bluuebunny/crossref_metadata_2025 huggingface dataset:
The Emergence of Organic Single‐Crystal Electronics
Authors: Jiang Hui , Hu Wenping
Published: March 2019

Organic semiconducting single crystals are perfect for both fundamental and application‐oriented research due to the advantages of free grain boundaries, few defects, and minimal traps and impurities, as well as their low‐temperature processability, high flexibility, and low cost. Carrier mobilities of greater than 10 cm2 V−1 s−1 in some organic single crystals indicate a promising application in electronic devices. The progress made, including the molecular structures and fabrication technologies of organic single crystals, is introduced and organic single‐crystal electronic devices, including field‐effect transistors, phototransistors, p‐n heterojunctions, and circuits, are summarized. Organic two‐dimensional single crystals, cocrystals, and large single crystals, together with some potential applications, are introduced. A state‐of‐the‐art overview of organic single‐crystal electronics, with their challenges and prospects, is also provided.
Possibilities and Limitations of Different Separation Techniques for the Analysis of the Protein Corona
Authors: Weber Claudia , Morsbach Svenja , Landfester Katharina
Published: April 2019

One of the biggest challenges in the field of nanomedicine is the adsorption of biomolecules on the nanomaterial upon contact with a biological medium. The interactions of the resulting protein corona are essential for their behavior in a biological system. Thus, it is now commonly accepted that understanding the formation and consequently understanding the influence of the protein corona on the biological response is crucial. However, the outcome of the protein corona characterization cannot easily be compared between different studies and techniques, since many different sample preparation procedures exist that are suitable for different materials or methods. Depending on the applied procedure, the nanomaterial–protein system will be altered in a certain way, so that it is necessary to consider the individual influence on the protein corona. Accordingly, the aim of this Minireview is to give an overview of the applied sample preparation methods for the analysis of the protein corona and to evaluate their influence on the outcome of the results especially with regard to the introduced terms “soft” and “hard protein corona”. Special focus will be placed on the comparison of the most commonly used techniques such as centrifugation, magnetic, and chromatographic separation.
Evaluation of prenatal diabetes mellitus and other risk factors for craniofacial microsomia
Authors: Siebold Babette , Heike Carrie L. , Leroux Brian G. , Speltz Matthew L. , Drake Amelia F. , Johns Alexis L. , Kapp‐Simon Kathleen A. , Magee Leanne , Luquetti Daniela V.
Published: March 2019

Objectives

Craniofacial microsomia (CFM) is a congenital condition that typically involves hypoplasia of the ear and jaw. It is often associated with adverse effects such as hearing loss and sleep‐disordered breathing. There is little research on its etiology.

Methods

We conducted a case–control study from maternal interview data collected from mothers of infants with and without CFM. The study included 108 children with and 84 children without CFM. Logistic regression with adjustment for demographic factors was used to evaluate associations between maternal exposures of interest and risk for CFM overall, as well as for different phenotypic sub‐groups of children on the CFM spectrum.

Results

We found a statistically significant association between diabetes mellitus (DM) and CFM (OR 4.01, 95% CI 1.6–10.5). The association was slightly attenuated after adjustment for BMI. Higher parity was also associated with increased risk for CFM (OR 2.0, 95% CI 1.0–4.0). Vitamin A consumption and/or liver consumption was associated with a 70% lower risk compared with non‐users (OR 0.3, 95% 0.1–0.8). Maternal age at the time of pregnancy was not associated with CFM.

Conclusions

These analyses contribute evidence linking maternal DM with an elevated risk of having an infant with CFM, which is consistent with previous research and adds to the body of knowledge about the strength of this association. Further study is warranted to understand the potential mechanisms underlying the effect of DM in the developing embryo.
Next‐Generation Industrial Biotechnology‐Transforming the Current Industrial Biotechnology into Competitive Processes
Authors: Yu Lin‐Ping , Wu Fu‐Qing , Chen Guo‐Qiang
Published: March 2019

The chemical industry has made a contribution to modern society by providing cost‐competitive products for our daily use. However, it now faces a serious challenge regarding environmental pollutions and greenhouse gas emission. With the rapid development of molecular biology, biochemistry, and synthetic biology, industrial biotechnology has evolved to become more efficient for production of chemicals and materials. However, in contrast to chemical industries, current industrial biotechnology (CIB) is still not competitive for production of chemicals, materials, and biofuels due to their low efficiency and complicated sterilization processes as well as high‐energy consumption. It must be further developed into “next‐generation industrial biotechnology” (NGIB), which is low‐cost mixed substrates based on less freshwater consumption, energy‐saving, and long‐lasting open continuous intelligent processing, overcoming the shortcomings of CIB and transforming the CIB into competitive processes. Contamination‐resistant microorganism as chassis is the key to a successful NGIB, which requires resistance to microbial or phage contaminations, and available tools and methods for metabolic or synthetic biology engineering. This review proposes a list of contamination‐resistant bacteria and takesHalomonasspp. as an example for the production of a variety of products, including polyhydroxyalkanoates under open‐ and continuous‐processing conditions proposed for NGIB.
Evolutionary engineering of Corynebacterium glutamicum
Authors: Stella Roberto G. , Wiechert Johanna , Noack Stephan , Frunzke Julia
Published: March 2019

