bluuebunny/crossref_metadata_2025 huggingface dataset:
Indications for pancreaticoduodenectomy affected postoperative outcomes in octogenarians
Authors: Okabayashi Takehiro , Sui Kenta , Murokawa Takahiro , Kimura Jiro , Iwata Jun , Morita Sojiro , Iiyama Tatsuo , Shimada Yasuhiro
Published: August 2020

Aims

The safety and efficacy of pancreaticoduodenectomy (PD) in patients over the age of 80 years remain controversial. We aimed to examine post‐PD outcomes and to determine the age limit for PD.

Methods

Patients were divided into two subgroups: the younger (<80 years) group and octogenarian (≥80 years) group. We retrospectively evaluated the clinical benefit of PD for periampullary diseases in the younger and octogenarian groups, focusing on short‐ and long‐term outcomes.

Results

From March 2005 to December 2018, 586 consecutive surgically curable patients with diagnosed periampullary diseases were studied, among whom 122 (20.8%) were ≥80 years old. The general preoperative physical condition (G8 screening, instrumental activities of daily living, and Charlson comorbidity index) and nutritional status were significantly worse in the octogenarian group. However, there were no significant differences between the younger and octogenarian groups in postoperative severe complication rates (34% vs 36%) or perioperative mortality rates (1.5% vs 0.0%). We observed significantly poorer 3‐, 5‐, and 10‐year overall survivals in the octogenarian group than in the younger group (P = .007). In the younger group, the main cause of death (89.6%) was cancer recurrence. However, only 60% of patients in the octogenarian group developed and died from cancer recurrence. Increased neutrophilic/lymphocyte ratio and elevated Controlling Nutritional Status score were associated with worse outcomes.

Conclusions

It is important to carefully determine the indication for PD in octogenarian patients with periampullary diseases, although patient age over 80 years should not be a contraindication for PD.
Genome‐wide genotyping estimates mating system parameters and paternity in the island species Tolpis succulenta
Authors: Gibson Matthew J. S. , Crawford Daniel J. , Holder Mark T. , Mort Mark E. , Kerbs Benjamin , de Sequeira Miguel Menezes , Kelly John K.
Published: August 2020

Premise

The mating system has profound consequences, not only for ecology and evolution, but also for the conservation of threatened or endangered species. Unfortunately, small populations are difficult to study owing to limits on sample size and genetic marker diversity. Here, we estimated mating system parameters in three small populations of an island plant using genomic genotyping. Although self‐incompatible (SI) species are known to often set some self‐seed, little is known about how “leaky SI” affects selfing rates in nature or the role that multiple paternity plays in small populations.

Methods

We generalized the BORICE mating system program to determine the siring pattern within maternal families. We applied this algorithm to maternal families from three populations of Tolpis succulenta from Madeira Island and genotyped the progeny using RADseq. We applied BORICE to estimate each individual offspring as outcrossed or selfed, the paternity of each outcrossed offspring, and the level of inbreeding of each maternal plant.

Results

Despite a functional self‐incompatibility system, these data establish T. succulenta as a pseudo‐self‐compatible (PSC) species. Two of 75 offspring were strongly indicated as products of self‐fertilization. Despite selfing, all adult maternal plants were fully outbred. There was high differentiation among and low variation within populations, consistent with a history of genetic isolation of these small populations. There were generally multiple sires per maternal family. Twenty‐two percent of sib contrasts (between outcrossed offspring within maternal families) shared the same sire.

Conclusions

Genome‐wide genotyping, combined with appropriate analytical methods, enables estimation of mating system and multiple paternity in small populations. These data address questions about the evolution of reproductive traits and the conservation of threatened populations.
The interaction between FTO rs9939609 and physical activity is associated with a 2‐fold reduction in the risk of obesity in Korean population
Authors: Cho Hye‐Won , Jin Hyun‐Seok , Eom Yong‐Bin
Published: August 2020

Objective

FTO (fat mass and obesity‐associated) gene is a well‐known genetic risk factor for obesity. We investigated whether physical activity modulates the effect of FTO rs9939609 on obesity in Korean population.

Methods

The study analyzed the correlation between physical activity and obesity in 8840 individuals representing the Korea Association Resource (KARE). The association between obesity‐related traits and single‐nucleotide polymorphisms (SNPs) was assessed using linear regression models. Physical activity was defined as 3 hours or more of daily intense activity.

Results

Participants carrying rs9939609 (AT+AA) genotypes showed higher BMI compared with those carrying the wild‐type (TT) homozygote. The highest significant association was observed between obesity‐related traits (ß = .334, P value = 1.76 × 10−6). FTO rs9939609 (AT+AA) increased the risk of obesity (OR = 1.42, CI [1.13‐1.79]), which was correlated with BMI correlations. However, active exercise by subjects carrying the same genotype reduced the risk of obesity by nearly 2‐fold (OR = 0.62, CI [0.25‐0.84]). In contrast, TT genotype was not statistically significant in reducing the risk of obesity in the active exercise group.

Conclusions

Our results support a previous finding correlating FTO and obesity‐related traits and suggest that the interaction with genetic variation and physical activity is an important risk factor for obesity.
morphomap: An R package for long bone landmarking, cortical thickness, and cross‐sectional geometry mapping
Authors: Profico Antonio , Bondioli Luca , Raia Pasquale , O'Higgins Paul , Marchi Damiano
Published: August 2020

Objectives

This study describes and demonstrates the functionalities and application of a new R package,morphomap, designed to extract shape information as semilandmarks in multiple sections, build cortical thickness maps, and calculate biomechanical parameters on long bones.

