bluuebunny/crossref_metadata_2025 huggingface dataset:
Consensus Treatment Plans for Severe Pediatric Antineutrophil Cytoplasmic Antibody–Associated Vasculitis
Authors: Morishita Kimberly A. , Wagner‐Weiner Linda , Yen Eric Y. , Sivaraman Vidya , James Karen E. , Gerstbacher Dana , Szymanski Ann M. , O'Neil Kathleen M. , Cabral David A. ,   Childhood Arthritis and Rheumatology Research Alliance (CARRA) Antineutrophil Cytoplasmic Antibody–Associated Vasculitis Workgroup
Published: March 2021

Objective

There is no standardized approach to the treatment of pediatric antineutrophil cytoplasmic antibody–associated vasculitis (AAV). Because of the rarity of pediatric AAV, randomized trials have not been feasible. The present study of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) was undertaken to establish consensus treatment plans (CTPs) for severe pediatric AAV to enable the future study of comparative effectiveness and safety.

Methods

A workgroup of CARRA members (rheumatologists and nephrologists) formed the AAV Workgroup. This group performed a literature review on existing evidence‐based treatments and guidelines for the management of AAV. They determined that the target population for CTP development was patients <18 years of age with new‐onset granulomatosis with polyangiitis (GPA), microscopic polyangiitis, or renal‐limited AAV (eosinophilic GPA was excluded), with presentation confined to those with severe disease (i.e., organ‐ or life‐threatening). Face‐to‐face consensus conferences employed nominal group techniques to identify treatment strategies for remission induction and remission maintenance, data elements to be systematically collected, and outcomes to be measured over time.

Results

The pediatric AAV Workgroup developed 2 CTPs for each of the remission induction and remission maintenance of severe AAV. A glucocorticoid‐weaning regimen for induction and maintenance, a core data set, and outcome measures were also defined. A random sample of CARRA membership voted acceptance of the CTPs for remission induction and remission maintenance, with a 94% (75 of 80) and 98% (78 of 80) approval rate, respectively.

Conclusion

Consensus methodology established standardized CTPs for treating severe pediatric AAV. These CTPs were in principle accepted by CARRA‐wide membership for the evaluation of pragmatic comparative effectiveness in a long‐term registry.
Bioinspired Tunable Structural Color Film with Janus Wettability and Interfacial Floatability towards Visible Water Quality Monitoring
Authors: Zhang Xinran , Liu Cihui , Zhang Lulu , Jia Linnan , Shi Maqian , Chen Liang , Di Yunsong , Gan Zhixing
Published: March 2021

Superwettability materials from existing natural creatures have been widely studied to enable artificial manufacture. Variable wettability states, especially Janus wettability, have attracted particular interest because of the applications in various intelligent systems. However, to date, most of these existing Janus wettability surfaces lack stimuli‐response visualization, which requires the connection of electrical instruments to process and display external stimulus signals. Inspired by the functional performance of lotus leaf and Betta splendens, a multifunctional asymmetric film is designed by using the superhydrophobic/superhydrophilic binary cooperative strategy and tunable structural color feature. Thus, it is demonstrated that the Janus membrane could not only timely report the arrival of the environmental variables via directional migration induced by Marangoni effect, but also quantitively feedback the stimuli through visible structural color variations. These features indicate that the Janus wettability structural color film may open a potential chapter in designing and fabricating the multifunctional robotic environmental detector.
A Multichannel Ca2+ Nanomodulator for Multilevel Mitochondrial Destruction‐Mediated Cancer Therapy
Authors: Zheng Pan , Ding Binbin , Shi Run , Jiang Zhongyu , Xu Weiguo , Li Gao , Ding Jianxun , Chen Xuesi
Published: March 2021

Subcellular organelle‐targeted nanoformulations for cancer theranostics are receiving increasing attention owing to their benefits of precise drug delivery, maximized therapeutic index, and reduced off‐target side effects. Herein, a multichannel calcium ion (Ca2+) nanomodulator (CaNMCUR+CDDP), i.e., a cisplatin (CDDP) and curcumin (CUR) co‐incorporating calcium carbonate (CaCO3) nanoparticle, is prepared by a facile one‐pot strategy in a sealed container with in situ synthesized polydopamine (PDA) as a template to enhance Ca2+‐overload‐induced mitochondrial dysfunction in cancer therapy. After systemic administration, the PEGylated CaNMCUR+CDDP (PEGCaNMCUR+CDDP) selectively accumulates in tumor tissues, enters tumor cells, and induces multilevel destruction of mitochondria by the combined effects of burst Ca2+ release, Ca2+ efflux inhibition by CUR, and chemotherapeutic CDDP, thereby observably boosting mitochondria‐targeted tumor inhibition. Fluorescence imaging of CUR combined with photoacoustic imaging of PDA facilitates the visualization of the nanomodulator. The facile and practical design of this multichannel Ca2+ nanomodulator will contribute to the development of multimodal bioimaging‐guided organelle‐targeted cancer therapy in the future.
Lewis Acidity Organoboron‐Modified Li‐Rich Cathode Materials for High‐Performance Lithium‐Ion Batteries
Authors: Nie Xiangkun , Hou Guangmei , Xu Zhou , Li Jianwei , Li Yuanyuan , Sun Qing , Qiao Ying , Li Deping , Ci Lijie
Published: March 2021