A unique feature of biotechnology is that we can harness the power of evolution to improve process performance. Rational engineering of microbial strains has led to the establishment of a variety of successful bioprocesses, but it is hampered by the overwhelming complexity of biological systems. Evolutionary engineering represents a straightforward approach for fitness‐linked phenotypes (e.g., growth or stress tolerance) and is successfully applied to select for strains with improved properties for particular industrial applications. In recent years, synthetic evolution strategies have enabled selection for increased small molecule production by linking metabolic productivity to growth as a selectable trait. This review summarizes the evolutionary engineering strategies performed with the industrial platform organism Corynebacterium glutamicum. An increasing number of recent studies highlight the potential of adaptive laboratory evolution (ALE) to improve growth or stress resistance, implement the utilization of alternative carbon sources, or improve small molecule production. Advances in next‐generation sequencing and automation technologies will foster the application of ALE strategies to streamline microbial strains for bioproduction and enhance our understanding of biological systems.
In Silico Metabolic Design of Two‐Strain Biofilm Systems Predicts Enhanced Biomass Production and Biochemical Synthesis
Authors: Patel Ayushi , Carlson Ross P. , Henson Michael A.
Published: March 2019

Engineered biofilm consortia have the potential to solve important biotechnological problems that have proved difficult for monoculture biofilms and planktonic consortia, such as conversion of lignocellulosic material to useful biochemicals. While considerable experimental progress has been reported for engineering and characterizing biofilm consortia, the field still lacks in silico tools for simulation, design, and optimization of stable, robust, and productive designed consortia. We developed biofilm consortia metabolic models for two coculture systems centered around the ecological design motif of a primary cell type that utilizes a supplied electron donor and secretes acetate as a byproduct and a secondary cell type that consumes the acetate, relieving byproduct inhibition on the primary cell type and enhancing overall system biomass. The models presented in this paper predict that distinct metabolic niches for the two cell types could be established by supplying electron donors and acceptors at opposite ends of the biofilm and that acetate consumption by the secondary cell type could increase total biomass accumulation and the synthesis of valuable biochemicals, such as isobutanol, by the primary cell type. System tunability is enhanced when each cell type is supplied with a unique terminal electron acceptor at opposite ends of the biofilm rather than competing for a common electron acceptor. Our model provides good qualitative agreement with data for a synthetic Escherichia coli coculture system, suggesting that the proposed design rules may have wide applicability to engineered biofilm consortia.
Efficient Human Genome Editing Using SaCas9 Ribonucleoprotein Complexes
Authors: Wang Yufei , Wang Bang , Xie Haihua , Ren Qianwen , Liu Xiexie , Li Fanfan , Lv Xiujuan , He Xiubin , Cheng Congsheng , Deng Ruzhi , Li Jin , Zhao Junzhao , Song Zongming , Gu Feng
Published: March 2019

Genome editing using RNA‐guided nucleases in their ribonucleoprotein (RNP) form represents a promising strategy for gene modification and therapy because they are free of exogenous DNA integration and have reduced toxicity in vivo and ex vivo. However, genome editing by Cas9 nuclease from Staphylococcus aureus (SaCas9) has not been reported in its RNP form, which recognizes a longer protospacer adjacent motif (PAM), 5′‐NNGRRT‐3′, compared with Streptococcus pyogenes Cas9 (SpCas9) of 5′‐NGG‐3′ PAM. Here, SaCas9‐RNP‐mediated genome editing is reported in human cells. The SaCas9‐RNP displayed efficient genome editing activities of enhanced green fluorescent protein (EGFP) coding gene as well as three endogenous genes (OPA1, RS1, and VEGFA). Further, SaCas9‐RNP is successfully implemented to correct a pathogenic RS1 mutation for X‐linked juvenile retinoschisis. It is also shown that off‐target effects triggered by SaCas9‐RNP are undetectable by targeted deep sequencing. Collectively, this study demonstrates the potential of SaCas9‐RNP‐mediated genome editing in human cells, which could facilitate genome‐editing‐based therapy.
An engineered mouse embryonic stem cell model with survivin as a molecular marker and EGFP as the reporter for high throughput screening of embryotoxic chemicals in vitro
Authors: Zang Ru , Xin Xin , Zhang Fengli , Li Ding , Yang Shang‐Tian
Published: April 2019

Embryonic stem cell test (EST) is the only generally accepted in vitro method for assessing embryotoxicity without animal sacrifice. However, the implementation and application of EST for regulatory embryotoxicity screening are impeded by its technical complexity, long testing period, and limited endpoint data. In this study, a high throughput embryotoxicity screening based on mouse embryonic stem cells (mESCs) expressing enhanced green fluorescent protein (EGFP) driven by a human survivin promoter and a human cytomegalovirus promoter, respectively, was developed. These EGFP expressing mESCs were cultured in three‐dimensional (3D) fibrous scaffolds in microbioreactors on a multiwell plate with EGFP fluorescence signals as cell responses to chemicals monitored noninvasively in a high throughput manner. Nine chemicals with known developmental toxicity were used to validate the survivin‐based embryotoxicity assay, which showed that strongly embryotoxic compounds such as 5‐fluorouracil, retinoic acid, and methotrexate downregulated survivin expression by more than 50% in 3 days, while weakly embryotoxic compounds such as boric acid, methoxyacetic acid, and tetracyclin showed modest downregulation effect and nonembryotoxic saccharin, penicillin G, and acrylamide had negligible downregulation effect on survivin expression, confirming that survivin can be used as a molecular endpoint for high throughput screening of embryotoxicants. The potential developmental toxicity of three Chinese herbal medicines were also evaluated using this assay, demonstrating its application in in vitro developmental toxicity test for drug safety assessment.
Analysis of population‐based colorectal cancer screening in Guangzhou, 2011‐2015
Authors: Zhiqiang Feng , Jie Cao , Yuqiang Nie , Chenghua Gong , Hong Wang , Zheng Sun , Wanglin Li , Yongjian Zhou , Liping Dai , Lizhong Zeng , DeJian Zhao
Published: March 2019

Objective

To analyze the detection rates of colorectal cancer (CRC) and polyps by population‐based screening in Guangzhou.