Methods

morphomapcreates, from a single input (an oriented 3D mesh representing the long bone surface), multiple evenly spaced virtual sections.morphomapthen directly and rapidly computes morphometric and biomechanical parameters on each of these sections.

The R package comprises three modules: (a) to place semilandmarks on the inner and outer outlines of each section, (b) to extract cortical thicknesses for 2D and 3D morphometric mapping, and (c) to compute cross‐sectional geometry.

Results

In this article, we applymorphomapto femora fromHomo sapiensandPan troglodytesto demonstrate its utility and show its typical outputs.morphomapgreatly facilitates rapid analysis and functional interpretation of long bone form and should prove a valuable addition to the osteoarcheological analysis software toolkit.

Conclusions

Long bone loading history is commonly retrodicted by calculating biomechanical parameters such as area moments of inertia, analyzing external shape and measuring cortical thickness.morphomapis a software written in the open source R environment, it integrates the main methodological approaches (geometric morphometrics, cortical morphometric maps, and cross‐sectional geometry) used to parametrize long bones.
Zwitterionic Peptide Cloak Mimics Protein Surfaces for Protein Protection
Authors: Yuan Zhefan , Li Bowen , Niu Liqian , Tang Chenjue , McMullen Patrick , Jain Priyesh , He Yuwei , Jiang Shaoyi
Published: August 2020

Inspired by the amino acid composition of natural protein surfaces, we developed a zwitterionic cloak containing multi‐layers of short alternating glutamic acid and lysine (EK) peptides as a facile, highly effective and low‐immunogenicity approach for the protection and delivery of biotherapeutics. Each EK layer grafted to proteins provides multiple times of new lysine reaction sites for the growth of subsequent EK layers. This unique design allows EK peptides to achieve high coating density on proteins, overcoming the limitation of traditional conjugation strategies that rely on the number of innate lysine groups. A triple‐layer EK cloak manifests to successfully eliminate the specific and non‐specific interactions of protected asparaginase with biological media while prolong the drug circulation time and significantly mitigate its immunogenicity in vivo, suggesting an EK peptide cloak as a promising approach to improve the safety and efficacy of biotherapeutics.
Anschauliche Bezeichnungen der Chemie von Metallocen‐Komplexen der Gruppe 4
Authors: Rosenthal Uwe
Published: August 2020

Drei Beispiele für die Verwendung einfacher und anschaulicher Benennungen in der Organometallchemie von Metallocen‐Komplexen der Gruppe 4 werden erklärt und diskutiert. Die Bezeichnung “tuck(ed)‐in” betrifft das Verhalten des Decamethyltitanocens [(C5Me5)2Ti] oder ähnlicher Komplexe, bei dem eine oder zwei Methylgruppen Titanhydrid‐Komplexe wie [(C5Me5)(C5Me4CH2)TiH] oder andere Hydridkomplexe durch C‐H‐Aktivierung bilden. In der “merry‐go‐round‐reaction” wird die Umlagerung von C‐Atomen am Titan in Organometallmolekülen beschrieben, bei der eine Rotation von zwei C‐Atomen mit einer Rotation der sechsgliedrigen Dihydroindenyl‐Einheit am Titan erfolgt. Das dritte Beispiel “migration” oder “tobogganing” betrifft das “sliding” von Titanocen an der Kette eines linearen Polyins durch Koordinierung von einer oder mehreren Dreifachbindungen. In allen diesen Reaktionen wechselt die Koordinationsweise des Metalls am Cp‐ oder dem Substratliganden, was mit einer intramolekularen Dynamik verbunden ist.
How Big is the Pinacol Boronic Ester as a Substituent?
Authors: Fasano Valerio , McFord Aidan W. , Butts Craig P. , Collins Beatrice S. L. , Fey Natalie , Alder Roger W. , Aggarwal Varinder K.
Published: August 2020

The synthetically versatile pinacol boronic ester group (Bpin) is generally thought of as a bulky moiety because of the two adjacent quaternary sp3‐hydribized carbon atoms in its diol backbone. However, recent diastereoselective reactions reported in the literature have cast doubt on this perception. Reported herein is a detailed experimental and computational analysis of Bpin and structurally related boronic esters which allows determination of three different steric parameters for the Bpin group: the A‐value, ligand cone angle, and percent buried volume. All three parameters suggest that the Bpin moiety is remarkably small, with the planarity of the oxygen‐boron‐oxygen motif playing an important role in minimising steric interactions. Of the three steric parameters, percent buried volume provides the best correlation between steric size and diastereoselectivity in a Diels–Alder reaction.
Aptamer‐Mediated Reversible Transactivation of Gene Expression by Light
Authors: Renzl Christian , Kakoti Ankana , Mayer Günter
Published: August 2020

The investigation and manipulation of cellular processes with subcellular resolution requires non‐invasive tools with spatiotemporal precision and reversibility. Building on the interaction of the photoreceptor PAL with an RNA aptamer, we describe a variation of the CRISPR/dCAS9 system for light‐controlled activation of gene expression. This platform significantly reduces the coding space required for genetic manipulation and provides a strong on‐switch with almost no residual activity in the dark. It adds to the current set of modular building blocks for synthetic biological circuit design and is broadly applicable.
Synthesis of 2D Germanane (GeH): a New, Fast, and Facile Approach
Authors: Giousis Theodosis , Potsi Georgia , Kouloumpis Antonios , Spyrou Konstantinos , Georgantas Yiannis , Chalmpes Nikolaos , Dimos Konstantinos , Antoniou Myrsini‐Kiriaki , Papavassiliou Georgios , Bourlinos Athanasios B. , Kim Hae Jin , Wadi Vijay Kumar Shankarayya , Alhassan Saeed , Ahmadi Majid , Kooi Bart J. , Blake Graeme , Balazs Daniel M. , Loi Maria A. , Gournis Dimitrios , Rudolf Petra
Published: August 2020

