system. Among Saudi nationals, there is a significant underrepresentation of females except in the nursing profession. The health workforce is beleaguered with numerical inadequacy, skill imbalance, gender disparity, and access issues.

Conclusion

Health system needs to adopt a rigorous approach by investing heavily on medical, nursing, and other specialized fields of education. Planning for the health workforce needs to adopt appropriate strategies that reflect all aspects including the number, skills, and gender distribution for meeting the future health needs of population to facilitate achievement of Vision.
Identification of a multidimensional transcriptome prognostic signature for lung adenocarcinoma
Authors: Ye Jing , Liu Hui , Xu Zhi‐Li , Zheng Ling , Liu Rong‐Yu
Published: August 2019

Background

Lung adenocarcinoma (LUAD) is one of the leading contributors to cancer‐related deaths worldwide. The objective of the current study is to identify a multidimensional transcriptome prognostic signature by combining protein‐coding gene (PCG) with long non‐coding RNA (lncRNA) for patients with LUAD.

Methods

We obtained LUAD PCG and lncRNA expression profile data from three datasets in the Gene Expression Omnibus database and conducted survival analyzes for these individuals.

Results

We established a predictive model comprising the three PCGs (NHLRC2, PLIN5, GNAI3), and one lncRNA (AC087521.1). This model segregated patients with LUAD into low‐ and high‐risk groups based on significant differences in survival in the training dataset (GSE31210, n = 226, log‐rank test P < .001). Risk stratification of the model was subsequently validated in other two test datasets (GSE37745, n = 106, log‐rank test P < .001; GSE30219, n = 85, log‐rank test P = .006). Time‐dependent receiver operating characteristic (timeROC) curve analysis demonstrated that the model correlated strongly with disease progression and outperformed pathological stage in terms of prognostic ability. Cox proportional hazards regression analysis revealed that the signature could serve as an independent predictor of clinical outcomes in patients with LUAD.

Conclusions

We describe a novel multidimensional transcriptome signature that can predict survival probabilities in patients with LUAD.
Fabrication of PLLA with High Ductility and Transparence by Blending with Tiny Amount of PVDF and Compatibilizers
Authors: Zhang Yan , Li Fei , Yu Qunli , Ni Chunjun , Gu Xiaoying , Li Yongjin , You Jichun
Published: August 2019

Poly(L‐lactic acid) (PLLA) with high ductility and transparence is fabricated by a blending tiny amount of polyvinylidene fluoride (PVDF) and reactive comb compatibilizers (RCC). Upon blending, the reaction between terminal carboxyl groups in PLLA and expoxy groups in RCC produces graft copolymer (PLLA‐g‐poly(methyl methacrylate) (PMMA)), which locates at the PVDF/PLLA interface due to the balanced stress on two sides. On the one hand, the PVDF domain size decreases remarkably with the help of compatibilization, accounting for the excellent transparence. On the other hand, the interface is enhanced significantly, resulting in an activated PLLA layer surrounding PVDF domains. The thickness exhibits higher magnitude because of the high molecular weight of grafted PLLA (relative to premade compatibilizers). During uniaxial tension, the activated PLLA layers (in addition to PVDF) can cause effective energy absorption and dissipation in the case of percolation of them, which is the reason for the better ductility. These results provide an efficient strategy to improve the ductility and transparence simultaneously.
A note on a smooth projective surface with Picard number 2
Authors: Li Sichen
Published: August 2019

We characterize the integral Zariski decomposition of a smooth projective surface with Picard number 2 to partially solve a problem of B. Harbourne, P. Pokora, and H. Tutaj‐Gasinska [Electron. Res. Announc. Math. Sci. 22 (2015), 103–108].
Wastewater To Resource: Design of a Sustainable Phosphorus Recovery System
Authors: Duan Menglin , O'Dwyer Edward , Stuckey David C. , Guo Miao
Published: August 2019

To enable a more sustainable wastewater treatment processes, a transition towards resource recovery methods that have minimal environmental impact while being financially viable is imperative. Phosphorus (P) is a finite resource that is being discharged into the aqueous environment in excessive quantities. As such, understanding the financial and environmental effectiveness of different approaches for removing and recovering P from wastewater streams is important to reduce the overall impact of wastewater treatment. In this study, a process‐systems modelling framework for comprehensively evaluating these approaches in terms of both economic and environmental impacts is developed. Applying this framework, treatment pathways are designed, simulated and analysed to determine the most suitable approaches for P removal and recovery. The purpose of this methodology is not only to assist with plant design, but also to identify the principal economic and environmental factors acting as barriers to implementing a given technology, incorporating the impact of waste recovery. The results suggest that the chemical and ion‐exchange approaches studied deliver sustainable advantages over biological pathways, both economically and environmentally, with each possessing different strengths. The assessment methodology developed enables a more rational and environmentally sound wastewater plant design approach to be taken.
Pediatric Pulmonology Year in Review 2018: Rare lung disease, neuromuscular disease, and diagnostic testing
Authors: Gower William A. , Birnkrant David J. , Black Jane B. , Noah Terry L.
Published: August 2019

Pediatric Pulmonology publishes original research, case reports, and review articles on topics related to a wide range of children's respiratory disorders. In this article, we highlight the past year's publications in the topic areas of rare lung diseases, respiratory complications of neuromuscular disorders, and diagnostic testing, as well as selected literature in these areas from other journals.
Synthesis and In Vitro Biological Evaluation of New Pyrido[2,3‐b]pyrazinone‐Based Cytotoxic Agents and Molecular Docking as BRAF Inhibitors
Authors: Amin Kamelia , El‐Badry Ossama , Abdel Rahman Doaa , Ammar Usama
Published: August 2019