Methods

From January 2011 to December 2015, the residents aged 30‐79 were selected for CRC screening. The residents were conducted Questionnaires and/or FOBT to assess high‐risk groups, the free colonoscopy examination was recommended, and the results were evaluated in detail.

Results

There were 98 927 residents involving screening, 5306 high‐risk residents identified (males 1859 and females 3447), and 4713 subjects underwent colonoscopy (males 1690 and females 3023). CRC was seen in 55 individuals (males 28 and females 27), and the detection rates in male were higher than in female (P = 0.019). And the detection rates increasing with age, for people over 60 years old, were obviously higher than those younger (x2 = 18.64, P = 0.000924).

The polyps were seen in 1458 (30.94%) cases， and 1420 subjects received pathological examination (adenomas 971 and non‐adenomatous polyps 449). Advanced adenomas were seen in 462 cases (males 240 and females 222) and 509 cases of non‐advanced adenomas (males 255 and females 254). For advanced adenomas, the detection rates in male were higher than female (14.20% vs 7.34%, P = 2.64 × 10−14). For the detection rates of adenomas or advanced adenomas by age, the people over 40 years were higher than younger (20.91% vs 3.61% P = 7.87 × 10−6; 9.94% vs 2.41%, P = 0.009).

Conclusions

For Guangzhou residents, the detection rates of CRC and adenoma were 1.17% and 20.60%. The detection rates of CRC increasing with age, for people over 60 years old, were obviously higher than those younger. But for people over 40 years, the detection rate of adenoma and advanced adenoma was higher than younger. So for people over 40 years, the CRC screening is recommended.
Short‐ and long‐term results with a percutaneous treatment in critical hand ischaemia
Authors: Ruzsa Zoltán , Berta Balázs , Tóth Júlia , Nemes Balázs , Katona András , Hüttl Arthúr , Ungi Imre , Bertrand Olivier F. , Merkely Béla
Published: March 2019

Background

The aim of this prospective registry was to determine the feasibility, safety, and outcomes of percutaneous transluminal angioplasty and thrombolysis in the treatment of critical hand ischemia (CHI).

Methods

One‐hundred one patients (aged 60.6 ± 15.3 years) were treated for CHI between 2012 and 2016 in three cardiovascular centers. Anatomically, the upper arm was divided into three segments (I‐subclavian, II‐brachial, and III‐forearm). We examined the rates of technical and clinical success, major adverse events (MAEs), and vascular complications at 1 year and at long‐term follow‐up.

Results

Nineteen patients (18.8%) were treated for acute CHI, and 82 (81.2%) for chronic CHI. Median follow‐up was 36.9 (19.6–68.3) months. Clinical symptoms were isolated rest pain in 91 patients (90.1%) and digital ulcer or gangrene in 10 patients (9.9%). The technical and clinical success rate of intervention was 96.0% (97/101) and 84.2% (85/101) at 1 year. Angioplasty was performed in Segments I, II, and III in 28 (27.7%), in 29 (28.7%), and 44 (43.5%) patients. Stent implantation was necessary in 47 patients (46.8%). Vascular access site complications were found in 2.1% of the sample. After 1 year, MAEs occurred in 27 patients (26.9%), and the target lesion revascularization rate was 11.9%. In two patients (1.9%), thoracic sympatectomy was necessary, and two patients (1.9%) underwent minor finger amputations.

Conclusions

Angioplasty of hand vessels for CHI is a feasible and safe procedure with acceptable rates of technical success and hand healing. MAEs are frequent because the rate of severe comorbidities is high.
Biopharmacological considerations for accelerating drug development of deguelin, a rotenoid with potent chemotherapeutic and chemopreventive potential
Authors: Varughese Rahel Sarah , Lam Walter Sze‐Tung , Marican Ahmad Abdurrahman bin Hanifah , Viganeshwari S. Hema , Bhave Anuja Satish , Syn Nicholas L. , Wang Jigang , Wong Andrea Li‐Ann , Kumar Alan Prem , Lobie Peter E. , Lee Soo Chin , Sethi Gautam , Goh Boon Cher , Wang Lingzhi
Published: April 2019

Deguelin is a rotenoid compound that exists in abundant quantities in the bark, roots, and leaves of the Leguminosae family of plants. An analysis of evidence from both in vitro and in vivo studies suggests that deguelin displays potent anticancer activity against multiple cancer types and exhibits chemopreventive potential in Akt‐inducible transgenic mouse models. Deguelin appears to impede carcinogenesis by enhancing cell apoptosis and hindering malignant transformation and tumor cell propagation. Crucial oncogenic pathways likely targeted by deguelin include the epithelial‐to‐mesenchymal transition; angiogenesis‐related pathways; and the phosphoinositide 3‐kinase/Akt, Wnt, epidermal growth factor receptor, c‐Met, and hedgehog signal transduction cascades. This review article provides a comprehensive summary of current preclinical research featuring deguelin as a leading chemotherapeutic and chemopreventive compound, and it highlights the importance of identifying companion molecular biomarkers and performing systemic pharmacokinetic studies for accelerating the process of developing deguelin as a clinical anticancer agent.
Population Pharmacokinetics and Pharmacodynamics of Teicoplanin and C‐Reactive Protein in Hospitalized Patients With Gram‐Positive Infections
Authors: Ogami Chika , Tsuji Yasuhiro , Muraki Yuichi , Mizoguchi Akiko , Okuda Masahiro , To Hideto
Published: April 2019

