bluuebunny/crossref_metadata_2025 huggingface dataset:
Priors Bias Perceptual Decisions in Autism, But Are Less Flexibly Adjusted to the Context
Authors: Sapey‐Triomphe Laurie‐Anne , Timmermans Laura , Wagemans Johan
Published: December 2020

According to the predictive coding framework, percepts emerge from combinations of sensory input and prior knowledge, whose relative contributions depend on their reliability. Recent predictive coding theories suggest that Autism Spectrum Disorder (ASD) could be characterized by an atypical weighting of priors. Here, we assessed whether individuals with ASD can flexibly adjust the weight (precision) of the prior to the context. Thirty‐one neurotypical adults (NT) and 26 adults with ASD participated in a visual discrimination task designed to elicit a time‐order effect (TOE). The TOE reflects the integration of priors with sensory estimates. We used two experimental contexts: a narrow stimulus range (Narrow condition) and a broader range (Broad condition) in order to induce a prior with a higher and lower precision, respectively. Both groups learned a prior that biased their perception, as shown with the TOE. As expected, the NT group had a larger TOE in the Narrow condition than in the Broad condition, revealing a contextual adjustment of the prior precision. In contrast, ASD participants were more inflexible: the extent of the TOE was not modulated by the context. In addition, the accuracy increased when the stimulus range decreased in both group, which may be interpreted as a contextual adjustment of the sensory precision. To conclude, adults with and without ASD implicitly learned a prior mean, but ASD participants failed to flexibly adjust the prior precision to the context. This increased inflexibility in ASD could account for many symptoms, such as their intolerance of uncertainty.

Lay Summary

Based on our experience, we have expectations about our environment. Theories suggest that the symptoms encountered in autism could be due to atypical expectations, leading to an impression of an unpredictable world. Using a visual discrimination task, we showed that adults with and without autism were biased by their expectations. Yet, the extent to which expectations biased perception did not depend on the context in autism. This higher inflexibility found in autism may explain symptoms such as resistance to change.
Laser Patterning of High‐Mass‐Loading Graphite Anodes for High‐Performance Li‐Ion Batteries
Authors: Dubey Romain , Zwahlen Marcel‐David , Shynkarenko Yevhen , Yakunin Sergii , Fuerst Axel , Kovalenko Maksym V. , Kravchyk Kostiantyn V.
Published: December 2020

Given the ongoing efforts to build Li‐ion batteries with higher volumetric energy and power densities, the research on enhancing Li‐ion transport within compressed high‐mass‐loading electrodes at fast cycling conditions is imperative. In this work, we show that the rate capability of graphite electrodes with high areal capacity of 4.5 mAh cm−2 and density of 1.79 g cm−3 (15 % of porosity) can be considerably improved by laser patterning, namely by the fabrication of arrays of vertically aligned channels serving as diffusion paths for rapid Li‐ion transport. Resultant laser patterned graphite electrodes delivered enhanced volumetric capacity as compared to that of non‐patterned electrodes (450 vs. 396 mAh cm−3 at C/2 rate). The reduction of the total steady‐state concentration drop within the graphite electrodes after their patterning was also assessed.
RNA‐protein interactions: Central players in coordination of regulatory networks
Authors: Armaos Alexandros , Zacco Elsa , Sanchez de Groot Natalia , Tartaglia Gian Gaetano
Published: December 2020

Changes in the abundance of protein and RNA molecules can impair the formation of complexes in the cell leading to toxicity and death. Here we exploit the information contained in protein, RNA and DNA interaction networks to provide a comprehensive view of the regulation layers controlling the concentration‐dependent formation of assemblies in the cell. We present the emerging concept that RNAs can act as scaffolds to promote the formation ribonucleoprotein complexes and coordinate the post‐transcriptional layer of gene regulation. We describe the structural and interaction network properties that characterize the ability of protein and RNA molecules to interact and phase separate in liquid‐like compartments. Finally, we show that presence of structurally disordered regions in proteins correlate with the propensity to undergo liquid‐to‐solid phase transitions and cause human diseases. Also see the video abstract here https://youtu.be/kfpqibsNfS0
Macroscopic modeling of bioreactors for recombinant protein producingPichia pastorisin defined medium
Authors: Hong Moo Sun , Velez‐Suberbie M. Lourdes , Maloney Andrew J. , Biedermann Andrew , Love Kerry R. , Love J. Christopher , Mukhopadhyay Tarit K. , Braatz Richard D.
Published: December 2020

The methylotrophic yeastPichia pastorisis widely used as a microbial host for recombinant protein production. Bioreactor models forP. pastoriscan inform understanding of cellular metabolism and can be used to optimize bioreactor operation. This article constructs an extensive macroscopic bioreactor model forP. pastoriswhich describes substrates, biomass, total protein, other medium components, and off‐gas components. Species and elemental balances are introduced to describe uptake and evolution rates for medium components and off‐gas components. Additionally, a pH model is constructed using an overall charge balance, acid/base equilibria, and activity coefficients to describe production of recombinant protein and precipitation of medium components. The extent of run‐to‐run variability is modeled by distributions of a subset of the model parameters, which are estimated using the maximum likelihood method. Model prediction from the extensive macroscopic bioreactor model well describes experimental data with different operating conditions. The probability distributions of the model predictions quantified from the parameter distribution are quantifiably consistent with the run‐to‐run variability observed in the experimental data. The uncertainty description in this macroscopic bioreactor model identifies the model parameters that have large variability and provides guidance as to which aspects of cellular metabolism should be the focus of additional experimental studies. The model for medium components with pH and precipitation can be used for improving chemically defined medium by minimizing the amount of components needed while meeting cellular requirements.
Der Mann aus dem Eis
Authors: Zink Albert
Published: December 2020

