bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenetic modifications in chronic myeloid leukemia cells through ruxolitinib treatment
Authors: Biray Avci Cigir , Goker Bagca Bakiye , Tetik Vardarli Asli , Saydam Guray , Gunduz Cumhur
Published: September 2018

Chronic myeloid leukemia is a clonal malignancy of hematopoietic stem cell that is characterized by the occurrence of t(9;22)(q34;q11.2) translocation, named Philadelphia chromosome. Ruxolitinib is a powerful Janus tyrosine kinase 1 and 2 inhibitor that is used for myelofibrosis treatment. DNA‐histone connection mediates a wide range of genes that code methylation, demethylation, acetylation, deacetylation, ubiquitination, and phosphorylation enzymes. Epigenetic modifications regulate chromatin compactness, which plays pivotal roles in critical biological processes including the transcriptional activity and cell proliferation as well as various pathological mechanisms, including CML. This study is aimed to determine the alterations of the expression levels of epigenetic modification–related genes after ruxolitinib treatment. Total RNA was isolated from K‐562 cells treated with the IC50 value of ruxolitinib and untreated K‐562 control cells. A reverse transcription procedure was performed for complementary DNA synthesis, and gene expressions were detected by real‐time polymerase chain reaction compared with the untreated cells. Ruxolitinib treatment caused a significant alteration in the expression levels of epigenetic regulation‐related genes in K‐562 cells. Our novel results suggested that ruxolitinib has inhibitor effects on epigenetic modification–regulator genes.
Tangeretin protects human brain microvascular endothelial cells against oxygen‐glucose deprivation‐induced injury
Authors: Wu Chunfang , Zhao Jun , Chen Yong , Li Ting , Zhu Ruiming , Zhu Baihui , Zhang Youran
Published: September 2018

Tangeretin, a citrus flavonoid extracted from the peel of citrus fruits, was reported to possess antiasthmatic, antioxidant, anti‐inflammatory, and neuroprotective properties. However, the effect of tangeretin on human brain microvascular endothelial cells (HBMECs) has not been examined. This study was designed to investigate the protective effects of tangeretin on oxygen‐glucose deprivation (OGD)‐induced injury of HBMECs, and explore the underlying mechanisms. Our results showed that tangeretin improved HBMECs viability in response to OGD. In addition, tangeretin was able to increase the activity of superoxide dismutase and decrease the levels of reactive oxygen species and malondialdehyde (MDA), as well as ameliorate cell apoptosis in OGD‐stimulated HBMECs. Mechanistic studies showed that tangeretin prevented the activation of JNK signaling pathway in OGD‐stimulated HBMECs. Taken together, our current study demonstrated that tangeretin could ameliorate OGD‐induced HBMECs injury through the JNK signaling pathway. Thus, tangeretin might be used as a therapeutic strategy for ischemia‐reperfusion brain injury and related diseases.
An analytical enrichment‐based review of structural genetic studies on keratoconus
Authors: Panahi Yunes , Azimi Ali , Naderi Mostafa , Jadidi Khosrow , Sahebkar Amirhossein
Published: September 2018

Keratoconus is a progressive bilateral corneal protrusion that leads to irregular astigmatism and impairment of vision. Keratoconus is an etiologically heterogeneous corneal dystrophy and both environmental and genetic factors play a role in its etiopathogenesis. In this analytical review, we have studied all the genes that are structurally associated with keratoconus and have tried to explain the function of each gene and its association with other eye disorders in a concise way. In addition, using gene set enrichment analysis, it was attempted to find the most important impaired metabolic pathways in keratoconus. Several genetic studies have been carried out on keratoconus and several genes have been identified as risk factors involved in the etiology of the disease. In the current study, 16 studies, including nine association studies, five genome‐wide association studies, one linkage study, and one meta‐analysis, were reviewed and based on the 19 genes found, enrichment was performed and the most important metabolic pathways involved in the disease were identified. The enrichment results indicated that the two pathways, interleukin 1 processing and assembly of collagen fibrils, are significantly associated with the disease. Obviously, the results of this study, in addition to providing information about the genes involved in the disease, can provide an integrated insight into the gene‐based etiology of keratoconus and therapeutic opportunities thereof.
Building strength, endurance, and mobility using an astaxanthin formulation with functional training in elderly
Authors: Liu Sophia Z. , Ali Amir S. , Campbell Matthew D. , Kilroy Kevin , Shankland Eric G. , Roshanravan Baback , Marcinek David J. , Conley Kevin E.
Published: September 2018

Background

Building both strength and endurance has been a challenge in exercise training in the elderly, but dietary supplements hold promise as agents for improving muscle adaptation. Here, we test a formulation of natural products (AX: astaxanthin, 12 mg and tocotrienol, 10 mg and zinc, 6 mg) with both anti‐inflammatory and antioxidant properties in combination with exercise. We conducted a randomized, double‐blind, placebo‐controlled study of elderly subjects (65–82 years) on a daily oral dose with interval walking exercise on an incline treadmill.

Methods

Forty‐two subjects were fed AX or placebo for 4 months and trained 3 months (3×/week for 40–60 min) with increasing intervals of incline walking. Strength was measured as maximal voluntary force (MVC) in ankle dorsiflexion exercise, and tibialis anterior muscle size (cross‐sectional area, CSA) was determined from magnetic resonance imaging.