Teicoplanin is an antibiotic agent used for the treatment of Gram‐positive infections. The clinical benefit of teicoplanin is associated with its blood concentrations, but the optimal dosing regimen is not yet known. To explore the optimal individual dosing regimen, we performed a population pharmacokinetic (PK) and pharmacodynamic (PD) analysis targeting a large‐scale population, including patients with a wide range of ages, body weights, and renal functions. The PK of teicoplanin was described with a 2‐compartment model, and the PD of C‐reactive protein (CRP) concentrations was described with a turnover maximum inhibition model. The elimination half‐life of teicoplanin calculated from the final estimated parameters was 169 hours, and renal function was a significant covariate of teicoplanin clearance. The teicoplanin concentration producing 50% of the maximum inhibition of CRP production was estimated to be 2.66 mg/L. The minimum concentration of teicoplanin in patients with higher loading doses (15 mg/kg) reached the target range (15‐30 mg/L) with a probability of >50% in the dosing simulation. We described the influence of body size, body composition, and renal function on the PK of teicoplanin. The population PKPD model of teicoplanin and CRP in this study should provide useful information for development of a dosing strategy including the sequential clinical benefit of teicoplanin.
Does oral fluid contribute to exhaled breath samples collected by means of an electret membrane?
Authors: Garzinsky Ann‐Marie , Walpurgis Katja , Krug Oliver , Thevis Mario
Published: March 2019

To date, blood (and serum) as well as urine samples are the most commonly collected specimens for routine doping controls, which allow for the analytical coverage of an extensive set of target analytes relevant to sports drug testing programs. In the course of studies to identify potential alternative matrices to complement current testing approaches, exhaled breath (EB) has been found to offer advantageous properties especially with regard to the sample collection procedure, which is less invasive, less intrusive, and less time‐consuming when compared to conventional blood and urine testing. A yet unaddressed question has been the potential contribution of oral fluid (OF) to EB samples. The current investigation focused on characterizing an electret membrane‐based EB collection device concerning a potential introduction of OF during the sampling procedure. For that purpose, EB and OF samples collected under varying conditions from a total of 14 healthy volunteers were tested for the presence of abundant salivary proteins using bottom‐up proteomics approaches such as SDS‐PAGE followed by tryptic digestion and chromatographic‐mass spectrometric analysis. The trapping baffles integrated into the mouthpiece of the EB collection device were found to effectively retain OF introduced into the unit during sample collection as no saliva breakthrough was detectable using the established analytical approach targeting predominantly the highly abundant salivary α‐amylase. Since α‐amylase was found unaffected by storage, smoking, food intake, and exercise, it appears to be a useful marker to reveal possible OF contaminations of EB collection devices.
Accounting for kin sampling reveals genetic connectivity in Tasmanian and New Zealand school sharks, Galeorhinus galeus
Authors: Devloo‐Delva Floriaan , Maes Gregory E. , Hernández Sebastián I. , Mcallister Jaime D. , Gunasekera Rasanthi M. , Grewe Peter M. , Thomson Robin B. , Feutry Pierre
Published: April 2019

Fishing represents a major problem for conservation of chondrichthyans, with a quarter of all species being overexploited. School sharks, Galeorhinus galeus, are targeted by commercial fisheries in Australia and New Zealand. The Australian stock has been depleted to below 20% of its virgin biomass, and the species is recorded as Conservation Dependent within Australia. Individuals are known to move between both countries, but it is disputed whether the stocks are reproductively linked. Accurate and unbiased determination of stock and population connectivity is crucial to inform effective management. In this study, we assess the genetic composition and population connectivity between Australian and New Zealand school sharks using genome‐wide SNPs, while accounting for non‐random kin sampling. Between 2009 and 2013, 88 neonate and juvenile individuals from Tasmanian and New Zealand nurseries were collected and genotyped. Neutral loci were analyzed to detect fine‐scale signals of reproductive connectivity. Seven full‐sibling groups were identified and removed for unbiased analysis. Based on 6,587 neutral SNPs, pairwise genetic differentiation from Tasmanian and New Zealand neonates was non‐significant (FST = 0.0003, CI95 = [−0.0002, 0.0009], p = 0.1163; Dest = 0.0006 ± 0.0002). This pattern was supported by clustering results. In conclusion, we show a significant effect of non‐random sampling of kin and identify fine‐scale reproductive connectivity between Australian and New Zealand school sharks.

