bluuebunny/crossref_metadata_2025_split huggingface dataset:
TBX5‐encoded T‐box transcription factor 5 variant T223M is associated with long QT syndrome and pediatric sudden cardiac death
Authors: Markunas Alexandra M. , Manivannan Perathu K. R. , Ezekian Jordan E. , Agarwal Agnim , Eisner William , Alsina Katherina , Allen Hugh D. , Wray Gregory A. , Kim Jeffrey J. , Wehrens Xander H. T. , Landstrom Andrew P. 
Published: December 2020

AbstractLong QT syndrome (LQTS) is a genetic disease resulting in a prolonged QT interval on a resting electrocardiogram, predisposing affected individuals to polymorphic ventricular tachycardia and sudden death. Although a number of genes have been implicated in this disease, nearly one in four individuals exhibiting the LQTS phenotype are genotype‐negative. Whole‐exome sequencing identified a missense T223M variant in TBX5 that cosegregates with prolonged QT interval in a family with otherwise genotype‐negative LQTS and sudden death. The TBX5‐T223M variant was absent among large ostensibly healthy populations (gnomAD) and predicted to be pathogenic by in silico modeling based on Panther, PolyPhen‐2, Provean, SIFT, SNAP2, and PredictSNP prediction tools. The variant was located in a highly conserved region of TBX5 predicted to be part of the DNA‐binding interface. A luciferase assay identified a 57.5% reduction in the ability of TBX5‐T223M to drive expression at the atrial natriuretic factor promotor compared to wildtype TBX5 in vitro. We conclude that the variant is pathogenic in this family, and we put TBX5 forward as a disease susceptibility allele for genotype‐negative LQTS. The identification of this familial variant may serve as a basis for the identification of previously unknown mechanisms of LQTS with broader implications for cardiac electrophysiology.
Asymmetric Synthesis of 3‐Pyrrolines through an Aryne‐Induced Domino Process
Authors: Hwu Jih Ru , Panja Avijit , Gupta Nitesh K. , Huang Wen‐Chieh , Hu Yu‐Chen , Lin Chun‐Cheng , Hwang Kuo‐Chu , Chan Wei‐Jen , Tsay Shwu‐Chen 
Published: December 2020

AbstractProduction of chiral compounds by green processes like domino reactions is of importance to environmental protection and sustainable development. Nevertheless, finding an appropriate catalyst to control enantioselectivity with satisfaction is a major challenge. Here, we report the accomplishment of a newly developed domino reaction for synthesizing optically active 3‐pyrrolines, a class of compounds with various biological properties. The reaction involves the use of (trimethylsilyl)aryl triflates, Schiff bases, and alkynes in the presence of a chiral catalyst (R)‐(−)‐1,1′‐binaphthyl‐2,2′‐diyl hydrogenphosphate. The key features of this new reaction include the generation of a single product in very good yields (75–85%) with high stereo‐ and enantio‐selectivity; the enantiomeric ratio reaches as high as 98.5 : 1.5. Moreover, it involves an aryne‐induced domino reaction and an unusual 1,4‐intramolecular proton transfer, which overwhelms the well‐established 1,5‐proton transfer.
Self‐Injurious behavior in rhesus macaques: Issues and challenges
Authors: Novak Melinda A. 
Published: December 2020