Layered Li‐rich manganese‐based oxides (LLMO) with high capacity are a promising cathode material. However, the capacity loss and voltage decay issues hinder its application. Herein, Lewis acidity material bis(catecholato)diboron (BCD) with unique Lewis basic groups and reduction ability is employed for forming surface B3+‐doped LiMn2O4‐type spinel structure coated and (BO3)3–‐doped LLMO (SLLMO), which efficiently protects the surface and adjusts the electronic structure of MO (M = Mn, Co, Ni) bond of LLMO. Furthermore, the Jahn–Teller effect of coating layer is suppressed by B3+ doping, the oxygen release is alleviated by hindering the formation of oxygen electronic holes and the layered structure is stabilized by high energy of BO bonding. After modification, the diffusion rate of Li‐ion and the stability of the LLMO are significantly improved. As a result, the SLLMO electrode exhibits excellent rate and cycle performance with a capacity retention of 97% (224 mAh g−1) at 0.5 C after 100 cycles and 72.5% (151.8 mAh g−1) at 1 C after 400 cycles. This work provides a novel and effective strategy to modify LLMO, which broaden its pathways toward practical applications.
Stratified Zinc‐Binding Strategy toward Prolonged Cycling and Flexibility of Aqueous Fibrous Zinc Metal Batteries
Authors: Shen Zhaoxi , Luo Lei , Li Chaowei , Pu Jun , Xie Junpeng , Wang Litong , Huai Zhe , Dai Ziyi , Yao Yagang , Hong Guo
Published: March 2021

As one of the most promising candidates in wearable energy storage devices, aqueous fibrous zinc metal batteries (AFZMBs) remain limited by some severe challenges, such as short life span and unstable capacity performance, etc. In this work, the stability of AFZMB is extended by fabricating an innovative stratified deposition framework (SDF) anode. The as‐prepared SDF electrode can achieve a stratified deposition of Zn metals from the bottom layer to the top layer due to the different overpotentials and binding energy of Zn deposition. Compared with commercial Zn fibers, this dexterous structure provides enough deposition space for Zn metals between the separator and the electrode, dramatically alleviating conventional dendrite puncture and prolonging life expectancy by an order of magnitude. It is found that SDF/AFZMB exhibits a long circulation of 2000 cycles with 89.0% capacity retention at 5 C with superior flexibility, demonstrating potential for application in future wearable electronics.
The “evil tribe” spreads across the land: A dated molecular phylogeny provides insight into dispersal, expansion, and biogeographic relationships within one of the largest tribes of the sunflower family (Vernonieae: Compositae)
Authors: Keeley Sterling C. , Cantley Jason T. , Gallaher Timothy J.
Published: March 2021

PREMISE

With over 1500 species, the globally distributed Vernonieae is one of the most successful members of the largest family of flowering plants, the Compositae. However, due to its morphological complexity and limited geographic representation in previous studies, subtribal and biogeographic relationships are unclear. Here, new DNA sequence data spanning the geographic range of the tribe provides a taxonomically robust time‐calibrated phylogeny, estimates migration pathways and timing of important biogeographic events, and allows inference of environmental factors that have contributed to the success of the Vernonieae worldwide.

METHODS

Phylogenetic relationships were estimated for 368 taxa representing all Vernonieae subtribes. Molecular clock and ancestral range estimation analyses provide a framework for inference of the biogeographic history of the tribe.

RESULTS

Relationships among the subtribes were established and correct placement determined for problematic taxa, along with the first model‐based assessment of the biogeographic history of the tribe. The Vernonieae were estimated to have evolved ~50 mya. Africa was the first center of diversity, from which a single dispersal event established the monophyletic New World lineage. Long‐distance dispersal from Africa and Brazil established the tribe on five continents and Oceania.

CONCLUSIONS

The New World lineage is monophyletic, but Old World taxa are not. New subtribal taxonomies are needed. Moquinieae are nested in Vernonieae. Long‐distance dispersal from Africa beginning 45 mya was key to establishing the tribe’s near‐global distribution. Migration corridors created by volcanic mountain chains and iron‐rich soils in Africa and the Americas promoted radiation and range expansion.
The evolution of the human trophic level during the Pleistocene
Authors: Ben‐Dor Miki , Sirtoli Raphael , Barkai Ran
Published: March 2021

The human trophic level (HTL) during the Pleistocene and its degree of variability serve, explicitly or tacitly, as the basis of many explanations for human evolution, behavior, and culture. Previous attempts to reconstruct the HTL have relied heavily on an analogy with recent hunter‐gatherer groups' diets. In addition to technological differences, recent findings of substantial ecological differences between the Pleistocene and the Anthropocene cast doubt regarding that analogy's validity. Surprisingly little systematic evolution‐guided evidence served to reconstruct HTL. Here, we reconstruct the HTL during the Pleistocene by reviewing evidence for the impact of the HTL on the biological, ecological, and behavioral systems derived from various existing studies. We adapt a paleobiological and paleoecological approach, including evidence from human physiology and genetics, archaeology, paleontology, and zoology, and identified 25 sources of evidence in total. The evidence shows that the trophic level of theHomolineage that most probably led to modern humans evolved from a low base to a high, carnivorous position during the Pleistocene, beginning withHomo habilisand peaking inHomo erectus. A reversal of that trend appears in the Upper Paleolithic, strengthening in the Mesolithic/Epipaleolithic and Neolithic, and culminating with the advent of agriculture. We conclude that it is possible to reach a credible reconstruction of the HTL without relying on a simple analogy with recent hunter‐gatherers' diets. The memory of an adaptation to a trophic level that is embedded in modern humans' biology in the form of genetics, metabolism, and morphology is a fruitful line of investigation of past HTLs, whose potential we have only started to explore.
Charge dynamics and thermal properties of epoxy based micro and nano hybrid composites at high temperatures
Authors: Chen Xiangrong , Dai Chao , Hong Zelin , Awais Muhammad , Paramane Ashish , Tanaka Yasuhiro
Published: March 2021

