bluuebunny/crossref_metadata_2025 huggingface dataset:
Sinonasal renal cell‐like adenocarcinoma: Easily misdiagnosed sinonasal tumor
Authors: Wu Ching‐Nung , Chuang I‐Chieh , Chuang Ming‐Jung , Chen Wei‐Chih
Published: July 2018

Background

Sinonasal renal cell‐like adenocarcinoma is rare and exhibits unique pathological and clinical manifestations. Correct diagnosis and treatment of this newly described entity are challenging for both clinicians and pathologists.

Methods

We report a female patient with sinonasal renal cell‐like adenocarcinoma who initially presented with right intermittent epistaxis.

Results

A 26‐year‐old woman presented with a 1‐year history of right intermittent epistaxis and hyposmia. Nasal endoscopy revealed a reddish tumor in the right nasal cavity. An MRI revealed a hyperintense tumor arising from the right olfactory cleft accompanied by prominent feeding vessels originating from the anterior ethmoid artery (AEA). We performed a bicoronal incision with ligation of the AEA followed by endoscopic resection of the skull base tumor. The patient is currently free of recurrence.

Conclusion

This is the first study to review the clinical features of sinonasal renal cell‐like adenocarcinoma. We recommend surgical resection as the mainstay of treatment.
Lingual lymph nodes in patients with squamous cell carcinoma of the tongue and the floor of the mouth
Authors: Jia Jun , Jia Meng‐qi , Zou Hai‐xiao
Published: July 2018

Background

The treatment failure for oral squamous cell carcinoma (SCC) frequently takes the form of local and regional recurrences. We investigated the role of lingual lymph nodes (LLNs) in the recurrence of SCC of the tongue and the floor of the mouth.

Methods

A total of 111 patients with SCC of the tongue and the floor of the mouth who received treatment between 2012 and 2017 were included in this study. The patients with lingual lymph nodes that were confirmed to be metastasis on pathological examination were classified into the LNN group. The demographic and clinical data differences between the No‐LLN group and the LLN group were compared. Statistical analyses were performed using the Pearson chi‐square test

Results

The total incidence of LLNs was 17.12% (19/111) and 5 patients (4.5%) demonstrated LLN metastases. All the patients with LLN metastases had a neck lymph node status of N2 classification. The incidence and metastasis of the LLNs were associated with pathological classifications of SCC of the tongue and the floor of the mouth.

Conclusions

LLNs are rare in patients with SCC of the tongue and the floor of the mouth, and they would be ready to be omitted. The dissection of these LLNs would be of benefit to those patients with advanced pathological grade.
Schistosoma mansoni Egg–Secreted Antigens Activate Hepatocellular Carcinoma–Associated Transcription Factors c‐Jun and STAT3 in Hamster and Human Hepatocytes
Authors: Roderfeld Martin , Padem Sevinc , Lichtenberger Jakob , Quack Thomas , Weiskirchen Ralf , Longerich Thomas , Schramm Gabriele , Churin Yuri , Irungbam Karuna , Tschuschner Annette , Windhorst Anita , Grevelding Christoph G. , Roeb Elke
Published: July 2018

Clinical data have provided evidence that schistosomiasis can promote hepatocellular carcinogenesis. c‐Jun and STAT3 are critical regulators of liver cancer development and progression. The aim of the present study was to investigate the hepatocellular activation of c‐Jun and STAT3 by Schistosoma mansoni infection. Expression and function of c‐Jun and STAT3 as well as proliferation and DNA repair were analyzed by western blotting, electrophoretic mobility‐shift assay, and immunohistochemistry in liver of S. mansoni–infected hamsters, Huh7 cells, primary hepatocytes, and human liver biopsies. Hepatocellular activation of c‐Jun was demonstrated by nuclear translocation of c‐Jun, enhanced phosphorylation (Ser73), and AP‐1/DNA‐binding in response to S. mansoni infection. Nuclear c‐Jun staining pattern around lodged eggs without ambient immune reaction, and directionally from granuloma to the central veins, suggested that substances released from schistosome eggs were responsible for the observed effects. In addition, hepatocytes with c‐Jun activation show cell activation and DNA double‐strand breaks. These findings from the hamster model were confirmed by analyses of human biopsies from patients with schistosomiasis. Cell culture experiments finally demonstrated that activation of c‐Jun and STAT3 as well as DNA repair were induced by an extract from schistosome eggs (soluble egg antigens) and culture supernatants of live schistosome egg (egg‐conditioned medium), and in particular by IPSE/alpha‐1, the major component secreted by live schistosome eggs. The permanent activation of hepatocellular carcinoma–associated proto‐oncogenes such as c‐Jun and associated transcription factors including STAT3 by substances released from tissue‐trapped schistosome eggs may be important factors contributing to the development of liver cancer in S. mansoni–infected patients. Therefore, identification and therapeutic targeting of the underlying pathways is a useful strategy to prevent schistosomiasis‐associated carcinogenesis.
Long noncoding RNAs and their epigenetic function in hematological diseases
Authors: Huang Hanying , Sun Jingnan , Sun Yunpeng , Wang Cong , Gao Sujun , Li Wei , Hu Ji‐Fan
Published: July 2018