OPEN RESEARCH BADGES

This article has earned an Open Data Badge for making publicly available the digitally‐shareable data necessary to reproduce the reported results. The data is available at https://doi.org/10.5061/dryad.pd8612j.
Urbanization and the temporal patterns of social networks and group foraging behaviors
Authors: Jones Teri B. , Evans Julian C. , Morand‐Ferron Julie
Published: April 2019

Urbanization causes dramatic and rapid changes to natural environments, which can lead the animals inhabiting these habitats to adjust their behavioral responses. For social animals, urbanized environments may alter group social dynamics through modification of the external environment (e.g., resource distribution). This might lead to changes in how individuals associate or engage in group behaviors, which could alter the stability and characteristics of social groups. However, the potential impacts of urban habitat use, and of habitat characteristics in general, on the nature and stability of social associations remain poorly understood. Here, we quantify social networks and dynamics of group foraging behaviors of black‐capped chickadees (N = 82, Poecile atricapillus), at four urban and four rural sites weekly throughout the nonbreeding season using feeders with radio frequency identification of individual birds. Because anthropogenic food sources in urban habitats (e.g., bird feeders) provide abundant and reliable resources, we predicted that social foraging associations may be of less value in urban groups, and thus would be less consistent than in rural groups. Additionally, decreased variability of food resources in urban habitats could lead to more predictable foraging patterns (group size, foraging duration, and the distribution of foraging events) in contrast to rural habitats. Networks were found to be highly consistent through time in both urban and rural habitats. No significant difference was found in the temporal clumping of foraging events between habitats. However, as predicted, the repeatability of the clumping of foraging events in time was significantly higher in urban than rural habitats. Our results suggest that individuals living in urban areas have more consistent foraging behaviors throughout the nonbreeding season, whereas rural individuals adjust their tactics due to less predictable foraging conditions. This first examination of habitat‐related differences in the characteristics and consistency of social networks along an urbanization gradient suggests that anthropic habitat use results in subtle modifications in social foraging patterns. Future studies should examine potential implications of these differences for variation in predation risk, energy intake, and information flow.
Crossing the Pillars of Hercules: Understanding transoceanic migrations of seabirds throughout their breeding range
Authors: Ramos Raül
Published: April 2019

Variability in long‐distance migration strategies is still poorly understood due to the fact that individuals are often tracked from a single colony/population. Transoceanic migrations of Scopoli's shearwaters (Calonectris diomedea) across the Strait of Gibraltar (SoG) have been tracked from several breeding colonies isolatedly, and factors related to the variability in phenological schedules among different populations remain, therefore, not well‐understood. Using light‐level geolocator data, I examined the autumn (postbreeding) and spring (prebreeding) migratory passage dates through SoG of four populations of Scopoli's shearwater spread along the longitudinal breeding range of the species. Additionally, I also estimated the at‐sea activity patterns (from immersion data) during both migratory passages, as well as the body size (from morphometric data) of the individuals of these populations. On average, Scopoli's shearwaters leave the Mediterranean (cross SoG) on 31 October ± 1.8 days on their autumn migrations and return on 03 March ± 1.6 days on their spring migrations. At the population level, there was a clear gradient in the timing of crossing SoG: birds from the westernmost populations (Murcia, SE Spain) were the first ones in leaving the Mediterranean while easternmost breeders (Paximada, Crete) were the last ones. In spring, only birds from the largest breeding population (Zembra, Tunisia) seemed to advance their return and crossed SoG significantly earlier than birds tracked at the remaining populations. In both passages, shearwaters from central and eastern populations spent more time flying than their conspecifics from the western Mediterranean. Scopoli's shearwater populations display a differential phenology and behavior in their migratory passages through SoG. The longitudinal gradient in body size already reported for the species could be an evolutionary response to an obvious trade‐off between sharing common wintering grounds in the Atlantic Ocean and the temporal constraints of restoring physiological condition in those grounds.

OPEN RESEARCH BADGES

This article has earned an Open Data Badge for making publicly available the digitally‐shareable data necessary to reproduce the reported results. The data is available at https://hdl.handle.net/2445/128784.
Physicians' guideline adherence is associated with long‐term heart failure mortality in outpatients with heart failure with reduced ejection fraction: the QUALIFY international registry
Authors: Komajda Michel , Schöpe Jakob , Wagenpfeil Stefan , Tavazzi Luigi , Böhm Michael , Ponikowski Piotr , Anker Stefan D. , Filippatos Gerasimos S. , Cowie Martin R. ,   on behalf of the QUALIFY Investigators
Published: April 2019

Background

Physicians' adherence to guideline‐recommended therapy is associated with short‐term clinical outcomes in heart failure (HF) with reduced ejection fraction (HFrEF). However, its impact on longer‐term outcomes is poorly documented. Here, we present results from the 18‐month follow‐up of the QUALIFY registry.

Methods and results

Data at 18 months were available for 6118 ambulatory HFrEF patients from this international prospective observational survey. Adherence was measured as a continuous variable, ranging from 0 to 1, and was assessed for five classes of recommended HF medications and dosages. Most deaths were cardiovascular (CV) (228/394) and HF‐related (191/394) and the same was true for unplanned hospitalizations (1175 CV and 861 HF‐related hospitalizations, out of a total of 1541). According to univariable analysis, CV and HF deaths were significantly associated with physician adherence to guidelines. In multivariable analysis, HF death was associated with adherence level [subdistribution hazard ratio (SHR) 0.93, 95% confidence interval (CI) 0.87–0.99 per 0.1 unit adherence level increase; P = 0.034] as was composite of HF hospitalization or CV death (SHR 0.97, 95% CI 0.94–0.99 per 0.1 unit adherence level increase; P = 0.043), whereas unplanned all‐cause, CV or HF hospitalizations were not (all‐cause: SHR 0.99, 95% CI 0.9–1.02; CV: SHR 0.98, 95% CI 0.96–1.01; and HF: SHR 0.99, 95% CI 0.96–1.02 per 0.1 unit change in adherence score; P = 0.52, P = 0.2, and P = 0.4, respectively).