Germanane (GeH), a germanium analogue of graphane, has recently attracted considerable interest because its remarkable combination of properties makes it an extremely suitable candidate to be used as 2D material for field effect devices, photovoltaics, and photocatalysis. Up to now, the synthesis of GeH has been conducted by substituting Ca by H in a β‐CaGe2 layered Zintl phase through topochemical deintercalation in aqueous HCl. This reaction is generally slow and takes place over 6 to 14 days. The new and facile protocol presented here allows to synthesize GeH at room temperature in a significantly shorter time (a few minutes), which renders this method highly attractive for technological applications. The GeH produced with this method is highly pure and has a band gap (Eg) close to 1.4 eV, a lower value than that reported for germanane synthesized using HCl, which is promising for incorporation of GeH in solar cells.
A Fully Non‐fused Ring Acceptor with Planar Backbone and Near‐IR Absorption for High Performance Polymer Solar Cells
Authors: Chen Ya‐Nan , Li Miao , Wang Yunzhi , Wang Jing , Zhang Ming , Zhou Yuanyuan , Yang Jianming , Liu Yahui , Liu Feng , Tang Zheng , Bao Qinye , Bo Zhishan
Published: August 2020

Fused‐ring electron acceptors have made significant progress in recent years, while the development of fully non‐fused ring acceptors has been unsatisfactory. Here, two fully non‐fused ring acceptors, o‐4TBC‐2F and m‐4TBC‐2F, were designed and synthesized. By regulating the location of the hexyloxy chains, o‐4TBC‐2F formed planar backbones, while m‐4TBC‐2F displayed a twisted backbone. Additionally, the o‐4TBC‐2F film showed a markedly red‐shifted absorption after thermal annealing, which indicated the formation of J‐aggregates. For fabrication of organic solar cells (OSCs), PBDB‐T was used as a donor and blended with the two acceptors. The o‐4TBC‐2F‐based blend films displayed higher charge mobilities, lower energy loss and a higher power conversion efficiency (PCE). The optimized devices based on o‐4TBC‐2F gave a PCE of 10.26 %, which was much higher than those based on m‐4TBC‐2F at 2.63 %, and it is one of the highest reported PCE values for fully non‐fused ring electron acceptors.
Cross‐Module Enoylreduction in the Azalomycin F Polyketide Synthase
Authors: Zhai Guifa , Wang Wenyan , Xu Wei , Sun Guo , Hu Chaoqun , Wu Xiangming , Cong Zisong , Deng Liang , Shi Yanrong , Leadlay Peter F. , Song Heng , Hong Kui , Deng Zixin , Sun Yuhui
Published: August 2020

The colinearity of canonical modular polyketide synthases, which creates a direct link between multienzyme structure and the chemical structure of the biosynthetic end‐product, has become a cornerstone of knowledge‐based genome mining. Herein, we report genetic and enzymatic evidence for the remarkable role of an enoylreductase in the polyketide synthase for azalomycin F biosynthesis. This internal enoylreductase domain, previously identified as acting only in the second of two chain extension cycles on an initial iterative module, is shown to also catalyze enoylreduction in trans within the next module. The mechanism for this rare deviation from colinearity appears to involve direct cross‐modular interaction of the reductase with the longer acyl chain, rather than back transfer of the substrate into the iterative module, suggesting an additional and surprising plasticity in natural PKS assembly‐line catalysis.
Vivid Wording for the Chemistry of Group 4 Metallocene Complexes
Authors: Rosenthal Uwe
Published: August 2020

Three selected examples for the use of unusual wording to describe the organometallic chemistry of Group 4 metallocenes are explained and discussed. The term “tuck(ed)‐in” concerns the behavior of decamethyltitanocene [(C5Me5)2Ti] and similar complexes in which one or two methyl groups form the titanium hydride complex [(C5Me5)(C5Me4CH2)TiH] or other hydride complexes by C−H activation. In the so‐called “merry‐go‐round reaction” the rearrangement of C atoms bound to titanium in organometallic molecules is described which corresponds to the rotation of two C atoms along with a rotation of the six‐membered ring in a dihydroindenyl moiety at titanium. In the third example “migration” or “tobogganing” concerns the “sliding” of titanocene along the chain of a linear polyyne by coordination to one or more triple bonds. In all these reactions changes of the coordination mode of the metal at Cp or substrate ligands by intramolecular dynamics occur.
Visible‐Light‐Induced Cysteine‐Specific Bioconjugation: Biocompatible Thiol–Ene Click Chemistry
Authors: Choi Hangyeol , Kim Myojeong , Jang Jaebong , Hong Sungwoo
Published: August 2020

