bluuebunny/crossref_metadata_2025 huggingface dataset:
eNOS-induced vascular barrier disruption in retinopathy by c-Src activation and tyrosine phosphorylation of VE-cadherin
Authors: Ninchoji Takeshi , Love Dominic T , Smith Ross O , Hedlund Marie , Vestweber Dietmar , Sessa William C , Claesson-Welsh Lena
Published: April 2021

Background:

Hypoxia and consequent production of vascular endothelial growth factor A (VEGFA) promote blood vessel leakiness and edema in ocular diseases. Anti-VEGFA therapeutics may aggravate hypoxia; therefore, therapy development is needed.

Methods:

Oxygen-induced retinopathy was used as a model to test the role of nitric oxide (NO) in pathological neovascularization and vessel permeability. Suppression of NO formation was achieved chemically using L-NMMA, or genetically, in endothelial NO synthase serine to alanine (S1176A) mutant mice.

Results:

Suppression of NO formation resulted in reduced retinal neoangiogenesis. Remaining vascular tufts exhibited reduced vascular leakage through stabilized endothelial adherens junctions, manifested as reduced phosphorylation of vascular endothelial (VE)-cadherin Y685 in a c-Src-dependent manner. Treatment with a single dose of L-NMMA in established retinopathy restored the vascular barrier and prevented leakage.

Conclusions:

We conclude that NO destabilizes adheren junctions, resulting in vascular hyperpermeability, by converging with the VEGFA/VEGFR2/c-Src/VE-cadherin pathway.

Funding:

This study was supported by the Swedish Cancer foundation (19 0119 Pj ), the Swedish Research Council (2020-01349), the Knut and Alice Wallenberg foundation (KAW 2020.0057) and a Fondation Leducq Transatlantic Network of Excellence Grant in Neurovascular Disease (17 CVD 03). KAW also supported LCW with a Wallenberg Scholar grant (2015.0275). WCS was supported by Grants R35 HL139945, P01 HL1070205, AHA MERIT Award. DV was supported by grants from the Deutsche Forschungsgemeinschaft, SFB1450, B03, and CRU342, P2.
The temporary cost of dominance
Authors: Ryan Calen P , Kuzawa Christopher W
Published: April 2021

In a population of wild baboons, a new way to assess biological age reveals a surprising effect of social hierarchy.
Common virulence gene expression in adult first-time infected malaria patients and severe cases
Authors: Wichers J Stephan , Tonkin-Hill Gerry , Thye Thorsten , Krumkamp Ralf , Kreuels Benno , Strauss Jan , von Thien Heidrun , Scholz Judith AM , Smedegaard Hansson Helle , Weisel Jensen Rasmus , Turner Louise , Lorenz Freia-Raphaella , Schöllhorn Anna , Bruchhaus Iris , Tannich Egbert , Fendel Rolf , Otto Thomas D , Lavstsen Thomas , Gilberger Tim W , Duffy Michael F , Bachmann Anna
Published: April 2021

Sequestration of Plasmodium falciparum(P. falciparum)-infected erythrocytes to host endothelium through the parasite-derived P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion proteins is central to the development of malaria pathogenesis. PfEMP1 proteins have diversified and expanded to encompass many sequence variants, conferring each parasite a similar array of human endothelial receptor-binding phenotypes. Here, we analyzed RNA-seq profiles of parasites isolated from 32 P. falciparum-infected adult travellers returning to Germany. Patients were categorized into either malaria naive (n = 15) or pre-exposed (n = 17), and into severe (n = 8) or non-severe (n = 24) cases. For differential expression analysis, PfEMP1-encoding var gene transcripts were de novo assembled from RNA-seq data and, in parallel, var-expressed sequence tags were analyzed and used to predict the encoded domain composition of the transcripts. Both approaches showed in concordance that severe malaria was associated with PfEMP1 containing the endothelial protein C receptor (EPCR)-binding CIDRα1 domain, whereas CD36-binding PfEMP1 was linked to non-severe malaria outcomes. First-time infected adults were more likely to develop severe symptoms and tended to be infected for a longer period. Thus, parasites with more pathogenic PfEMP1 variants are more common in patients with a naive immune status, and/or adverse inflammatory host responses to first infections favor the growth of EPCR-binding parasites.
Stable isotope compositions of precipitation over Central Asia
Authors: Yao Junqiang , Liu Xinchun , Hu Wenfeng
Published: April 2021

Central Asia is one of the driest regions in the world with a unique water cycle and a complex moisture transport process. However, there is little information on the precipitation δ18O content in Central Asia. We compiled a precipitation δ18O database from 47 meteorological stations across Central Asia to reveal its spatial-temporal characteristics. We determined the relationship between precipitation δ18O and environmental variables and investigated the relationship between δ18O and large-scale atmospheric circulation. The Central Asia meteoric water line was established as δ2H = 7.30 δ18O + 3.12 (R2 = 0.95, n = 727, p < 0.01), and precipitation δ18O ranged from +2‰ to −25.4‰ with a mean of −8.7‰. The precipitation δ18O over Central Asia was related to environmental variables. The δ18O had a significant positive correlation with temperature, and the δ18O-temperature gradient ranged from 0.28‰/°C to 0.68‰/°C. However, the dependence of δ18O on precipitation was unclear; a significant precipitation effect was only observed at the Zhangye and Teheran stations, showing δ18O-precipitation gradients of 0.20‰/mm and −0.08‰/mm, respectively. Latitude and altitude were always significantly correlated with annual δ18O, when considering geographical controls on δ18O, with δ18O/LAT and δ18O/ALT gradients of −0.42‰/° and −0.001‰/m, respectively. But both latitude and longitude were significantly correlated with δ18O in winter. The relationship between δ18O and large-scale atmospheric circulation suggested that the moisture in Central Asia is mainly transported by westerly circulation and is indirectly affected by the Indian monsoon. Meanwhile, the East Asian monsoon may affect the precipitation δ18O content in westerly and monsoon transition regions. These results improve our understanding of the precipitation δ18O and moisture transport in Central Asia, as well as the paleoclimatology and hydrology processes in Central Asia.
Structural Effects of Electrode Proximity in Vacuum‐Deposited Organic Semiconductors Studied by Microfocused X‐Ray Scattering
Authors: Huss-Hansen Mathias K. , Kjelstrup-Hansen Jakob , Knaapila Matti
Published: April 2021