Recent discoveries demonstrate the importance of long noncoding RNA (lncRNA) in the regulation of multiple major processes impacting development, differentiation, and metastasis of hematological diseases through epigenetic mechanisms. In contrast to genetic changes, epigenetic modification does not modify genes but is frequently reversible, thus providing opportunities for targeted treatment using specific inhibitors. In this review, we will summarize the function and epigenetic mechanism of lncRNA in malignant hematologic diseases.
Dark triad personalities and counterproductive work behaviors among physicians in China
Authors: Ying Liu , Cohen Aaron
Published: July 2018

The goal of this study was to examine the relationship between the dark triad personality (DTP) and organizational and individual counterproductive work behaviors (CWBs), based on the argument that situational variables mediate this relationship. The data were collected at Beijing Children's Hospital, the largest children's hospital in China. Paper and pencil questionnaires were distributed to 200 randomly selected physicians, of whom 168 responded, an 84% response rate. The findings of regression analysis and mediation analysis show a strong relationship between the DTP and CWBs. Of the three traits of the DTP, Machiavellianism was significantly related to both dimensions of CWBs, organizational and interpersonal. The findings also show that the relationship examined here was affected by mediators, particularly organizational commitment and organizational justice, emphasizing the effect of the environment on the behavior of dark personalities. The environment, represented by the mediators, had no effect on narcissists' CWB, and psychological contract breach was the only mediator found to have no mediating effect. The paper concludes with suggestions and recommendations for future research, in particular in different settings.
Health sector decentralisation in Tanzania: How do institutional capacities influence use of decision space?
Authors: Kigume Ramadhani , Maluka Stephen
Published: July 2018

While decentralisation of health systems has dominated political arena in the low‐income and middle‐income countries since the 1970s, there is scarcity of studies on how organisational capacities influence the ability of the decentralised local‐level officials to use the available decision space. Using qualitative approach through in‐depth interviews and focus group discussions in 4 districts in Tanzania, this study explored how organisational capacities influence the use of decision space available in the 5 broad categories namely planning, finance, human resources, service organisation, and governance. The findings of the study indicated that while the district health managers had authority in many health system functional areas, limited capacity of the local government in financial resources highly affected their capacity to make use of the available decision space. In addition, while the district health managers had skills, knowledge, and experiences in preparing district health plans, health facilities and community representatives had limited capacity. Most of the health facilities had critical shortage of skilled health providers. Similarly, health committees had limited capacity in knowledge and skills. This study concludes that decentralisation will only improve delivery of health services when an appropriate degree of discretion is combined with adequate institutional capacities to enable exercise of those authorities. The district councils and the Ministry of Health should strengthen the capacities of health service providers and members of health committees and boards.
Task sharing: Development of evidence‐based co‐management strategy model for screening, detection, and management of diabetic retinopathy
Authors: Shah Mufarriq , Noor Ayesha , Ormsby Gail M. , Islam Fakir Amirul , Harper Colin Alex , Keeffe Jill Elizabeth
Published: July 2018

Background

The number of adults with diabetes is increasing worldwide and also the number of people with diabetic retinopathy (DR), a major complication of diabetes. Task sharing in eye care for people with diabetes could address the shortage in the number of ophthalmologists and increase access to eye care services. This study investigated the opinion of eye care professionals for a checklist of tasks, which are involved in DR management, to be possibly shared by optometrists and mid‐level eye and health care workers with ophthalmologists.

Methods

The study used a purposive sampling technique. All available eye and health care workers from five selected hospitals in two provinces in Pakistan were recruited. A cross‐sectional survey was conducted to investigate the potential roles of various cadres in eye care delivery for people with diabetes.

Results

Ninety‐six (79%) participants including doctors (n = 56), optometrists (n = 29), and mid‐level eye care workers (n = 11) responded to the survey. Two‐thirds of the participants suggested mid‐level eye care workers, while 88.5% stated that lady health workers could provide education and health promotion to people with diabetes. Most of the participants (88.5%) suggested that optometrists could share the task of dilated ophthalmoscopy with ophthalmologists for detection of DR and make referrals to ophthalmologists if needed. Ophthalmologists remained the recommended cadre to undertake the eye examinations of patients with proliferative DR and diabetic macular edema.

Conclusion

This research provided an insight on how task sharing in DR management can be implemented by optimizing the roles of eye care workers.
Expected returns and expected dividend growth in Europe: Legal origin, institutional, and financial determinants
Authors: Rambaccussing Dooruj , Power David
Published: July 2018

This paper uses a present value approach to show that price movements for equity indices in a sample of European stock markets can be traced to legal origin, institutional, and corporate financial factors. The present value literature states that stock indices move due to changes either in discount rates, dividend growth, or a combination of the two. Empirically, little is known about the mechanism through which legal, institutional, and corporate financial factors influence these variables, especially in a European context. The current paper attempts to plug this gap in the literature. Using the state space approach, we show that although expected returns are highly persistent, expected dividend growth tends to vary across the sample. Movements in markets are mainly due to changes in the discount rate. However, there appears to be a difference in the proportion of movements attributable to discount rate and dividend growth components. Stock markets in civil law countries tend to have a stronger link with the dividend growth variables as well as market size and activity measures. Expected dividend growth is also driven by profitability factors in both types of country. By contrast, there is no strong evidence of corporate indicators influencing expected returns.
Inter‐annual variability of global monsoon precipitation in present‐day and future warming scenarios based on 33 Coupled Model Intercomparison Project Phase 5 models
Authors: Ni Yan , Hsu Pang‐Chi
Published: July 2018