Bioconjugation methods using visible‐light photocatalysis have emerged as powerful synthetic tools for the selective modification of biomolecules under mild reaction conditions. However, the number of photochemical transformations that allow successful protein bioconjugation is still limited because of the need for stringent reaction conditions. Herein, we report that a newly developed water‐compatible fluorescent photosensitizer QPEG can be used for visible‐light‐induced cysteine‐specific bioconjugation for the installation of QPEG by exploiting its intrinsic photosensitizing ability to activate the S−H bond of cysteine. The slightly modified QCAT enables the effective photocatalytic cysteine‐specific conjugation of biologically relevant groups. The superior reactivity and cysteine selectivity of this methodology was further corroborated by traceless bioconjugation with a series of complex peptides and proteins under biocompatible conditions.
Directed Reaction Engineering Boosts Succinate Formation of Synechocystis sp. PCC 6803_Δsll1625
Authors: Mock Magdalena , Schmid Andreas , Bühler Katja
Published: August 2020

It is known that Synechocystis sp. PCC 6803 carrying a partial deletion of the succinate dehydrogenase (Synechocystis_∆sll1625) secretes succinate during aerobic cultivation with continuous illumination and in the presence of CO2. Maximal succinate titers of 2 mM (236 mg L−1) are reported. CO2 is identified as a crucial parameter for product formation, however, a detailed characterization of different cultivation conditions is still missing. Here the focus is on further reaction engineering to improve the photoautotrophic production of succinate using Synechocystis_∆sll1625. Therefore the impact of light availability, illumination regimes, nutrient availability, and external pH on product formation are investigated. Results obtained in this study reveal the importance of these parameters on the formation of succinate and cultivation with light/dark cycles increases the succinate concentration to 3 mM (354 mg L−1) after 28 days of cultivation. Furthermore, cultivation in unbuffered medium under ambient CO2 conditions even doubled the final succinate titer to 4 mM (472 mg L−1) after 28 days. Taking biomass concentrations into account, a maximal yield of succinate on biomass of 215 mgSucc gCDW−1 is achieved, which is the highest so far reported for the production of succinate utilizing Synechocystis as host organism.
Assessing value chain interventions in Zambian and Ethiopian forest beekeeping systems
Authors: Meaton Julia , Lowore Janet , Wood Adrian
Published: August 2020

This paper explores the value chains of forest honey in Zambia and Ethiopia and considers a range of interventions that might deliver livelihood opportunities for forest based communities while simultaneously promoting forest conservation. Seven types of interventions are identified including those focused on rights, technological developments, gender issues, product quality, trade development, product processing and added value, such as fair trade certification. The paper draws on evidence provided by forest beekeeper stakeholders in the Mwinilunga area in Zambia, and from evidence of an action research project in South West Ethiopia. The paper finds that many common value chain interventions are inappropriate, with the so called “modernisation” of the activity particularly problematic. The paper concludes that traditional forest beekeeping practices should be encouraged, and only carefully considered interventions around quality and marketing should be considered as these support a sustainable honey economy that delivers both livelihood gains and forest maintenance.
A specific microRNA profile as predictive biomarker for systemic treatment in patients with metastatic colorectal cancer
Authors: Poel Dennis , Gootjes Elske C. , Bakkerus Lotte , Trypsteen Wim , Dekker Henk , van der Vliet Hans J. , van Grieken Nicole C. T. , Verhoef Cornelis , Buffart Tineke E. , Verheul Henk M. W.
Published: August 2020

Background

Palliative systemic therapy is currently standard of care for patients with extensive metastatic colorectal cancer (mCRC). A biomarker predicting chemotherapy benefit which prevents toxicity from ineffective treatment is urgently needed. Therefore, a previously developed tissue‐derived microRNA profile to predict clinical benefit from chemotherapy was evaluated in tissue biopsies and serum from patients with mCRC.

Methods

Samples were prospectively collected from patients (N = 132) who were treated with capecitabine or 5‐FU/LV with oxaliplatin ± bevacizumab. Response evaluation was performed according to RECIST 1.1 after three or four cycles, respectively. Baseline tissue and serum miRNAs expression levels of miR‐17‐5p, miR‐20a‐5p, miR‐30a‐5p, miR‐92a‐3p, miR‐92b‐3p, and miR‐98‐5p were quantified with RT‐qPCR and droplet digital PCR, respectively. Combined predictive performance of selected variables was tested using logistic regression analysis.

Results

From 132 patients, 81 fresh frozen tissue biopsies from metastases and 93 serum samples were available. Based on expression levels of miRNAs in tissue, progressive disease could be predicted with an AUC of 0.85 (95% CI:0.72‐0.91) and response could be predicted with an AUC of 0.70 (95% CI:0.56‐0.80). This did not outperform clinical parameters alone (respectively P = .14 and P = .27). Expression levels of miR‐92a‐3p and miR‐98‐5p in serum significantly improved the predictive value of clinical parameters for response to chemotherapy (AUC 0.74, 95% CI:0.64‐0.84, P = .003) in this cohort.

Conclusions

The additive predictive value to clinical parameters of the tissue‐derived six miRNA profile for clinical benefit could not be validated in patients with mCRC treated with first‐line systemic therapy. Although miR‐92a‐3p and miR‐98‐5p serum levels improved the predictive value of clinical parameters, it remained insufficient for clinical decision‐making.
Nucleosomes and Epigenetics from a Chemical Perspective
Authors: Feng Yihong , Endo Masayuki , Sugiyama Hiroshi
Published: August 2020