Organic semiconductors have seen widespread application in thin‐film devices, such as organic field‐effect transistors (OFETs), whose performance is closely linked to the molecular‐level microstructure and crystalline orientation. In actual OFETs, the microstructure varies significantly based on the local environment, for example, in the proximity of contact electrodes. This account highlights recent examples where microfocused grazing‐incidence wide‐angle X‐ray scattering (μGIWAXS) maps structural information in between the OFET electrodes. Also shown are results where μGIWAXS is used to study the microstructure of naphthyl end‐capped oligothiophenes across interdigitated electrode arrays in a bottom‐contact OFET identifying lateral proximity effects of the contact electrodes in terms of crystalline misorientation, crystallite size, and disorder. The results together with those highlighted, classify essential structural parameters on and in between the electrodes and demonstrate capabilities of microfocused X‐rays to map microstructures in actual devices. The ideas presented herein bring us toward guidelines for understanding electrode proximity and device performance in molecular semiconductors. It is also believed that they are readily expanded from OFETs to other devices and from small molecules to polymers and other materials.
Magnetorheological Elastomer‐Based Materials and Devices: State of the Art and Future Perspectives
Authors: Díez Ander García , Tubio Carmen Rial , Etxebarria Jon Gutiérrez , Lanceros-Mendez Senentxu
Published: April 2021

Magnetorheological elastomers based on the combination of a polymeric matrix with magnetic fillers allow the possibility of controlling their mechanical properties when an external magnetic field is applied. This so‐called magnetorheological effect can be exploited for a variety of applications. Herein, a comprehensive outlook at the state of the art is provided, in terms of the materials, effects, and applications. The physical effects that result in the magnetorheological effect are described, both from a micro and phenomenological points of view. Then, the possible combinations of different polymeric matrices and magnetic fillers, along with other additives, are presented, allowing to tune the mechanical properties, mainly dependent on the polymer matrix, and the magnetic field response, which is related to the magnetic filler. Finally, representative applications of magnetorheological elastomers are presented. This review represents an up‐to‐date state‐of‐the‐art in the field of magnetorheological elastomers as a ground to highlight the main achievements and point the specific needs to improve their response and applicability by further tuning materials and configurations.
Effects of Carbon Nanotube Infiltration on a Shape Memory Polymer‐Based Device for Brain Aneurysm Therapeutics: Design and Characterization of a Joule‐Heating Triggering Mechanism
Authors: Pineda-Castillo Sergio A. , Luo Jishan , Lee Hyowon , Bohnstedt Bradley N. , Liu Yingtao , Lee Chung-Hao
Published: April 2021

Current endovascular therapies for intracranial aneurysms face limitations that include aneurysm recurrence and incomplete occlusion. These challenges can potentially be addressed by occluding the aneurysm space with shape memory polymers (SMPs) that are tailorable to patient‐specific aneurysm geometries to improve the suboptimal treatment outcomes associated with coil embolization. However, deployment of the SMP‐based device into the aneurysm requires external stimuli to trigger shape recovery. Thus, herein, the infiltration of carbon nanotubes (CNTs) in a polyurethane SMP foam is investigated, and Joule‐heating triggering for SMP shape recovery in endovascular therapy applications is demonstrated. The results show that CNTs can be successfully infiltrated in the SMP foam, providing tunable resistivity and shape recovery time, and that CNT infiltration reduces the glass transition temperature of the SMP and alters its mechanical properties, which is evidenced with a cumulative stress reduction in cyclic compression tests. Finally, the Joule‐heating capability of the SMP material is examined using a proof‐of‐concept in vitro occlusion experiment of an idealized saccular aneurysm model. Collectively, this study indicates that CNT infiltration of SMP foams is a promising approach in the design of electrically triggered embolic devices for individualized treatment of intracranial aneurysms.
Enzymatic Synthesis of Phloretin α‐Glucosides Using a Sucrose Phosphorylase Mutant and its Effect on Solubility, Antioxidant Properties and Skin Absorption
Authors: Gonzalez‐Alfonso Jose L. , Ubiparip Zorica , Jimenez‐Ortega Elena , Poveda Ana , Alonso Cristina , Coderch Luisa , Jimenez‐Barbero Jesus , Sanz‐Aparicio Julia , Ballesteros Antonio O. , Desmet Tom , Plou Francisco J.
Published: April 2021

Glycosylation of polyphenols may increase their aqueous solubility, stability, bioavailability and pharmacological activity. Herein, we used a mutant of sucrose phosphorylase from Thermoanaerobacterium thermosaccharolyticum engineered to accept large polyphenols (variant TtSPP_R134A) to produce phloretin glucosides. The reaction was performed using 10% (v/v) acetone as cosolvent. The selective formation of a monoglucoside or a diglucoside (53% and 73% maximum conversion percentage, respectively) can be kinetically controlled. MS and 2D‐NMR determined that the monoglucoside was phloretin 4’‐O‐α‐D‐glucopyranoside and the diglucoside phloretin‐4’‐O‐[α‐D‐glucopyranosyl‐(1→3)‐O‐α‐D‐glucopyranoside], a novel compound. The molecular features that determine the specificity of this enzyme for 4’‐OH phenolic group were analysed by induced‐fit docking analysis of each putative derivative, using the crystal structure of TtSPP and changing the mutated residue. The mono‐ and diglucoside were, respectively, 71‐ and 1200‐fold more soluble in water than phloretin at room temperature. The α‐glucosylation decreased the antioxidant capacity of phloretin, measured by DPPH and ABTS assays; however, this loss was moderate and the activity could be recovered upon deglycosylation in vivo. Since phloretin attracts a great interest in dermocosmetic applications, we analyzed the percutaneous absorption of glucosides and the aglycon employing a pig skin model. Although the three compounds were detected in all skin layers (except the fluid receptor), the diglucoside was present mainly on superficial layers.