Results

Greater endurance (exercise time in incline walking, >50%) and distance in 6 min walk (>8%) accompanied training in both treatments. Increases in MVC by 14.4% (±6.2%, mean ± SEM, P < 0.02, paired t‐test), CSA by 2.7% (±1.0%, P < 0.01), and specific force by 11.6% (MVC/CSA, ±6.0%, P = 0.05) were found with AX treatment, but no change was evident in these properties with placebo treatment (MVC, 2.9% ± 5.6%; CSA, 0.6% ± 1.2%; MVC/CSA, 2.4 ± 5.7%; P > 0.6 for all).

Conclusions

The AX formulation improved muscle strength and CSA in healthy elderly in addition to the elevation in endurance and walking distance found with exercise training alone. Thus, the AX formulation in combination with a functional training programme uniquely improved muscle strength, endurance, and mobility in the elderly.
Differences in EMG–moment relationships between ACL‐injured and uninjured adults during a weight‐bearing multidirectional force control task
Authors: Flaxman Teresa E. , Alkjær Tine , Smale Kenneth B. , Simonsen Erik B. , Krogsgaard Michael R. , Benoit Daniel L.
Published: September 2018

Anterior cruciate ligament injury (ACLi) reduces mechanical knee joint stability. Differences in muscle activation patterns are commonly identified between ACLi individuals and uninjured controls (CON); however, how and which of these differences are adaptations to protect the knee or adversely increase risk of joint instability remain unclear. Since the neuromuscular system integrates activity of all muscles crossing the knee to create a moment‐of‐force that opposes an external load, this study sought to quantify differences in individual muscle electromyography (EMG)–moment relationships between ACLi and CON. Participants isometrically modulated ground reaction forces during a standing force matching protocol to elicit combinations of sagittal, frontal and transverse plane moments. Partial least squares regressions determined which internal joint moment(s) predicted activation of 10 leg muscles for each group. Compared to CON, ACLi demonstrated greater contribution of rectus femoris to knee extension, semitendinosus and gastrocnemii to knee flexion, and lateral gastrocnemii to knee external rotation moments. ACLi also showed lower contributions of biceps femoris to knee flexion, medial gastrocnemius to internal rotation, and varied hip muscle contributions to frontal plane hip moments. Between group differences in EMG–moment relationships during static conditions suggest neuromuscular contributions to sagittal plane stability increases after ACL injury, while knee stability during knee abduction and external rotation is reduced. Clinical Significance: Clinical assessments of ACLi should account for deficits in frontal and rotational plane stability by including tasks that elicit such loads. Improving hamstring muscle balance, hip abductor and gastrocnemius function may benefit ACLi rehabilitation interventions and should be studied further. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res
A model for predicting low probability of nonsentinel lymph node positivity in melanoma patients with a single positive sentinel lymph node
Authors: Bhutiani Neal , Egger Michael E. , Stromberg Arnold J. , Gershenwald Jeffrey E. , Ross Merrick I. ,  Philips Prejesh , Martin Robert C. G. , Scoggins Charles R. , McMasters Kelly M.
Published: September 2018

Background

Identifying factors associated with nonsentinel lymph node (NSN) metastases in melanoma patients with a single positive sentinel lymph node (SLN) could aid decision making regarding adjuvant therapy. We describe a model for identifying patients with a single positive SLN at low risk for NSN metastasis.

Methods

Factors associated with NSN metastasis in patients with a primary cutaneous melanoma and a single positive SLN who underwent completion lymph node dissection (CLND) were identified. These factors were used to construct a model for predicting the NSN status. The model was validated using a separate data set from another tertiary referral cancer center.

Results

In the training data set, 111 patients had a single positive SLN. Of these, 27 had positive NSN. SLN tumor deposit diameter ≥0.75 mm (OR, 3.43; P = 0.047), age ≥40 (OR, 12.14; P = 0.024), and multifocal SLN tumor deposit location (OR, 4.16; P = 0.0096) were independently associated with NSN positivity. Patients with 0 to 1 of these risk factors had a low risk of NSN metastasis in both the training (7.5%) and validation (4.6%) data sets.

Conclusions

A combination of patient and SLN tumor burden characteristics can help to identify patients with a single positive SLN who are at a low risk of NSN metastasis.
The prognosis of colorectal cancer liver metastases associated with inflammatory bowel disease: An exploratory analysis
Authors: Margonis Georgios Antonios , Buettner Stefan , Andreatos Nikolaos , Wagner Doris , Sasaki Kazunari , Galjart Boris , Kamphues Carsten , Pawlik Timothy M , Poultsides George , Kaczirek Klaus , Lønning Per Eystein , Verhoef Cornelis , Kreis Martin E , Wolfgang Christopher L , Weiss Matthew J.
Published: September 2018

Background and Objectives

In contrast with sporadic colorectal cancer liver metastases (CRLM), inflammatory bowel disease (IBD)‐related CRLM have not been studied to date.

Methods

Patients who underwent resection for IBD‐related and sporadic CRLM from 2000 to 2015 were identified from an international registry and matched for pertinent prognostic variables. Overall survival (OS) and recurrence‐free survival (RFS) were subsequently assessed.

Results

Twenty‐eight patients had IBD‐related CRLM. Synchronous extrahepatic disease was more common in IBD‐related CRLM patients than patients with sporadic CRLM (28.6% vs 8.3%; P < 0.001), most commonly located in the lungs. In multivariable analysis, IBD did not have a significant influence on OS (
P = 0.835), and had a hazard ratio (HR) close to 1 (HR, 0.95; 95% confidence interval [CI], 0.57‐1.57). IBD was also not associated with inferior RFS (HR, 1.07; 95%CI, 0.68‐1.68;
P = 0.780). Among patients with IBD‐related CRLM, 9(50%) had isolated intrahepatic recurrence and 8(44.4%) isolated extrahepatic recurrence, while only 1(5.6%) developed combined recurrence. Of those who experienced recurrence after resection of IBD‐related CRLM, 10 had their recurrence treated with curative intent.