In this study, synthesis of new pyrido[2,3‐b]pyrazinone derivatives were identified. The in vitro cytotoxic activity of synthesized compounds against human colon cancer cell line (HCT 116) and kinase assay (V600EBRAF) were investigated. The results revealed that compounds 4 b and 4 c (4‐nitro and 4‐methoxy benzylidene acid hydrazide substitution, respectively) were the most active compounds among the synthesized derivatives (IC50 12.120 and 13.103 μM, respectively). Moreover, they exhibited inhibitory activity against V600EBRAF (Inh % 79.23 and 81.33, respectively). In addition, the designed derivatives were subjected to be simulated with the active site of mutated BRAF kinase domain using a suitable molecular docking protocol. Docking results coincided with good activity of compound 4 c and showed high docking score with BRAF protein kinase domain −21.85171 kcal/mol better than native ligand. The results of this study consider pyridopyrazinone scaffold (with substituted phenyl ring through a spacer) a key nucleus for further molecular and structural optimization.
Ultraminiature and Flexible Sensor Based on Interior Corner Flow for Direct Pressure Sensing in Biofluids
Authors: Tang Longjun , Hong Wen , Wang Xiaolin , Sun Wenxi , Yang Bin , Wei Meng , Pan Jingwei , Liu Jingquan
Published: August 2019

Conventional pressure sensing devices are well developed for either indirect evaluation or internal measuring of fluid pressure over millimeter scale. Whereas, specialized pressure sensors that can directly work in various liquid environments at micrometer scale remain challenging and rarely explored, but are of great importance in many biomedical applications. Here, pressure sensor technology that utilizes capillary action to self‐assemble the pressure‐sensitive element is introduced. Sophisticated control of capillary flow, tunable sensitivity to liquid pressure in various mediums, and multiple transduction modes are realized in a polymer device, which is also flexible (thickness of 8 µm), ultraminiature (effective volume of 18 × 100 × 580 µm3), and transparent, enabling the sensor to work in some extreme situations, such as in narrow inner spaces (e.g., a microchannel of 220 µm in width and 100 µm in height), or on the surface of small objects (e.g., a 380 µm diameter needle). Potential applications of this sensor include disposables for in vivo and short‐term measurements.
Photocatalytic Micromotors Activated by UV to Visible Light for Environmental Remediation, Micropumps, Reversible Assembly, Transportation, and Biomimicry
Authors: Kong Lei , Mayorga‐Martinez Carmen C. , Guan Jianguo , Pumera Martin
Published: August 2019

Photocatalytic micromotors are light‐induced, chemically powered micromachines based on photocatalytic materials, activated by light illumination, and have redox reactions with environmental solutions to produce chemical gradients and bubbles that propel the micromachines through self‐diffusiophoresis, self‐electrophoresis, and bubble recoil. Due to the fact that excitation light relates largely to the bandgaps of selected materials, the development of photocatalytic micromotors has experienced an evolution from ultraviolet‐light‐activated to visible‐light‐activated and potentially biocompatible systems. Furthermore, due to the strong redox capacity and physical effects caused by the products or product gradients, photocatalytic micromotors have applications in environmental remediation, micropumps, reversible assembly, transportation, and biomimicry.
Trends in Demographics and Surgical Treatment of Weapon‐Related Limb Injuries Over Two Decades in a Resource‐Scarce Setting
Authors: Muhrbeck Måns , Holmgren Kaspar , Osman Zaher , von Schreeb Johan , Wladis Andreas , Andersson Peter
Published: August 2019

Background

In the past decades, surgical management of limb injuries in high‐resource settings has improved. The possibility of limb salvage has increased. It is not known whether similar changes have transpired in resource‐scarce conflict settings.

Methods

Retrospective cohort study using routinely collected patient data from the International Committee of the Red Cross hospitals in Pakistan was conducted. Consecutive data from 2009 to 2012 (535 patients) and randomly selected data from 1992 to 1995 (463 patients) were used. Only patients with weapon‐related limb injuries were included. Differences in surgical procedures were assessed with logistic regression to adjust for confounding factors.

Results

Less injuries were related to mines in 2009–2012 than in 1992–1995 (3.7% vs. 20.3%, p < 0.0001), but injuries from bombs, shells and fragments were more frequent (38.5% vs. 19.4%, p  < 0.0001) as were injuries with only a small degree of tissue damage (42.0% vs. 31.1%, p  = 0.0004). In the logistic regression, the time period did not affect the risk of amputation, debridement, length of hospital stay or in‐hospital mortality. The use of external fixation (OR 0.56, 95% CI 0.33–0.96, p  = 0.04), split skin grafts (OR 0.31, 95% CI 0.21–0.45, p  < 0.0001) and blood transfusion (OR 0.43, 95% CI 0.28–0.66, p  = 0.0001) was less frequent in 2009–2012.