Conclusion

These results suggest that physicians' adherence to guideline‐recommended HF therapies is associated with improved outcomes in HFrEF. Practical strategies should be established to improve physicians' adherence to guidelines.
Conversion of Isatins to Tryptanthrins, Heterocycles Endowed with a Myriad of Bioactivities
Authors: Amara Rim , Awad Haçan , Chaker Diana , Bentabed‐Ababsa Ghenia , Lassagne Frédéric , Erb William , Chevallier Floris , Roisnel Thierry , Dorcet Vincent , Fajloun Ziad , Vidal Joëlle , Mongin Florence
Published: April 2019

The numerous bioactivities exhibited by tryptanthrins led chemists to develop synthetic approaches towards this important scaffold. In particular, conversion of isatins into tryptanthrins has been the subject of several studies. In this context, by using iodine and potassium hydroxide at room temperature, we have discovered a simple way to convert isatin and seven of its 5‐substituted derivatives (Bu, F, Cl, Br, I, OMe and OCF3) into the corresponding tryptanthrins. Furthermore, a mechanism was proposed to explain this original reactivity. Finally, we evaluated the antibacterial, antifungal, antioxidant and cytotoxic properties of the synthesized tryptanthrins. The unprecedented inhibition of human 20S constitutive proteasome was finally evaluated.
Controls on the geotechnical response of sedimentary rocks to weathering
Authors: de Vilder S.J. , Brain M.J. , Rosser N.J.
Published: March 2019

Weathering reduces the strength of rocks and so is a key control on the stability of rock slopes. Recent research suggests that the geotechnical response of rocks to weathering varies with ambient stress conditions resulting from overburden loading and/or stress concentrations driven by near‐surface topography. In addition, the stress history experienced by the rock can influence the degree to which current weathering processes cause rock breakdown. To address the combined effect of these potential controls, we conducted a set of weathering experiments on two sedimentary lithologies in laboratory and field conditions. We firstly defined the baseline geotechnical behaviour of each lithology, characterising surface hardness and stress–strain behaviour in unconfined compression. Weathering significantly reduced intact rock strength, but this was not evident in measurements of surface hardness. The ambient compressive stress applied to samples throughout the experiments did not cause any observable differences in the geotechnical behaviour of the samples. We created a stress history effect in sub‐sets of samples by generating a population of microcracks that could be exploited by weathering processes. We also geometrically modified groups of samples to cause near‐surface stress concentrations that may allow greater weathering efficacy. However, even these pronounced sample modifications resulted in insignificant changes in geotechnical behaviour when compared to unmodified samples. The observed reduction in rock strength changed the nature of failure of the samples, which developed post‐peak strength and underwent multiple stages of brittle failure. Although weakened, these samples could sustain greater stress and strain following exceedance of peak strength. On this basis, the multi‐stage failure style exhibited by weaker weathered rock may permit smaller‐magnitude, higher‐frequency events to trigger fracture through intact rock bridges as well as influencing the characteristics of pre‐failure deformation. These findings are consistent with patterns of behaviour observed in field monitoring results. © 2019 John Wiley & Sons, Ltd.
Gallbladder Dyskinesia Is Associated With an Impaired Postprandial Fibroblast Growth Factor 19 Response in Critically Ill Patients
Authors: Koelfat Kiran V.K. , Plummer Mark P. , Schaap Frank G. , Lenicek Martin , Jansen Peter L.M. , Deane Adam M. , Olde Damink Steven W.M.
Published: April 2019

Critical illness is associated with a disturbed regulation of gastrointestinal hormones resulting in functional and metabolic anomalies. Fibroblast growth factor 19 (FGF19) is an ileum‐derived metabolic hormone induced by bile salts upon gallbladder emptying after enteral nutrient stimulation. Our aim was to study the nutrient‐stimulated FGF19 response in 24 patients admitted to the intensive care unit (ICU) compared with 12 healthy controls. All subjects received intraduodenal high‐lipid nutrient infusion for 120 minutes. Blood was collected every 30 minutes until 1 hour after infusion, and gallbladder emptying was studied by ultrasound. Serum levels of bile salts and FGF19 were assessed. ICU patients had significantly higher fasting bile salt serum levels compared with controls, whereas FGF19 serum levels were similar. In both groups, nutrient infusion elicited substantial bile salt elevations (P < 0.001), peaking at 90 minutes, albeit with a significantly lower peak in the ICU patients (P = 0.029). In controls, FGF19 was significantly elevated relative to baseline from 120 minutes onward (P < 0.001). In ICU patients, the FGF19 response was blunted, as reflected by significantly lower FGF19 elevations at 120, 150, and 180 minutes (P < 0.05) and significantly lower area under the curve (AUC) values compared with controls (P < 0.001). Gallbladder dysmotility was associated with the impaired FGF19 response in critical illness. The gallbladder ejection fraction correlated positively with FGF19 AUC values (ρ = +0.34, P = 0.045). In 10 of 24 ICU patients, gallbladder emptying was disturbed. These patients had significantly lower FGF19 AUC values (P < 0.001). Gallbladder emptying and the FGF19 response were respectively disturbed or absent in patients receiving norepinephrine. Conclusion: The nutrient‐stimulated FGF19 response is impaired in ICU patients, which is mechanistically linked to gallbladder dysmotility in critical illness. This may contribute to disturbed liver metabolism in these patients and has potential as a nutritional biomarker.
Hepatocyte Nuclear Factor 4‐Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver
Authors: Thakur Avinash , Wong Jasper C.H. , Wang Evan Y. , Lotto Jeremy , Kim Donghwan , Cheng Jung‐Chien , Mingay Matthew , Cullum Rebecca , Moudgil Vaishali , Ahmed Nafeel , Tsai Shu‐Huei , Wei Wei , Walsh Colum P. , Stephan Tabea , Bilenky Misha , Fuglerud Bettina M. , Karimi Mohammad M. , Gonzalez Frank J. , Hirst Martin , Hoodless Pamela A.
Published: April 2019