Simulations and future projections of year‐to‐year variation in global monsoon precipitation (GMP), defined as the summer precipitation amount per unit area within the global monsoon domain, are investigated using the 33 models that participated in Phase 5 of the Coupled Model Intercomparison Project (CMIP5). The inter‐annual standard deviation of GMP, which presents the amplitude of year‐to‐year variability in monsoon rainfall, is simulated well by the multi‐model ensemble (MME) mean of the 33 models and of the best five (B5) models. The B5 models show superior skills in reproducing the climatological monsoon precipitation and its inter‐annual variability. The inter‐annual standard deviations of 25‐year GMP in the present day (1979–2005) derived from the MME average of the 33 models and of the B5 models are 0.17 and 0.15 mm/day per unit area, respectively, both being close to the observation (0.16 mm/day per unit area). Consistent with the observed El Niño–Southern Oscillation (ENSO)–GMP relationship, the simulated variability of GMP is negatively correlated with the sea surface temperature in the Niño areas at the inter‐annual timescale.

Projections by the 33 CMIP5 models under the RCP4.5 scenario indicate that wet and dry monsoon years would occur more intensively in a warmer climate. Around 61% (20 out of the 33) of the models show enhanced inter‐annual variability of GMP by the end of the 21st century (2072–2098) compared to the period 1979–2005. The MME of the B5 models suggests that the amplitude of projected GMP variability would increase by ~20% from present day to the late 21st century. However, the increasing rate of GMP variability detected by the 33 models’ MME is relatively small (~6%), which is even smaller than the inter‐model standard deviation, suggesting the amplitude changes in GMP variability feature non‐negligible uncertainty among the 33 models. Under global warming, the inter‐annual variation of GMP would still be tightly connected with ENSO, although the projected amplitude changes in ENSO variability are noticeably diverse across the 33 CMIP5 models. The enhanced amplitude of inter‐annual GMP variability may be attributable to the increase in mean‐state moisture associated with global warming. The dynamic effect related to changes in the variability of monsoon circulation is small and less robust among the 33 CMIP5 models.
Using multi‐model ensembles of CMIP5 global climate models to reproduce observed monthly rainfall and temperature with machine learning methods in Australia
Authors: Wang Bin , Zheng Lihong , Liu De Li , Ji Fei , Clark Anthony , Yu Qiang
Published: July 2018

Global climate models (GCMs) are useful tools for assessing climate change impacts on temperature and rainfall. Although climate data from various GCMs have been increasingly used in climate change impact studies, GCMs configurations and module characteristics vary from one to another. Therefore, it is crucial to assess different GCMs to confirm the extent to which they can reproduce the observed temperature and rainfall. Rather than assessing the interdependence of each GCM, the purpose of this study is to compare the capacity of four different multi‐model ensemble (MME) methods (random forest [RF], support vector machine [SVM], Bayesian model averaging [BMA] and the arithmetic ensemble mean [EM]) in reproducing observed monthly rainfall and temperature. Of these four methods, the RF and SVM demonstrated a significant improvement over EM and BMA in terms of performance criteria. The relative importance of each GCM based on the RF ensemble in reproducing rainfall and temperature could also be ranked. We compared the GCMs importance and Taylor skill score and found that their correlation was 0.95 for temperature and 0.54 for rainfall. Our results also demonstrated that the number of GCMs ensemble simulations could be reduced from 33 to 25 in RF model while maintaining predictive error less than 2%. Having such a representative subset of simulations could reduce computational costs for climate impact modelling and maintain the quality of ensemble at the same time. We conclude that machine learning MME could be efficient and useful with improved accuracy in reproducing historical climate variables.
Posttraumatic Stress Disorder in Very Young Children: Diagnostic Agreement Between ICD‐11 and DSM‐5
Authors: Vasileva Mira , Haag Ann‐Christin , Landolt Markus A. , Petermann Franz
Published: July 2018

The prevalence of posttraumatic stress disorder (PTSD) in very young children depends on the diagnostic criteria. Thus far, studies have investigated the International Classification of Diseases (11th rev.; ICD‐11) criteria for PTSD only in samples of children older than 6 years of age. The aim of this study was to test the diagnostic agreement between the ICD‐11 and the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM‐5) criteria for children who are 6 years old and younger. Caregivers of children aged 3–6 years in foster care in Germany (N = 147) and parents of children aged 1–4 years who had attended a hospital in Switzerland following burn injuries (N  = 149) completed a questionnaire about children's PTSD. Rates of PTSD were calculated according to ICD‐11 (considering a specific and a more general conceptualization of intrusive memories) and DSM‐5 criteria and were compared using McNemar's tests and Cohen's kappa. The proportion of children who met the ICD‐11 criteria was 0.6–25.8% lower than the proportion of PTSD cases according to the DSM‐5 criteria. The diagnostic agreement between each ICD‐11 algorithm and DSM‐5 was moderate, κ = 0.52–0.66. A systematic investigation of adaptions of the ICD‐11 avoidance cluster identified alternative symptom combinations leading to higher agreement with the DSM‐5 requirements. Furthermore, DSM‐5 had higher predictive power for functional impairment than the ICD‐11 algorithms. In conclusion, the findings suggest that the ICD‐11 criteria show less sensitivity in very young children, which can be explained by the more stringent avoidance cluster.
Accuracy of Ultrasonography in the Evaluation of Tubal Sterilization Microinsert Positioning: Systematic Review and Meta‐analysis
Authors: Carretti Mayra , dos Santos Simões Ricardo , Bernardo Wanderley Marques , Pinheiro Walter , Pereira Anne Kristhine Cavalcante , Baracat Maria Candida Pinheiro , Soares Junior José Maria , Baracat Edmund Chada
Published: July 2018