Conclusions

Patients with IBD‐related CRLM had similar survival compared with patients with sporadic CRLM, even though they more often present with extrahepatic disease. In addition, patients with IBD‐related CRLM may experience patterns of recurrence different from patients with sporadic CRLM.
A catalyst based on 3,3′,5,5′‐tetra‐tert‐butyl‐4,4′‐stilbenequinone used in the liquid‐phase oxidation of sodium sulfide
Authors: Hoang H. Y. , Akhmadullin R. M. , Akhmadullina F. Y. , Zakirov R. K. , Akhmadullina A. G. , Dao M. U. , Sirotkin A. A.
Published: September 2018

This paper aims to investigate the liquid‐phase oxidation reaction mechanism of inorganic sulfide in the presence of a catalyst based on 3,3′,5,5′‐tetra‐tert‐butyl‐4,4′‐stilbenequinone dissolved in the kerosene fraction. The formation of intermediate and final products is also examined, pointing out that the products of catalytic sulfides oxidation are thiosulfate and sulfate. The study also looks at selective thiosulfate formation in the sulfide oxidation with stilbenequinone in an oxygen‐free environment. The research results show that the regeneration of a catalyst based on 3,3′,5,5′‐tetra‐tert‐butyl‐4,4′‐stilbenequinone is the rate‐limiting step of the reaction, and a considerable amount of hydrogen peroxide is formed during catalyst regeneration. Using wastewater industrial pyrolysis processes, the proposed catalytic system is also tested under laboratory conditions.
Peer review in the development of academic articles: Experiences of Finnish authors in the educational sciences
Authors: Atjonen Päivi
Published: September 2018

This research examined author experiences of the developmental feedback regarding peer review of journal articles. It focused on quite experienced authors in the educational sector of all eight universities in Finland. Data were gathered using an electronic questionnaire, which was completed by 121 respondents. The majority of authors perceived reviewer feedback as developmental and appreciated critical but constructive review. Over 60% of respondents found reviewers usually keen to improve the article and to provide pertinent critique. Less than 8% reported frequent experience of reviewers who were not experts or provided unjustified accusations. A third reported reviewer feedback that was frequently biased or based on different paradigms. The most published authors were the most satisfied with the developmental feedback, but postdoctoral researchers had received more developmental complementary feedback than any other groups. The results indicate that the peer review system remains useful for ensuring article quality, but some attention is still required to ensure developmental feedback that will help the authors enhance their manuscripts.
Krill motion in the Southern Ocean: quantifying in situ krill movement behaviors and distributions during the late austral autumn and spring
Authors: Kane Mary K. , Yopak Regina , Roman Christopher , Menden‐Deuer Susanne
Published: September 2018

Krill movement behaviors and vertical distributions were measured in spring and autumn using a profiling stereo‐camera and environmental sensor system to quantify seasonal changes in the role of krill in Southern Ocean food webs. Krill were observed in May–June 2013 and December 2014 in 3 bays in the Western Antarctic Peninsula. Krill abundances and movement behaviors were determined from in situ image sequences collected for up to 10 min throughout the water column, up to 625 m deep; 3,345 individual krill tracks were collected. Seasonal changes in individual krill behaviors coincided with seasonal shifts in krill vertical distributions. During late spring, net upward swimming direction (0.9 ± 2.1° from horizontal) and vertical velocity (0.3 ± 0.2 body lengths [BL] s−1) resulted in shallower maximum abundances of krill within the water column proximate to near‐surface phytoplankton distributions. During late autumn, krill swimming patterns tended downward, including swimming direction (−5.2 ± 0.8° from horizontal) and vertical velocity (−0.1 ± 0.0 BL s−1), leading to deeper distributions proximate to the benthos. Individual krill motility was greater in spring than autumn, as evidenced by an increase in swimming speeds (5.4 ± 0.2 vs. 2.8 ± 0.0 BL s−1) and turning rates (120 ± 5 vs. 107 ± 2° s−1). Remarkably, krill in autumn were capable of swimming as quickly as krill in spring. These results suggest seasonal shifts in krill movement behaviors have direct ramifications for krill distributions, proximity to food sources, and impacts on biogeochemical cycling in coastal Antarctic waters.
Enhanced biofilm formation aids adaptation to extreme warming and environmental instability in the diatom Thalassiosira pseudonana and its associated bacteria
Authors: Schaum C.‐E.
Published: September 2018