Conclusion

In this resource‐scarce conflict setting, the risk of amputation appears unchanged over time, while the use of external fixation and split skin grafts was less common in 2009–2012 than in 1992–1995. These results contrast with the improved limb salvage results seen in high‐resource settings. It likely reflects the challenges of providing advanced limb‐preserving techniques in a resource‐scarce setting.
Outcomes After Urgent Thyroidectomy Following Rapid Control of Thyrotoxicosis in Graves’ Disease are Similar to Those After Elective Surgery in Well‐Controlled Disease
Authors: Ali Adibah , Debono Miguel , Balasubramanian Sabapathy P.
Published: August 2019

Background

Surgery for Graves’ disease (GD) is usually performed after adequate control with medical treatment. Occasionally, rapid pre‐operative optimization is required. The primary objective was to compare the outcomes of patients undergoing elective surgery for well‐controlled GD with those undergoing rapid pre‐operative treatment. We also propose a formal treatment protocol for future use.

Methods

A retrospective cohort study in a tertiary referral centre included 247 patients with well‐controlled GD undergoing elective surgery and 19 patients with poorly controlled disease undergoing surgery after rapid optimization. The latter group did not respond well to thionamides (carbimazole and/or propylthiouracil) or had intolerance or side effects to thionamides and were treated with a range of non‐thionamide drugs, including Lugol's iodine, cholestyramine, beta blockers and steroids (with or without thionamides), and closely monitored for 1–2 weeks before surgery. Outcome measures included thyroid storm, hypoparathyroidism and recurrent laryngeal nerve palsy.

Results

In total, 266 patients with male‐to‐female ratio of 1:6 and median (interquartile range) age of 39 (31–51) were included. Overall, long‐term recurrent laryngeal palsy and hypoparathyroidism occurred in 1 (0.38%) and 13 (4.9%) patients, respectively. No patient had thyroid storm. There was no significant difference in hypoparathyroidism (p = 1), vocal cord palsy (p = 0.803) and post‐operative bleeding (p = 0.362), between elective surgery and rapid optimization groups.

Conclusion

Rapid pre‐operative treatment is effective, safe and is associated with similar outcomes compared to usual treatment. A rapid pre‐operative optimization protocol is proposed.
Solid-State Electrolytes for Lithium-Ion Batteries: Fundamentals, Challenges and Perspectives
Authors: Zhao Wenjia , Yi Jin , He Ping , Zhou Haoshen
Published: August 2019

With the rapid popularization and development of lithium-ion batteries, associated safety issues caused by the use of flammable organic electrolytes have drawn increasing attention. To address this, solid-state electrolytes have become the focus of research for both scientific and industrial communities due to high safety and energy density. Despite these promising prospects, however, solid-state electrolytes face several formidable obstacles that hinder commercialization, including insufficient lithium-ion conduction and surge transfer impedance at the interface between solid-state electrolytes and electrodes. Based on this, this review will provide an introduction into typical lithium-ion conductors involving inorganic, organic and inorganic–organic hybrid electrolytes as well as the mechanisms of lithium-ion conduction and corresponding factors affecting performance. Furthermore, this review will comprehensively discuss emerging and advanced characterization techniques and propose underlying strategies to enhance ionic conduction along with future development trends.

Graphical Abstract
Multiple BACE1 inhibitors abnormally increase the BACE1 protein level in neurons by prolonging its half‐life
Authors: Liu Lei , Lauro Bianca M. , Ding Li , Rovere Matteo , Wolfe Michael S. , Selkoe Dennis J.
Published: August 2019

Introduction

There is keen interest in elucidating the biological mechanisms underlying recent failures of β‐site amyloid precursor protein–cleaving enzyme‐1 (BACE1) inhibitors in Alzheimer's disease trials.

Methods

We developed a highly sensitive and specific immunoassay for BACE1 in cell lines and iPSC‐derived human neurons to systematically analyze the effects of eight clinically relevant BACE1 inhibitors.

Results

Seven of 8 inhibitors elevated BACE1 protein levels. Among protease inhibitors tested, the elevation was specific to BACE1 inhibitors. The inhibitors did not increase BACE1 transcription but extended the protein's half‐life. BACE1 became elevated at concentrations below the IC50 for amyloid β (Aβ).

Discussion

Elevation of BACE1 by 7 of 8 BACE1 inhibitors raises new concerns about advancing such β‐secretase inhibitors for AD. Chronic elevation could lead to intermittently uninhibited BACE1 when orally dosed inhibitors reach trough levels, abnormally increasing substrate processing. Compounds such as roburic acid that lower Aβ by dissociating β/γ secretase complexes are better candidates because they neither inhibit β‐ and γ‐secretase nor increase BACE1 levels.
AS DROPS IN THEIR SEA: ANGELOLOGY THROUGH ONTOLOGY IN FAḪR AL-DĪN AL-RĀZĪ’S AL-MAṬĀLIB AL-῾ĀLIYA
Authors: Hammed Nora Jacobsen Ben
Published: August 2019