The current reference standard to check the position of a tubal sterilization microinsert device after its insertion is hysterosalpingography. The objective of this study was to evaluate the accuracy of 2‐dimensional (2D) and 3‐dimensional (3D) ultrasonography (US) in the positioning of the tubal sterilization microinsert for definitive contraception. We searched MEDLINE, Embase, Cochrane, and Scopus databases through October 2017. Selection criteria included studies that analyzed the accuracy of 2D or 3D US, or both, with respect to the positioning of the microinsert. Data were displayed as forest plots and a summary receiver operating characteristic curves. Values for sensitivity, specificity, and positive and negative likelihood ratios (LRs) were calculated. The pooled analysis produced sensitivity and specificity values for 2D US in the positioning of the microinsert of 0.88 (95% confidence interval [CI], 0.47–1.0) and 0.92 (95% CI, 0.88–0.95), respectively, with positive and negative LRs of 8.68 (95% CI, 1.63–46.1) and 0.35 (95% CI, 0.11–1.11), respectively. Three studies analyzed the performance of 3D US, showing sensitivity, specificity, and positive and negative LRs of 0.75 (95% CI, 0.35–0.97), 0.82 (95% CI, 0.77–0.87), 3.65 (95% CI, 2.31–5.75), and 0.46 (95% CI, 0.2–1.09). In conclusion, 2D and 3D US are methods that show good accuracy in tubal sterilization microinsert positioning.
Upper airway reconstruction using long‐range optical coherence tomography: Effects of airway curvature on airflow resistance
Authors: Kimbell Julia S. , Basu Saikat , Garcia Guilherme J.M. , Frank‐Ito Dennis O. , Lazarow Frances , Su Erica , Protsenko Dimitry , Chen Zhongping , Rhee John S. , Wong Brian J.
Published: July 2018

Objectives

Adenotonsillectomy (AT) is commonly used to treat upper airway obstruction in children, but selection of patients who will benefit most from AT is challenging. The need for diagnostic evaluation tools without sedation, radiation, or high costs has motivated the development of long‐range optical coherence tomography (LR‐OCT), providing real‐time cross‐sectional airway imaging during endoscopy. Since the endoscope channel location is not tracked in conventional LR‐OCT, airway curvature must be estimated and may affect predicted airway resistance. The study objective was to assess effects of three realistic airway curvatures on predicted airway resistance using computational fluid dynamics (CFD) in LR‐OCT reconstructions of the upper airways of pediatric patients, before and after AT.

Methods

Eight subjects (five males, three females, aged 4–9 years) were imaged using LR‐OCT before and after AT during sedated endoscopy. Three‐dimensional (3D) airway reconstructions included three airway curvatures. Steady‐state, inspiratory airflow simulations were conducted under laminar conditions, along with turbulent simulations for one subject using the k‐ω turbulence model. Airway resistance (pressure drop/flow) was compared using two‐tailed Wilcoxon signed rank tests.

Results

Regardless of the airway curvatures, CFD findings corroborate a surgical end‐goal with computed post‐operative airway resistance significantly less than pre‐operative (P < 0.01). The individual resistances did not vary significantly for different airway curvatures (P > 0.25). Resistances computed using turbulent simulations differed from laminar results by less than ∼5%.

Conclusions

The results suggest that reconstruction of the upper airways from LR‐OCT imaging data may not need to account for airway curvature to be predictive of surgical effects on airway resistance. Lasers Surg. Med. 51:150–160, 2019. © 2018 Wiley Periodicals, Inc.
Experimental and theoretical studies of the inhibition performance of two furan derivatives on mild steel corrosion in acidic medium
Authors: Al‐Fakih Abdo M. , Abdallah Hassan H. , Aziz Madzlan
Published: July 2018

Inhibition performance of 2‐furanmethanethiol (FMT) and 2‐furonitrile (FN) against mild steel corrosion in 1 M hydrochloric acid was investigated using weight loss, adsorption isotherms, and electrochemical impedance spectroscopy (EIS). The surface morphology was studied by field emission scanning electron microscope (FESEM) and X‐ray photoelectron spectroscopy (XPS). Quantum chemical calculations were carried out to establish the active sites on the inhibitors. The results show that both inhibitors inhibit mild steel corrosion, and their inhibition efficiencies (IE) increase with increasing inhibitor concentration. FMT shows higher inhibiting effect with IE of 94.54% at 0.005 M. The adsorption of the inhibitors onto mild steel surface obeys Langmuir isotherm. FESEM analysis confirms the adsorption of both inhibitors on the surface. XPS analysis proves the adsorption of FMT onto the surface. The active sites on FMT and FN molecules were effectively established using density functional theory (DFT) based on natural atomic charge, Fukui indices, HOMO and LUMO frontier molecular orbitals. The experimental and quantum results prove the inhibition performances of both inhibitors. FMT performs as an efficient inhibitor with a significant and higher IE compared to FN.
A simplified curcumin targets the membrane of Bacillus subtilis
Authors: Morão Luana G. , Polaquini Carlos R. , Kopacz Malgorzata , Torrezan Guilherme S. , Ayusso Gabriela M. , Dilarri Guilherme , Cavalca Lúcia B. , Zielińska Aleksandra , Scheffers Dirk‐Jan , Regasini Luis O. , Ferreira Henrique
Published: July 2018