Seit seiner Entdeckung in den Ötztaler Alpen am 19. September 1991 gewährt uns der Mann aus dem Eis einen tiefen Einblick in die Lebensumstände einer bis dahin wenig erforschten Bevölkerung, die vor über 5000 Jahren im alpinen Raum heimisch war. Durch die Verwendung modernster medizinischer und naturwissenschaftlicher Untersuchungen ist es gelungen, zahllose Details über das Leben der weltbekannten Gletschermumie, aber vor allem auch zu ihren Krankheiten und zu ihrem gewaltsamen Tod am Hauslabjoch zu erforschen. Darüber hinaus bietet die moderne Mumienforschung die Möglichkeit, wichtige Erkenntnisse zum Auftreten und zur Entwicklung von Krankheiten zu erhalten. So konnten bei dem Mann aus dem Eis, mit Hilfe von modernen Hochdurchsatzsequenzierverfahren, eine genetische Veranlagung für Herz‐ und Kreislauferkrankungen festgestellt und der Krankheitserreger Helicobacter pylori im Magen des Ötzi nachgewiesen werden. Die Untersuchung unterschiedlicher Biomoleküle, einschließlich DNA, Lipiden und Proteinen, ermöglichte zudem die Rekonstruktion seiner letzten Mahlzeit, die im Wesentlichen aus getrocknetem und sehr fettreichem Wildfleisch und frühen Getreidearten wie dem Einkorn bestand.
Live‐Imaging – Mikroskopieren in Echtzeit
Authors: Uhlenküken Stefan
Published: December 2020

Zum Forschen gehört, dass die Ergebnisse festgehalten werden, und das kann ganz unterschiedlich aussehen. In der Zellbiologie wurde schon seit der Erfindung des Mikroskops zeichnerisch festgehalten, was man unter die Linse bekam. Heute stehen viele verschiedene Mikroskopiertechniken in den Laboren zur Verfügung, wobei das Live‐Imaging sicherlich eine der Interessantesten ist, denn es ermöglicht das Mikroskopieren von Lebewesen in Echtzeit.
An assay for cancer stem cell‐induced angiogenesis on chick chorioallantoic membrane
Authors: Nawara Hend M. , Afify Said M. , Hassan Ghmkin , Zahra Maram H. , Atallah Marwa N. , Seno Akimasa , Seno Masaharu
Published: December 2020

Angiogenesis is generally involved in tumor growth and metastasis. Cancer stem cells (CSCs) are considered to facilitate the angiogenesis. Therefore, CSCs could be the effective targets to stop angiogenesis. Recently, our group successfully generated CSC models from induced pluripotent stem cells (iPSCs) in the presence of conditioned medium derived from cancer derived cells. These novel model CSCs has been characterized by highly tumorigenic, angiogenic and metastatic potentials in vivo. The angiogenic potential of CSCs has been explained by the expression of both angiogenic factors and their receptors implying the angiogenesis in autocrine manner. In this protocol we optimized the method to evaluate tumor angiogenesis with the CSC model, which was described effective to assess sorafenib as an antiangiogenic drug, on chick chorioallantoic membrane (CAM) assay. Our results demonstrate that CSCs developed from iPSCs and CAM assay are a robust and cost‐effective tool to evaluate tumor angiogenesis with CSCs. Collectively, CSCs in CAM assay could serve as a very useful model for the screening of potential therapeutic agents targeting tumor angiogenesis.
Numerical Deconvolution of Surface Interrogation Scanning Electrochemical Microscopy Experiments on Platinum During Hydrogen Evolution
Authors: Jantz Dylan T. , Seuferling Tess E. , Leonard Kevin C.
Published: December 2020

Invited for this month's cover picture is the group of Prof. Kevin C. Leonard. The cover picture shows an artistic rendition of a surface interrogation scanning electrochemical microscopy experiment in the act of gathering fundamental insights into the adsorbed intermediates on an electrode surface during an electrocatalytic reaction. Read the full text of the Article at 10.1002/celc.202001082.
Effect of Transition Metals on the Oxygen Reduction Reaction Activity at Metal‐N3/C Active Sites
Authors: Fruehwald Holly M. , Ebralidze Iraklii I. , Zenkina Olena V. , Easton E. Bradley
Published: December 2020

Invited for this month's cover picture are the groups of Brad Easton and Olena Zenkina at Ontario Tech University (Canada). The cover picture shows an artistic dipcition of a treasure map quest for unique M‐N3 non‐platinum group metal fuel cell catalysts. Read the full text of the Article at 10.1002/celc.202000954.
Gold‐Based Pharmacophore Inhibits Intracellular MYC Protein
Authors: Ofori Samuel , Gukathasan Sailajah , Awuah Samuel G.
Published: December 2020

Direct targeting of intrinsically disordered proteins, including MYC, by small molecules for biomedical applications would resolve a longstanding issue in chemical biology and medicine. Thus, we developed gold‐based small‐molecule MYC reagents that engage MYC inside cells and modulate MYC transcriptional activity. Lead compounds comprise an affinity ligand and a gold(I) or gold(III) warhead capable of protein chemical modification. Cell‐based MYC target engagement studies via CETSA and co‐immunoprecipitation reveal specific interaction of compounds with MYC in cells. The lead gold(I) reagent, 1, demonstrates superior cell‐killing potential (up to 35‐fold) in a MYC‐dependent manner when compared to 10058‐F4 in cells including the TNBC, MDA‐MB‐231. Subsequently, 1 suppresses MYC transcription factor activity via functional colorimetric assays, and gene‐profiling using whole‐cell transcriptomics reveals significant modulation of MYC target genes by 1. These findings point to metal‐mediated ligand affinity chemistry (MLAC) based on gold as a promising strategy to develop chemical probes and anticancer therapeutics targeting MYC.
Obesity, comorbidities, and treatment selection in Black and White women with early breast cancer
Authors: Nyrop Kirsten A. , Damone Emily M. , Deal Allison M. , Carey Lisa A. , Lorentsen Michael , Shachar Shlomit S. , Williams Grant W. , Brenizer Addison (Tucker) , Wheless Amy , Muss Hyman B.
Published: December 2020