In this article, I examine key passages from the Aš῾arite theologian Faḫr al- Dīn al-Rāzī’s (d. 606/1210) final work, Al-Maṭālib al-῾āliya (“ The lofty inquiries ”), in order to theorize Rāzī’s cosmology and angelology. In his attempt to prove the existence of these beings, Rāzī divides reality into material and intelligible realms. Angels, which signify the celestial intellects and spheres, exist as non-space-occupying beings and represent an aspect of the intelligible world. Of these, some are associated with celestial bodies, and others are entirely unassociated with materiality. I then present evidence for the possibility that Rāzī believed that these celestial spiritual beings are pre-eternal with God. These positions indicate a certain degree of conceptual continuity with the falsafa tradition, and reflect al-Ġazālī’s (d. 505/1111) previous integration of the philosophical structure of reality into some of his texts. Additionally, one may look to other philosophical currents that developed in the Islamic world beyond the falāsifa, and connect Rāzī’s cosmology to both the Hermetic tradition and the Epistles of the Iḫwān al-Ṣafā᾿.
AḤMAD B. AL-ṬAYYIB AL-SARAḪSĪ, RÉVISEUR DE L’INTRODUCTION ARITHMÉTIQUE DE NICOMAQUE DE GÉRASE ET RÉDACTEUR DES RASĀ᾿IL IḪWĀN AL-ṢAFĀ᾿
Authors: de Vaulx D'Arcy Guillaume
Published: August 2019

Before Ṯābit b. Qurra's translation, there was a first Arabic version of Nicomachus’ Introduction to arithmetic. Full of mistakes, it was revised by an anonymous student of al-Kindī. Thanks to the part that Freudenthal and Levy have edited and translated, we are now able to identify this reviser as Aḥmad b. al-Ṭayyib al-Saraḫsī, who we also identified as the author of the Rasā᾿il Iḫwān al-Ṣafā᾿. The comparison of the gloss written by this reviser with a new fragment of Saraḫsī on one part, and with the “ Epistles of the Brethren in Purity ” on the other, corroborate Saraḫsī’s authorship of the epistles. Furthermore, studying the misunderstandings on Nicomachus’ text in this kindianised version gives a new light on al-Kindī’s attempt to unify philosophy and on the specific ontology of the Brethren in Purity.
When Passion Appears, Exercise Addiction Disappears
Authors: Szabo Attila , Kovacsik Rita
Published: August 2019

Abstract. There are approximately 1,000 published articles on exercise addiction, which is characterized by exaggerated training yielding adverse effects. In contrast, there are less than 20 identified cases of exercise addiction in the literature. Recently, it was reported that there is an association between exercise addiction and passion. To test the impact of the latter on exercise addiction, we reanalyzed the combined data from two recent studies. High- and low-exercise volume groups differed in exercise addiction even after controlling for age and sex ( p < .001). However, after adding obsessive and harmonious passion as continuous predictor variables, the statistical significance vanished, whereas both predictors emerged as significant ( p < .001). Further, when controlled for the effect of passion, the correlation between exercise addiction and weekly exercise volume turned out to be negative. Therefore, a conceptual confound between the presumed risk of exercise addiction and passion could render the results of several hundreds of published works questionable. The current findings send an important message to scholars in the field: Studying exercise addiction without controlling for passion may yield false results.
The epigenetic factor BORIS (CTCFL) controls the androgen receptor regulatory network in ovarian cancer
Authors: Salgado-Albarrán Marisol , González-Barrios Rodrigo , Guerra-Calderas Lissania , Alcaraz Nicolás , Estefanía Sánchez-Correa Thalía , Castro-Hernández Clementina , Sánchez-Pérez Yesennia , Aréchaga-Ocampo Elena , García-Carrancá Alejandro , Cantú de León David , Herrera Luis A. , Baumbach Jan , Soto-Reyes Ernesto
Published: August 2019

The identification of prognostic biomarkers is a priority for patients suffering from high-grade serous ovarian cancer (SOC), which accounts for >70% of ovarian cancer (OC) deaths. Meanwhile, borderline ovarian cancer (BOC) is a low malignancy tumor and usually patients undergo surgery with low probabilities of recurrence. However, SOC remains the most lethal neoplasm due to the lack of biomarkers for early diagnosis and prognosis. In this regard, BORIS (CTCFL), a CTCF paralog, is a promising cancer biomarker that is overexpressed and controls transcription in several cancer types, mainly in OC. Studies suggest that BORIS has an important function in OC by altering gene expression, but the effect and extent to which BORIS influences transcription in OC from a genome-wide perspective is unclear. Here, we sought to identify BORIS target genes in an OC cell line (OVCAR3) with potential biomarker use in OC tumor samples. To achieve this, we performed in vitro knockout and knockdown experiments of BORIS in OVCAR3 cell line followed by expression microarrays and bioinformatics network enrichment analysis to identify relevant BORIS target genes. In addition, ex vivo expression data analysis of 373 ovarian cancer patients were evaluated to identify the expression patterns of BORIS target genes. In vitro, we uncovered 130 differentially expressed genes and obtained the BORIS-associated regulatory network, in which the androgen receptor (AR) acts as a major transcription factor. Also, FN1, FAM129A, and CD97 genes, which are related to chemoresistance and metastases in OC, were identified. In SOC patients, we observed that malignancy is associated with high levels of BORIS expression while BOC patients show lower levels. Our study suggests that BORIS acts as a main regulator, and has the potential to be used as a prognostic biomarker and to yield novel drug targets among the genes BORIS controls in SOC patients.
Dynamic responses, GPS positions and environmental conditions of two light rail vehicles in Pittsburgh
Authors: Liu Jingxiao , Chen Siheng , Lederman George , Kramer David B. , Noh Hae Young , Bielak Jacobo , Garrett James H. , Kovačević Jelena , Bergés Mario
Published: August 2019