Curcumin is the main constituent of turmeric, a seasoning popularized around the world with Indian cuisine. Among the benefits attributed to curcumin are anti‐inflammatory, antimicrobial, antitumoral, and chemopreventive effects. Besides, curcumin inhibits the growth of the gram‐positive bacterium Bacillus subtilis. The anti‐B. subtilis action happens by interference with the division protein FtsZ, an ancestral tubulin widespread in Bacteria. FtsZ forms protofilaments in a GTP‐dependent manner, with the concomitant recruitment of essential factors to operate cell division. By stimulating the GTPase activity of FtsZ, curcumin destabilizes its function. Recently, curcumin was shown to promote membrane permeabilization in B. subtilis. Here, we used molecular simplification to dissect the functionalities of curcumin. A simplified form, in which a monocarbonyl group substituted the β‐diketone moiety, showed antibacterial action against gram‐positive and gram‐negative bacteria of clinical interest. The simplified curcumin also disrupted the divisional septum of B. subtilis; however, subsequent biochemical analysis did not support a direct action on FtsZ. Our results suggest that the simplified curcumin exerted its function mainly through membrane permeabilization, with disruption of the membrane potential necessary for FtsZ intra‐cellular localization. Finally, we show here experimental evidence for the requirement of the β‐diketone group of curcumin for its interaction with FtsZ.
Computational Approaches to Develop Isoquinoline Based Antibiotics through DNA Gyrase Inhibition Mechanisms Unveiled through Antibacterial Evaluation and Molecular Docking
Authors: Alagumuthu Manikandan , Muralidharan Vivek Panyam , Andrew Monic , Ahmed Mohammed Habeeb , Iyer Sathiyanarayanan Kulathu , Arumugam Sivakumar
Published: July 2018

Developing a new antibacterial drug by using (Z/E)‐4‐(4‐substituted‐benzylidene)‐2‐isoquinoline‐1,3(2H,4H)‐diones (5a–h) via DNA gyrase inhibition mechanism is the main aim of this study. DNA gyrase inhibition assay was executed to confirm the DNA gyrase inhibition potentials of 5a–h. DNA gyrase inhibitory potentials were further validated through molecular docking. Docking study was also intended to get more insight into the binding mode of 5a–h into the active site of DNA gyrase A. Agar well diffusion method antimicrobial activity on Gram−ve bacteria Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 424), and Gram+ve bacteria (Staphylococcus aureus (MTCC 96) and Streptococcus pyogenes (MTCC 442) was evaluated. Excellent DNA gyrase inhibition was exhibited by the compound 5c, IC50 0.55±0.12 μM; 5d, IC50 0.65±0.075 μg/mL; 5e, IC50 0.45±0.035 μM; 5f, IC50 0.58±0.025 μM; 5h, IC50 0.25±0.015 μM while Clorobiocin (standard) showed IC50 0.5±0.05 μM. Apart from all the in vitro studies, a plausible mechanism of DNA gyrase inhibition was also proposed through the in silico validations that are including molecular docking, predicted SAR, functional group availability, pharmacokinetic, and ADMET properties. These predictions are well supported to confirm the druggability possibility of the most potent compounds among (Z/E)‐4‐(4‐substituted‐benzylidene)‐2‐isoquinoline‐1,3(2H,4H) ‐diones (5a–h).
Chemistry‐driven Hit‐to‐lead Optimization Guided by Structure‐based Approaches
Authors: Hoffer Laurent , Muller Christophe , Roche Philippe , Morelli Xavier
Published: July 2018

For several decades, hit identification for drug discovery has been facilitated by developments in both fragment‐based and high‐throughput screening technologies. However, a major bottleneck in drug discovery projects continues to be the optimization of primary hits from screening campaigns in order to derive lead compounds. Computational chemistry or molecular modeling can play an important role during this hit‐to‐lead (H2L) stage by both suggesting putative optimizations and decreasing the number of compounds to be experimentally synthesized and evaluated. However, it is also crucial to consider the feasibility of organically synthesizing these virtually designed compounds. Furthermore, the generated molecules should have reasonable physicochemical properties and be medicinally relevant. This review focuses on chemistry‐driven and structure‐based computational methods that can be used to tackle the difficult problem of H2L optimization, with emphasis being placed on the strategy developed in our laboratory.
Galactomannan More than Pectin Exacerbates Liver Injury in Mice Fed with High‐Fat, High‐Cholesterol Diet
Authors: Shtriker Miriam G. , Peri Irena , Taieb Elise , Nyska Abraham , Tirosh Oren , Madar Zecharia
Published: July 2018

Scope

Galactomannan and citrus pectin are considered ‘super fibers’ known for altering gut microbiota composition and improving glucose and lipid metabolism. The study aims to investigate the fiber's effect on a nonalcoholic steatohepatitis (NASH) model.

Methods and results

Two feeding experiments are carried out using groups of 7–8 week‐old male C57BL/6J mice. The diets used are based on a high cholesterol/cholate diet (HCD), such as a nutritional NASH model. Mice are fed a diet with or without 15% fiber‐citrus pectin (HCD‐CP) or galactomannan (HCD‐G) together with the HCD (first experiment), which commenced 3 weeks prior to the HCD (second experiment). Liver damage is evaluated by histological and biochemical parameters. Galactomannan leads to lesser weight gain and improved glucose tolerance, but increased liver damage. This is shown by elevated levels of liver enzymes compared to that with HCD alone. Fibers induce higher steatosis, as evaluated by liver histology. This intriguing result is linked to various changes in the gut microbiota, such as elevated Proteobacteria levels in the galactomannan group, which are correlated with disturbed metabolism and dysbiosis.