Recent studies have highlighted the capacity of marine diatoms at the foundation of ocean food webs and biogeochemical cycles to respond to environmental change. These responses are a combination of physiological acclimation and evolutionary responses. The latter occur rapidly within a few hundred generations (translating to a scale of months to years), due to the large standing genetic variation and short generation times of diatom populations. Studies are usually carried out on diatom species in their planktonic state, but this may constitute a stark oversimplification: diatoms readily form biofilms in the water column of shallow coastal areas, where biofilm formation affects carbon export, and in the benthos, where biofilms contribute significantly to sediment stability. Here, I have carried out a 400‐generation selection experiment, where I evolved the diatom Thalassiosira pseudonana and its associated bacteria. Bacteria and diatom were cultured in their planktonic form, and under strong selection for rapid biofilm formation in temperature and nutrient regimes differing in their severity and stability. I find that biofilm formation is enhanced under mild warming and rapid thermal fluctuations but not under extreme warming regardless of nutrient availability. Evolutionary responses are slower in biofilms under benign conditions but speed up under extreme and fluctuating conditions. Taxonomic composition of the associated bacteria is driven by the temperature selection regime in biofilms but not in planktonic samples. I also show that T. pseudonana, when selected for biofilm formation, presents predictable and sequential morphologies that are not usually observed in planktonic T. pseudonana.
Cholesterol Modification Enhances Antimetastatic Activity and siRNA Delivery Efficacy of Poly(ethylenimine)‐Based CXCR4 Antagonists
Authors: Wu Pengkai , Luo Xingping , Wu Hui , Yu Fei , Wang Kaikai , Sun Minjie , Oupicky David
Published: September 2018

Chemokine receptor CXC receptor 4 (CXCR4) plays a crucial role in cell invasion and metastasis of multiple types of cancer. Dual‐function polymeric CXCR4 antagonists based on cyclam‐modified poly(ethylenimine) (C‐PEI) have been shown to have potential as nucleic acid delivery vectors and antimetastatic therapeutics in recent studies. How cholesterol modification of C‐PEI affects the ability of the polycation to deliver siRNA and inhibit CXCR4 is tested here. It is shown that the C‐PEI with the lower content of cholesterol exhibits the highest siRNA transfection efficiency and demonstrates enhanced CXCR4 antagonism and antimetastatic activity in a breast cancer model in vivo. Overall, the cholesterol modification of C‐PEI is a viable strategy to achieve efficient delivery of siRNA and simultaneous CXCR4 inhibition for combined antimetastatic therapies is validated by this study.
Injectable Supramolecular Hydrogel/Microgel Composites for Therapeutic Delivery
Authors: Chen Minna H. , Chung Jennifer J. , Mealy Joshua E. , Zaman Samir , Li Elizabeth C. , Arisi Maria F. , Atluri Pavan , Burdick Jason A.
Published: September 2018

Shear‐thinning hydrogels are useful for biomedical applications, from 3D bioprinting to injectable biomaterials. Although they have the appropriate properties for injection, it may be advantageous to decouple injectability from the controlled release of encapsulated therapeutics. Toward this, composites of hydrogels and encapsulated microgels are introduced with microgels that are fabricated via microfluidics. The microgel cross‐linker controls degradation and entrapped molecule release, and the concentration of microgels alters composite hydrogel rheological properties. For the treatment of myocardial infarction (MI), interleukin‐10 (IL‐10) is encapsulated in microgels and released from composites. In a rat model of MI, composites with IL‐10 reduce macrophage density after 1 week and improve scar thickness, ejection fraction, cardiac output, and the size of vascular structures after 4 weeks when compared to saline injection. Improvements are also observed with the composite without IL‐10 over saline, emphasizing the role of injectable hydrogels alone on tissue repair.
Exploring materialism and frugality in determining product end‐use consumption behaviors
Authors: Evers Uwana , Gruner Richard L. , Sneddon Joanne , Lee Julie A.
Published: September 2018

Materialism is often blamed for consumers’ unsustainable consumption behaviors and its contribution to a growing “throwaway culture.” Conversely, frugal consumers are regarded as both restrained in their acquisition, and resourceful in their use and disposal of products. In this paper, the authors challenge and empirically test these prevailing beliefs. The authors focus on a much‐neglected aspect of the consumption continuum: the disposal of products at the end‐use of consumption, and how key consumer traits (i.e., materialism and frugality) influence behaviors at this stage. Specifically, the authors examined three creative end‐use consumption behaviors with a sample of 398 US consumers. Results support the counter‐intuitive notion that materialism, alongside frugality, has a positive impact on consumers’ sustainable consumption behaviors. The data suggest that materialistic consumers are prone to finding new and different uses for products and alternative methods of product disposal. The study’s results also support the notion that frugality interacts with materialism to increase intentions to find alternative methods of product disposal. The authors discuss the implications pertaining to their findings and pave the way for future research in sustainable consumption.
Plausible versus implausible tensile price claim: Selective accessibility model approach
Authors: Lee Jung Eun
Published: September 2018

Retailers frequently use exaggerated price discount advertisements with a tensile price claim (TPC; e.g., “Save up to 70%”) to attract consumers because they expect that once consumers enter a store, they will purchase low‐ or medium‐discounted products. Drawing on the selective accessibility model, this study investigated the way in which an implausibly high maximum level of savings stated in a TPC influences consumers’ expected price discount (EPD) and perceptions of actual price discounts across different types of TPCs (i.e., TPC stating a maximum level and TPC stating a range of savings). This study also investigated two situations in which consumers have previous knowledge of a product’s price discount versus when they have less or no knowledge of the discount. For both conditions, a single‐anchor TPC (i.e., “Save up to Y%”) that stated an implausible maximum level of savings led to a higher EPD and lower perceptions of the deal (i.e., perceived savings, price fairness, and perceived value) with respect to the actual price discount than did a TPC with a plausible maximum level of savings. In contrast, when the TPC stated two anchors (i.e., “Save X–Y%”) and consumers had knowledge of the price discount, their EPDs assimilated only toward the plausible anchor (X), and ignored the implausibly high maximum price discount (Y), resulting in a lower EPD and higher perceptions of the deal of the actual price discounts than a TPC that stated a plausibly high maximum level of savings. In contrast, when consumers had no knowledge of the price discount, their EPDs only adjusted toward the more plausible anchor (X), regardless of whether they perceived the maximum anchor as plausible or implausible. Thus, there was no difference in consumers’ perceptions of “Save X–Y%” between implausibly and plausibly high Y%.
Data Visualization, Regression, Applicability Domains and Inverse Analysis Based on Generative Topographic Mapping
Authors: Kaneko Hiromasa
Published: September 2018