This paper presents the effects of the filler type and testing temperature on the charge dynamics and thermal properties of the epoxy resin. The micro‐nano hybrid composites with different content of the micro and nano aluminum nitride (AlN) fillers are fabricated. The morphology of micro‐nano hybrid composites is characterized. Electrical testing and thermal analysis methods are adopted to analyze its electrical and thermal performance. The results show that the space charge accumulation is suppressed and the charge decay process is facilitated in the hybrid composites. The electrical performances of the hybrid composites are enhanced by the nano‐fillers. The apparent mobility and activation energy are decreased with nano‐AlN fillers in the composites at the high temperature. The glass transition temperature and thermal stability of the materials is improved with the nano‐AlN. A hypothetical mechanism is proposed to explain the charge carrier injection and transport of the composites at different temperatures.
Polycaprolactone/alendronate systems intended for production of biomaterials
Authors: Goulart da Silva Talita , Baptista Pereira Debora , Ferreira de Carvalho Patricio Beatriz , Alvares Sarcinelli Michelle , Antunes Rocha Helvécio Vinícius , Letichevsky Sonia , Evelise Ribeiro da Silva Cristiane , Mendonça Roberta Helena
Published: March 2021

Sodium alendronate (ALD) is a bisphosphonate used to treat osteoporosis. However, its oral administration has been associated with side effects as gastroesophageal reflux. Moreover, there are some particularities for the intake of the medicine, which also hinder the patient's compliance, for example, the instruction that it has to be taken with an empty stomach, 30 to 60 min before breakfast and avoid the decubitus position after using the drug. Therefore, biomaterials for applications in osteoporotic bones are a good alternative. Thus, this work aimed to produce a Polycaprolactone (PCL) and ALD‐based powder as a supply to build biomaterials by selective laser sintering, compression molding (CM), solvent casting (SC), among others. The powder was produced by coating the ALD particles with PCL and films were produced by SC and CM techniques. The samples were characterized by Scanning Electron Microscopy, Energy‐dispersive X‐ray spectroscopy, X‐ray diffraction, Fourier transform infrared spectrometry and thermal analysis. Furthermore, the drug release was evaluated by UV–Vis spectroscopy. Results showed that ALD particles were successfully coated by PCL and applied to the production of biomaterials, highlighting its potential in the treatment of osteoporosis.
Polychalcones based on triphenylamine and carbazole building blocks via Claisen–Schmidt route
Authors: Jayalakshmi Arumugam , Keerthika Nagarajan , Santhanagopal Ramkumar
Published: March 2021

Alternating and random copolymers of carbazole and triphenylamine containing polychalcones are prepared by adopting simple Claisen–Schmidt route via A2 + B2 approach. Terephthaldehyde derivative was used as an additional comonomer along with bisaldehyde of triphenylamine to obtain a random copolymer. The prepared polymers are readily soluble in common organic solvents and the polymers exhibited narrow poly dispersity. The polymers are thermally stable and no observable degradation is observed until 350°C. Further, the spin cast thermally annealed films on glass substrate indicated corrugated surface as measured by scanning electron microscope and atomic force microscopy, which could facilitate for greater interaction at the interfaces. Photophysical properties of the polymers in solution and in thin film showed excellent emission characteristics. Both alternating and random copolymers showed a high quantum yield of 0.74 on comparison with quinine sulfate. Polychalcones with triphenylamine/carbazole showed oxidative response in cyclic voltammetry which suggested the suitability as electrochemical sensors and antioxidant coating material.
Developing an analytical method by HPLC for simultaneous quantification of methylene blue and metformin applied to in vitro skin permeation and retention studies
Authors: de Carvalho Matos Lisa , Calixto Leandro Augusto , Junqueira Garcia Maria Teresa
Published: March 2021

The aim of this study was to develop an HPLC method for simultaneous quantification of metformin (MET) and methylene blue (MB) in in vitro skin permeation/retention studies, in which retention was evaluated in the different layers of the skin [stratum corneum (SC) and the viable epidermis + dermis (VE + D)]. The method was validated considering the following parameters: specificity, linearity, quantitation limit (LOQ), recovery, precision and accuracy. Calibration curves were obtained using the following six matrices: methanol, water, methanolic extracts from the SC and VE + D spiked with the drugs and drugs extracted from the SC and VE + D. The precision, accuracy and LOQ of the method were evaluated in water and in VE + D and SC, applying the drug extraction process. The results show that the method is selective and linear for both drugs. The precision and accuracy values, independent of matrix and drug, were below the limit of 15%. The LOQ of MB was defined as 0.4 μg/ml in the VE + D and SC and 0.8 μg/ml in water. The LOQ of MET was defined as 0.8 μg/ml in the VE + D and SC and 0.4 μg/ml in the water. The recovery of the method was adequate, consistent and reproducible for the concentration range of 0.4–10 μg/ml for MB (73.3–92.1%) and 0.8–10.0 μg/mL for MET (72.4–94.4%). This method has a potential application in the development of formulation for skin delivery of MB and MET.
Advanced Aqueous Zinc‐Ion Batteries Enabled by 3D Ternary MnO/Reduced Graphene Oxide/Multiwall Carbon Nanotube Hybrids
Authors: Mao Xianxing , Zhang Xinyi , Zeng Yanfei , Halima Ahmed Farid , Shen Pei Kang
Published: March 2021