Background

This study investigates obesity and comorbidity in Black and White women with early breast cancer (stages I‐III) and their potential impact on treatment decisions for patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2–) tumors.

Methods

In this retrospective chart review, comparisons of frequencies for Black and White patients were calculated with the Fisher exact test. Log binomial regression was used to estimate prevalence ratios (PRs) with 95% confidence intervals for total and individual comorbidities, and multivariable modeling was used to estimate PRs adjusted for age and body mass index (BMI).

Results

In a sample of 548 patients, 26% were Black, and 74% were White. Sixty‐two percent of Black patients and 32% of White patients were obese (BMI ≥ 30 kg/m2; P < .0001). Seventy‐five percent of Black patients and 87% of White patients had HR+ tumors (P = .001). Significant intergroup differences were seen for 2 or more total comorbidities (62% of Blacks vs 47% of Whites; P = .001), 2 or more obesity‐related comorbidities (33% vs 10%; P < .0001), hypertension (60% vs 32%; P < .0001), diabetes mellitus (23% vs 6%; P < .0001), hypercholesterolemia or hyperlipidemia (28% vs 18%; P = .02), and hypothyroidism (4% vs 11%; P = .012). In women with HR+/HER2– tumors, there were no intergroup differences in treatment decisions regarding the type of surgery, chemotherapy regimen, radiation, or endocrine treatment despite significant differences in the prevalence of obesity and comorbidities.

Conclusions

This study documents significant disparities between Black and White women with early breast cancer with regard to high rates of obesity, overall comorbidities, and obesity‐related comorbidities, and it highlights the prevalence of competing risks that may complicate outcomes in breast cancer.
From Cd‐Rich to Se‐Rich – The Manipulation of CdSe Nanocluster Structure and Optical Absorption
Authors: Jäger Marc , Schäfer Rolf
Published: December 2020

A combined experimental and quantum‐chemical study of the structure and optoelectronic properties of isolated non‐stoichiometric CdxSey+ clusters with x=3, 4 and y=3, 4 is presented. The consistency of optical response calculations with the measured absorption spectra reveals that the theoretically predicted lowest energy structural isomers have been formed in the molecular beam experiments. The Se‐rich nanocluster Cd3Se4+ contains a Se2− unit which is responsible for the enhanced light absorption in the visible spectral range. In contrast, the radical electron of the Cd‐rich species Cd4Se3+ is localized at a Cd+ centre which is attached to a six‐membered Cd3Se3 ring. The excess Cd atom is partly responsible for an intense optical absorption in the near ultraviolet. The variation of the geometry and the optical behaviour in dependence of the stoichiometry is discussed with respect to the photocatalytic properties of CdSe nanoparticles
Epigenetic consequences of hormonal interactions between opposite‐sex twin fetuses
Authors: Kong Siming , Peng Yong , Chen Wei , Ma Xinyi , Wei Yuan , Zhao Yangyu , Li Rong , Qiao Jie , Yan Liying
Published: December 2020

Previous studies reported inconsistent evidence about some phenotypic traits of females in human opposite‐sex twins (opposite‐sex females [OSF]) being distinct from females in same‐sex twins (SSF). Comparatively, less evidence showed significant differences between males in OS twins (opposite‐sex males [OSM]) and males in same‐sex twins (SSM). The twin testosterone transfer hypothesis suggests that prenatal exposure of testosterone in utero may be a possible explanation for the differential traits in OSF; however, the underlying mechanism is unknown. Here, we investigated the potential epigenetic effects of hormone interactions and their correlation to the observed phenotypic traits. In the study, DNA methylomic data from 54 newborn twins and histone modification data (H3K4me3, H3K4me1, H3K27me3, and H3K27ac) from 14 newborn twins, including same‐sex females (SSF), OS twins, and same‐sex males (SSM) were generated. We found that OSF were clearly distinguishable from SSF by DNA methylome, while OSM were distinguishable from SSM by H3K4me1 and H3K4me3. To be more specific, compared to SSF, OSF showed a stronger correlation to males (OSM and SSM) in genome‐wide DNA methylation. Further, the DNA methylomic differences between OSF and SSF were linked to the process involving cognitive functions and nervous system regulation. The differential H3K4me3 between OSM and SSM was linked to immune responses. These findings provide epigenetic evidence for the twin testosterone transfer hypothesis and offer novel insights on how prenatal hormone exposure in utero may be linked to the reported differential traits of OS twins.
An in vitro assay approach to investigate the potential impact of different doping agents on the steroid profile
Authors: Piper Thomas , Heimbach Sonja , Adamczewski Martin , Thevis Mario
Published: December 2020