We present DR-Train, the first long-term open-access dataset recording dynamic responses from in-service light rail vehicles. Specifically, the dataset contains measurements from multiple sensor channels mounted on two in-service light rail vehicles that run on a 42.2-km light rail network in the city of Pittsburgh, Pennsylvania. This dataset provides dynamic responses of in-service trains via vibration data collected by accelerometers, which enables a low-cost way of monitoring rail tracks more frequently. Such an approach will result in more reliable and economical ways to monitor rail infrastructure. The dataset also includes corresponding GPS positions of the trains, environmental conditions (including temperature, wind, weather, and precipitation), and track maintenance logs. The data, which is stored in a MAT-file format, can be conveniently loaded for various potential uses, such as validating anomaly detection and data fusion as well as investigating environmental influences on train responses.
GCN250, new global gridded curve numbers for hydrologic modeling and design
Authors: Jaafar Hadi H. , Ahmad Farah A. , El Beyrouthy Naji
Published: August 2019

The USDA curve-number (CN) method is fundamental for rainfall-runoff modeling. A global CN database is not currently available for geospatial hydrologic analysis at a resolution higher than 0.1°. We developed a globally consistent, gridded dataset defining CNs at the 250 m spatial resolution from new global land cover (300 m) and soils data (250 m). The resulting data product – GCN250 – represents runoff for a combination of the European space agency global land cover dataset for 2015 (ESA CCI-LC) resampled to 250 m and geo-registered with the hydrologic soil group global data product (HYSOGs250m) released in 2018. Our analysis indicated that medium to high runoff potential currently dominates the globe, with curve numbers ranging between 75 and 85. Global curve numbers were 62, 78, and 90 for dry, average, and wet antecedent runoff conditions, respectively. Australia has the highest runoff potential, while Europe has the lowest. Runoff ratios compare well with GLDAS. The potential application of this data includes hydrologic design, land management applications, flood risk assessment, and groundwater recharge modeling.
The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids
Authors: Prill Sebastian , Caddeo Andrea , Baselli Guido , Jamialahmadi Oveis , Dongiovanni Paola , Rametta Raffaela , Kanebratt Kajsa P. , Pujia Arturo , Pingitore Piero , Mancina Rosellina Margherita , Lindén Daniel , Whatling Carl , Janefeldt Annika , Kozyra Mikael , Ingelman-Sundberg Magnus , Valenti Luca , Andersson Tommy B. , Romeo Stefano
Published: August 2019

There is a high unmet need for developing treatments for nonalcoholic fatty liver disease (NAFLD), for which there are no approved drugs today. Here, we used a human in vitro disease model to understand mechanisms linked to genetic risk variants associated with NAFLD. The model is based on 3D spheroids from primary human hepatocytes from five different donors. Across these donors, we observed highly reproducible differences in the extent of steatosis induction, demonstrating that inter-donor variability is reflected in the in vitro model. Importantly, our data indicates that the genetic variant TM6SF2 E167K, previously associated with increased risk for NAFLD, induces increased hepatocyte fat content by reducing APOB particle secretion. Finally, differences in gene expression pathways involved in cholesterol, fatty acid and glucose metabolism between wild type and TM6SF2 E167K mutation carriers (N = 125) were confirmed in the in vitro model. Our data suggest that the 3D in vitro spheroids can be used to investigate the mechanisms underlying the association of human genetic variants associated with NAFLD. This model may also be suitable to discover new treatments against NAFLD.
Climate and Soil Characteristics Determine Where No-Till Management Can Store Carbon in Soils and Mitigate Greenhouse Gas Emissions
Authors: Ogle Stephen M. , Alsaker Cody , Baldock Jeff , Bernoux Martial , Breidt F. Jay , McConkey Brian , Regina Kristiina , Vazquez-Amabile Gabriel G.
Published: August 2019

Adoption of no-till management on croplands has become a controversial approach for storing carbon in soil due to conflicting findings. Yet, no-till is still promoted as a management practice to stabilize the global climate system from additional change due to anthropogenic greenhouse gas emissions, including the 4 per mille initiative promoted through the UN Framework Convention on Climate Change. We evaluated the body of literature surrounding this practice, and found that SOC storage can be higher under no-till management in some soil types and climatic conditions even with redistribution of SOC, and contribute to reducing net greenhouse gas emissions. However, uncertainties tend to be large, which may make this approach less attractive as a contributor to stabilize the climate system compared to other options. Consequently, no-till may be better viewed as a method for reducing soil erosion, adapting to climate change, and ensuring food security, while any increase in SOC storage is a co-benefit for society in terms of reducing greenhouse gas emissions.
Visual inputs and postural manipulations affect the location of somatosensory percepts elicited by electrical stimulation
Authors: Christie Breanne P. , Charkhkar Hamid , Shell Courtney E. , Marasco Paul D. , Tyler Dustin J. , Triolo Ronald J.
Published: August 2019