Nucleosomes, which are the fundamental building blocks of chromatin, are highly dynamic, they play vital roles in the formation of higher‐order chromatin structures and orchestrate gene regulation. Nucleosome structures, histone modifications, nucleosome‐binding proteins, and their functions are being gradually unravelled with the development of epigenetics. With the continuous development of research approaches such as cryo‐EM, FRET and next‐generation sequencing for genome‐wide analysis of nucleosomes, the understanding of nucleosomes is getting wider and deeper. Herein, we review recent progress in research on nucleosomes and epigenetics, from nucleosome structure to chromatin formation, with a focus on chemical aspects. Basic knowledge of the nucleosome (nucleosome structure, nucleosome position sequence, nucleosome assembly and remodeling), epigenetic modifications, chromatin structure, chemical biology methods and nucleosome, observation nucleosome by AFM, phase separation and nucleosomes are described in this review.
Multivalent, Stabilized Mannose‐6‐Phosphates for the Targeted Delivery of Toll‐Like Receptor Ligands and Peptide Antigens
Authors: Reintjens Niels R. M. , Tondini Elena , Vis Christopher , McGlinn Toroa , Meeuwenoord Nico J. , Hogervorst Tim P. , Overkleeft Herman S. , Filippov Dmitri V. , van der Marel Gijsbert A. , Ossendorp Ferry , Codée Jeroen D. C.
Published: August 2020

Mannose‐6‐phosphate (M6P) is recognized by the mannose‐6‐phosphate receptor and plays an important role in the transport of cargo to the endosomes, making it an attractive tool to improve endosomal trafficking of vaccines. We describe herein the assembly of peptide antigen conjugates carrying clusters of mannose‐6‐C‐phosphonates (M6Po). The M6Po's are stable M6P mimics that are resistant to cleavage of the phosphate group by endogenous phosphatases. Two different strategies for the incorporation of the M6Po clusters in the conjugate have been developed: the first relies on a “post‐assembly” click approach employing an M6Po bearing an alkyne functionality; the second hinges on an M6Po C‐glycoside amino acid building block that can be used in solid‐phase peptide synthesis. The generated conjugates were further equipped with a TLR7 ligand to stimulate dendritic cell (DC) maturation. While antigen presentation is hindered by the presence of the M6Po clusters, the incorporation of the M6Po clusters leads to increased activation of DCs, thus demonstrating their potential in improving vaccine adjuvanticity by intraendosomally active TLR ligands.
4‐Thiouridine‐Enhanced Peroxidase‐Generated Biotinylation of RNA
Authors: Huang Jinguo , Zhao Ruiqi , Qin Shanshan , Yang Shixi , Li Wei , Mo Jing , Wang Fang , Du Yuhao , Weng Xiaocheng , Zhou Xiang
Published: August 2020

Peroxidase‐generated proximity labeling is in widespread use to study subcellular proteomes and the protein interaction networks in living cells, but the development of subcellular RNA labeling is limited. APEX‐seq has emerged as a new method to study subcellular RNA in living cells, but the labeling of RNA still has room to improve. In this work, we describe 4‐thiouridine (s4U)‐enhanced peroxidase‐generated biotinylation of RNA with high efficiency. The incorporation of s4U could introduce additional sites for RNA labeling, enhanced biotinylation was observed on monomer, model oligo RNA and total RNA. Through the s4U metabolic approach, the in vivo RNA biotinylation efficiency by peroxidase catalysis was also dramatically increased, which will benefit RNA isolation and study for the spatial transcriptome.
Bullous pemphigoid associated with dipeptidyl peptidase‐4 inhibitor showing unfavorable outcomes despite immediate discontinuation of medication
Authors: Shinohara Yasutake , Iijima Toshie , Sakurai Shintaro , Jojima Teruo , Ohira Eriko , Hayashi Shujiro , Usui Isao , Igawa Ken , Aso Yoshimasa
Published: August 2020

We experienced two cases of dipeptidyl peptidase‐4 (DPP‐4) inhibitor‐associated bullous pemphigoid (BP) showing an unfavorable course despite its discontinuation. Clinicians should carefully monitor the course of DPP‐4 inhibitor‐associated BP even after withdrawal of DPP‐4 inhibitor therapy, especially in very elderly patients.
Extensive amyloid deposits in bone marrow aspirate smears
Authors: Li Ting Hon Stanford , Wong Kit Fai , Wong Wai Shan
Published: August 2020

Amyloid light‐chain (AL) amyloidosis is the most common form of systemic amyloidosis. It can cause progressive organ dysfunction and eventually death, mainly due to cardiac involvement. Amyloidosis may rarely present as extensive amorphous, purplish‐blue deposits in marrow aspirate smears. Demonstration of congophilic property and apple‐green birefringence under polarized light in aspirate smears can allow a rapid diagnosis of amyloidosis.
Brief action planning targeting prognostic factors for an adult with persistent low back pain without radiculopathy: A case report
Authors: Connell Gaelan , Verville Leslie , Cancelliere Carol , Wong Jessica J. , Yu Hainan , Shearer Heather M.
Published: August 2020

We describe the implementation of brief action planning in conjunction with evidence‐based clinical practice guideline recommendations to improve self‐efficacy in a patient with psychosocial barriers and persistent nonspecific low back pain.
Luminescent Bimetallic IrIII/AuI Peptide Bioconjugates as Potential Theranostic Agents
Authors: Luengo Andrés , Marzo Isabel , Reback Matthew , Daubit Isabelle M. , Fernández‐Moreira Vanesa , Metzler‐Nolte Nils , Gimeno M. Concepción
Published: August 2020