Cell‐fate determination is influenced by interactions between master transcription factors (TFs) and cis‐regulatory elements. Hepatocyte nuclear factor 4 alpha (HNF4A), a liver‐enriched TF, acts as a master controller in specification of hepatic progenitor cells by regulating a network of TFs to control onset of hepatocyte cell fate. Using analysis of genome‐wide histone modifications, DNA methylation, and hydroxymethylation in mouse hepatocytes, we show that HNF4A occupies active enhancers in hepatocytes and is essential for active histone and DNA signatures, especially acetylation of lysine 27 of histone 3 (H3K27ac) and 5‐hydroxymethylcytosine (5hmC). In mice lacking HNF4A protein in hepatocytes, we observed a decrease in both H3K27ac and hydroxymethylation at regions bound by HNF4A. Mechanistically, HNF4A‐associated hydroxymethylation (5hmC) requires its interaction with ten‐eleven translocation methylcytosine dioxygenase 3 (TET3), a protein responsible for oxidation from 5mC to 5hmC. Furthermore, HNF4A regulates TET3 expression in liver by directly binding to an enhancer region. Conclusion: In conclusion, we identified that HNF4A is required for the active epigenetic state at enhancers that amplifies transcription of genes in hepatocytes.
Screening of Three Transition Metal‐Mediated Reactions Compatible with DNA‐Encoded Chemical Libraries
Authors: Favalli Nicholas , Bassi Gabriele , Zanetti Tania , Scheuermann Jörg , Neri Dario
Published: April 2019

The construction of DNA‐encoded chemical libraries (DECLs) crucially relies on the availability of chemical reactions, which are DNA‐compatible and which exhibit high conversion rates for a large number of diverse substrates. In this work, we present our optimization and validation procedures for three copper and palladium‐catalyzed reactions (Suzuki cross‐coupling, Sonogashira cross‐coupling, and copper(I)‐catalyzed alkyne‐azide cycloaddition (CuAAC)), which have been successfully used by our group for the construction of large encoded libraries.
A population‐based study of the relationship between endometrial thickness and prevalence of breast mass in postmenopausal women
Authors: Li Hao , Ran Liang , Wu He , Xu Zhou , Wu Kai‐Nan , Kong Ling‐Quan
Published: March 2019

Objectives

To determine the relationship between endometrial thickness and the prevalence of breast mass in postmenopausal women.

Methods

The prevalence of breast mass was investigated in 6759 postmenopausal women (≥60 years) with different endometrial thicknesses who underwent breast and transvaginal ultrasonography from January 2015 to June 2017. Multivariable logistic regression analysis was used to obtain odds ratios and 95% confidence intervals for breast mass in postmenopausal women with increased endometrial thickness after adjusting for age, height, and body mass index.

Results

Compared with a baseline endometrial thickness of less than 3 mm, the prevalence of breast mass increased in patients with endometrial thickness ≥3–4.9 mm (OR 1.077; 95% CI, 0.868–1.338), ≥5–9.9 mm (OR 1.910; 95% CI, 1.189–3.067), and ≥10 mm (OR 3.546; 95% CI, 1.458–8.620) (Ptrend=0.0026). In subgroup analysis, correlations between endometrial thickness and prevalence of breast mass with malignant possibility (BI‐RADS ≥3) were similar and remained significant (Ptrend=0.035).

Conclusion

Postmenopausal women with endometrial thickness greater than or equal to 5 mm have a significantly increased prevalence of breast mass and breast mass with malignant possibility (BI‐RADS ≥3). Breast cancer screening for postmenopausal women with increased endometrial thickness should be given greater attention.
Effects of allyl isothiocyanate on insulin resistance, oxidative stress status, and transcription factors in high‐fat diet/streptozotocin‐induced type 2 diabetes mellitus in rats
Authors: Sahin Nurhan , Orhan Cemal , Erten Fusun , Tuzcu Mehmet , Defo Deeh Patrick B. , Ozercan Ibrahim H. , Juturu Vijaya , Kazim Sahin
Published: March 2019

Allyl isothiocyanate (AITC), a dietary phytochemical found in some cruciferous vegetables, is commonly used as an antimicrobial, anticancer, and antioxidant agent. In the present study, we investigated the effects of AITC on insulin resistance and transcription factors in a diabetic rat model. A total of 42 Wistar rats were divided into six groups and orally treated for 12 weeks as follows: (i) control; (ii) AITC (100 mg/kg body weight [BW]); (iii) high fat diet (HFD); (iv) HFD + AITC (100 mg/kg BW); (v) HFD + streptozotocin (STZ, 40 mg/kg BW); and (vi) HFD + STZ + AITC. Administration of AITC reduced blood glucose, total cholesterol, triglycerides, and creatinine levels, but increased (P < 0.001) total antioxidant capacity. In AITC‐treated rats, the glucose transporter‐2, peroxisome proliferator‐activated receptor gamma, p‐insulin receptor substrate‐1, and nuclear factor erythroid‐derived 2 in the liver and kidney were increased while nuclear factor‐kappa B was downregulated (P < 0.05). In conclusion, AITC possesses antidiabetic, antioxidant, and anti‐inflammatory activities in HFD/STZ‐induced T2DM in rats. These findings may further justify the importance of AITC in phytomedicine.
Experimental and computational study of the pKa of coumaric acid derivatives
Authors: Benvidi Ali , Dadras Abbas , Abbasi Saleheh , Tezerjani Marzieh D. , Rezaeinasab Masoud , Tabaraki Reza , Namazian Mansour
Published: April 2019