AbstractSome monkeys housed in research facilities develop abnormal behavior ranging from stereotypic to the more serious condition of self‐injurious behavior (SIB). We initially sought to understand how and why monkeys engaged in SIB and more importantly why only a small percentage of laboratory monkeys, with seemingly similar housing and background, developed this disorder. Of particular importance was the recognition that different pathways might lead to SIB and that strong individual differences would affect the manifestation of this disorder and the response to treatment. We developed a comprehensive plan to identify effective treatment and prevention strategies. We started with characterizing the disorder in terms of prevalence and types of environments in which it was found. We then conducted observations on a cohort of SIB and control monkeys to identify conditions associated with SIB (e.g., disordered sleep) as well as clinical disease states and congenital defects that could be precipitating factors. We examined the environmental events that triggered episodes of SIB in monkeys with the disorder and evaluated three models that might explain the reinforcement contingencies associated with SIB, including tension reduction, self‐stimulation, and social communication. Possible treatments for SIB such as environmental enrichment, social housing, and pharmacotherapy were tested by our group and others. To date, no single treatment has been found to abolish SIB, and each of these treatments is impacted by individual differences. To develop possible prevention strategies, we examined colony management and health records to find risk factors for SIB. These risk factors generalized to other facilities, and considerable effort was expended by all behavioral managers at these facilities to reduce early life stress exposure, to minimize the length of individual cage housing by emphasizing pair housing, and to reduce the possible stressfulness of various veterinary/medical procedures by implementing positive reinforcement training.
Covalent Cell Surface Conjugation of Nanoparticles by a Combination of Metabolic Labeling and Click Chemistry
Authors: Lamoot Alexander , Uvyn Annemiek , Kasmi Sabah , De Geest Bruno G. 
Published: December 2020

AbstractConjugation of nanoparticles (NP) to the surface of living cells is of interest in the context of exploiting the tissue homing properties of ex vivo engineered T cells for tumor‐targeted delivery of drugs loaded into NP. Cell surface conjugation requires either a covalent or non‐covalent reaction. Non‐covalent conjugation with ligand‐decorated NP (LNP) is challenging and involves a dynamic equilibrium between the bound and unbound state. Covalent NP conjugation results in a permanently bound state of NP, but the current routes for cell surface conjugation face slow reaction kinetics and random conjugation to proteins in the glycocalyx. To address the unmet need for alternative bioorthogonal strategies that allow for efficient covalent cell surface conjugation, we developed a 2‐step click conjugation sequence in which cells are first metabolically labeled with azides followed by reaction with sulfo‐6‐methyl‐tetrazine‐dibenzyl cyclooctyne (Tz‐DBCO) by SPAAC, and subsequent IEDDA with trans‐cyclooctene (TCO) functionalized NP. In contrast to using only metabolic azide labeling and subsequent conjugation of DBCO‐NP, our 2‐step method yields a highly specific cell surface conjugation of LNP, with very low non‐specific background binding.
A Highly Ordered Quantum Dot Supramolecular Assembly Exhibiting Photoinduced Emission Enhancement
Authors: Yamauchi Mitsuaki , Yamamoto Seiya , Masuo Sadahiro 
Published: December 2020

AbstractMulticomponent supramolecular assembly systems enable the generation of materials with outstanding properties, not obtained from single‐component systems, via a synergetic effect. Herein, we demonstrate a novel supramolecular coassembly system rendering highly ordered quantum dot (QD) arrangement structures formed via the self‐assembly of azobenzene derivatives, where the photocontrollable photoluminescence (PL) properties of the QDs are realized based on photoisomerization. Upon mixing the assembled azobenzene derivatives and QDs in apolar media, a time‐evolution coaggregation into hierarchical nanosheets with a highly ordered QD arrangement structure occurs. Upon photoirradiation, the nanosheets transform into ill‐defined aggregates without arranged QDs together with enhancing the PL intensity. In days, the photoirradiated coaggregates undergo recovery of the PL properties corresponding to the arranged QDs through thermal isomerization.
Comparative investigation of raw and processed products of Gardeniae Fructus and Gardenia jasminoides var. radicans using HPLC coupled with chemometric methods
Authors: Li Huanhuan , Mao Yingying , Liu Yanan , Li Di , Wang Meng , Ren Xiaoliang , Dou Zhiying 
Published: December 2020