The steroid profile, that is, the urinary concentrations and concentration ratios of selected steroids, is used in sports drug testing to detect the misuse of endogenous steroids such as testosterone. Since several years, not only population‐based thresholds are applied but also the steroid profile is monitored via the Athlete Biological Passport whereby the individual reference ranges derived from multiple test results of the same athlete are compared to population‐based thresholds. In order to maintain a high probative force of the passport, samples collected or analyzed under suboptimal conditions should not be included in the longitudinal review. This applies to biologically affected or degraded samples and to samples excluded owing to the presence of other substances potentially (or evidently) altering the steroid profile. Nineteen different doping agents comprising anabolic steroids, selective androgen receptor modulators, selective estrogen receptor modulators, ibutamoren, and tibolone were investigated for their effect on the steroid profile using an androgen receptor activation test, an androgen receptor binding assay, an aromatase assay, and a steroidogenesis assay. The in vitro tests were coupled with well‐established liquid chromatography/mass spectrometry‐based analytical approaches and for a subset of steroidal analytes by gas chromatography/mass spectrometry. The variety of tests employed should produce a comprehensive data set to better understand how a compound under investigation may impact the steroid profile. Although our data set may allow an estimate of whether or not a substance will have an impact on the overall steroid metabolism, predicting which parameter in particular may be influenced remains difficult.
Clinical effects of cardiac contractility modulation in heart failure with mildly reduced systolic function
Authors: Tschöpe Carsten , Butler Javed , Farmakis Dimitrios , Morley Deborah , Rao Ishu , Filippatos Gerasimos
Published: December 2020

Aims

Increasing attention is being given to patients with heart failure and ‘mid‐range’ left ventricular ejection fraction (LVEF, ≥40% and <50%) for whom there are no approved therapies that improve prognosis. We aim to assess for the first time the effects of cardiac contractility modulation (CCM) therapy in this patient population.

Methods and results

We assessed the effects of 6‐  month CCM therapy on functional status, exercise tolerance and quality of life in a subgroup of 53 patients with a LVEF of 40–45% recruited in previous CCM studies, including 37 patients in the CCM group and 16 in the control group. New York Heart Association classification improved by ≥1 class from baseline to 24 weeks in 80.6% (95% confidence interval [62.5%, 92.5%]) of patients in the CCM group compared with 57.1% in the control group (95% confidence interval [28.9%, 82.3%], P = 0.15). Six‐minute walk distance increased significantly in the CCM group with a net between‐group treatment effect of 53.9 ± 74.2 m (P = 0.05). Peak VO2 improved in the CCM group with a net between‐group treatment effect of 2.0 ± 2.8 mL/kg/min (P = 0.02). Minnesota Living with Heart Failure Questionnaire score decreased from baseline to 24 weeks with a net between‐group treatment effect of −13.1 ± 21.0 (P = 0.10). There were no significant differences in the adverse event rate between the CCM and control groups.

Conclusions

These preliminary results suggest that CCM exerts favourable effects on exercise tolerance and quality of life in patients with LVEF in the range of 40–45% with an acceptable safety profile. Further randomized controlled studies are planned to prove these effects.
Selective Vicinal Diiodination of Polycyclic Aromatic Hydrocarbons
Authors: Kaehler Tanja , John Alexandra , Jin Tao , Bolte Michael , Lerner Hans‐Wolfram , Wagner Matthias
Published: December 2020

Vicinally diiodinated polycyclic aromatic hydrocarbons (I2‐PAHs) are accessible from the corresponding diborylated B2‐PAHs through boron/iodine exchange. The B2‐PAHs have been prepared via twofold electrophilic borylation reactions templated by a vicinally disilylated benzene. Our protocol is applicable to fluorenes, acenes, annulated acenes, oligoaryls, and even [5]helicene. Using B2‐naphthalene as the example, we have shown that the reaction scope can, in principle, be expanded to include the synthesis of vicinally dibrominated and dihydroxylated PAHs. The usefulness of the building blocks provided by our method in the field of optoelectronic materials was demonstrated by the successful conversion of I2‐fluoranthene to the analogous doubly alkynylated fluoranthene emitter.
Indenofluorene‐Extended Tetrathiafulvalene Scaffolds for Dye‐Sensitized Solar Cells
Authors: Mogensen Josefine , Michaels Hannes , Roy Rajarshi , Broløs Line , Kilde Martin Drøhse , Freitag Marina , Nielsen Mogens Brøndsted
Published: December 2020

Indenofluorene‐extended tetrathiafulvalenes (IF‐TTFs) comprise a class of π‐conjugated sensitizers that exhibit strong absorptions in the visible region and two reversible one‐electron oxidations. Herein we present the synthesis and optical as well as redox properties of novel IF‐TTF donor‐acceptor scaffolds that were integrated in dye‐sensitized solar cells (DSCs) via anchoring of a carboxylic acid end‐group on the scaffolds to TiO2. Synthetically, the scaffolds were constructed by Sonogashira coupling reactions between an iodo‐functionalized IF‐TTF and an acceptor moeity containing a terminal alkyne. These very first IF‐TTF based candidates for DSCs exhibited high performances, in particular a dye incorporating a benzothiadiazole acceptor moiety, showing a conversion efficiency of 6.4 %. This result signals that IF‐TTF derivatives present a promising class of compounds for further structural modifications. Such modifications will benefit from the readiness of the iodo‐funcitonalized IF‐TTF building block to undergo Pd‐catalyzed coupling reactions.
Metabolomic and kinetic investigations on the electricity‐aided production of butanol by Clostridium pasteurianum strains
Authors: Arbter Philipp , Sabra Wael , Utesch Tyll , Hong Yaeseong , Zeng An‐Ping
Published: December 2020