The perception of somatosensation requires the integration of multimodal information, yet the effects of vision and posture on somatosensory percepts elicited by neural stimulation are not well established. In this study, we applied electrical stimulation directly to the residual nerves of trans-tibial amputees to elicit sensations referred to their missing feet. We evaluated the influence of congruent and incongruent visual inputs and postural manipulations on the perceived size and location of stimulation-evoked somatosensory percepts. We found that although standing upright may cause percept size to change, congruent visual inputs and/or body posture resulted in better localization. We also observed visual capture: the location of a somatosensory percept shifted toward a visual input when vision was incongruent with stimulation-induced sensation. Visual capture did not occur when an adopted posture was incongruent with somatosensation. Our results suggest that internal model predictions based on postural manipulations reinforce perceived sensations, but do not alter them. These characterizations of multisensory integration are important for the development of somatosensory-enabled prostheses because current neural stimulation paradigms cannot replicate the afferent signals of natural tactile stimuli. Nevertheless, multisensory inputs can improve perceptual precision and highlight regions of the foot important for balance and locomotion.
Stimulation of P2Y11 receptor protects human cardiomyocytes against Hypoxia/Reoxygenation injury and involves PKCε signaling pathway
Authors: Benoist Lauriane , Chadet Stéphanie , Genet Thibaud , Lefort Claudie , Heraud Audrey , Danila Maria D. , Muntean Danina M. , Baron Christophe , Angoulvant Denis , Babuty Dominique , Bourguignon Thierry , Ivanes Fabrice
Published: August 2019

Sterile inflammation is a key determinant of myocardial reperfusion injuries. It participates in infarct size determination in acute myocardial infarction and graft rejection following heart transplantation. We previously showed that P2Y11 exerted an immunosuppressive role in human dendritic cells, modulated cardiofibroblasts’ response to ischemia/reperfusion in vitro and delayed graft rejection in an allogeneic heterotopic heart transplantation model. We sought to investigate a possible role of P2Y11 in the cellular response of cardiomyocytes to ischemia/reperfusion. We subjected human AC16 cardiomyocytes to 5 h hypoxia/1 h reoxygenation (H/R). P2Y11R (P2Y11 receptor) selective agonist NF546 and/or antagonist NF340 were added at the onset of reoxygenation. Cellular damages were assessed by LDH release, MTT assay and intracellular ATP level; intracellular signaling pathways were explored. The role of P2Y11R in mitochondria-derived ROS production and mitochondrial respiration was investigated. In vitro H/R injuries were significantly reduced by P2Y11R stimulation at reoxygenation. This protection was suppressed with P2Y11R antagonism. P2Y11R stimulation following H2O2-induced oxidative stress reduced mitochondria-derived ROS production and damages through PKCε signaling pathway activation. Our results suggest a novel protective role of P2Y11 in cardiomyocytes against reperfusion injuries. Pharmacological post-conditioning targeting P2Y11R could therefore contribute to improve myocardial ischemia/reperfusion outcomes in acute myocardial infarction and cardiac transplantation.
Autosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein
Authors: Schaeffer Céline , Izzi Claudia , Vettori Andrea , Pasqualetto Elena , Cittaro Davide , Lazarevic Dejan , Caridi Gianluca , Gnutti Barbara , Mazza Cinzia , Jovine Luca , Scolari Francesco , Rampoldi Luca
Published: August 2019

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a genetically heterogeneous renal disorder leading to progressive loss of renal function. ADTKD-REN is due to rare mutations in renin, all localized in the protein leader peptide and affecting its co-translational insertion in the endoplasmic reticulum (ER). Through exome sequencing in an adult-onset ADTKD family we identified a new renin variant, p.L381P, mapping in the mature protein. To assess its pathogenicity, we combined genetic data, computational and predictive analysis and functional studies. The L381P substitution affects an evolutionary conserved residue, co-segregates with renal disease, is not found in population databases and is predicted to be deleterious by in silico tools and by structural modelling. Expression of the L381P variant leads to its ER retention and induction of the Unfolded Protein Response in cell models and to defective pronephros development in zebrafish. Our work shows that REN mutations outside of renin leader peptide can cause ADTKD and delineates an adult form of ADTKD-REN, a condition which has usually its onset in childhood. This has implications for the molecular diagnosis and the estimated prevalence of the disease and points at ER homeostasis as a common pathway affected in ADTKD-REN, and possibly more generally in ADTKD.
Geometric principles of second messenger dynamics in dendritic spines
Authors: Cugno Andrea , Bartol Thomas M. , Sejnowski Terrence J. , Iyengar Ravi , Rangamani Padmini
Published: August 2019

Dendritic spines are small, bulbous protrusions along dendrites in neurons and play a critical role in synaptic transmission. Dendritic spines come in a variety of shapes that depend on their developmental state. Additionally, roughly 14–19% of mature spines have a specialized endoplasmic reticulum called the spine apparatus. How does the shape of a postsynaptic spine and its internal organization affect the spatio-temporal dynamics of short timescale signaling? Answers to this question are central to our understanding the initiation of synaptic transmission, learning, and memory formation. In this work, we investigated the effect of spine and spine apparatus size and shape on the spatio-temporal dynamics of second messengers using mathematical modeling using reaction-diffusion equations in idealized geometries (ellipsoids, spheres, and mushroom-shaped). Our analyses and simulations showed that in the short timescale, spine size and shape coupled with the spine apparatus geometries govern the spatiotemporal dynamics of second messengers. We show that the curvature of the geometries gives rise to pseudo-harmonic functions, which predict the locations of maximum and minimum concentrations along the spine head. Furthermore, we showed that the lifetime of the concentration gradient can be fine-tuned by localization of fluxes on the spine head and varying the relative curvatures and distances between the spine apparatus and the spine head. Thus, we have identified several key geometric determinants of how the spine head and spine apparatus may regulate the short timescale chemical dynamics of small molecules that control synaptic plasticity.
Sources of mercury in deep-sea sediments of the Mediterranean Sea as revealed by mercury stable isotopes
Authors: Ogrinc Nives , Hintelmann Holger , Kotnik Jože , Horvat Milena , Pirrone Nicola
Published: August 2019