AbstractAs a commonly used traditional Chinese medicine (TCM), Gardeniae Fructus (GF) and its processed products, GF (stir‐baked) and GF Praeparatus, have important medicinal value in clinical practice. Gardenia jasminoides var. radicans (GJVR) is a variant of GF, and because of the naming GJVR is often confused in the clinic with GF, resulting in medical misprescriptions. To distinguish GF and GJVR and study the changes before and after processing, the fingerprints of GF and GJVR are presented using HPLC, followed by hierarchical cluster analysis (HCA), principal component analysis (PCA), and partial least squares–discriminant analysis (PLS–DA). GF has purging and choleretic effects, and in this study, we determined the content of main active ingredients to preliminarily assess the GF and GJVR quality from the perspective of material basis. For PCA score plot, the samples fell into six clusters, the cross‐validity Q2 (cum) = 0.842 and the cumulative contribution rate R2x (cum) = 0.988, indicating that the model has a good precision. The results were then corroborated by HCA and PLS–DA method, showing that this methodology can distinguish GF and GJVR and can be used for the comparison of raw and two processed products. According to the model established by PLS–DA, eight components were identified as the most significant variables for discrimination. The results obtained by multiple model methods are consistent and verified by each other, providing a scientific reference for further clarification of the medicinal properties of GF and GJVR.
Sequential CD19 and BCMA‐specific CAR T‐cell treatment elicits sustained remission of relapsed and/or refractory myeloma
Authors: Yan Lingzhi , Qu Su , Shang Jingjing , Shi Xiaolan , Kang Liqing , Xu Nan , Zhu Mingqing , Zhou Jin , Jin Song , Yao Weiqin , Yao Ying , Chen Guanghua , Chang Huirong , Zhu Xiaming , Yu Lei , Wu Depei , Fu Chengcheng 
Published: December 2020

AbstractThe low rate of durable response against relapsed and/or refractory multiple myeloma (RRMM) in recent studies indicates that chimeric antigen receptor T‐cell (CART) treatment is yet to be optimized. This study aims to investigate the safety and efficacy of sequential infusion of CD19‐CART and B‐cell maturation antigen (BCMA)‐CARTs for RRMM with a similar 3 + 3 dose escalation combined with a toxicity sentinel design. We enrolled 10 patients, among whom 7 received autologous infusion and 3 received allogeneic infusion. The median follow‐up time was 20 months. The most common grade 3/4 treatment‐emergent toxicities were hematological toxicities. Cytokine‐release syndrome (CRS) adverse reactions were grade 1/2 in 9 out of 10 subjects. No dose‐limited toxicity (DLT) was observed for BCMA‐CAR‐positive T cells ≤5 × 107/kg), while two patients with dose‐levels of 5–6.5 × 107/kg experienced DLTs. The overall response rate was 90% (five partial responses and four stringent complete responses). Three out of four patients with stringent complete responses to autologous CART had progression‐free survival for over 2 years. The three patients with allogeneic CART experienced disease progression within 2 months. These results evidence the sequential infusion's preliminarily tolerability and efficacy in RRMM, and present a simple and safe design applicable for the establishment of multiple CART therapy.
Patient‐derived scaffolds as a model of colorectal cancer
Authors: Parkinson Gabrielle T. , Salerno Simona , Ranji Parmida , Håkansson Joakim , Bogestål Yalda , Wettergren Yvonne , Ståhlberg Anders , Bexe Lindskog Elinor , Landberg Göran 
Published: December 2020

AbstractBackgroundColorectal cancer is the second most common cause of cancer‐related death worldwide and standardized therapies often fail to treat the more aggressive and progressive types of colorectal cancer. Tumor cell heterogeneity and influence from the surrounding tumor microenvironment (TME) contribute to the complexity of the disease and large variability in clinical outcomes.MethodsTo model the heterogeneous nature of colorectal cancer, we used patient‐derived scaffolds (PDS), which were obtained via decellularization of surgically resected tumor material, as a growth substrate for standardized cell lines.ResultsAfter confirmation of native cell absence and validation of the structural and compositional integrity of the matrix, 89 colorectal PDS were repopulated with colon cancer cell line HT29. After 3 weeks of PDS culture, HT29 cells varied their gene and protein expression profiles considerably compared to 2D‐grown HT29 cells. Markers associated with proliferation were consistently decreased, while markers associated with pluripotency were increased in PDS‐grown cells compared to their 2D counterparts. When comparing the PDS‐induced changes in HT29 cells with clinically relevant tumor information from individual patients, we observed significant associations between stemness/pluripotency markers and tumor location, and between epithelial‐to‐mesenchymal transition (EMT) markers and cancer mortality. Kaplan–Meier analysis revealed that low PDS‐induced EMT correlated with worse cancer‐specific survival.ConclusionsThe colorectal PDS model can be used as a simplified personalized tool that can potentially reveal important diagnostic and pathophysiological information related to the TME.
Fecal microbiota transplantation for rheumatoid arthritis: A case report
Authors: Zeng Jiaqi , Peng Lihua , Zheng Wei , Huang Feng , Zhang Nana , Wu Di , Yang Yunsheng 
Published: December 2020