This paper introduces two generative topographic mapping (GTM) methods that can be used for data visualization, regression analysis, inverse analysis, and the determination of applicability domains (ADs). In GTM‐multiple linear regression (GTM‐MLR), the prior probability distribution of the descriptors or explanatory variables (X) is calculated with GTM, and the posterior probability distribution of the property/activity or objective variable (y) given X is calculated with MLR; inverse analysis is then performed using the product rule and Bayes’ theorem. In GTM‐regression (GTMR), X and y are combined and GTM is performed to obtain the joint probability distribution of X and y; this leads to the posterior probability distributions of y given X and of X given y, which are used for regression and inverse analysis, respectively. Simulations using linear and nonlinear datasets and quantitative structure‐activity relationship (QSAR) and quantitative structure‐property relationship (QSPR) datasets confirm that GTM‐MLR and GTMR enable data visualization, regression analysis, and inverse analysis considering appropriate ADs. Python and MATLAB codes for the proposed algorithms are available at https://github.com/hkaneko1985/gtm‐generativetopographicmapping.
Imperfect magnetic field gradients in radial k‐space encoding—Quantification, correction, and parameter dependency
Authors: Moussavi Amir , Boretius Susann
Published: September 2018

Purpose

Sensitivity to imperfections of image‐encoding gradient fields may significantly impair widespread use of radial MR data acquisition. Such imperfections can cause individual echo shifts for each spoke acquired in the k‐space and may produce severe image artifacts. Therefore, fast and robust methods to quantify and correct for those echo shifts are required.

Theory and Methods

Echo shifts can be induced by inhomogeneities of the static magnetic field (δnB) and by imbalances of the imaging gradients (δnG) mainly caused by eddy currents. However, mismatch between data acquisition and gradient switching may additionally play a role. From the position of the echo maxima of 2 opposing spokes, δnG and δnB can be determined and corrected by adapting the read‐dephasing gradient accordantly. This approach was implemented on MR‐systems of different field strengths, gradient systems, and vendors, and the dependencies of echo shift and acquisition parameters were analyzed. Data sets of phantoms and of mice under in vivo conditions were obtained using RF‐spoiled 2D radial‐FLASH.

Results

The presented method allowed for echo‐shift detection and correction of < 1 data point, significantly improving the image quality in vitro and in vivo. Moreover, the method separated the effect of imbalanced gradients from those of magnetic inhomogeneities. The observed echo shifts were MR system‐specifically dependent on acquisition parameters such as gradient strengths and dwell time.

Conclusions

By acquiring 12 spokes for a certain set of acquisition parameters, the proposed method successfully corrects echo shift‐related image artifacts independently of the MR system.
Prediction of cross‐clade HIV‐1 T‐cell epitopes using immunoinformatics analysis
Authors: Khairkhah Niloofar , Namvar Ali , Kardani Kimia , Bolhassani Azam
Published: September 2018

Epitope mapping has emerged as a powerful tool to develop peptide vaccines against hypervariable viruses such as HIV. This method has led to stimulate a specific immune response and achieve advanced vaccine formulations. In this study, we identified peptides that were potentially immunostimulatory and highly conserved in HIV‐1 main group. The analyses included were CTL assay, Tap transport, and the potential allergenicity. The highest population coverage rate was also found for all potential T‐cell epitopes in 16 specified geographic regions of the world. The current study is the first attempt to explore peptide‐protein flexible docking across all the major epitopes of HIV‐1. Our data indicated that REV54‐63and VPU58‐66 with the highest epitope identification scores, GP16037‐46 and VPR38‐47 with the highest conservation (98.89%), and NEF134‐144 and GP16037‐46 epitopes with a higher quality of peptide‐protein interaction models in docking procedure were chosen as putative epitopes among all HLA class I epitopes. TAT40‐67, VPR65‐82, and VPU30‐44 with the highest score of binding affinity, VPR65‐82 with the highest conservation (97.55%), and GP160481‐498 epitope with a higher quality of peptide‐protein interaction models in docking procedure were determined as putative epitopes among all HLA‐DR epitopes. Furthermore, two epitopes of GP160481‐498 and VIF144‐159 were predicted to bind 22 and 21 HLA‐II alleles, respectively. Accumulative population coverage of potential helper T‐cell epitopes and CTL epitopes varied between 90.82% and 100%. Generally, these predicted highly immunogenic T‐cell epitopes can contribute to design HIV‐1 peptide vaccine candidates. Combination of bioinformatics tools with in vivo methods will be necessary for HIV‐1 vaccine development.
Exploring molecular mechanism of allosteric inhibitor to relieve drug resistance of multiple mutations in HIV‐1 protease by enhanced conformational sampling
Authors: Chen Jianzhong , Peng Cheng , Wang Jinan , Zhu Weiliang
Published: September 2018