Invited for the cover of this issue are Vanesa Fernández‐Moreira, Nils Metzler‐Nolte, M. Concepción Gimeno and co‐workers at Universidad de Zaragoza and Ruhr‐Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.
Hydrogen‐Bond Structure and Low‐Frequency Dynamics of Electrolyte Solutions: Hydration Numbers from ab Initio Water Reorientation Dynamics and Dielectric Relaxation Spectroscopy
Authors: Kim Seonmyeong , Wang Xiangwen , Jang Jeongmin , Eom Kihoon , Clegg Simon L. , Park Gun‐Sik , Di Tommaso Devis
Published: August 2020

We present an atomistic simulation scheme for the determination of the hydration number (h) of aqueous electrolyte solutions based on the calculation of the water dipole reorientation dynamics. In this methodology, the time evolution of an aqueous electrolyte solution generated from ab initio molecular dynamics simulations is used to compute the reorientation time of different water subpopulations. The value of h is determined by considering whether the reorientation time of the water subpopulations is retarded with respect to bulk‐like behavior. The application of this computational protocol to magnesium chloride (MgCl2) solutions at different concentrations (0.6–2.8 mol kg−1) gives h values in excellent agreement with experimental hydration numbers obtained using GHz‐to‐THz dielectric relaxation spectroscopy. This methodology is attractive because it is based on a well‐defined criterion for the definition of hydration number and provides a link with the molecular‐level processes responsible for affecting bulk solution behavior. Analysis of the ab initio molecular dynamics trajectories using radial distribution functions, hydrogen bonding statistics, vibrational density of states, water‐water hydrogen bonding lifetimes, and water dipole reorientation reveals that MgCl2 has a considerable influence on the hydrogen bond network compared with bulk water. These effects have been assigned to the specific strong Mg‐water interaction rather than the Cl‐water interaction.
Identification of Appropriate Endogenous Biomarker for Risk Assessment of Multidrug and Toxin Extrusion Protein‐Mediated Drug‐Drug Interactions in Healthy Volunteers
Authors: Miyake Takeshi , Kimoto Emi , Luo Lina , Mathialagan Sumathy , Horlbogen Lauren M. , Ramanathan Ragu , Wood Linda S. , Johnson Jillian G. , Le Vu H. , Vourvahis Manoli , Rodrigues A. David , Muto Chieko , Furihata Kenichi , Sugiyama Yuichi , Kusuhara Hiroyuki
Published: August 2020

Endogenous biomarkers are emerging to advance clinical drug‐drug interaction (DDI) risk assessment in drug development. Twelve healthy subjects received a multidrug and toxin exclusion protein (MATE) inhibitor (pyrimethamine, 10, 25, and 75 mg) in a crossover fashion to identify an appropriate endogenous biomarker to assess MATE1/2‐K‐mediated DDI in the kidneys. Metformin (500 mg) was also given as reference probe drug for MATE1/2‐K. In addition to the previously reported endogenous biomarker candidates (creatinine and N1‐methylnicotinamide (1‐NMN)), N1‐methyladenosine (m1A) was included as novel biomarkers. 1‐NMN and m1A presented as superior MATE1/2‐K biomarkers since changes in their renal clearance (CLr) along with pyrimethamine dose were well‐correlated with metformin CLr changes. The CLr of creatinine was reduced by pyrimethamine, however, its changes poorly correlated with metformin CLr changes. Nonlinear regression analysis (CLr vs. mean total concentration of pyrimethamine in plasma) yielded an estimate of the inhibition constant (Ki) of pyrimethamine and the fraction of the clearance pathway sensitive to pyrimethamine. The in vivo Ki value thus obtained was further converted to unbound Ki using plasma unbound fraction of pyrimethamine, which was comparable to the in vitro Ki for MATE1 (1‐NMN) and MATE2‐K (1‐NMN and m1A). It is concluded that 1‐NMN and m1A CLr can be leveraged as quantitative MATE1/2‐K biomarkers for DDI risk assessment in healthy volunteers.
Tolerance to Opioid‐Induced Respiratory Depression in Chronic High‐Dose Opioid Users: A Model‐Based Comparison With Opioid‐Naïve Individuals
Authors: Algera Marijke Hyke , Olofsen Erik , Moss Laurence , Dobbins Robert L. , Niesters Marieke , van Velzen Monique , Groeneveld Geert Jan , Heuberger Jules , Laffont Celine M. , Dahan Albert
Published: August 2020

Chronic opioid consumption is associated with addiction, physical dependence, and tolerance. Tolerance results in dose escalation to maintain the desired opioid effect. Intake of high‐dose or potent opioids may cause life‐threatening respiratory depression, an effect that may be reduced by tolerance. We performed a pharmacokinetic‐pharmacodynamic analysis of the respiratory effects of fentanyl in chronic opioid users and opioid‐naïve subjects to quantify tolerance to respiratory depression. Fourteen opioid‐naïve individuals and eight chronic opioid users received escalating doses of intravenous fentanyl (opioid‐naïve subjects: 75–350 µg/70 kg; chronic users: 250–700 µg/70 kg). Isohypercapnic ventilation was measured and the fentanyl plasma concentration‐ventilation data were analyzed using nonlinear mixed‐effects modeling. Apneic events occurred in opioid‐naïve subjects after a cumulative fentanyl dose (per 70 kg) of 225 (n = 3) and 475 µg (n = 6), and in 7 chronic opioid users after a cumulative dose of 600 (n = 2), 1,100 (n = 2), and 1,800 µg (n = 3). The time course of fentanyl’s respiratory depressant effect was characterized using a biophase equilibration model in combination with an inhibitory maximum effect (Emax) model. Differences in tolerance between populations were successfully modeled. The effect‐site concentration causing 50% ventilatory depression, was 0.42 ± 0.07 ng/mL in opioid‐naïve subjects and 1.82 ± 0.39 ng/mL in chronic opioid users, indicative of a 4.3‐fold sensitivity difference. Despite higher tolerance to fentanyl‐induced respiratory depression, apnea still occurred in the opioid‐tolerant population indicative of the potential danger of high‐dose opioids in causing life‐threatening respiratory depression in all individuals, opioid‐naïve and opioid‐tolerant.
Extrapolating Pharmacodynamic Effects From Adults to Pediatrics: A Case Study of Ustekinumab in Pediatric Patients With Moderate to Severe Plaque Psoriasis
Authors: Zhou Wangda , Hu Chuanpu , Zhu Yaowei , Randazzo Bruce , Song Michael , Sharma Amarnath , Xu Zhenhua , Zhou Honghui
Published: August 2020