Conclusions

In a NASH mouse model, galactomannan increases liver damage but improves glucose metabolism. Changes in the microbiota composition may answer this enigmatic observation.
On the strength of transversely isotropic rocks
Authors: Zhao Yang , Semnani Shabnam J. , Yin Qing , Borja Ronaldo I.
Published: July 2018

Accurate prediction of strength in rocks with distinct bedding planes requires knowledge of the bedding plane orientation relative to the load direction. Thermal softening adds complexity to the problem since it is known to have significant influence on the strength and strain localization properties of rocks. In this paper, we use a recently proposed thermoplastic constitutive model appropriate for rocks exhibiting transverse isotropy in both the elastic and plastic responses to predict their strength and strain localization properties. Recognizing that laboratory‐derived strengths can be influenced by material and geometric inhomogeneities of the rock samples, we consider both stress‐point and boundary‐value problem simulations of rock strength behavior. Both plane strain and 3D loading conditions are considered. Results of the simulations of the strength of a natural Tournemire shale and a synthetic transversely isotropic rock suggest that the mechanical model can reproduce the general U‐shaped variation of rock strength with bedding plane orientation quite well. We show that this variation could depend on many factors, including the stress loading condition (plane strain versus 3D), degree of anisotropy, temperature, shear‐induced dilation versus shear‐induced compaction, specimen imperfections, and boundary restraints.
Brain investigations of rodent disease models by chemical exchange saturation transfer at 21.1 T
Authors: Roussel Tangi , Rosenberg Jens T. , Grant Samuel C. , Frydman Lucio
Published: July 2018

This study explores opportunities opened up by ultrahigh fields for in vivo saturation transfer brain magnetic resonance imaging experiments. Fast spin‐echo images weighted by chemical exchange saturation transfer (CEST) effects were collected on Sprague–Dawley rats at 21.1 T, focusing on two neurological models. One involved a middle cerebral artery occlusion emulating ischemic stroke; the other involved xenografted glioma cells that were followed over the course of several days as they developed into brain tumors. A remarkably strong saturation‐derived contrast was observed for the growing tumors when calculating magnetization transfer ratios atc. 3.8 ppm. This large contrast originated partially from an increase in the contribution of the amide CEST effect, but mostly from strong decreases in the Overhauser and magnetization transfer contributions to the upfield region, whose differential attenuations could be clearly discerned thanks to the ultrahigh field. The high spectral separation arising at 21.1 T also revealed numerous CEST signals usually overlapping at lower fields. Ischemic lesions were also investigated but, remarkably, magnetization and saturation transfer contrasts were nearly absent when computing transfer asymmetries using either high or low saturation power schemes. These behaviors were consistently observed at 24 hours post‐occlusion, regardless of the data processing approach assayed. Considerations related to how various parameters defining these experiments depend on the magnetic field, primarily chemical shifts andT1values, are discussed.
Provider bias as a function of patient genotype: polygenic score analysis among diabetics from the Health and Retirement Study
Authors: Huibregtse B. M. , Boardman J. D.
Published: July 2018

Objective

Poor patient–provider interactions due to provider bias are associated with worse physiological and behavioural health outcomes for patients. Prior research has shown that patients with obesity perceive less favourable interactions compared with those with lower weights. This paper explores whether this association depends on patients' cumulative polygenic score with respect to genes linked to obesity (i.e. a single variable quantifying the individual's genome‐wide risk factors for high body mass index [BMI] or genetic liability) and whether providers react differentially to patients whose obesity is more genetic in nature compared with patients with diabetes caused by environmental factors.

Methods

The association between patients' BMI category, their polygenic score for high BMI and their interaction was assessed for two measures of the patient–provider interaction within a sample of 521 older patients with diabetes from the Health and Retirement Study.

Results

Particularly for patients with obesity, the quality of the patient–provider interaction depended on genetic liability for high BMI controlling for demographic and clinical covariates. Providers responded less favourably to patients with diabetes influenced by environmental factors compared with individuals with high genetic liability.

Conclusions

Results of this study suggest that a patient's genotype may elicit particular responses from their healthcare provider. When a provider judges a patient's high BMI to be environmentally driven rather than genetically oriented, patients receive reduced quality of care.
Enthalpic stabilization of an SH3 domain by D2O
Authors: Stadmiller Samantha S. , Pielak Gary J.
Published: July 2018

The stability of a protein is vital for its biological function, and proper folding is partially driven by intermolecular interactions between protein and water. In many studies, H2O is replaced by D2O because H2O interferes with the protein signal. Even this small perturbation, however, affects protein stability. Studies in isotopic waters also might provide insight into the role of solvation and hydrogen bonding in protein folding. Here, we report a complete thermodynamic analysis of the reversible, two‐state, thermal unfolding of the metastable, 7‐kDa N‐terminal src‐homology 3 domain of the Drosophila signal transduction protein drk in H2O and D2O using one‐dimensional 19F NMR spectroscopy. The stabilizing effect of D2O compared with H2O is enthalpic and has a small to insignificant effect on the temperature of maximum stability, the entropy, and the heat capacity of unfolding. We also provide a concise summary of the literature about the effects of D2O on protein stability and integrate our results into this body of data.
A new structural class of bacterial thioester domains reveals a slipknot topology
Authors: Miller Ona K. , Banfield Mark J. , Schwarz‐Linek Ulrich
Published: July 2018