Recently, allosteric regulations of HIV‐1 protease (PR) are suggested as a promising approach to relieve drug resistance of mutations toward inhibitors targeting the active site of PR. Replica‐exchange molecular dynamics (REMD) simulations and normal mode analysis (NMA) are integrated to enhance conformational sampling of PR. Molecular mechanics generalized Born surface area (MM‐GBSA) method was applied to calculate binding free energies of three inhibitors APV, DRV, and NIT to the wild‐type (WT) and multidrug resistance (MDR) PRs. The results suggest that binding free energies of APV and DRV are decreased in the MDR PR relative to the WT PR, suggesting drug resistance of mutations on these two inhibitors. However, the binding ability of the allosteric inhibitor NIT is not impaired in the MDR PR. In addition, internal dynamics analysis based on REMD simulations proves that mutations hardly produce obvious effect on the conformation of the MDR PR in comparison to the WT PR. Scanning of hydrophobic contacts and hydrogen bond contacts of inhibitors with residues of PRs on the concatenated trajectories of REMD demonstrates that mutations change the symmetric interaction networks of APV and DRV with PR, but do not generate obvious influence on the asymmetric interaction network of NIT with PR. In summary, allosteric inhibitor NIT can adapt the MDR PR better than those inhibitors toward the active site of PR, thus allosteric inhibitors of PR may be a possible channel to overcome drug resistance of PR.
Population Pharmacokinetics of Apixaban in Subjects With Nonvalvular Atrial Fibrillation
Authors: Cirincione Brenda , Kowalski Kenneth , Nielsen Jace , Roy Amit , Thanneer Neelima , Byon Wonkyung , Boyd Rebecca , Wang Xiaoli , Leil Tarek , LaCreta Frank , Ueno Takayo , Oishi Masayo , Frost Charles
Published: September 2018

This analysis describes the population pharmacokinetics (PPK) of apixaban in nonvalvular atrial fibrillation (NVAF) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I–III studies. Apixaban exposure was characterized by a two‐compartment PPK model with first‐order absorption and elimination. Predictive covariates on apparent clearance included age, sex, Asian race, renal function, and concomitant strong/moderate cytochrome P450 (CYP)3A4/P‐glycoprotein (P‐gp) inhibitors. Individual covariate effects generally resulted in < 25% change in apixaban exposure vs. the reference NVAF subject (non‐Asian, male, aged 65 years, weighing 70 kg without concomitant CYP3A4/P‐gp inhibitors), except for severe renal impairment, which resulted in 55% higher exposure than the reference subject. The dose‐reduction algorithm resulted in a ~27% lower median exposure, with a large overlap between the 2.5‐mg and 5‐mg groups. The impact of Asian race on apixaban exposure was < 15% and not considered clinically significant.
Establishing a Multidisciplinary Framework to Study Drug‐Drug Interactions of Hormonal Contraceptives: An Invitation to Collaborate
Authors: Lesko Lawrence J. , Vozmediano Valvanera , Brown Joshua D. , Winterstein Almut , Zhao Ping , Lippert Jörg , Höchel Joachim , Chaturvedula Ayyappa , White Annesha , Schmidt Stephan
Published: September 2018

Hormonal contraceptive agents (HCAs) are widely used throughout the world, and women taking HCAs are likely to take other medications. However, little is known about the clinical effect of most drug‐drug interactions (DDIs) associated with HCAs. A team of interdisciplinary outcomes and pharmacometric researchers from academia and industry jointly engage in a research project to (i) quantitatively elucidate DDI impacts on unintended pregnancies and breakthrough bleeding, and (ii) establish a DDI‐prediction framework to inform optimal use of HCAs.
Using the Callaway Model to Deduce Relevant Phonon Scattering Processes: The Importance of Phonon Dispersion
Authors: Schrade Matthias , Finstad Terje G.
Published: September 2018

The thermal conductivity κ of a material is an important parameter in many different applications. Optimization strategies of κ often require insight into the dominant phonon scattering processes of the material under study. The Callaway model is widely used as an experimentalist's tool to analyze the lattice part of the thermal conductivity, κl. Here, we investigate how deviations from the implicitly assumed linear phonon dispersion relation affect κl and in turn conclusions regarding the relevant phonon scattering processes. As an example, we show for the half‐Heusler system (Hf,Zr,Ti)NiSn, that relying on the Callaway model in its simplest form has earlier resulted in a misinterpretation of experimental values by assigning the low measured κl with unphysically strong phonon scattering in these materials. Instead, we propose an implementation of more realistic phonon dispersion curves, combined with empirical expressions for typical phonon scattering processes, which leads to far better quantitative agreement with both theoretical and experimental values. This method can easily be extended to other materials with known phonon dispersion relations.
Crystal Growth, Magnetic Properties and Analysis of Possible Magnetic Ordering of Ni5Sn(BO5)2 with Ludwigite Structure
Authors: Sofronova Svetlana , Bezmaternykh Leonard , Eremin Evgeniy , Chernyshov Artem , Bovina Asya
Published: September 2018

The ludwigite Ni5Sn(BO5)2 belongs to a family of oxyborates, and has an ordered distribution of nonmagnetic Sn ions. This material is studied here using magnetic measurements. Ni5Sn(BO5)2 does not show full long‐range magnetic order, but exhibits a partial ordering at 73 K. A theoretical group analysis is performed and different models of the magnetic structure of Ni5Sn(BO5)2 are discussed.
Adaptive protocols based on predictions from a mechanistic model of the effect of IL7 on CD4 counts
Authors: Villain Laura , Commenges Daniel , Pasin Chloé , Prague Mélanie , Thiébaut Rodolphe
Published: September 2018