Aqueous zinc‐ion batteries (AZIBs) are becoming increasingly popular energy storage technology compared with conventional lithium‐ion and other rechargeable batteries. However, the poor structural stability and low conductivity remain a significant challenge in the development of the cathode material. This renders AZIBs with limitation of commercial secondary batteries. Herein, cathode optimization is demonstrated through precise control of the coupling of MnO with reduced graphene oxide (rGO) and multiwall carbon nanotubes (MWCNTs). 3D ternary MnO/rGO/MWCNTs (MPGC) nanostructures are synthesized by combining MnO nanoparticles with rGO and MWCNTs using a scalable hydrothermal and solid thermal reduction method. The MPGC cathode delivers a high specific capacity of 267.4 mAh g−1 at 0.2 A g−1 and improved stability with retention rate of 96.2% after 200 cycles at 0.5 A g−1 and 94.7% after 550 cycles at 1.2 A g−1. This simple synthesis method has great potential in practical application of AZIBs as next‐generation rechargeable batteries.
Astrocyte glutamate uptake coordinates experience‐dependent, eye‐specific refinement in developing visual cortex
Authors: Sipe Grayson O. , Petravicz Jeremy , Rikhye Rajeev V. , Garcia Rodrigo , Mellios Nikolaos , Sur Mriganka
Published: March 2021

The uptake of glutamate by astrocytes actively shapes synaptic transmission, however its role in the development and plasticity of neuronal circuits remains poorly understood. The astrocytic glutamate transporter, GLT1 is the predominant source of glutamate clearance in the adult mouse cortex. Here, we examined the structural and functional development of the visual cortex in GLT1 heterozygous (HET) mice using two‐photon microscopy, immunohistochemistry and slice electrophysiology. We find that though eye‐specific thalamic axonal segregation is intact, binocular refinement in the primary visual cortex is disrupted. Eye‐specific responses to visual stimuli in GLT1 HET mice show altered binocular matching, with abnormally high responses to ipsilateral compared to contralateral eye stimulation and a greater mismatch between preferred orientation selectivity of ipsilateral and contralateral eye responses. Furthermore, we observe an increase in dendritic spine density in the basal dendrites of layer 2/3 excitatory neurons suggesting aberrant spine pruning. Monocular deprivation induces atypical ocular dominance plasticity in GLT1 HET mice, with an unusual depression of ipsilateral open eye responses; however, this change in ipsilateral responses correlates well with an upregulation of GLT1 protein following monocular deprivation. These results demonstrate that a key function of astrocytic GLT1 function during development is the experience‐dependent refinement of ipsilateral eye inputs relative to contralateral eye inputs in visual cortex.
Clinical Implications of HBV PreS/S Mutations and the Effects of PreS2 Deletion on Mitochondria, Liver Fibrosis, and Cancer Development
Authors: Liang Yuh‐Jin , Teng Wei , Chen Chih‐Li , Sun Cheng‐Pu , Teng Rui‐Dung , Huang Yen‐Hua , Liang Kung‐Hao , Chen Yi‐Wen , Lin Chung‐Chih , Su Chien‐Wei , Tao Mi‐Hua , Wu Jaw‐Ching
Published: March 2021

Background and Aims

PreS mutants of HBV have been reported to be associated with HCC. We conducted a longitudinal study of the role of HBV preS mutations in the development of HCC, particularly in patients with chronic hepatitis B (CHB) having low HBV DNA or alanine aminotransferase (ALT) levels, and investigated the effects of secretion‐defective preS2 deletion mutant (preS2ΔMT) on hepatocyte damage in vitro and liver fibrosis in vivo.

Approach and Results

Association of preS mutations with HCC in 343 patients with CHB was evaluated by a retrospective case–control follow‐up study. Effects of preS2ΔMT on HBsAg retention, endoplasmic reticulum (ER) stress, calcium accumulation, mitochondrial dysfunction, and liver fibrosis were examined. Multivariate analysis revealed a significant association of preS mutations with HCC (HR, 3.210; 95% CI, 1.072‐9.613; P = 0.037) including cases with low HBV DNA or ALT levels (HR, 2.790; 95% CI, 1.133‐6.873; P = 0.026). Antiviral therapy reduced HCC risk, including cases with preS mutations. PreS2ΔMT expression promoted HBsAg retention in the ER and unfolded protein response (UPR). Transmission electron microscopic examination, MitoTracker staining, real‐time ATP assay, and calcium staining of preS2ΔMT‐expressing cells revealed aberrant ER and mitochondrial ultrastructure, reduction of mitochondrial membrane potential and ATP production, and calcium overload. Serum HBV secretion levels were ~100‐fold lower in preS2ΔMT‐infected humanized Fah–/–/ Rag2–/–/Il2rg–/– triple knockout mice than in wild‐type HBV‐infected mice. PreS2ΔMT‐infected mice displayed up‐regulation of UPR and caspase‐3 and enhanced liver fibrosis.