An increasing number of surface‐associated proteins identified in Gram‐positive bacteria are characterized by intramolecular cross‐links in structurally conserved thioester, isopeptide, and ester domains (TIE proteins). Two classes of thioester domains (TEDs) have been predicted based on sequence with, to date, only representatives of Class I structurally characterized. Here, we present crystal structures of three Class II TEDs from Bacillus anthracis, vancomycin‐resistant Staphylococcus aureus, and vancomycin‐resistant Enterococcus faecium. These proteins are structurally distinct from Class I TEDs due to a β‐sandwich domain that is inserted into the conserved TED fold to form a slipknot structure. Further, the B. anthracis TED domain is presented in the context of a full‐length sortase‐anchored protein structure (BaTIE). This provides insight into the three‐dimensional arrangement of TIE proteins, which emerge as very abundant putative adhesins of Gram‐positive bacteria.
A protein–protein host–guest complex: Thermostable ferritin encapsulating positively supercharged green fluorescent protein
Authors: Pulsipher Katherine W. , Bulos Joshua A. , Villegas José A. , Saven Jeffery G. , Dmochowski Ivan J.
Published: July 2018

We characterize the encapsulation of supercharged green fluorescent protein, GFP(+36), by thermophilic ferritin from Archaeoglobus fulgidus (AfFtn). The AfFtn–GFP(+36) assembly is rapid, nearly stoichiometric, and robust. Using a more stably assembled mutant AfFtn, we show that encapsulation can occur in the presence of mostly assembled cages, in addition to encapsulation starting from AfFtn individual subunits. Assembly and encapsulation do not occur with non‐supercharged GFP or the alternately supercharged GFP(−30), highlighting the role of complementary electrostatic interactions between the cargo and AfFtn cage interior. We also present a method for verifying protein–protein encapsulation, using nickel nitrilotriacetic acid agarose resin. AfFtn‐supercharged protein host‐guest complexes could find applications in enzyme studies, protein separations, and in vivo protein stabilization and targeted delivery.
Comparison of ERG and SPINK1 expression among incidental and metastatic prostate cancer in Japanese men
Authors: Koide Haruhisa , Kimura Takahiro , Inaba Hiroyuki , Sato Shun , Iwatani Kosuke , Yorozu Takashi , Furusato Bungo , Kamata Yuko , Miki Jun , Kiyota Hiroshi , Takahashi Hiroyuki , Egawa Shin
Published: July 2018

Background

TMPRSS2:ERG fusion is the most common genetic event in prostate cancer (PCa). However, its association with prognosis is controversial. Overexpression of serine protease inhibitor Kazal‐type 1 (SPINK1) was almost exclusively defined in ERG‐negative PCa in most studies. This study aimed to determine the association between ERG and SPINK1 expression and the biological aggressiveness of PCa by analyzing their expression in incidental and metastatic cohorts.

Methods

A total of 143 cystoprostatectomy specimens of invasive bladder cancer and 98 biopsy specimens from de novo metastatic PCa were analyzed. The prostate gland of cystoprostatectomy specimens was fixed and sliced in step sections. Immunohistochemistry of ERG and SPINK1 was conducted, and the results were correlated with the clinicopathological characteristics of the patients.

Results

The overall prevalence of incidental cancer was 32.2% (46/143). The frequencies of both ERG and SPINK1 expression were not significantly different between incidental and metastatic cohorts (15.2% and 14.3%; P = 1.00, and 6.5% and 12.2%; P = 0.38, respectively). In the metastatic cohort, any pre‐treatment factors were not significantly associated with the frequencies of ERG and SPINK1 expression. However, SPINK1 expression was significantly associated with a shorter time to castration‐resistant PCa (CRPC) (P = 0.048). Meanwhile, overall survival was not significantly associated with the expression status of ERG and SPINK1 (P = 0.71).

Conclusions

ERG and SPINK1 expression may not have significant influence on the metastatic behavior of PCa. SPINK1 expression was significantly associated with a shorter time to CRPC in metastatic PCa. The expression profile of ERG and SPINK1 may be a useful predictor for effect of androgen deprivation therapy in patients with metastatic castration‐sensitive PCa.
The effects of Enterolobium contortisiliquum serine protease inhibitor on the survival of the termite Nasutitermes corniger, and its use as affinity adsorbent to purify termite proteases
Authors: da Silva Ferreira Rodrigo , Napoleão Thiago Henrique , Silva‐Lucca Rosemeire A , Silva Mariana Cristina Cabral , Paiva Patrícia Maria Guedes , Oliva Maria Luiza Vilela
Published: July 2018

BACKGROUND

Termites are one of the main wood destroying insects. Nasutitermes corniger (Isoptera: Termitidae), can invade and attack urban wooden environments used in the structures of buildings. The use of synthetic pesticides is the traditional method used to prevent termite attack; however, these compounds generally cause harm to the environment. This paper describes the insecticidal activity of Enterolobium contortisiliquum protease inhibitor (EcTI) on Nasutitermes corniger workers and soldiers.