In human immunodeficiency virus–infected patients, antiretroviral therapy suppresses the viral replication, which is followed in most patients by a restoration of CD4+ T cells pool. For patients who fail to do so, repeated injections of exogenous interleukin 7 (IL7) are experimented. The IL7 is a cytokine that is involved in the T cell homeostasis and the INSPIRE study has shown that injections of IL7 induced a proliferation of CD4+ T cells. Phase I/II INSPIRE 2 and 3 studies have evaluated a protocol in which a first cycle of three IL7 injections is followed by a new cycle at each visit when the patient has less than 550 CD4 cells/μL. Restoration of the CD4 concentration has been demonstrated, but the long‐term best adaptive protocol is yet to be determined. A mechanistic model of the evolution of CD4 after IL7 injections has been developed, which is based on a system of ordinary differential equations and includes random effects. Based on the estimation of this model, we use a Bayesian approach to forecast the dynamics of CD4 in new patients. We propose four prediction‐based adaptive protocols of injections to minimize the time spent under 500 CD4 cells/μL for each patient, without increasing the number of injections received too much. We show that our protocols significantly reduce the time spent under 500 CD4 over a period of two years, without increasing the number of injections. These protocols have the potential to increase the efficiency of this therapy.
Stereoinversion of R‐Configured Secondary Alcohols Using a Single Enzymatic Approach
Authors: Musa Musa M. , Karume Ibrahim , Takahashi Masateru , Hamdan Samir M. , Ullah Nisar
Published: September 2018

Here, we achieved a single‐enzymatic stereoinversion of R‐configured alcohols to their corresponding S enantiomers in high percent conversion and high enantioselectivity. A single mutant of Thermoanaerobacter pseudoethanolicus secondary alcohol dehydrogenase (TeSADH) oxidized R alcohols to their corresponding ketones under conditions that allow selectivity mistakes and then reduced them under stereoselective conditions to generate the corresponding S‐configured alcohols. The success of this stereoinversion relies on controlling the stereoselectivity of the oxidation and the reduction reactions by varying the amounts of acetone and 2‐propanol, respectively. Furthermore, the deployment of the TeSADH mutants W110A and W110G led to stereoinversion of enantiopure R alcohols to their S enantiomers in medium to high enantiomeric excess (up to >99% ee). The disclosed approach of single enzymatic stereoinversion presents a biocatalytic alternative to Mitsunobu inversion reaction.
The effect of childhood sexual assault history on outpatient cognitive processing therapy for military sexual trauma‐related posttraumatic stress disorder: A preliminary investigation
Authors: Holder Nicholas , Holliday Ryan , Surís Alina
Published: September 2018

History of childhood sexual assault (CSA) may result in poorer emotion regulation and interpersonal functioning, potentially affecting the tolerability and effectiveness of evidence‐based treatments (EBTs) for posttraumatic stress disorder (PTSD). Survivors of military sexual trauma (MST) have an increased incidence of CSA; however, research examining the role of CSA in EBTs for veterans with MST‐related PTSD is limited. Data from 32 (9 male; 23 female) veterans with MST‐related PTSD were used from a previously conducted randomized clinical trial examining the efficacy of an outpatient PTSD EBT (i.e., cognitive processing therapy [CPT]). Self‐rated PTSD symptom severity was assessed at pretreatment, during treatment, and up to 6 months following treatment completion. Number of CPT sessions attended and treatment completion were also examined. Using a hierarchical linear modelling approach, results indicated both veterans with and without a history of CSA were found to benefit from CPT, and history of CSA did not significantly predict treatment response. Additionally, number of sessions attended and treatment completion did not significantly vary based on history of CSA. These preliminary findings provide support for the tolerability and efficacy of outpatient CPT in veterans with MST‐related PTSD regardless of CSA history.
Noble‐Metal‐Free Ni‐MoOx Nanoparticles Supported on BN as a Highly Efficient Catalyst toward Complete Decomposition of Hydrazine Borane
Authors: Li Si‐Jia , Kang Xia , Wulan Ba‐Ri , Qu Xian‐Lin , Zheng Kun , Han Xiao‐Dong , Yan Jun‐Min
Published: September 2018

Hydrazine borane (HB) has been considered as a promising hydrogen storage material due to its high hydrogen content and stability at room temperature. For the first time, a facile wet‐chemical method is developed to synthesize amorphous/low crystalline noble‐metal‐free Ni‐MoOx/BN composite as a low‐cost and high‐efficient catalyst for hydrogen generation from HB decomposition. The as‐prepared Ni‐MoOx/BN hybrid exerts 100% selective conversion and can catalyze HB complete decomposition within 5 min, corresponding to a turnover frequency (TOF) value of 600.0 h−1 at 323 K. The excellent catalytic activity may be attributed to the good dispersion, uniform particle size (≈2.6 nm), and electronic effect between nanoparticles (NPs) and support material. On further reducing the dosage of Ni, the catalyst still exhibits supreme performance, with the TOF value of 2370 h−1 (nNi = 0.008 mmol) at 323 K, which is the highest one among all the reported catalysts for full decomposition of HB. Thus, the excellent catalytic results provide more possibilities for the effective application of HB as a promising hydrogen storage material.
Dopant‐Free Hole Transporting Materials for Perovskite Solar Cells
Authors: Rezaee Ehsan , Liu Xiaoyuan , Hu Qikun , Dong Lei , Chen Qian , Pan Jia‐Hong , Xu Zong‐Xiang
Published: September 2018