The dissociation constant (pKa) of a drug is a key parameter in drug discovery and pharmaceutical formulation. The hydroxy substituent has a significant effect on the acidity of hydroxycinnamic acid. In this work, the acidic constants of coumaric acids are obtained experimentally by spectrophotometry using the chemometric method and calculated theoretically using ab initio quantum mechanical method at the HF/6‐31G* level of theory in combination with the SMD continuum solvation method. Rank annihilation factor analysis (RAFA) is an efficient chemometric technique based on the elimination of the contribution of one of the chemical components from the data matrix. RAFA cannot be performed because the pure spectrum of HA− is not available. So, two‐rank annihilation factor analysis (TRAFA) is proposed for the determination of the pKa OF H2A. A comparison between the pKa values obtained previously by TRAFA for the molecules o‐coumaric acid (4.13, 9.58), m‐coumaric acid (4.48, 10.35), and p‐coumaric acid (4.65, 9.92) makes it clear that there is good agreement between the results obtained by TRAFA and ab initio quantum mechanical method.
Thermogenic flux induced by lignoceric acid in peroxisomes isolated from HepG2 cells and from X‐adrenoleukodystrophy and control fibroblasts
Authors: Petroni Anna , Paroni Rita , Aloisi Anna Maria , Blasevich Milena , Haman Nabil , Fessas Dimitrios
Published: April 2019

This work analyzes the thermogenic flux induced by the very long‐chain fatty acid (VLCFA) lignoceric acid (C24:0) in isolated peroxisomes.

Specific metabolic alterations of peroxisomes are related to a variety of disorders, the most frequent one being the neurodegenerative inherited disease X‐linked adrenoleukodystrophy (X‐ALD). A peroxisomal transport protein is mutated in this disorder. Due to reduced catabolism and enhanced fatty acid (FA) elongation, VLCFA accumulates in plasma and in all tissues, contributing to the clinical manifestations of this disorder. During peroxisomal metabolism, heat is produced but it is considered lost. Instead, it is a form of energy that could play a role in molecular mechanisms of this pathology and other neurodegenerative disorders.

The thermogenic flux induced by lignoceric acid (C24:0) was estimated by isothermal titration calorimetry in peroxisomes isolated from HepG2 cells and from fibroblasts obtained from patients with X‐ALD and healthy subjects.

Heat flux induced by lignoceric acid in HepG2 peroxisomes was exothermic, indicating normal peroxisomal metabolism. In X‐ALD peroxisomes the heat flux was endothermic, indicating the requirement of heat/energy, possibly for cellular metabolism. In fibroblasts from healthy subjects, the effect was less pronounced than in HepG2, a kind of cell known to have greater FA metabolism than fibroblasts.

Our hypothesis is that heat is not lost but it could act as an activator, for example on the heat‐sensitive pathway related to TRVP2 receptors. To investigate this hypothesis we focused on peroxisomal metabolism, considering that impaired heat generation could contribute to the development of peroxisomal neurodegenerative disorders.
Evidence for the impact of BAG3 on electrophysiological activity of primary culture of neonatal cardiomyocytes
Authors: Tahrir Farzaneh G. , Gordon Jennifer , Feldman Arthur M. , Cheung Joseph , Khalili Kamel , Mohseni Ahooyi Taha
Published: April 2019

Homeostasis of proteins involved in contractility of individual cardiomyocytes and those coupling adjacent cells is of critical importance as any abnormalities in cardiac electrical conduction may result in cardiac irregular activity and heart failure. Bcl2‐associated athanogene 3 (BAG3) is a stress‐induced protein whose role in stabilizing myofibril proteins as well as protein quality control pathways, especially in the cardiac tissue, has captured much attention. Mutations of BAG3 have been implicated in the pathogenesis of cardiac complications such as dilated cardiomyopathy. In this study, we have used an in vitro model of neonatal rat ventricular cardiomyocytes to investigate potential impacts of BAG3 on electrophysiological activity by employing the microelectrode array (MEA) technology. Our MEA data showed that BAG3 plays an important role in the cardiac signal generation as reduced levels of BAG3 led to lower signal frequency and amplitude. Our analysis also revealed that BAG3 is essential to the signal propagation throughout the myocardium, as the MEA data‐based conduction velocity, connectivity degree, activation time, and synchrony were adversely affected by BAG3 knockdown. Moreover, BAG3 deficiency was demonstrated to be connected with the emergence of independently beating clusters of cardiomyocytes. On the other hand, BAG3 overexpression improved the activity of cardiomyocytes in terms of electrical signal amplitude and connectivity degree. Overall, by providing more in‐depth analyses and characterization of electrophysiological parameters, this study reveals that BAG3 is of critical importance for electrical activity of neonatal cardiomyocytes.