Conclusions

PreS mutations were significantly associated with HCC development in patients with CHB, including those with low HBV DNA or ALT levels. Antiviral therapy reduced HCC occurrence in patients with CHB, including those with preS mutations. Intracellular accumulation of mutated HBsAg induced or promoted ER stress, calcium overload, mitochondrial dysfunction, impaired energy metabolism, liver fibrosis, and HCC.
The hippocampal‐entorhinal system represents nested hierarchical relations between words during concept learning
Authors: Viganò Simone , Piazza Manuela
Published: March 2021

A fundamental skill of an intelligent mind is that of being able to rapidly discover the structural organization underlying the relations across the objects or the events in the world. Humans, thanks to language, master this skill. For example, a child learning thatdolphinsandcatscan also be referred to asmammals, not only will infer the presence of a hierarchical organization for which dolphins and cats are subordinate exemplars of the categorymammals, but will also derive that dolphins are, at least at one conceptual level, more similar to cats than to sharks, despite their indisputable higher perceptual similarity to the latter. The hippocampal‐entorhinal system, classically known for its involvement in relational and inferential memory, is a likely candidate to construct and hold these complex relational structures between concepts. To test this hypothesis, we trained healthy human adults to organize a novel audio‐visual object space into categories labeled with novel words. Crucially, a hierarchical taxonomy existed between the object categories, and participants discovered it via inference during a simple associative object‐to‐word training. Using functional MRI after learning, and a combination of ROI‐based multivariate analyses, we found that both the mid‐anterior hippocampus and the entorhinal cortex represented the inferred hierarchical structure between words: subordinate‐level words were represented more similarly to their related superordinate than to unrelated ones. This was paired, in the entorhinal cortex, by an additional signature of internalized structural representation of nested hierarchy: words referring to subordinate concepts belonging to the same superordinate category were represented more similarly compared with those not belonging to the same superordinate level: interestingly, this similarity was never directly taught to subjects nor it was made explicit during the task, but only indirectly derived through a logical inferential process and, crucially, contrasted the evidence coming from the definitional perceptual properties of the concepts. None of these results were observed before learning, when the same words were not yet semantically organized. A whole‐brain searchlight revealed that the effect in the entorhinal cortex extends to a wider network of areas, encompassing the prefrontal, temporal, and parietal cortices, partially overlapping with the semantic network.
PI3 kinase signaling pathway in hematopoietic cancers: A glance in miRNA's role
Authors: Roshandel Elham , Noorazar Leila , Farhadihosseinabadi Behrouz , Mehdizadeh Mahshid , Kazemi Mohammad Hossein , Parkhideh Sayeh
Published: March 2021

Hematopoietic cancers are among the most common malignancies worldwide, which are divided into different types depending on the origin of tumor cells. In recent years, the pivotal role of different signaling pathways in the onset and progression of these cancer types has been well established. One of these pathways, whose role in blood malignancies has been well‐defined, is PI3K/mTOR/AKT axis. The signaling pathway involves in a wide variety of important biological events in cells. It is clear that dysregulation of mediators involved in PI3 kinase signaling takes a pivotal role in cancer development. Considering the undeniable role of miRNAs, as one of the well‐known families of non‐coding RNAs, in gene regulation, we aimed to review the role of miRNAs in regulation of PI3 kinase signaling effectors in hematopoietic cancers.
Synthesis of [H‐3]‐ and [C‐14]‐labeled elagolix
Authors: Soli Eric D. , Surber Bruce W. , Reed Aimee D.
Published: March 2021

Gonadotropin‐releasing hormone (GnRH) receptor antagonists are an important class of compounds designed to block the pituitary gland from synthesizing follicle‐stimulating hormone and luteinizing hormone for the treatment of sex hormone dependent disorders. Elagolix (ABT‐620) is currently approved for the treatment of pain associated with endometriosis and as a combination with estradiol and norethindrone acetate is approved for management of heavy menstrual bleeding due to uterine fibroids. In order to support the development of elagolix, we prepared [3H]elagolix for preclinical metabolism studies and [14C]elagolix for environmental risk assessment studies.
Targeting the mitochondrial permeability transition pore for neuroprotection in a piglet model of neonatal hypoxic‐ischemic encephalopathy
Authors: Chen May W. , Santos Polan , Kulikowicz Ewa , Koehler Raymond C. , Lee Jennifer K. , Martin Lee J.
Published: March 2021

Neonatal hypoxic‐ischemic encephalopathy (HIE) causes significant morbidity despite treatment with therapeutic hypothermia. Mitochondrial dysfunction may drive the mechanisms underlying neuronal cell death, thereby making mitochondria prime targets for neuroprotection. The mitochondrial permeability transition pore (mPTP) is one such target within mitochondria. In adult animal models, mPTP inhibition is neuroprotective. However, evidence for mPTP inhibition in neonatal models of neurologic disease is less certain. We tested the therapeutic efficacy of the mPTP small molecule inhibitor GNX‐4728 and examined the developmental presence of brain mPTP proteins for drug targeting in a neonatal piglet model of hypoxic‐ischemic brain injury. Male neonatal piglets were randomized to hypoxia‐ischemia (HI) or sham procedure with GNX‐4728 (15 mg/kg, IV) or vehicle (saline/cyclodextrin/DMSO, IV). GNX‐4728 was administered as a single dose within 5 min after resuscitation from bradycardic arrest. Normal, ischemic, and injured neurons were counted in putamen and somatosensory cortex using hematoxylin and eosin staining. In separate neonatal and juvenile pigs, western blots of putamen mitochondrial‐enriched fractions were used to evaluate mitochondrial integrity and the presence of mPTP proteins. We found that a single dose of GNX‐4728 did not protect putamen and cortical neurons from cell death after HI. However, loss of mitochondrial matrix integrity occurred within 6h after HI, and while mPTP components are present in the neonatal brain their levels were significantly different compared to that of a mature juvenile brain. Thus, the neonatal brain mPTP may not be a good target for current neurotherapeutic drugs that are developed based on adult mitochondria.
Signal averaged ECG in patients with early repolarization
Authors: Hassanzadeh Mani , Mardani Ehsan , Hosseinpour Alireza , Mehdipour Namdar Zahra , Shahrzad Shahab , Aslani Amir
Published: March 2021

Background

Early repolarization (ER) pattern is diagnosed when the J‐point is elevated on the patient's electrocardiogram. The aim of this study was to evaluate signal‐averaged electrocardiography (SAECG) in patients with ER pattern.