Ustekinumab (STELARA) is a human monoclonal antibody against interleukins‐12 and −23 for the treatment of adult and adolescent (≥ 12 to < 18 years of age) patients with moderate‐to‐severe plaque psoriasis. A phase III study was recently completed in pediatric patients (≥ 6 to < 12 years of age) with psoriasis. The objectives of the current analysis were to develop a population pharmacokinetic (PK) model and a joint longitudinal exposure‐response model using ordered categorial end points derived from Psoriasis Area and Severity Index (PASI) and Physician’s Global Assessment (PGA) scores (namely a joint PASI response criteria (PRC) and PGA model) to characterize the PK and exposure‐response relationship of ustekinumab in pediatric patients with psoriasis. The developed pediatric models reasonably predicted the PK of ustekinumab, as well as the PRC and PGA clinical response in pediatric patients with psoriasis. In addition, the joint PRC and PGA modeling framework was able to adequately extrapolate clinical response in pediatric patients using data collected from clinical studies in adult patients with psoriasis.
Coral cover a stronger driver of reef fish trophic biomass than fishing
Authors: Russ Garry R. , Rizzari Justin R. , Abesamis Rene A. , Alcala Angel C.
Published: August 2020

An influential paradigm in coral reef ecology is that fishing causes trophic cascades through reef fish assemblages, resulting in reduced herbivory and thus benthic phase shifts from coral to algal dominance. Few long‐term field tests exist of how fishing affects the trophic structure of coral reef fish assemblages, and how such changes affect the benthos. Alternatively, benthic change itself may drive the trophic structure of reef fish assemblages. Reef fish trophic structure and benthic cover were quantified almost annually from 1983 to 2014 at two small Philippine islands (Apo, Sumilon). At each island a No‐Take Marine Reserve (NTMR) site and a site open to subsistence reef fishing were monitored. Thirteen trophic groups were identified. Large planktivores often accounted for >50% of assemblage biomass. Significant NTMR effects were detected at each island for total fish biomass, but for only 2 of 13 trophic components: generalist large predators and large planktivores. Fishing‐induced changes in biomass of these components had no effect on live hard coral (HC) cover. In contrast, HC cover affected biomass of 11 of 13 trophic components significantly. Positive associations with HC cover were detected for total fish biomass, generalist large predators, piscivores, obligate coral feeders, large planktivores, and small planktivores. Negative associations with HC cover were detected for large benthic foragers, detritivores, excavators, scrapers, and sand feeders. These associations of fish biomass to HC cover were most clear when environmental disturbances (e.g., coral bleaching, typhoons) reduced HC cover, often quickly (1–2 yr), and when HC recovered, often slowly (5–10 yr). As HC cover changed, the biomass of 11 trophic components of the fish assemblage changed. Benthic and fish assemblages were distinct at all sites from the outset, remaining so for 31 yr, despite differences in fishing pressure and disturbance history. HC cover alone explained ~30% of the variability in reef fish trophic structure, whereas fishing alone explained 24%. Furthermore, HC cover affected more trophic groups more strongly than fishing. Management of coral reefs must include measures to maintain coral reef habitats, not just measures to reduce fishing by NTMRs.
Disordered eating,self‐esteem, and depression symptoms in Iranian adolescents and young adults: A network analysis
Authors: Sahlan Reza N. , Williams Brenna M. , Forrest Lauren N. , Saunders Jessica F. , Fitzsimmons‐Craft Ellen E. , Levinson Cheri A.
Published: August 2020

Objective

The network theory of psychopathology examines networks of interconnections across symptoms. Several network studies of disordered eating have identified central and bridge symptoms in Western samples, yet network models of disordered eating have not been tested in non‐Western samples. The current study tested a network model of disordered eating in Iranian adolescents and college students, as well as models of co‐occurring depression and self‐esteem.

Method

Participants were Iranian college students (n= 637) and adolescents (n= 1,111) who completed the Eating Disorder Examination‐Questionnaire (EDE‐Q), Rosenberg Self‐Esteem Scale (RSES) and Beck Depression Inventory, Second Edition (BDI‐II). We computed six Glasso networks and identified central and bridge symptoms.

Results

Central disordered eating nodes in most models were a desire to lose weight and discomfort when seeing one's own body. Central self‐esteem and depression nodes were feeling useless and self‐dislike, respectively. Feeling like a failure was the most common bridge symptom between disordered eating and depression symptoms. With exception of a few differences in some edges, networks did not significantly differ in structure.