RESULTS

EcTI induced mortality in Nasutitermes corniger workers (LC50 0.242 mg mL−1 at 6 days of exposure). Gut extracts from workers and soldiers showed protease activity on the H‐D‐Pro‐Phe‐Arg‐pNan substrate. EcTI inhibited gut proteases in N. corniger at nM concentrations in vitro. The inhibitory activity towards termite enzymes was stable within the range of 25–65 °C. The inhibitor's unordered structure showed a high content of β‐sheets; its secondary structure and the thermal denaturation monitored by CD showed a two‐state transition and melting temperature (Tm) of approximately 73 °C.

CONCLUSION

Our results contribute to the understanding of Nasutitermes corniger complexity and provide new clues to achieve a better comprehension of the molecular mechanism of action of insecticides to this pest. © 2018 Society of Chemical Industry
Photocatalytic Activity of Laser‐Processed ZnO Micro/Nanocrystals
Authors: Rodrigues Joana , Pimentel Ana , Fortunato Elvira , Monteiro Teresa , Costa Florinda M.
Published: July 2018

With a bandgap energy of ≈3.3 eV at room temperature, zinc oxide (ZnO) exhibits physical properties that make it a potential candidate for several technological applications. Sustainable development requires, among other actions, removal of organic pollutants by employing non‐toxic structures, which can be achieved considering the photocatalytic properties of ZnO. In this work, high optical and structural quality ZnO crystals with distinct morphologies (nanotetrapods and microrods) are produced by laser‐processing. By adding silver to the growth precursors it is possible to produce ZnO/Ag composites in a single and short step, boosting a synergetic conjugation of the properties of both materials. The ZnO structures produced with and without silver are fully characterized by electronic microscopy and optical spectroscopy. Moreover, their photocatalytic activity is analyzed using methylene blue as a model‐test contaminant, revealing that the nanotetrapods exhibit a better performance than the microrods. This effect is further enhanced by the presence of silver on the ZnO surface, hindering the photoinduced carriers’ recombination, as corroborated by the photoluminescence results.
Higher use of techniques studied and performance in melee combat produce a higher psychophysiological stress response
Authors: Diaz‐Manzano Montaña , Fuentes Juan P. , Fernandez‐Lucas Jesús , Aznar‐Lain Susana , Clemente‐Suárez Vicente Javier
Published: July 2018

We aimed to analyse the effectiveness of an operative training in soldiers' psychophysiological and melee combat performance. Nineteen soldiers performed a 50‐hr training for 10 weeks. After training, they were divided into two groups: higher performance group (HPG) and lower performance group (LPG), then they conducted a realistic melee simulation where psychophysiological response, task performance, and the utilization of techniques learned were measured. HPG presented a significantly (p < 0.05) higher heart rate, blood lactate, and jump height; a lower blood oxygen saturation, task performance mark, use of studied techniques than LPG after the simulation; and a higher low frequency/high frequency ratio of heart rate variability previous the simulation than LPG. Independent of performance and the use of studied techniques by the participants, the melee simulation produced an increase in fight or flight response, increasing rated of stress and perceived exertion, sympathetic modulation, and physiological response. A specific melee combat training program induced different modifications in psychophysiological and task performance depending on the level of studied technique used. HPG presented a significantly higher cardiovascular response than LPG and time perception, and memory presented no differences between groups; also HPG presented a significantly higher use of studied techniques.
Ecosystem traps and where to find them
Authors: Bosch Jan , Olsson Helena Holmström
Published: July 2018

Today, companies operate in business ecosystems where they collaborate, compete, share, and learn from others with benefits such as to present more attractive offerings and sharing innovation costs. With ecosystems being the new way of operating, the ability to strategically reposition oneself to increase or shift power balance is becoming key for competitive advantage. However, companies run into a number of traps when trying to realize strategical changes in their ecosystems. In this paper, we identify 5 traps that companies fall into. First, the “descriptive versus prescriptive trap” is when companies assume that current boundaries between partners are immutable. Second, the “assumptions trap” is when powerful ecosystem partners assume that they understand what others regard as value‐adding without validating their assumptions. Third, the “keeping it too simple trap” is when companies overlooks the effort required to align interests. Fourth, the “doing it all at once trap” is when companies disrupt an ecosystem assuming that all partners can change direction at the same time. Finally, the “planning trap” is when companies are unable to move forward without a complete plan. We provide empirical evidence for each trap, and we propose an ecosystem engagement process for how to avoid falling into these.
Shear Strength of Reactive Resistance Welded Ti6Al4V Parts with the Use of Ni(V)/Al Multilayers
Authors: Maj Łukasz , Morgiel Jerzy , Mars Krzysztof , Tarasek Anna , Godlewska Elżbieta
Published: July 2018

The Ti6Al4V/(Ni/Al)/Ti6Al4V joints were obtained through reactive resistance welding which takes advantage of electric current heating to initiate the rapid exothermic reaction of Ni(V)/Al multilayers and activate diffusion of elements across the Ni/Al-Ti6Al4V interfaces. Simulations of temperature distribution, carried out using COMSOL® software, showed temperature gradient in the joint being a result of differences in resistivity of the Ti6Al4V alloy and the (Ni/Al)/Ti6Al4V interface. Shear tests revealed that extending duration of the process from 2 to 6 minutes helped to improve the shear strength from ~ 240 to ~ 335 MPa. The microstructure observations of the samples after those tests showed that de-cohesion of the joint occurred along the filler material/base material interface. A microcrack network characteristic for reacted Ni/Al foil with small ridges was found on the flat surfaces of fractured samples.