Methods

Subjects were divided into three groups: 1‐patients with normal ECG pattern (control group); 2‐patients with J‐point elevation in the inferior leads; and 3‐patients with J‐point elevation in non‐inferior leads.

Results

The mean filtered QRS duration in groups with J‐point elevation in inferior leads and non‐inferior leads and in the control, was 86.4 ± 23.4 msec, 84.8 ± 26.6 msec, and 85.8 ± 24.8 msec, respectively, indicating no significant difference across the three groups. The mean duration of terminal QRS < 40µV was 21.2 ± 4.2 msec, 22.8 ± 4.6 msec, and 23.1 ± 4.5 msec in the mentioned groups, respectively, without a significant difference between the groups. Additionally, the mean root‐mean‐square voltage of terminal 40 msec was 34.5 ± 8.3 µV, 35.3 ± 8.6µV, and 35.7 ± 9.2 µV in patients with increased J‐point in inferior leads, non‐inferior leads, and the control group, respectively, showing no difference between the groups.

Conclusion

In conclusion, we found that parameters in SAECG did not have any significant difference between patients with ER pattern and healthy individuals. Moreover, we concluded that SAECG cannot distinguish the patients with elevated J‐point in inferior leads from non‐inferior leads. Overall, SAECG does not appear to be a reliable diagnostic tool for the assessment of ER pattern.
Impact of Using Abdominal Circumference Independently in the Diagnosis of Fetal Growth Restriction
Authors: Pressman Katherine , Odibo Linda , Duncan Jose R. , Odibo Anthony O.
Published: March 2021

Objective

Society for Maternal‐Fetal Medicine guidelines for diagnosing fetal growth restriction (FGR) have broadened the definition to include abdominal circumference (AC) <10th percentile for gestational age (GA) regardless of estimated fetal weight (EFW). We aimed to compare the ability of three definitions of FGR to predict small for gestational age (SGA) neonates and adverse outcomes.

Methods

We performed a secondary analysis of a prospective cohort of patients who underwent assessment of fetal growth between GA of 26 and 36 weeks. We compared three definitions of FGR: EFW <10th percentile; AC <10th percentile; either EFW or AC <10th percentile. The primary outcome was successful prediction of neonatal SGA. Secondary outcomes included a composite adverse neonatal outcome (CANO). We further compared these definitions of FGR using area under receiver operative curves (AUC) to measure their discriminatory abilities.

Results

About 1054 women met inclusion criteria. Ninety‐one (8.6%) had EFW <10th percentile, 122 (11.6%) had AC <10th percentile, and 137 (12.9%) had either EFW or AC <10th percentile. SGA was seen in 139 (13.2%); CANO was seen in 139 (13.2%). Ability for detecting neonatal SGA was significantly better when the definition included both EFW or AC <10th percentile compared to either variable independently. The AUC were: 0.74, 0.73, 0.69; P = .0003. There was no statistical significance in ability for predicting CANO (AUC 0.51, 0.51, 0.50; P = .7447).

Conclusions

Addition of AC as a criterion for diagnosing FGR improves our ability to predict neonatal SGA compared to using EFW alone. All three definitions were poorly predictive of neonates at risk for adverse outcomes.
Hyperbranched Rigid Aromatic Phosphorus‐Containing Flame Retardants for Epoxy Resins
Authors: Battig Alexander , Müller Patrick , Bertin Annabelle , Schartel Bernhard
Published: March 2021

A rigid aromatic phosphorus‐containing hyperbranched flame retardant structure is synthesized from 10‐(2,5‐dihydroxyphenyl)‐10H‐9‐oxa‐10‐phosphaphenanthrene‐10‐oxide (DOPO‐HQ), tris(4‐hydroxyphenyl)phosphine oxide (THPPO), and 1,4‐terephthaloyl chloride (TPC). The resulting poly‐(DOPO‐HQ/THPPO‐terephthalate) (PDTT) is implemented as a flame retardant into an epoxy resin (EP) at a 10 wt% loading. The effects on EP are compared with those of the monomer DOPO‐HQ and triphenylphosphine oxide (OPPh3) as low molar mass flame retardants. The glass transition temperature, thermal decomposition, flammability (reaction to small flame), and burning behavior of the thermosets are investigated using differential scanning calorimetry, thermogravimetric analysis, pyrolysis combustion flow calorimetry, UL 94‐burning chamber testing, and cone calorimeter measurements. Although P‐contents are low at only 0.6 wt%, the study aims not at attaining V‐0, but at presenting a proof of principle: Epoxy resinswith PDTT show promising fire performance, exhibiting a 25% reduction in total heat evolved (THE), a 30% reduction in peak heat release rate (PHRR) due to flame inhibition (21% reduction in effective heat of combustion (EHC)), and an increase in Tg at the same time. This study indicates that rigid aromatic hyperbranched polymeric structures offer a promising route toward multifunctional flame retardancy.
Women are started on a lower daily dose of metoprolol than men irrespective of dose recommendations: A potential source of confounding by contraindication in pharmacoepidemiology
Authors: Hendriksen Linda C. , Verhamme Katia M. C. , Van der Linden Paul D. , Stricker Bruno H. , Visser Loes E.
Published: March 2021

Purpose

Current guidelines have no sex‐specific dosage advice for metoprolol. To evaluate whether women and men are prescribed the same dose a cohort analysis was performed in the population‐based Rotterdam Study (RS). Results were replicated in the Integrated Primary Care Information (IPCI) database of automated general practice data.