Mercury (Hg) and its stable isotope composition were used to determine the sources of Hg in deep-sea sediments of the Mediterranean Sea. Surface and down-core sediment δ202Hg values varied widely between −2.30 and +0.78‰, showed consistently positive values for mass independent fractionation of odd Hg isotopes (with average values of Δ199Hg = +0.10 ± 0.04‰ and Δ201Hg = +0.04 ± 0.02‰) and near-zero Δ200Hg values, indicating either multiple Hg sources or a combination of different Hg isotope fractionating processes before and after sediment deposition. Both mass-dependent and mass-independent fractionation processes influence the isotopic composition of Hg in the Mediterranean Sea. Positive Δ199Hg values are likely the result of enhanced Hg2+ photoreduction in the Mediterranean water column before incorporation of Hg into sediments, while mass-dependent fractionation decreases δ202Hg values due to kinetic isotope fractionation during deposition and mobilization. An isotope mixing model based on mass-dependent and mass-independent fractionation (δ202Hg and Δ199Hg) suggests at least three primary Hg sources of atmospheric deposition in the surface sediments: urban, industrial and global precipitation-derived. Industry is the main source of Hg in Algerian and Western Basin surface sediments and at two sites in the Adriatic Sea, while the urban contribution is most prominent at the Strait of Otranto (MS3) and in Adriatic surface sediments. The contribution from precipitation ranged from 10% in Algerian to 37% in W Basin sediments. Overall, results suggest that atmospheric Hg deposition to Mediterranean surface sediments is dominated by gaseous elemental mercury (58 ± 11%) rather than wet deposition.
Dexras1 Deletion and Iron Chelation Promote Neuroprotection in Experimental Optic Neuritis
Authors: Khan Reas S. , Baumann Bailey , Dine Kimberly , Song Ying , Dunaief Joshua L. , Kim Sangwon F. , Shindler Kenneth S.
Published: August 2019

Dysregulation of iron metabolism, and resultant cytotoxicity, has been implicated in the pathogenesis of multiple sclerosis (MS) and other neurodegenerative processes. Iron accumulation promotes cytotoxicity through various mechanisms including oxidative stress and glutamate toxicity, and occurs in both MS patients and in the experimental autoimmune encephalomyelitis (EAE) model of MS. Divalent Metal Transporter1, a major iron importer in cells, is stimulated by signaling of Dexras1, a small G protein member of the Ras family. Dexras1 is activated by S-nitrosylation by nitric oxide (NO) produced by either inducible nitric oxide synthase in activated microglia/macrophages or neuronal nitric oxide synthase in neurons. Here we show Dexras1 exacerbates oxidative stress-induced neurodegeneration in experimental optic neuritis, an inflammatory demyelinating optic nerve condition that occurs in MS and EAE. Dexras1 deletion, as well as treatment with the iron chelator deferiprone, preserves vision and attenuates retinal ganglion cell (RGC) and axonal loss during EAE optic neuritis. These results suggest that iron entry triggered by NO-activated Dexras1 signaling is a potential mechanism of neuronal death in experimental optic neuritis. The current data suggest modulation of Dexras1 signaling and iron chelation are potential novel treatment strategies for optic neuritis and MS, and possibly other optic neuropathies as well.
CYLD dysregulation in pathogenesis of sporadic inclusion body myositis
Authors: Yamashita Satoshi , Matsuo Yoshimasa , Tawara Nozomu , Hara Kentaro , Yamamoto Masanori , Nishikami Tomo , Kawakami Kensuke , Zhang Xiao , Zhang Ziwei , Doki Tsukasa , Ando Yukio
Published: August 2019

Sporadic inclusion body myositis (sIBM) is the most commonly acquired myopathy in middle-aged and elderly people. The muscle histology is characterized by both inflammation and degeneration, including sarcoplasmic aggregation of TDP-43. Cylindromatosis (CYLD) is a deubiquitinating enzyme that targets Lys63-linked ubiquitin chains and negatively regulates signal transduction pathways, such as NF-κB signalling pathways. We examined localization of CYLD as well as phosphorylated TDP-43, phosphorylated p62, and Lys63-linked ubiquitin in muscle tissues of sIBM patients and muscle-specific wild-type TDP-43 transgenic (TDP-43 TG) mice. We investigated whether overexpression of CYLD can affect muscle toxicity in the cell models treated by endoplasmic reticulum (ER) stress inducers tunicamycin and thapsigargin. CYLD expressed with phosphorylated TDP-43, phosphorylated p62, and Lys63-linked ubiquitin in the nuclear and perinuclear regions of muscle fibres of wild-type TDP-43 TG mice and the degenerative myofibres of sIBM patients with rimmed vacuoles and endomysial cellular infiltration. Although expression levels of CYLD decreased and cell viability was reduced in cells treated with ER stress inducers, wild-type CYLD, but not the catalytic mutant, substantially improved cell viability based on the deubiquitinase activity. Dysregulation of CYLD may reinforce myodegeneration in the pathophysiology of sIBM by attenuating autophagic clearance of protein aggregates. Regulating CYLD in muscle fibres might serve as a novel therapeutic strategy for sIBM treatment.
Unraveling structural and compositional information in 3D FinFET electronic devices
Authors: Trombini Henrique , Marmitt Gabriel Guterres , Alencar Igor , Baptista Daniel Lorscheitter , Reboh Shay , Mazen Frédéric , Pinheiro Rafael Bortolin , Sanchez Dario Ferreira , Senna Carlos Alberto , Archanjo Bráulio Soares , Achete Carlos Alberto , Grande Pedro Luis
Published: August 2019