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Aniline‐Type Hypervalent Iodine(III) for Intramolecular Cyclization via C−H Bond Abstraction of Hydrocarbons Containing N‐ and O‐Nucleophiles
Authors: Nishiguchi Yuna , Moriyama Katsuhiko
Published: April 2021

We developed a method for the preparation of (diacetoxyiodo)‐2‐(N‐alkylamido)benzene as an aniline‐type hypervalent iodine(III). We also achieved direct cyclizations via C−H bond abstraction, such as the Hofmann‐Löffler‐Freytag reaction, a direct amination, and a direct lactonization, using the aniline‐type hypervalent iodine(III) to obtain corresponding products in high yields.

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Gemischtvalente Verbindungen als polarisierende Mittel für die dynamische Kern‐Overhauser‐Polarisation in Festkörpern**
Authors: Gurinov Andrei , Sieland Benedikt , Kuzhelev Andrey , Elgabarty Hossam , Kühne Thomas D. , Prisner Thomas , Paradies Jan , Baldus Marc , Ivanov Konstantin L. , Pylaeva Svetlana
Published: April 2021

Wir untersuchen eine neuartige Gruppe von Polarisationsmitteln – gemischtvalente Verbindungen – mittels theoretischer und experimenteller Methoden und demonstrieren ihre Leistungsfähigkeit in NMR‐Experimenten mit Hochfeld‐DNP (DNP=Dynamic Nuclear Polarization, dynamische Kernpolarisation) im festen Zustand. Diese gemischtvalenten Verbindungen stellen eine Gruppe von Molekülen dar, bei denen die molekulare Mobilität auch in Festkörpern erhalten bleibt. Folglich können solche Polarisationsmittel unter günstigen Bedingungen für die dynamische Kernpolarisationsbildung bei ultrahohen Magnetfeldern verwendet werden, um Overhauser‐DNP‐Experimente im Festkörper durchzuführen.
Strukturelle und mechanistische Einblicke in die Bildung der C‐S‐Bindungen in Gliotoxin
Authors: Scherlach Kirstin , Kuttenlochner Wolfgang , Scharf Daniel H. , Brakhage Axel A. , Hertweck Christian , Groll Michael , Huber Eva M.
Published: April 2021

Glutathion‐S‐Transferasen (GSTs) entgiften gewöhnlich Fremdstoffe. Der Pilz Aspergillus fumigatus nutzt jedoch die GST GliG, um zwei Schwefelatome in seinen Virulenzfaktor Gliotoxin einzufügen. Wir beschreiben Strukturen von GliG mit Glutathion (GSH) sowie dem Reaktionsprodukt zyklo[‐l‐Phe‐l‐Ser]‐bis‐Glutathion, welches aus einem genetisch modifizierten Aspergillus‐fumigatus‐Stamm gewonnen wurde. Die Kristallstrukturen legen eine schrittweise Modifikation von zuerst dem von der Aminosäure Phe abgeleiteten und dann dem von Ser stammenden Anteil nahe. GSH wird dabei durch eine Enzym‐vermittelte Dehydratisierung des Substrates aktiviert. Das resultierende Anion wird über einen Helixdipol und ein gebundenes Wassermolekül für den anschließenden nukleophilen Angriff stabilisiert. Aktivitätsstudien mit mutierten Enzymvarianten bestätigen die Interaktionen von GliG mit den Liganden und bereichern unser Wissen über die enzymatische Bildung der C‐S‐Bindungen in Gliotoxin sowie Epipolythiodioxopiperazin (ETP)‐Verbindungen im Allgemeinen.
Novel nanoformulated combination of Se and CeO2 particles loaded polylactic‐co‐glycolic acid vesicle to improved anti‐inflammation and auto‐regenerative for the treatment and care of spinal cord injury
Authors: Wang Xiaoying , Li Biao , Fan Jingjing , Tian Shanshan , Wei Xiangyang
Published: April 2021

Polymer functionalized nanoparticles (NPs) have a great attention in biomedical applications owing to their unique properties like regenerative antioxidant, anti‐inflammatory, auto‐catalytic properties, and biocompatibility. In this current work, we demonstrated a facile synthesis of Se‐CeO2 via chemical method followed by precipitation method. The prepared Se NPs were characterized by ultraviolet–visible (UV‐vis) spectroscopy, and the size and morphology of the NPs were analysed using transmission electron microscopy (TEM). Meanwhile, Se‐CeO2 NPs loaded on polylactic‐co‐glycolic acid (PLGA) nanocarrier were characterised by Fourier transform infrared (FT‐IR), scanning electron microscopy (SEM), X‐ray photoelectron spectroscopy (XPS), TEM, and energy dispersive X‐ray analysis (EDAX) mapping techniques. The morphological and spectroscopic investigations of prepared nanomaterials have exhibited favourable morphological structure and chemical interactions with respective polymeric molecules, which established that nanovesicle suitability for the SCI functional recovery. We first investigated Se nanoformulated CeO2 material for the potential healing of in vitro spinal cord study. Our results demonstrated that preparation of NPs loaded PLGA nanocarrier has provide effective spinal cord regeneration and imply that it was explored that promising nanocarrier in the SCI treatment. Se‐NPs encapsulated CeO2 nanostructures administrations for SCI therapies have greatly suppressed oxidative stress and induced anti‐inflammatory action, which leads to prospective therapeutic benefits of spinal cord regeneration. These investigative results demonstrate that Se‐CeO2 NPs with PLGA carrier could have great attention for effecient functional recovery treatment and care for spinal cord injury.
Oleogels of Some Plant Waxes: Characterization and Comparison with Sunflower Wax Oleogel
Authors: Yilmaz Emin , Keskin Uslu Eda , Öz Ceren
Published: April 2021