Methods

The mean daily starting doses of metoprolol in both sexes were compared with independent‐samples t‐tests and a linear regression analysis was used to adjust in the RS for co‐variables, notably, cardiovascular comorbidity, migraine, age, SBP, DBP, BMI, socioeconomic status, use of other antihypertensive drugs, smoking, and alcohol. In the IPCI‐database, adjustment was for age only.

Results

The mean daily starting dose was statistically significantly lower in women than in men in both the RS and IPCI database, with a mean difference of 4.8 mg (95%CI −7.8, −1.8) and 4.6 mg (95%CI −5.3,‐4.0), respectively. Statistical significance remained after adjustment in both databases.

Conclusions

Women received lower starting doses of metoprolol than men in two independent data collections despite non‐sex specific cardiovascular guideline recommendations. This example of real‐life pharmacotherapy can lead to a form of confounding by contraindication in pharmacoepidemiology.
Theoretical investigation of Prolyl‐Histidine‐catalyzed intermolecular aldol reaction
Authors: Zhang Peihuan , Zhang Yufeng , Li Zhewei , Gao Yang , Lei Ming , Yang Zuoyin , Pu Min
Published: March 2021

The mechanism of aldol reaction of acetone and benzaldehyde catalyzed by Prolyl‐Histidine dipeptide was studied using density functional theory (DFT) method at ωB97XD/6‐31G(d,p) level. The calculated results indicated that this reaction consisted of the following processes: (I) the formation of alcohol intermediate with acetone and Pro‐His by water assistance; (II) the formation of enamine by alcohol dehydration; (III) the formation of imine complexes by electrophilic addition of enamine and benzaldehyde; and (IV) the formation of aldol products by imine complex combining with water to obtain S or R type products after removing the catalyst. The calculated results show that the generation of enamine is the rate‐determining step, and the main product is cis‐enamine with a free energy barrier of 19.6 kcal/mol. The calculated enantiomeric excess (ee) value of aldol product is 100%.
Matrix decomposition in meta‐analysis for extraction of adverse event pattern and patient‐level safety profile
Authors: Matsuura Kentaro , Tsuchida Jun , Ando Shuji , Sozu Takashi
Published: March 2021

The purpose of assessing adverse events (AEs) in clinical studies is to evaluate what AE patterns are likely to occur during treatment. In contrast, it is difficult to specify which of these patterns occurs in each patient. To tackle this challenging issue, we constructed a new statistical model including nonnegative matrix factorization by incorporating background knowledge of AE‐specific structures such as severity and drug mechanism of action. The model uses a meta‐analysis framework for integrating data from multiple clinical studies because insufficient information is derived from a single trial. We demonstrated the proposed method by applying it to real data consisting of three Phase III studies, two mechanisms of action, five anticancer treatments, 3317 patients, 848 AE types, and 99,546 AEs. The extracted typical treatment‐specific AE patterns coincided with medical knowledge. We also demonstrated patient‐level safety profiles using the data of AEs that were observed by the end of the second cycle.
A bird in the hand is worth two in the bush: Technology search strategies and competition due to import penetration
Authors: Morandi Stagni Raffaele , Fosfuri Andrea , Santaló Juan
Published: March 2021

Research Summary

Do firms respond to tougher competition by searching for completely new technological solutions (exploration), or do they work to defend their position by improving current technologies (exploitation)? Considering the different times to fruition for exploration versus exploitation, in the presence of heightened competition, we argue that firms might not be able to wait for the benefits of technological exploration to materialize. With a panel data set of U.S. manufacturing firms, we show that tougher competition, due to import penetration, leads to a decrease in technological exploration and an increase in technological exploitation. These effects are heterogeneous across industries, firms, and time. To obtain exogenous variation in competition we rely on both instrumental variable regressions and a difference‐in‐differences design exploiting large changes in import tariffs.

Managerial Summary

A firm's R&D strategy is one of the fundamental determinants of success or failure when responding to competitive threats. In this study, we examine how firms change the knowledge sources used in their R&D efforts in response to substantial increases in import penetration in their domestic market. We find that in the years that immediately follow an increase in import penetration, firms tend to rely more on familiar knowledge in the development of innovations and less on knowledge sources that were not previously used. This switch in R&D strategy also appears to be temporary (reversed in later years), and it is positively associated with an increased likelihood of survival.
Monitoring the volatile language of fungi using gas chromatography-ion mobility spectrometry
Authors: Speckbacher Verena , Zeilinger Susanne , Zimmermann Stefan , Mayhew Christopher A. , Wiesenhofer Helmut , Ruzsanyi Veronika
Published: March 2021