Non-planar Fin Field Effect Transistors (FinFET) are already present in modern devices. The evolution from the well-established 2D planar technology to the design of 3D nanostructures rose new fabrication processes, but a technique capable of full characterization, particularly their dopant distribution, in a representative (high statistics) way is still lacking. Here we propose a methodology based on Medium Energy Ion Scattering (MEIS) to address this query, allowing structural and compositional quantification of advanced 3D FinFET devices with nanometer spatial resolution. When ions are backscattered, their energy losses unfold the chemistry of the different 3D compounds present in the structure. The FinFET periodicity generates oscillatory features as a function of backscattered ion energy and, in fact, these features allow a complete description of the device dimensions. Additionally, each measurement is performed over more than thousand structures, being highly representative in a statistical meaning. Finally, independent measurements using electron microscopy corroborate the proposed methodology.
3D multiscale-imaging of processing-induced defects formed during sintering of hierarchical powder packings
Authors: Okuma Gaku , Watanabe Shuhei , Shinobe Kan , Nishiyama Norimasa , Takeuchi Akihisa , Uesugi Kentaro , Tanaka Satoshi , Wakai Fumihiro
Published: August 2019

The characterization of the processing-induced defects is an essential step for developing defect-free processing, which is important to the assurance of structural reliability of brittle ceramics. The multiscale X-ray computed tomography, consisting of micro-CT as a wide-field and low-resolution system and nano-CT as a narrow-field and high-resolution system, is suitable for observing crack-like defects with small length and with very small crack opening displacement. Here we applied this powerful imaging tool in order to reveal the complicated three-dimensional morphology of defects evolved during sintering of alumina. The hierarchical packing structure of granules was the origin of several types of strength-limiting defects, which could not be eliminated due to the differential sintering of heterogeneous microstructures. This imaging technique of internal defects provides a link between the processing and the fracture strength for the development of structural materials.
Identification of methotrexate as a heterochromatin-promoting drug
Authors: Loyola Andre C. , Zhang Lin , Shang Robin , Dutta Pranabananda , Li Jinghong , Li Willis X.
Published: August 2019

Heterochromatin is a tightly packed form of DNA involved in gene silencing, chromosome segregation, and protection of genome stability. Heterochromatin is becoming more recognized in tumor suppression and may thus serve as a potential target for cancer therapy. However, to date there are no drugs that are well established to specifically promote heterochromatin formation. Here, we describe a screening method using Drosophila to identify small molecule compounds that promote heterochromatin formation, with the purpose of developing epigenetic cancer therapeutics. We took advantage of a Drosophila strain with a variegated eye color phenotype that is sensitive to heterochromatin levels, and screened a library of 97 FDA approved oncology drugs. This screen identified methotrexate as the most potent small molecule drug, among the 97 oncology drugs screened, in promoting heterochromatin formation. Interestingly, methotrexate has been identified as a JAK/STAT inhibitor in a functional screen, causing reduced phosphorylation of STAT proteins. These findings are in line with our previous observation that unphosphorylated STAT (uSTAT) promotes heterochromatin formation in both Drosophila and human cells and suppresses tumor growth in mouse xenografts. Thus, Drosophila with variegated eye color phenotypes could be an effective tool for screening heterochromatin-promoting compounds that could be candidates as cancer therapeutics.
SMARCA2-deficiency confers sensitivity to targeted inhibition of SMARCA4 in esophageal squamous cell carcinoma cell lines
Authors: Ehrenhöfer-Wölfer Katharina , Puchner Teresa , Schwarz Cornelia , Rippka Janine , Blaha-Ostermann Silvia , Strobl Ursula , Hörmann Alexandra , Bader Gerd , Kornigg Stefan , Zahn Stephan , Sommergruber Wolfgang , Schweifer Norbert , Zichner Thomas , Schlattl Andreas , Neumüller Ralph A. , Shi Junwei , Vakoc Christopher R. , Kögl Manfred , Petronczki Mark , Kraut Norbert , Pearson Mark A. , Wöhrle Simon
Published: August 2019

SMARCA4/BRG1 and SMARCA2/BRM, the two mutually exclusive catalytic subunits of the BAF complex, display a well-established synthetic lethal relationship in SMARCA4-deficient cancers. Using CRISPR-Cas9 screening, we identify SMARCA4 as a novel dependency in SMARCA2-deficient esophageal squamous cell carcinoma (ESCC) models, reciprocal to the known synthetic lethal interaction. Restoration of SMARCA2 expression alleviates the dependency on SMARCA4, while engineered loss of SMARCA2 renders ESCC models vulnerable to concomitant depletion of SMARCA4. Dependency on SMARCA4 is linked to its ATPase activity, but not to bromodomain function. We highlight the relevance of SMARCA4 as a drug target in esophageal cancer using an engineered ESCC cell model harboring a SMARCA4 allele amenable to targeted proteolysis and identify SMARCA4-dependent cell models with low or absent SMARCA2 expression from additional tumor types. These findings expand the concept of SMARCA2/SMARCA4 paralog dependency and suggest that pharmacological inhibition of SMARCA4 represents a novel therapeutic opportunity for SMARCA2-deficient cancers.