This study aimed to develop the oleogels of tea wax (TWO), rapeseed wax (RWO), orange peel wax (OWO), rose wax (RsWO), and beery wax (BWO), and to compare their properties with sunflower wax oleogel (SWO). Since the literature lacks most of these new oleogels, the gained information would be valuable. The wax oleogels were analyzed for their main physicochemical, thermal, structural, rheological, and sensory properties. The minimum gelation concentrations (C*) ranged from 1.0% (SWO) to 25% (RWO), with gelation times of 0.3–205 min, respectively. While polarized light microscopy images showed large crystal aggregates, X‐ray diffraction patterns proved the presence of β' polymorph crystals and some amorphous solids. Rheological analyses indicated that the samples had a weak‐gel structure, and were stable until around 30–70 °C temperatures. Further, the oleogel samples showed a thixotropic rheological behavior with force‐related recovery at 10 °C. Quantitative sensory descriptive analysis (QDA) proved that there were some differences among the samples for sensory hardness, spreadability, liquefaction, rancid, waxy, and cooling attributes. Also, tea aroma in TWO, bitterness in OWO, and rose aroma in RsWO were quite dominant. In conclusion, RWO and OWO seemed unsuitable for food applications due to very high C* and bitterness, while RsWO and BWO could be used in food formulations.
A direct multiplex loop‐mediated isothermal amplification method to detect three CITES‐listed shark species
Authors: Lin Tzu‐Chun , Hsiao Wanchien Victoria , Han Shang‐Jung , Joung Shoou‐Jeng , Shiao Jen‐Chieh
Published: April 2021

Species identification of sharks under catch or trade regulations is important for law enforcement and species conservation. Rapid detection of Convention on the International Trade in Endangered Species (CITES)‐listed species is needed for on‐site screening.

Species‐specific primers were designed to target three mitochondrial genes (ND2, COI, and CytB) in both the simplex and multiplex loop‐mediated isothermal amplification (LAMP) assay for the pelagic thresher shark (Alopias pelagicus), the bigeye thresher shark (Alopias superciliosus), and the scalloped hammerhead shark (Sphyrna lewini), respectively. Another primer set designed to target S. lewini was used for detection‐limit testing of the LAMP assay.

The refined direct multiplex LAMP was used to detect the three CITES‐listed shark species and omitted the lengthy DNA extraction process. A homogenizer was used to release the DNA from the shark tissues, and a simplex or multiplex LAMP reaction was conducted for 30 min in an incubator at 65°C using species‐specific primer sets.

Positive LAMP reactions showed a colour change from pink to yellow, whereas negative reactions showed no colour change. Multiplex LAMP assays were performed using 84 samples, which successfully identified the target and non‐target species and provided a fast (<1 h), simple, and reliable method to distinguish three CITES‐listed shark species from the other non‐target species, for either fresh or dry fin products.

Results of this study and the method developed will play a critical role in assisting fishery agencies and customs officials in identifying the illegal catch and trade of CITES‐listed shark species.
Novel WS2/Fe0.95S1.05 Hierarchical Nanosphere as a Highly Efficient Electrocatalyst for Hydrogen Evolution Reaction
Authors: Sun Lei , Geng Jiahui , Gao Mengyou , Zheng Dehua , Jing Zhongxin , Zhao Qingyun , Lin Jianjian
Published: April 2021

Fe0.95S1.05 with high reactivity and stability was incorporated into WS2 nanosheets via a one‐step solvothermal method for the first time. The resulted hybrid catalyst has much higher catalytic activity than WS2 and Fe0.95S1.05 alone, and the optimal WS2/Fe0.95S1.05 hybrid catalyst was found by adjusting the feed ratio. The addition of Fe0.95S1.05 was proven to be able to enhance the hydrogen evolution reaction (HER) activity of WS2, and vice versa. At the same time, it was found that the catalytic effect of the hybrid catalyst was the best when the feed ratio was W : Fe=2 : 1. In other words, we confirmed that there is a synergistic effect between W‐ and Fe‐based sulfide hybrid catalysts, and validated that the reason for the improved HER performance is the strong interaction between the two in the middle sulfur. WS2/Fe0.95S1.05‐2 hybrid catalyst leads to enhanced HER activity, which shows a low overpotential of ∼0.172 V at 10 mA cm−2, low Tafel slope of ∼53.47 mV/decade. This study supplies innovative synthesis of a highly active WS2/Fe0.95S1.05 hybrid catalyst for HER.
Multigram‐scale HPLC enantioseparation as a rescue pathway for circumventing racemization problem during enantioselective synthesis of ethyl 3,4‐dihydro‐2H‐1,4‐benzoxazine‐2‐carboxylate
Authors: Pham Hong‐Ngoc , Arrault Axelle , Vanthuyne Nicolas , Acherar Samir
Published: April 2021