In this contribution, we studied the effect of electro‐fermentation on the butanol production of Clostridium pasteurianum strains by a targeted metabolomics approach. Two strains were examined: an electrocompetent wild type strain (R525) and a mutant strain (dhaB mutant) lacking formation of 1,3‐propanediol (PDO). The dhaB‐negative strain was able to grow on glycerol without formation of PDO, but displayed a high initial intracellular NADH/NAD ratio which was lowered subsequently by upregulation of the butanol production pathway. Both strains showed a 3–5 fold increase of the intracellular NADH/NAD ratio when exposed to cathodic current in a bioelectrochemical system (BES). This drove an activation of the butanol pathway and resulted in a higher molar butanol to PDO ratio for the R525 strain. Nonetheless, macroscopic electron balances suggest that no significant amount of electrons derived from the BES was harvested by the cells. Overall, this work points out that electro‐fermentation can be used to trigger metabolic pathways and improve product formation, even when the used microbe cannot be considered electroactive. Accordingly, further studies are required to unveil the underlying (regulatory) mechanisms.
Parameter and state estimation of backers yeast cultivation with a gas sensor array and unscented Kalman filter
Authors: Yousefi‐Darani Abdolrahimahim , Paquet‐Durand Olivier , Hinrichs Jörg , Hitzmann Bernd
Published: December 2020

Real‐time information about the concentrations of substrates and biomass is the key to accurate monitoring and control of bioprocess. However, on‐line measurement of these variables is a challenging task and new measurement systems are still required. An alternative are software sensors, which can be used for state and parameter estimation in bioprocesses. The software sensors predict the state of the process by using mathematical models as well as data from measured variables. The Kalman filter is a type of such sensors.

In this paper, we have used the Unscented Kalman Filter (UKF) which is a nonlinear extension of the Kalman filter for on‐line estimation of biomass, glucose and ethanol concentration as well as for estimating the growth rate parameters in S. cerevisiae batch cultivation, based on infrequent ethanol measurements. The UKF algorithm was validated on three different cultivations with variability of the substrate concentrations and the estimated values were compared to the off‐line values.

The results obtained showed that the UKF algorithm provides satisfactory results with respect to estimation of concentrations of substrates and biomass as well as the growth rate parameters during the batch cultivation.
Morphology and evolution of supraglacial hummocks on debris‐covered Himalayan glaciers
Authors: Bartlett Oliver T. , Ng Felix S.L. , Rowan Ann V.
Published: December 2020

Thick supraglacial debris layers often have an undulating, hummocky topography that influences the lateral transport of debris and meltwater and provides basins for supraglacial ponds. The role of ablation and other processes associated with supraglacial debris in giving rise to this hummocky topography is poorly understood. Characterizing hummocky topography is a first step towards understanding the feedbacks driving the evolution of debris‐covered glacier surfaces and their potential impacts on mass balance, hydrology and glacier dynamics. Here we undertake a geomorphological assessment of the hummocky topography on five debris‐covered glaciers in the Everest region of the central Himalaya. We characterize supraglacial hummocks through statistical analyses of their vertical relief and horizontal geometry. Our results establish supraglacial hummocks as a distinct landform. We find that a typical hummock has an elongation ratio of 1.1:1 in the direction of ice flow, length of 214 ± 109 m and width of 192 ± 88 m. Hummocky topography has a greater amplitude across‐glacier (15.4 ± 10.9 m) compared to along the glacier flow line (12.6 ± 8.3 m). Consequently, hummock slopes are steeper in the across‐glacier direction (8.7 ± 4.3°) than in the direction of ice flow (5.6 ± 4.0°). Longer, wider and higher‐amplitude hummocks are found on larger glaciers. We postulate that directional anisotropy in the hummock topography arises because, while the pattern of differential ablation driving topography evolution is moderated by processes including the gravitational redistribution of debris across the glacier surface, it also inherits an orientation preference from the distribution of englacial debris in the underlying ice. Our morphometric data inform future efforts to model these interactions, which should account for additional factors such as the genesis of supraglacial ponds and ice cliffs and their impact on differential ablation.
A new reconstruction of numerical fluxes for conservation laws using fuzzy operators
Authors: Lochab Ruchika , Kumar Vivek
Published: December 2020

This article develops a new hybrid flux‐limited scheme for a numerical solution of the hyperbolic conservation laws by applying fuzzy logic‐based operator functions. The construction of the proposed flux‐limiter is explored using a fuzzy modifier function, having a suitable intensity. The purpose of this article is to present an efficient finite volume flux‐limited technique, derived from an entirely different subject of fuzzy mathematics, for tackling hyperbolic partial differential equations. Several standard test cases in one and two dimensions are solved numerically for demonstrating the robustness of the proposed new hybrid flux‐limited scheme.
Risk factors for subsequent recurrence after surgical treatment of recurrent pleomorphic adenoma of the parotid gland
Authors: Rooker Steven A. , Van Abel Kathryn M. , Yin Linda X. , Nagelschneider Alex A. , Price Daniel L. , Olsen Kerry D. , Janus Jeffrey R. , Kasperbauer Jan L. , Moore Eric J.
Published: December 2020

Background

Recurrent pleomorphic adenoma (PA) can be a lifelong disease, and rates of subsequent recurrence are high.

Methods

Patients between 2000 and 2015 were identified. Primary outcome was subsequent recurrence after surgical salvage.

Results

Twenty‐seven of 84 patients developed a subsequent recurrence. Risk factors for subsequent recurrence included a higher number of previous recurrences (P < .01), worse preoperative facial nerve function (P < .01), and deep parotid lesion(s) (P < .01). Interval since last surgery was protective (P < .01), specifically >10 years since last surgery (P < .01). For patients with a >10‐year interval since their last surgery, the subsequent recurrence‐free rate at 10 years follow‐up was 80.2% vs 31.8%.