Fusarium oxysporum is a plant pathogenic fungus leading to severe crop losses in agriculture every year. A sustainable way of combating this pathogen is the application of mycoparasites—fungi parasitizing other fungi. The filamentous fungus Trichoderma atroviride is such a mycoparasite that is able to antagonize phytopathogenic fungi. It is therefore frequently applied as a biological pest control agent in agriculture. Given that volatile metabolites play a crucial role in organismic interactions, the major aim of this study was to establish a method for on-line analysis of headspace microbial volatile organic compounds (MVOCs) during cultivation of different fungi. An ion mobility spectrometer with gas chromatographic pre-separation (GC-IMS) enables almost real-time information of volatile emissions with good selectivity. Here we illustrate the successful use of GC-IMS for monitoring the time- and light-dependent release of MVOCs by F. oxysporum and T. atroviride during axenic and co-cultivation. More than 50 spectral peaks were detected, which could be assigned to 14 volatile compounds with the help of parallel gas chromatography-mass spectrometric (GC-MS) measurements. The majority of identified compounds are alcohols, such as ethanol, 1-propanol, 2-methyl propanol, 2-methyl butanol, 3-methyl-1-butanol and 1-octen-3-ol. In addition to four ketones, namely acetone, 2-pentanone, 2-heptanone, 3-octanone, and 2-octanone; two esters, ethyl acetate and 1-butanol-3-methylacetate; and one aldehyde, 3-methyl butanal, showed characteristic profiles during cultivation depending on axenic or co-cultivation, exposure to light, and fungal species. Interestingly, 2-octanone was produced only in co-cultures of F. oxysporum and T. atroviride, but it was not detected in the headspace of their axenic cultures. The concentrations of the measured volatiles were predominantly in the low ppbv range; however, values above 100 ppbv were detected for several alcohols, including ethanol, 2-methylpropanol, 2-methyl butanol, 1- and 3-methyl butanol, and for the ketone 2-heptanone, depending on the cultivation conditions. Our results highlight that GC-IMS analysis can be used as a valuable analytical tool for identifying specific metabolite patterns for chemotaxonomic and metabolomic applications in near-to-real time and hence easily monitor temporal changes in volatile concentrations that take place in minutes.
Efficacy of microwave ablation versus radiofrequency ablation for hepatocellular carcinoma: a propensity score analysis
Authors: Suwa Kanehiko , Seki Toshihito , Aoi Kazunori , Yamashina Masao , Murata Miki , Yamashiki Noriyo , Nishio Akiyoshi , Shimatani Masaaki , Naganuma Makoto
Published: March 2021

Purpose

To evaluate the efficacy and safety of radiofrequency ablation (RFA) and new-generation microwave ablation (MWA) for the treatment of hepatocellular carcinoma (HCC).

Methods

The propensity score matching method was applied to patients with HCC treated with MWA (93 patients) or RFA (156 patients) at a single institution from January 2014 to April 2020. The local tumor progression (LTP), intrahepatic distant recurrence (IDR), and recurrence-free survival (RFS) of the two matched therapies were analyzed using the Kaplan–Meier method. Cox proportional hazard models were used to identify risk factors for LTP and RFS. The therapeutic effects and complications of the two treatments were also compared.

Results

The LTP, IDR, and RFS of MWA and RFA were equivalent (LTP: hazard ratio [HR] = 0.87; 95% confidence interval [95% CI] 0.36- 2.07; P = 0.746, IDR: HR = 1.03; 95% CI 0.61–1.73; P = 0.890, RFS: HR = 1.15; 95% CI 0.69–1.91; P = 0.566). Para-vessel lesions was the only risk factor for LTP, whereas age, previous treatment, Albumin-Bilirubin score, and tumor diameter were risk factors for RFS. On the other hand, the ablation time per nodule (6.79 ± 2.73 and 9.21 ± 4.90 min; P = 0.008) and number of sessions per nodule required to achieve technical success (1.16 ± 0.39 and 1.34 ± 0.57; P = 0.009) were significantly lower in MWA than in RFA. The major complication rate of MWA and RFA was also equivalent.

Conclusion

MWA and RFA have similar therapeutic effects and safety, although MWA has advantages over RFA regarding efficacy, including shorter ablation time and fewer sessions required.
Late-life intermittent fasting decreases aging-related frailty and increases renal hydrogen sulfide production in a sexually dimorphic manner
Authors: Henderson Yoko O. , Bithi Nazmin , Link Christopher , Yang Jie , Schugar Rebecca , Llarena Natalia , Brown J. Mark , Hine Christopher
Published: March 2021

Global average life expectancy continues to rise. As aging increases the likelihood of frailty, which encompasses metabolic, musculoskeletal, and cognitive deficits, there is a need for effective anti-aging treatments. It is well established in model organisms that dietary restriction (DR), such as caloric restriction or protein restriction, enhances health and lifespan. However, DR is not widely implemented in the clinic due to patient compliance and its lack of mechanistic underpinnings. Thus, the present study tested the effects of a somewhat more clinically applicable and adoptable DR regimen, every-other-day (EOD) intermittent fasting, on frailty in 20-month-old male and female C57BL/6 mice. Frailty was determined by a series of metabolic, musculoskeletal, and cognitive tasks performed prior to and toward the end of the 2.5-month dietary intervention. Late-life EOD fasting attenuated overall energy intake, hypothalamic inflammatory gene expression, and frailty in males. However, it failed to reduce overall caloric intake and had a little positive effect in females. Given that the selected benefits of DR are dependent on augmented production of the gasotransmitter hydrogen sulfide (H2S) and that renal H2S production declines with age, we tested the effects of EOD fasting on renal H2S production capacity and its connection to frailty in males. EOD fasting boosted renal H2S production, which positively correlated with improvements in multiple components of frailty tasks. Therefore, late-life initiated EOD fasting is sufficient to reduce aging-related frailty, at least in males, and suggests that renal H2S production capacity may modulate the effects of late-life EOD fasting on frailty.