Racemic ethyl 3,4‐dihydro‐2H‐1,4‐benzoxazine‐2‐carboxylate is a key synthon for the design of promising therapeutic drugs. It is mainly synthesized from racemic ethyl 2,3‐dibromopropionate and 2‐aminophenol in presence of K2CO3in refluxed acetone. Unfortunately, synthesis of (R)‐ and (S)‐enantiomers using the enantioselective version of this reaction, which should normally be performed with a double SN2 mechanism, is unsuitable due to a racemization process involving the dehydrobromination of enantiopure ethyl 2,3‐dibromopropionate into ethyl 2‐bromoacrylate. For the first time, the enantioselective version is studied (ee ≈ 55–66%), and the percentage of racemization process has estimated to around 34–46% after determination of the optimal experimental conditions for analytical HPLC enantioseparation of racemate. The influence of the experimental and purification conditions on the racemization rate is also studied. The results indicate that racemization occurs faster at the beginning of the reaction but the initiation of the double SN2 process takes place more faster to limit the racemization rate. The study of the influence of experimental conditions (reaction times, temperature, solvent or type of base, etc.) on the degree of racemization of the (R)‐ enantiomer is performed and shows that despite changes in the experimental conditions, the synthesis of the (R)‐ enantiomer is always accompanied by a racemization rate which is difficult in reducing. In parallel, (R)‐ and (S)‐enantiomers are obtained in high enantiopurity (ee > 99.5%) by preparative HPLC enantioseparation of racemate on multigram scale and characterized by optical rotation measurements, ECD and UV spectra.
Risk of cardiovascular mortality with androgen deprivation therapy in prostate cancer: A secondary analysis of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Randomized Controlled Trial
Authors: Butler Santino S. , Mahal Brandon A. , Moslehi Javid J. , Nohria Anju , Dee Edward C. , Makkar Rishi , Whitbeck Amanda , Wangoe Janet , Mouw Kent W. , Nguyen Paul L. , Muralidhar Vinayak
Published: April 2021

BACKGROUND

For men with radiation‐managed prostate cancer, there is conflicting evidence regarding the association between androgen deprivation therapy (ADT) and cardiovascular mortality (CVM), particularly among those who have with preexisting comorbidities. The objective of this study was to analyze the association between ADT and CVM across patient comorbidity status using prospectively collected data from a large clinical trial.

METHODS

In total, 1463 men were identified who were diagnosed with clinically localized, intermediate‐risk/high‐risk prostate cancer (T2b‐T4, Gleason 7‐10, or prostate‐specific antigen >10 ng/mL) from 1993 to 2001 and managed with either radiation therapy (RT) alone or RT plus ADT during the randomized Prostate, Lung, Colon, and Ovarian (PLCO) Cancer Screening Trial. Adjusted hazard ratios (aHRs) for cause‐specific mortality (prostate cancer‐specific mortality vs other‐cause mortality—including the primary end point of CVM [death from ischemic heart disease, cerebrovascular accident, or other circulatory disease]) were determined using Fine and Gray competing‐risk regression analysis and stratified by comorbidity history.

RESULTS

There was no difference in the risk of 5‐year CVM between ADT plus RT and RT alone (2.3% vs 3.3%, respectively; aHR, 0.69; 95% CI, 0.38‐1.24; P = .21) overall or on subgroup analysis among men with a history of ≥1 preexisting comorbidities (3.2% vs 5.3%, respectively; aHR, 0.83; 95% CI, 0.43‐1.60; P = .58), ≥2 preexisting comorbidities (6.9% vs 8.3%, respectively; aHR, 0.95; 95% CI, 0.40‐2.25; P = .90), or cardiovascular disease/risk factors (3.6% vs 4.3%, respectively; aHR, 0.85; 95% CI, 0.44‐1.65; P = .63). These results were all similar when each component of CVM was analyzed separately—either cardiac, stroke, or other vascular mortality (P > .05).

CONCLUSIONS

This study provides prospectively collected evidence that the use of ADT plus RT, compared with RT alone, is not associated with an increased risk of CVM, even among subgroups of men who have preexisting comorbidities and cardiovascular disease.
Cancer pain self‐management in the context of a national opioid epidemic: Experiences of patients with advanced cancer using opioids
Authors: Azizoddin Desiree R. , Knoerl Robert , Adam Rosalind , Kessler Daniela , Tulsky James A. , Edwards Robert R. , Enzinger Andrea C.
Published: April 2021

BACKGROUND

The US opioid epidemic has prompted dramatic changes in public attitudes and regulations governing opioid prescribing. Little is known about the experiences of patients with advanced cancer using opioids in the context of the epidemic.

METHODS

Semistructured interviews of 26 patients with advanced cancer were conducted between May 2019 and April 2020; their experiences self‐managing chronic pain with opioids were evaluated.

RESULTS

Patients consistently described the negative impact of the opioid epidemic on their ability to self‐manage pain. Negative media coverage and personal experiences with the epidemic promoted stigma, fear, and guilt surrounding opioid use. As a result, many patients delayed initiating opioids and often viewed their decision to take opioids as a moral failure—as “caving in.” Patients frequently managed this internal conflict through opioid‐restricting behaviors (eg, skipping or taking lower doses). Stigma also impeded patient‐clinician communication; patients often avoided discussing opioids or purposely conveyed underusing them to avoid being labeled a “pill seeker.” Patients experienced structural barriers to obtaining opioids such as prior authorizations, delays in refills, or being questioned by pharmacists about their opioid use. Barriers were stressful, amplified stigma, interfered with pain control, and reinforced ambivalence about opioids.

CONCLUSIONS

The US opioid epidemic has stigmatized opioid use and undermined pain management in individuals with advanced cancer. Interventions seeking to alleviate cancer pain should attend to the multiple, negative influences of the opioid crisis on patients' ability to self‐manage.

LAY SUMMARY

Patients with advanced cancer suffer from significant pain and frequently receive opioids to manage their pain. Of the 26 patients with advanced cancer interviewed, the majority of patients experienced stigma about their opioid use for cancer pain management.

All patients felt that the opioid epidemic fostered this stigma. Several struggled to use opioids for pain because of this stigma and the logistical complications they experienced with pharmacies and insurance coverage.

Many were afraid to share their concerns about opioids with their providers.