Conclusions

For patients presenting with a >10‐year interval since their last surgery, subsequent recurrence rates are low, which may allow for as needed surveillance recommendations. For patients presenting with recurrent PA and ≤10 years since their last surgery, a closer surveillance is warranted.
Unsteady flow and heat transfer of tangent‐hyperbolic fluid: Legendre wavelet‐based analysis
Authors: Usman Muhammad , Zubair Tamour , Hamid Muhammad , Haq Rizwan Ul , Khan Zafar Hayat
Published: December 2020

The objective of the current article is to explore the unsteady flow and heat transfer of magnetohydrodynamics tangent‐hyperbolic fluid flow over a stretching sheet. The governing flow model is transformed into a nonlinear set of ordinary differential equations by utilizing the appropriate similarity techniques. A new modification is introduced into the traditional Legendre wavelet method to obtain the results of the model mentioned above. The classic wavelet scheme is unable to find the solution for an infinite domain. Hence, we successfully extended it for an infinite domain and used it to attain the significant findings of the fluid problem. Additionally, the study of emerging parameters on temperature and velocity profiles is reported graphically. The velocity behavior is decreasing for the physical parameters, namely, power‐lax index, unsteadiness, Hartmann number, and Weissenberg number. The temperature profile is an increasing function for power‐law index and Eckert number while the behavior is the opposite for the Prandtl number. Moreover, a tabular form comparison of outcomes with existing literature, convergence, and error analysis is provided in our study, which confirms the credibility of the suggested method. The obtained results endorse the credibility and reliability of the proposed method; therefore, it could be extended for other nonlinear problems of complex nature.
Multiregional assessment of CIMP in primary colorectal cancers: Phenotype concordance but marker variability
Authors: Flatin Bjørnar T.B. , Vedeld Hege Marie , Pinto Rita , Langerud Jonas , Lind Guro E. , Lothe Ragnhild A. , Sveen Anita , Jeanmougin Marine
Published: December 2020

Intratumor heterogeneity of colorectal cancers (CRCs) is manifested both at the genomic and epigenomic levels. Early genetic aberrations in carcinogenesis are clonal and present throughout the tumors, but less is known about the heterogeneity of the epigenetic CpG island methylator phenotype (CIMP). CIMP characterizes a subgroup of CRCs thought to originate from specific precursor lesions, and it is defined by widespread DNA methylation within promoter regions. In this work, we investigated CIMP in two to four multiregional samples from 30 primary tumors (n = 86 samples) using the consensus Weisenberger gene panel (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1). Twenty‐nine of 30 tumors (97%) showed concordant CIMP status in all samples, and percent methylated reference (PMR) values of all five markers had higher intertumor than intratumor variation (P value = 1.5e−09). However, a third of the CIMP+ tumors exhibited discrepancies in methylation status in at least one of the five gene markers. To conclude, CIMP status was consistent within primary CRCs, and it is likely a clonal phenotype. However, spatial discordances of the individual genes suggest that large‐scale analysis of multiregional samples could be of interest for identifying CIMP markers that are robust to intratumor heterogeneity.
Deep learning‐assisted magnetic resonance imaging prediction of tumor response to chemotherapy in patients with colorectal liver metastases
Authors: Zhu Hai‐Bin , Xu Da , Ye Meng , Sun Li , Zhang Xiao‐Yan , Li Xiao‐Ting , Nie Pei , Xing Bao‐Cai , Sun Ying‐Shi
Published: December 2020

Accurate evaluation of tumor response to preoperative chemotherapy is crucial for assigning appropriate patients with colorectal liver metastases (CRLM) to surgery or conservative therapy. However, there is no well‐recognized method for predicting pathological response before surgery. Our study constructed and validated a deep learning algorithm using prechemotherapy and postchemotherapy magnetic resonance imaging (MRI) to predict pathological response in CRLM. CRLM patients from center one who had ≤5 lesions and were scheduled to receive preoperative chemotherapy followed by liver resection between January 2013 and November 2016, were included prospectively and chronologically divided into a training cohort (80% of patients) and a testing cohort (20% of patients). Patients from center two were included January 2017 and December 2018 as an external validation cohort. MRI‐based models were constructed to discriminate according to pathology tumor regression grade (TRG) between the response (TRG1/2) and nonresponse (TRG3/4/5) groups at the lesion level. From center one, 155 patients (328 lesions) were included; chronologically, 101 (264 lesions) in the training cohort and 54 (64 lesions) in the testing cohort. The model achieved better accuracy (0.875 vs 0.578) and AUC (0.849 vs 0.615) than RECIST for discriminating response; it also distinguished the survival outcomes after hepatectomy better than the RECIST criteria. Evaluations of the external validation cohort (25 patients, 61 lesions) also showed good ability with an AUC of 0.833. In conclusion, the MRI‐based deep learning model provided accurate prediction of pathological tumor response to preoperative chemotherapy in patients with CRLM and may inform individualized treatment.
Optimized segmentation and classification for liver tumor segmentation and classification using opposition‐based spotted hyena optimization
Authors: Rela Munipraveena , Nagaraja Rao Suryakari , Ramana Reddy Patil
Published: December 2020