Discussion

Desire to lose weight was the most central node in the networks, which is consistent with sociocultural theories of disordered eating development, as well as prior network models from Western‐culture samples. Feeling like a failure was the most central bridge symptom between depression and disordered eating, suggesting that very low self‐esteem may be a shared correlate or risk factor for disordered eating and depression in Iranian adolescents and young adults.
Forest landscape structure influences the cyclic‐eruptive spatial dynamics of forest tent caterpillar outbreaks
Authors: Robert Louis‐Etienne , Sturtevant Brian R. , Kneeshaw Daniel , James Patrick M. A. , Fortin Marie‐Josée , Wolter Peter T. , Townsend Philip A. , Cooke Barry J.
Published: August 2020

A fundamental question in forest insect ecology is the role of forest landscape structure, particularly the amount and spatial configuration of host tree species, in shaping the dynamics of recurring forest insect outbreaks. For forest tent caterpillar (FTC), independent studies do not converge on a singular conclusion, although all indicate that forest structure influences outbreak dynamics. These studies also vary in how they treat climate as a covariate. We evaluated the relative importance of host forest landscape composition and configuration, as well as climate, for their influence on FTC outbreak cycling in the twentieth century. We predicted that FTC outbreaks would exhibit greater synchrony and intensity within areas associated with higher abundance of host trees. We reconstructed FTC outbreaks from 1928 to 2006 using tree‐ring analysis within a well‐structured experimental landscape located in northwestern Ontario and northern Minnesota. Time‐series clustering and spatial nonparametric covariance were used to determine whether similarities in time series and patterns in spatial synchrony corresponded with land management history. Using constrained ordination, we compared statistical properties of outbreak time series to landscape variables representing host abundance, forest configuration, and climate. We found no evidence of climatic effects at the scale of this study, but a significant albeit small influence of landscape structure on outbreak dynamics. Outbreaks were more synchronous and more cyclic within managed zones containing a greater relative abundance of aspen and other hardwood host tree species, compared with the more conifer‐dominated Wilderness area. Yet, we also observed asynchronous outbreak dynamics across the study area, such that correlations with slower‐changing forest landscape variables varied starkly among outbreak pulses. Consequently, the strength of relationship between landscape variables and FTC outbreak patterns varied strongly through time—a result that may explain why short‐term studies yield conclusions that are at odds with one another. Our results speak to the importance of long time series, contrasting landscape structure, use of multivariate methods, and controlling for climatic variation when investigating the effects of forest landscape structure on the cyclic‐eruptive spatial dynamics for forest defoliators.
Stable generalist species anchor a dynamic pollination network
Authors: Zografou Konstantina , Swartz Mark T. , Tilden Virginia P. , McKinney Erika N. , Eckenrode Julie A. , Sewall Brent J.
Published: August 2020

The application of complex network theory to community ecology has enabled quantification of interactions among large suites of species and clarified patterns of community structure across systems. Past analyses, however, have assumed that ecological networks are temporally static and persistent and spatially homogeneous, which could confound inference if species interactions vary over time and space. To evaluate temporal and spatial variation in mutualistic networks, therefore, we evaluated the consistency of a nectarivory/pollination network across years, by season, and over space. We tracked nectaring interactions among 37 butterfly and 58 flowering plant taxa during an 11‐yr period (2007–2017), across each summer and over a grassland landscape in Pennsylvania, USA. The composition of butterflies, plants, and their interactions varied markedly across years, months, and sites. Despite this compositional variation, one metric of network structure, nestedness, was invariant, with interactions much more nested than random across all years, months, and sites. Together with previous studies, this result suggests ecological interaction networks are generally more nested than expected by chance. Other measures of network structure were more variable, especially over time. Numbers of plants and interactions varied by year, month, and site. Connectance and numbers of butterflies varied annually and seasonally. Temporal variation in specialization was also evident for some species at an annual level and for the community across the season. We further found highly stable species were almost always generalists, while highly specialized species were almost always temporally and spatially variable, with few exceptions. Together, these results suggest communities are comprised of a reliable core of generalist species, accompanied by a changing suite of specialist species that, when participating in the network, primarily interact with the reliable core species. Our finding of nested mutualistic network centered on stable‐generalist species accompanied by a changing suite of sporadic specialists indicates dynamic changes in ecological communities vary with topological position. This finding further suggests that, even as rare species are highly threatened by species invasion, climate change, and other anthropogenic perturbations, network structure may be robust to species loss and compositional change from these perturbations.
Multi‐year experiment shows no impact of artificial light at night on arthropod trophic structure or abundance
Authors: Firebaugh Ariel , Haynes Kyle J.
Published: August 2020

Prior studies of how artificial light at night (ALAN) alters the abundances of herbivores, predators, and other trophic groups have yielded evidence of the alteration of energy and nutrient flows through ecosystems. Because the impacts of ALAN on arthropod assemblages may be context‐dependent, there is a need for more experimental work across a range of habitat types and time frames. To examine longer‐term impacts of ALAN on community and trophic structure, we experimentally manipulated ALAN in a grassland ecosystem and compared arthropod abundance and trophic structure between plots exposed to ALAN and plots exposed only to ambient light over two years. In 2015, arthropod density was 61% higher in plots with ALAN added than in plots with no ALAN added, but this difference was not statistically significant. In 2016, arthropod densities were nearly identical between plots with ALAN added and plots not exposed to ALAN. Contrasting with prior research on ground‐dwelling arthropods, we found no evidence that the effects of ALAN on abundance differed between herbivores and predators inhabiting the canopy of grassland vegetation. To better understand the ecological consequences of ALAN, we recommend experimental manipulation of ALAN in a variety of habitat types followed by repeated sampling of trophic structure over time frames that span multiple generations for the species within the focal community.