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CRISPR Genome Editing Made Easy Through the CHOPCHOP Website
Authors: Labun Kornel , Krause Maximilian , Torres Cleuren Yamila , Valen Eivind
Published: April 2021

The design of optimal guide RNA (gRNA) sequences for CRISPR systems is challenged by the need to achieve highly efficient editing at the desired location (on‐target editing) with minimal editing at unintended locations (off‐target editing). Although laboratory validation should ideally be used to detect off‐target activity, computational predictions are almost always preferred in practice due to their speed and low cost. Several studies have therefore explored gRNA‐DNA interactions in order to understand how CRISPR complexes select their genomic targets. CHOPCHOP (https://chopchop.cbu.uib.no/) leverages these developments to build a user‐friendly web interface that helps users design optimal gRNAs. CHOPCHOP supports a wide range of CRISPR applications, including gene knock‐out, sequence knock‐in, and RNA knock‐down. Furthermore, CHOPCHOP offers visualization that enables an informed choice of gRNAs and supports experimental validation. In these protocols, we describe the best practices for gRNA design using CHOPCHOP. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC.

Basic Protocol 1: Design of gRNAs for gene knock‐out

Alternate Protocol 1: Design of gRNAs for dCas9 fusion/effector targeting

Support Protocol: Design of gRNAs for targeting transgenic or plasmid sequences

Basic Protocol 2: Design of gRNAs for RNA targeting

Basic Protocol 3: Design of gRNAs for sequence knock‐in

Alternate Protocol 2: Design of gRNAs for knock‐in using non‐homologous end joining

Basic Protocol 4: Design of gRNAs for knock‐in using Cas9 nickases
Area Oversizing of Lithium Metal Electrodes in Solid‐State Batteries: Relevance for Overvoltage and thus Performance?
Authors: Stolz Lukas , Homann Gerrit , Winter Martin , Kasnatscheew Johannes
Published: April 2021

Invited for this month′s cover is the group of Dr. Johannes Kasnatscheew from the Research Center Jülich GmbH. The image shows how area oversizing of lithium can affect the overall power of batteries, in particular at lower temperature. The Full Paper itself is available at 10.1002/cssc.202100213.
Systematic evaluation of a panel of 30 synthetic cannabinoid receptor agonists structurally related to MMB‐4en‐PICA, MDMB‐4en‐PINACA, ADB‐4en‐PINACA, and MMB‐4CN‐BUTINACA using a combination of binding and different CB1 receptor activation assays. Part III: The G protein pathway and critical comparison of different assays
Authors: Grafinger Katharina Elisabeth , Vandeputte Marthe M. , Cannaert Annelies , Ametovski Adam , Sparkes Eric , Cairns Elizabeth , Juchli Patrick Osamu , Haschimi Belal , Pulver Benedikt , Banister Samuel D. , Stove Christophe P. , Auwärter Volker
Published: April 2021

The present work is the last of a three‐part study investigating a panel of 30 systematically designed synthetic cannabinoid receptor agonists (SCRAs) including features such as the 4‐pentenyl tail and varying head groups including amides and esters ofl‐valine (MMB, AB),l‐tert‐leucine (ADB), andl‐phenylalanine (APP), as well as adamantyl (A) and cumyl moieties (CUMYL). Here, we evaluated these SCRAs for their capacity to activate the human cannabinoid receptor 1 (CB1) via indirect measurement of G protein recruitment. Furthermore, we comparatively evaluated the results obtained from three in vitro assays, based on the recruitment of β‐arrestin 2 (βarr2 assay) or Gαiprotein (mini‐Gαiassay), or binding of [35S]‐GTPγS. The observed efficacies (Emax) varied depending on the conducted assay. Statistical analysis suggests that the population means of the relative intrinsic activity (RAi) significantly differ for the [35S]‐GTPγS assay and the other two assays, but the population means of the βarr2 and mini‐Gαiassays were not statistically different. Our data suggest that differences observed between the βarr2 and mini‐Gαiassays are the best predictor for ‘biased agonism’ towards βarr or G protein recruitment in our study. SCRAs carrying an ADB or MPP moiety as a head group tended to produce elevatedEmaxvalues in the βarr2 assay, which might result in a tendency of these compounds to cause pronounced tolerance in users—a hypothesis that should be evaluated further by future studies. In general, a comparison of efficacies derived from different assays is difficult and should only be conducted very cautiously.
Theoretical Investigation of Hydrogen‐Bond‐Assisted Tetradentate N4 Copper(I) Chloride andtrans‐1,2‐Peroxodicopper Complexes
Authors: Zhang Min , Liang Guangchao , Xing Mengjiang
Published: April 2021

Biological oxygenation catalyzed by copper‐containing enzymes involves a dicopper O2adduct as the key intermediate. Significant insights were offered by thetrans‐1,2‐peroxodicopper intermediates. To understand the activity of thetrans‐1,2‐peroxodicopper intermediate in the oxygenation, a series of hydrogen‐bond‐assisted CuI(L)−Cl andtrans‐1,2‐peroxodicopper complexes [Cu2−O2]2+were investigated by DFT computations. A reasonable two‐parameter structure‐activity model (R2=0.8611) and a three‐parameter structure‐activity model (R2=0.8773) for chloride dissociation (ΔG1RXN) were established. The critical intramolecular out‐sphere hydrogen bonds assist the formation of stabletrans‐1,2‐peroxodicopper complexes, which overcome the steric hindrances and electrostatic repulsion. An acceptable two‐parameter structure‐activity model (R2=0.7051) for O2binding (ΔG2RXN) was obtained. The fundamental structure‐activity interpretation of the hydrogen bonding interactions provides an insight into the modelling oftrans‐1,2‐peroxodicopper mimics.
The Use of Voltammetry for Sorption Studies of Arsenic (III) Ions by Magnetic Beads Functionalized with Nucleobase Hydrazide Derivatives
Authors: Sawan Simona , Hamze Khalil , Youssef Ali , Bouhadir Kamal , Errachid Abdelhamid , Maalouf Rita , Jaffrezic‐Renault Nicole
Published: April 2021