In today's world, liver cancers are one of the mainly popular cancers occurring in the human body. The greater part of liver carcinomas is more prone to alcohol‐related hepatitis and cirrhosis conditions. Moreover, there is another form of cancer namely, metastatic liver cancer, where the tumor is initiated from other organs and extends to the liver. Early and premature diagnosis of liver cancer is necessary as it tends to improvise life expectancy. Nowadays, discriminating the liver and tumor parts from medical images with the aid of completely automated computer‐aided software is a more challenging task, since the liver disease can vary from person to person. This article attempts to implement the novel liver tumor segmentation and classification model using the optimization driven segmentation and classification model. The developed model carries out the task in five steps (a) Pre‐processing, (b) liver segmentation, (c) tumor segmentation, (d) feature extraction, and (e) classification. At first, the gathered CT images are subjected to pre‐processing with three steps that follow contrast enhancement by histogram equalization and noise filtering by the median filter. Next to the pre‐processing of the image, the liver is segmented from the CT abdominal image using adaptive thresholding pursued by level set segmentation. Further, a modified algorithm termed as Fuzzy Centroid‐based Region Growing Algorithm with tolerance optimization is developed and used for the tumor segmentation. From the segmented tumor image, three sets of features like gray‐level co‐occurrence matrix (GLCM), shape features, and local binary pattern (LBP) is utilized for the classifier training. In the classification side, two deep learning algorithms are used: recurrent neural network (RNN), and convolutional neural network (CNN). The tumor segmented image is given as input to the CNN, and the extracted features are given as input to the RNN. As an improvement, an optimized hybrid classifier is adopted for the hidden neuron optimization. Moreover, an improved meta‐heuristic algorithm called opposition‐based spotted hyena optimization (O‐SHO) is introduced to perform the optimized segmentation and classification. The experimental results show that the overall accuracy attained by the proposed model is efficient, less sensitive to noise, and performs superior on a diverse set of CT images.
In vitro and in vivo comparative performance studies of gadolinium‐loaded zeolites and Gd‐DOTA as contrast agents for MRI applications
Authors: Contro Janine , Silva Danilo Antonio , Santisteban Oscar A. N. , Narayana Ponnada A. , Nery José G.
Published: December 2020

Gadolinium‐based contrast agents (CAs) were synthesized using faujasite zeolite (NaX) and zeolite beta (BEA) and their performances in vitro and in vivo were compared to the widely used commercial CA, gadoteric acid (Gd‐DOTA). Magnetic resonance imaging (MRI) relaxometry studies (considering longitudinal [T1] and transverse [T2] relaxation times) were performed using Gd‐DOTA and the zeolitic materials loaded with Gd3+. The Gd‐loaded NaX, which presented large pores and cavities (7.35 and 11.24 Å, respectively), exhibited relaxivity values of around 52 mM−1 s−1, while BEA, which presented smaller pore and cavity diameters (5.95 and 6.68 Å, respectively) showed lower relaxivity values of ~4.8 mM−1 s−1. The effect of the Gd‐loaded NaX as MRI CA was tested in vivo in Sprague–Dawley rats, employing a 7 T scanner, with comparison to Gd‐DOTA MRI angiography. The relaxivity measurements showed that the Gd‐loaded NaX (50 mM−1 s−1) provided better image contrast than Gd‐DOTA (5.1 mM−1 s−1). Clearance studies of the CAs using urine and blood showed that both Gd‐loaded NaX and Gd‐DOTA were eliminated from the body after 2 days, demonstrating the potential of Gd‐loaded NaX for use as an MRI CA.
Bone Mineral Density in Antiretroviral Therapy‐Naïve HIV‐1–Infected Young Adult ‐Women Using Depot Medroxyprogesterone Acetate or Nonhormonal Contraceptives in Uganda
Authors: Matovu Flavia Kiweewa , Nabwana Martin , Kiwanuka Noah , Scholes Delia , Isingel Esther , Nolan Monica L , Fowler Mary G , Musoke Philippa , Pettifor John M , Brown Todd T , Beksinska Mags E ,   for the BONE CARE Study Team
Published: December 2020

Most studies evaluating BMD in human immunodeficiency virus (HIV)‐infected populations have focused on antiretroviral therapy (ART)‐experienced patients. In this study, the association between HIV‐1 and/or depot medroxyprogesterone acetate (DMPA) and BMD among untreated HIV‐1–infected women in a resource‐limited setting was assessed before long‐term exposure to ART. The data were then compared with that of the 2005–2008 United States National Health and Nutrition Examination Survey data for non‐Hispanic White and Black women. Women aged 18–35 years, recruited from health facilities in Kampala, Uganda, were classified based on their combination of HIV‐1 status and DMPA use: (i) HIV‐1–infected current DMPA users, (ii) HIV‐1–infected previous DMPA users, (iii) HIV‐1–infected nonhormonal‐contraceptive users, and (iv) HIV‐uninfected nonhormonal‐contraceptive users. All HIV‐1–infected women reported being ART‐naïve at baseline. BMD was measured at the lumbar spine, total hip, and femoral neck using DXA. Multivariate linear regression was used to assess the association between HIV‐1 and/or DMPA and BMD Z‐scores. Baseline data were analyzed for 452 HIV‐1–infected (220 nonhormonal users, and 177 current and 55 previous DMPA users) and 69 HIV‐1–uninfected nonhormonal‐contraceptive users. The mean age was 26.1 years (SD, 4.2) with a median duration of DMPA use among current users of 24.0 months [medians (interquartile range), 12‐48]. A higher proportion of HIV‐1–infected previous (12.7%) or current DMPA users (20.3%) and nonhormonal users (15.0%) had low BMD (Z‐score ≤−2 at any of the three sites) compared with age‐matched HIV‐1–uninfected women (2.9%). HIV‐1 infection and DMPA use were independently associated with significantly lower mean BMD Z‐scores at all sites, with the greatest difference being among HIV‐1–infected current DMPA users (5.6%–8.0%) versus uninfected nonhormonal users. Compared with non‐Hispanic White and Black women, the Ugandan local reference population had generally lower mean BMD at all sites. Newer treatment interventions are needed to mitigate BMD loss in HIV‐1–infected women in resource‐limited settings. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
A green one‐pot pseudo‐five‐component sequential protocol for the synthesis of novel 6,6′‐(arylmethylene)bis(benzo[a]phenazin‐5‐ol) derivatives
Authors: Olyaei Abolfazl , Aghajanzadeh Atiye , Feizy Elaheh , Sadeghpour Mahdieh
Published: December 2020