This article reviews various dopant‐free hole transporting materials (HTMs) used in perovskite solar cells (PSCs) in three main categories including inorganic, polymeric, and small molecule HTMs. PSCs have undergone rapid progress, achieving power conversion efficiencies (PCEs) above 22%. With their low production cost and high efficiencies, PSCs are considered promising next‐generation solar cell technology. In all developed architectures for PSCs, including planar and mesoscopic with conventional and inverted structures, HTMs play a significant role in determining the photovoltaic performance of PSCs. Using p‐type dopants, however, is considered a common strategy to increase the hole conductivity of HTM, which is usually compensated by a more complicated fabrication procedure, higher production costs, and lower stability of PSC. Although several reviews on HTMs have been published, progress on dopant free HTMs needs to be reviewed and analyzed. Here, a review covering most of the published reports on dopant‐free HTMs is presented, and the device structure and fabrication method, HTM layer deposition techniques, and the efficiency and the stability of PSCs are addressed during discussions in each main category. Finally, an outlook on stability and PCE growth in PSCs based on dopant‐free HTMs is presented.
Ameliorative effect of Rutin on sodium fluoride‐induced hypertension through modulation of Kim‐1/NF‐κB/Nrf2 signaling pathway in rats
Authors: Oyagbemi Ademola Adetokunbo , Omobowale Temidayo Olutayo , Ola‐Davies Olufunke Eunice , Asenuga Ebunoluwa Racheal , Ajibade Temitayo Olabisi , Adejumobi Olumuyiwa Abiola , Afolabi Jeremiah Moyinoluwa , Ogunpolu Blessing Seun , Falayi Olufunke Olubunmi , Ayodeji Fatimah , Hassan Fasilat Oluwakemi , Saba Adebowale Bernard , Adedapo Adeolu Alex , Yakubu Momoh Audu
Published: September 2018

Sodium fluoride is one of the neglected environmental contaminants. Inorganic fluorides in the environment are found in the air, water, and land. In the study, forty‐male Wistar albino rats were randomly divided into four groups with 10 rats in a group. Group A was the control group which was given normal saline, Group B was exposed to 300 ppm of NaF in drinking water, while Groups C and D received NaF along Rutin (100 mg/kg and 200 mg/kg) orally daily for a week. Administration of NaF alone led to significant increases in blood pressure, and deceased serum nitric oxide. Immunohistochemistry revealed higher expressions of kidney injury molecule I (Kim‐1), nuclear factor kappa beta (NF‐κB), and down regulation of nuclear factor erythroid 2‐related factor 2 (Nrf2) in rats administered NaF. Rutin co‐treatment with NaF normalized blood pressure, lowered Kim‐1 and NF‐κB expressions, and improved nitric oxide bioavailability.
EPA publishes final reporting requirements for TSCA mercury inventory
Authors: Bergeson Lynn L.
Published: September 2018

Section 8(b)(10)(B) of the Toxic Substances Control Act, as amended by the Frank R. Lautenberg Chemical Safety for the 21st Century Act (Lautenberg), directs that “[n]ot later than April 1, 2017, and every 3 years thereafter, the Administrator shall carry out and publish” (Environmental Protection Agency [EPA], 2018a, Federal Register, 83, pp. 30054–30077) an inventory of mercury or mercury‐added products or uses of mercury in a manufacturing process. On June 27, 2018, the U.S. EPA published a final rule responding to this legislative mandate. The rule requires certain entities to provide information to assist in the preparation of this inventory. This column outlines the final rule and discusses its implications.
Biomolecular simulations: From dynamics and mechanisms to computational assays of biological activity
Authors: Huggins David J. , Biggin Philip C. , Dämgen Marc A. , Essex Jonathan W. , Harris Sarah A. , Henchman Richard H. , Khalid Syma , Kuzmanic Antonija , Laughton Charles A. , Michel Julien , Mulholland Adrian J. , Rosta Edina , Sansom Mark S. P. , van der Kamp Marc W.
Published: September 2018

Biomolecular simulation is increasingly central to understanding and designing biological molecules and their interactions. Detailed, physics‐based simulation methods are demonstrating rapidly growing impact in areas as diverse as biocatalysis, drug delivery, biomaterials, biotechnology, and drug design. Simulations offer the potential of uniquely detailed, atomic‐level insight into mechanisms, dynamics, and processes, as well as increasingly accurate predictions of molecular properties. Simulations can now be used as computational assays of biological activity, for example, in predictions of drug resistance. Methodological and algorithmic developments, combined with advances in computational hardware, are transforming the scope and range of calculations. Different types of methods are required for different types of problem. Accurate methods and extensive simulations promise quantitative comparison with experiments across biochemistry. Atomistic simulations can now access experimentally relevant timescales for large systems, leading to a fertile interplay of experiment and theory and offering unprecedented opportunities for validating and developing models. Coarse‐grained methods allow studies on larger length‐ and timescales, and theoretical developments are bringing electronic structure calculations into new regimes. Multiscale methods are another key focus for development, combining different levels of theory to increase accuracy, aiming to connect chemical and molecular changes to macroscopic observables. In this review, we outline biomolecular simulation methods and highlight examples of its application to investigate questions in biology.

This article is categorized under:

Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods

Structure and Mechanism > Computational Biochemistry and Biophysics

Molecular and Statistical Mechanics > Free Energy Methods