In this work the interaction characteristics of nucleobases with As(III) are studied. Novel materials consisting of magnetic nanoparticles (MNPs) functionalized with adenine hydrazide (AH), guanine hydrazide (GH) and uracil hydrazide (UH) were elaborated. The adsorption isotherms were investigated electrochemically and it was shown that the adsorption capacity of the nanoparticles towards arsenic (III) increased in the following order: AH<UH<GH. The electrochemical detection of As(III) using the GH functionalized MNPs offered better results compared with the other functionalizations, with a sensitivity of 1.92 μA μg−1 L and a limit of detection of 1.6 μg/L (21 nM).
High Sensitive Electrochemiluminescence Biosensor Based on Ru(phen)32+‐loaded Double Strand DNA as Signal Tags use to Detect DNA Methyltransferase Activity
Authors: Yang Ming , Chen Liping , Guo Longhua , Qiu Bin , Lin Zhenyu
Published: April 2021

DNA methyltransferase (DNA MTase) can act as biomarker for many diseases and it is important to develop some new methods for sensitive detection of DNA MTase. In this work, a highly efficient electrochemiluminescence (ECL) sensor had been designed for detection of DNA MTase based on Ru(phen)32+ loaded double strand DNA (dsDNA‐ Ru(phen)32+) as signal tags. Ru(phen)32+ had been efficiently embed in the dsDNA produced through a simple hybridization chain reaction. First, a hairpin probe was designed, which can be specifically recognized by Dam MTase and modified with ‐SH at one end. It was modified on the surface of gold electrode by ‐SH as an immobilization probe (IP). This IP will be methylated in the present of Dam MTase and digested by DpnI following. Results in the release of capture probe (CP) which remains on the surface of gold electrode. The CP can hybridize with the single stand part of the dsDNA‐ Ru(phen)32+ and make the immobilization of ECL tags on the electrode surface, which results in a strong ECL signals detected. However, without the effect of Dam MTase, the hairpin structure of IP remains stable and cannot capture signal tags, and can only detecte weak ECL signals. The biosensor can detect the activity of Dam MTase in the concentration range of 0.01 U/mL to 20 U/mL with the ECL intensity and the logarithm of the concentration have a linear relationship, and the detection limit is calculated to be 7.6 mU/mL. The developed sensor has the ability to specifically detect Dam MTase, which can be differentiated from other types of DNA MTase. In addition, the designed method has good applicability to detect Dam MTase activity in serum samples and been applied to detect its inhibitor with high efficiency.
Microfacies and stable isotope features of the Lower–Middle Jurassic carbonate rocks of Western Saharan Atlas (Aïn Ouarka area, Algeria)
Authors: Mahboubi Chikh Younes , Ouali Mehadji Abdelkader , Chevalier Nicolas
Published: April 2021

The Jurassic Lower Carbonate Group in the Aïn Ouarka area of Western Saharan Atlas, Algeria, is represented by six formations, from base to top: Hettangian Chemarikh Dolostone, Early Sinemurian–Pliensbachian Aïn Ouarka Limestone, Toarcian Aïn Rhezala Limestone, Aalenian–Late Bajocian Raknet El Kahla Limestone Breccia, Late Bajocian Theniet El Klakh, and Late Bajocian–Bathonian Tifkirt Limestone formations. From the microfacies analysis, six microfacies types (MF1–MF6) have been recognized and grouped into three associations developed during a transgressive–regressive cycle: (a) inner ramp facies association; (b) middle ramp facies association; and (c) outer ramp facies association. The mineralogical analysis of the carbonate rocks reveals that they contain mostly low‐Mg calcite associated with ankerite, pyrite, and other detrital minerals such as quartz, chlorite, illite, feldspar (albite), and a few clay minerals. These minerals could be related to the deep fluid and hydrocarbon circulations during deposition. The isotopic data display a variation of δ13C isotopic values between −5.14‰ and +2.21‰ (VPDB) and between −8.12‰ and −4.95‰ for δ18O values (VPDB). The set of δ13C values is similar to the signature of marine dissolved inorganic carbon. First of all, the positive values of δ13C show that the origin of carbon is not from the organic‐rich zone (microbial zone), but probably derived from pore‐water and/or biogenic carbonate precursors. On the other hand, the negative values of δ13C indicate that the carbon may result from organic sources linked to the sulphate reduction bacteria activity, or by a heightened volcanic and/or hydrothermal activities releasing light carbon (12C). The negative δ18O values are not consistent with marine water ambient temperature, but with a possible influence of diagenesis or increasing of temperature by hydrothermal water. This hydrothermal activity is controlled by synsedimentary faults during the Early Jurassic and related to a late pulse of the Central Atlantic Magmatic Province (CAMP) volcanism and by regional volcanism during the Middle Jurassic (Bajocian–Bathonian).
A thermal nonequilibrium model to natural convection inside non‐Darcy porous layer surrounded by horizontal heated plates with periodic boundary temperatures
Authors: Alomar Omar Rafae , Mohamed Ibrahim A. , Yousif Qais A. , Abd Hareth M.
Published: April 2021

This article displays a numerical investigation on natural convection within non‐Darcy porous layer surrounded by two horizontal surfaces having sinusoidal temperature profiles with difference in phase and wave number. The Darcy–Brinkman–Forchheimer model and local thermal nonequilibrium condition have been employed. Simulations have been performed for wide ranges of inertia coefficient (10–4 ≤ Fs/Pr* ≤ 10–2), thermal conductivity ratio (0.1 ≤ K
r ≤ 100), phase difference (0 ≤ β ≤ π), modified Rayleigh number (200 ≤ Ra* ≤ 1000), wavelength (3 ≤ k ≤ 12), and nondimensional heat transfer coefficient (0.1 ≤ H ≤ 100). Results demonstrate that Nusselt number highly relies on Fs/Pr*, K
r, β, Ra*, and k as compared to H. A considerable enhancement in fluid, solid, and overall Nusselt numbers has been observed with diminishing Fs/Pr* and β and increasing k, K
r, and H. The raising in β has a significant impact on Nu for smaller k and this effect is almost ignored when k > 12. The increase in Ra*, K
r, β, and H and decrease in Fs/Pr* and k acts to reduce the severity of nonequilibrium zone and increase the size of thermal equilibrium zone. The influence of H on nonequilibrium area is more evident than K
r.
Heat transfer improvement in a tube by inserting perforated conical ring and wire coil as turbulators
Authors: Abbaspour Mohammadreza , Mousavi Ajarostaghi Seyed Soheil , Hejazi Rad Seyyed A. H. , Nimafar Mohammad
Published: April 2021