A simple and efficient synthesis of novel 6,6′‐(arylmethylene)bis(benzo[a]phenazin‐5‐ol) derivatives has been developed via a sequential one‐pot, two‐step, pseudo‐five‐component tandem reaction starting from 2‐hydroxynaphthalene‐1,4‐dione, o‐phenylenediamine, and aromatic aldehydes in the presence of 2‐aminopyridine as co‐catalyst and p‐TsOH as catalyst at 90°C under solvent‐free conditions. This sequential green process offers several advantages, such as operational simplicity, high yield, low cost, easy handling, clean reactions, absence of any tedious work‐up, and purification of products by non‐chromatographic methods.
The Importance of Clinical Research in Pregnant Women to Inform Prescription Drug Labeling
Authors: Dinatale Miriam , Roca Catherine , Sahin Leyla , Johnson Tamara , Mulugeta Lily Yeruk , Fletcher Elimika Pfuma , Yao Lynne
Published: December 2020

Pregnant women have historically been an understudied population and have been excluded from clinical trials. Recent efforts by stakeholders have raised awareness of the importance of clinical research in pregnant women to inform prescribing decisions. The Food and Drug Administration continues working to improve the format and content of prescription drug labeling for pregnant and lactating women, as demonstrated with the Pregnancy and Lactation Labeling Rule (PLLR), effective in 2015. The pregnancy labeling subsection now includes a subheading dedicated to the inclusion of pharmacokinetic (PK) data that inform the need for dose adjustments during pregnancy and the postpartum period. In addition, the PLLR also requires prescription drug labeling to be updated when important pregnancy information becomes available. Although PLLR improved the presentation of pregnancy‐related information in labeling, there is a need to increase the quality and quantity of human data on the use of prescription drugs during pregnancy. PK studies in pregnant women should be incorporated into drug development programs and prioritized to obtain important information about safe and appropriate doses of a drug when used during pregnancy. In addition, opportunistic PK studies, postapproval pregnancy safety studies, ex vivo studies, and in silico modeling can be leveraged to better inform the risks and benefits of using a drug during pregnancy to inform study design and to further understand various mechanisms impacting pharmacokinetic/pharmacodynamic of drugs during pregnancy. It is important to address the significant existing data gaps and better inform the safety and dosing of prescription drugs for pregnant women.
Drug‐Drug Interaction Studies With Oral Contraceptives: Pharmacokinetic/Pharmacodynamic and Study Design Considerations
Authors: Sun Haiying , Sivasubramanian Rama , Vaidya Soniya , Barve Avantika , Jarugula Venkateswar
Published: December 2020

Oral contraceptives (OCs) are the most widely used form of birth control among women of childbearing potential. Knowledge of potential drug‐drug interactions (DDIs) with OCs becomes imperative to provide information on the medication to women of childbearing potential and enable their inclusion in clinical trials, especially if the new molecular entity is a teratogen. Although a number of DDI guidance documents are available, they do not provide recommendations for the design and conduct of OC DDI studies. The evaluation of DDI potential of a new molecular entity and OCs is particularly challenging because of the availability of a wide variety of combinations of hormonal contraceptives, different doses of the ethinyl estradiol, and different metabolic profiles of the progestin component. The aim of this review is to comprehensively discuss factors to be considered such as pharmacokinetics (PK), pharmacodynamics (PD), choice of OC, and study population for the conduct of in vivo OC DDI studies. In this context, metabolic pathways of OCs, the effect of enzyme inhibitors and inducers, the role of sex hormone–binding globulin in the PK of progestins, current evidence on OC DDIs, and the interpretation of PD end points are reviewed. With the emergence of new tools like physiologically based PK modeling, the decision to conduct an in vivo study can be made with much more confidence. This review provides a comprehensive overview of various factors that need to be considered in designing OC DDI studies and recommends PK‐based DDI studies with PK end points as adequate measures to establish clinical drug interaction and measurement of PD end points when there is basis for PD interaction.
Acalabrutinib‐related second primary malignancies and nonmelanoma skin cancers in patients with chronic lymphocytic leukaemia (CLL): A systematic review and meta‐analysis of randomised controlled trials (RCTs)
Authors: Htut Thura W. , Han Myat M. , Thein Kyaw Z.
Published: December 2020

Acalabrutinib is a second generation Bruton's tyrosine kinase inhibitor and was recently approved in the treatment of chronic lymphocytic leukaemia. We undertook a systematic review and meta‐analysis of randomised controlled trials to determine the risks of acalabrutinib‐related second primary malignancies (SPM) and nonmelanoma skin cancers (NMSC). The incidence of SPM was 4.7% higher in the acalabrutinib arm compared to control arm with risk ratio (RR) of 1.76 (5.32 vs 3.2 per 100 person‐years). Notably, NMSC was the most common SPM, and the incidence was 2.56 per 100 person‐years in the acalabrutinib group versus 1.12 per 100 person‐years in the control group (RR 2.43). Long‐term follow‐up and future studies are necessary to define the actual relationship and their risk factors.