In the present study, two various passive methods for heat transfer enhancement, including conical ring and wire coil are placed in a tube as turbulators. Four conical rings with four side holes are utilized with the same distance. The wire coil is employed at the center of the tube. The considered Reynolds numbers are between 4000 and 10,000. The studied geometrical parameters contain the pitch and diameter of a wire coil. Four different pitches of wire coil, including 10, 12, 14, and 16 mm, are evaluated. Furthermore, four values of wire coil diameter such as 2, 4, 6, and 8 mm are certain. The obtained numerical results displayed that by declining the pitch of a wire coil (37.5%), the average Nusselt number increases by about 143%. Also, augmentation in wire coil diameter by 300% leads to a growth in average Nusselt number by about 131%. Moreover, owing to utilizing two various turbulators, the pressure drop is significantly high in comparison with the bare tube. At Re = 10,000, growth in the inner diameter of the wire coil by 300% leads to an increase in thermal performance by about 36.12%. Moreover, as the pitch of the wire coil rises by 60%, the thermal performance declines by about 35.71%.
Monolithic flow reactor for enzymatic oxidations
Authors: Zverina Libor , Pinelo Manuel , Woodley John M , Daugaard Anders E
Published: April 2021

BACKGROUND

Oxidation is among the most important reactions in organic chemistry. Enzymatic oxidation offers a greener alternative to a conventional chemo‐catalytic approach and opens the potential for new reactions. However, inefficient use of expensive enzymes and oxygen (O2) limitations represent particular challenges for biocatalytic reactor design. This work reports a new tubular reactor for continuous flow enzymatic oxidations.

RESULTS

The reactor comprises a thiol‐functional porous monolith (0.93 ± 0.16 m2 g−1) and an O2‐permeable wall (115 600 ± 1500 mL m−2 day−1). The monolith retains enzyme inside the reactor leading to efficient use. The wall acts as a membrane contactor providing transport of O2 from atmospheric air to the immediate proximity of the enzyme inside the reactor, without any pressure and sparging required. The reactor performance was demonstrated using oxidation of glucose by glucose oxidase (EC 1.1.3.4) coupled with in situ consumption of hydrogen peroxide by horseradish peroxidase (EC 1.11.1.7). At a constant flow rate of 0.1 mL min−1, the product concentration reached 0.10 mmol L−1 after 1.5 h and continued to be relatively high for the next ≥10 h. Overall, the reactor remained active for >40 h using only 15 μg glucose oxidase. Furthermore, the reactor could be rejuvenated by periodic injection of fresh enzyme and thus can operate continuously for extended periods.

CONCLUSION

We have shown here an alternative approach to efficient enzyme use and O2 delivery. Moreover, with its flexible design, the reactor can be optimized to accommodate a range of gas‐dependent biocatalytic transformations. © 2021 Society of Chemical Industry (SCI).
Acute diffuse thyroid swelling after fine‐needle aspiration: A case report and review of the literature
Authors: Imaoka Kouki , Nishihara Masahiro , Nambu Junko , Yamaguchi Megumi , Kawasaki Yukari , Sugino Keizo
Published: April 2021

Fine‐needle aspiration (FNA) is the first‐line and a cost‐effective examination method of nonfunctional thyroid nodules. Acute transient thyroid swelling after an FNA is a rare complication, and to date, only 14 cases have been reported in the English literature. Herein, we report a case of a 26‐year‐old woman with acute transient thyroid swelling, which occurred after an ultrasound‐guided FNA of a thyroid nodule. Although the patient had undergone an FNA without complication 2 years previously, the second FNA caused acute thyroid swelling. The present case emphasizes the potential risk of acute thyroid swelling associated with every FNA procedure.
Comparative taxonomic variation in fruits and seeds' surface morphology among populations of alpine Rosa sericea complex (Rosaceae)
Authors: Ullah Fazal , Gao Yundong , Jiao Rui‐Fang , Gao Xin‐Fen
Published: April 2021

In this research, the fruits and seeds' surface morphological features and their taxonomic significance were determined. Additionally, useful traits for delimitation of taxa of Rosa sericea complex were studied. In this research, three taxa of the complex R. sericea, R. omeiensis, and R. sikangensis have been studied. A total of 41 populations and 130 specimens of seeds, and 35 populations and 168 specimens of fruits from 10 different geographical regions of southwest China have been examined. The surface micro‐morphological characters of the seeds have been studied through scanning electron microscopy to distinguish important characteristics of the complex taxa. Forty‐four different qualitative and quantitative characteristics were observed. Principal component analysis was used to simplify and elucidate the relationship between the studied characters of different population based on the morphology of fruits and seeds' features. Moreover, the numerical taxonomic characters and their variation with elevation have been studied in these species. The most interesting characters observed on the surface of the seeds were stomata, and trichomes, for which density was more at the dorsal and ventral parts, while rarely present on the lateral parts. The fruits and seeds' surface morphology of the studied species was complicated and some variation in the characters, that is, persistent calyx shape, the shape of fruits and seeds, stomata shape, and trichomes size were found significant for delimitation of taxa in the complex. The purpose of this study is to identify the taxa of R. sericea complex based on fruits and seeds' morphological characters, and identification keys.