AbstractNo previous case of using fecal microbiota transplantation (FMT) to treat rheumatoid arthritis (RA) has been reported. We report a case of a patient with refractory RA successfully treated with FMT indicating that FMT may have a good therapeutic effect on RA.
Deciphering the Chemical Basis of Fluorescence of a Selenium‐Labeled Uracil Probe when Bound at the Bacterial Ribosomal A‐Site
Authors: Cardenas Gustavo , Menger Maximilian F. S. J. , Ramos‐Berdullas Nicolás , Sánchez‐Murcia Pedro A. 
Published: December 2020

AbstractWe unveil in this work the main factors that govern the turn‐on/off fluorescence of a Se‐modified uracil probe at the ribosomal RNA A‐site. Whereas the constraint into an “in‐plane” conformation of the two rings of the fluorophore is the main driver for the observed turn‐on fluorescence emission in the presence of the antibiotic paromomycin, the electrostatics of the environment plays a minor role during the emission process. Our computational strategy clearly indicates that, in the absence of paromomycin, the probe prefers conformations that show a dark S1 electronic state with participation of nπ* electronic transition contributions between the selenium atom and the π‐system of the uracil moiety.
Synthesis and Biological Evaluation of Quinazolonethiazoles as New Potential Conquerors towards Pseudomonas Aeruginosa
Authors: Wang Jie , Battini Narsaiah , Ansari Mohammad Fawad , Zhou Cheng‐He 
Published: December 2020

Main observation and conclusionNovel quinazolonthiazoles were designed and synthesized as new potential antimicrobial agents by facile multi‐step procedure from o‐aminobenzoic acids and 2‐acetylthiazole. A series of biological evaluation showed that compound 7d was the most effective quinazolonethiazole with superior activity to reference drugs chloramphenicol and norfloxacin. This active molecule displayed unobvious bacterial resistance against P. aeruginosa, the low toxicity to normal hepatocytes, suitable pharmacokinetics and drug‐likeness. The preliminary biological interaction suggested that quinazolonethiazole 7d might induce bacterial death by disturbing the membrane permeability, whilst preventing bacteria from growth by integrating into DNA and binding with topoisomerase IV. These findings provided significant background for the further development of quinazolonethiazoles as new potential drugs in combating drug‐resistant pathogens.
Real‐World Infliximab Pharmacokinetic Study Informs an Electronic Health Record‐Embedded Dashboard to Guide Precision Dosing in Children with Crohn’s Disease
Authors: Xiong Ye , Mizuno Tomoyuki , Colman Ruben , Hyams Jeffrey , Noe Joshua D. , Boyle Brendan , Tsai Yi‐Ting , Dong Min , Jackson Kimberly , Punt Nieko , Rosen Michael J. , Denson Lee A. , Vinks Alexander A. , Minar Phillip 
Published: December 2020

Standard‐of‐care infliximab dosing regimens were developed prior to the routine use of therapeutic drug monitoring and identification of target concentrations. Not surprisingly, subtherapeutic infliximab concentrations in pediatric Crohn’s disease (CD) are common. The primary aim was to conduct a real‐world pharmacokinetic (PK) evaluation to discover blood biomarkers of rapid clearance, identify exposure targets, and a secondary aim to translate PK modeling to the clinic. In a multicenter observational study, 671 peak and trough infliximab concentrations from 78 patients with CD were analyzed with a drug‐tolerant assay (Esoterix; LabCorp, Calabasas, CA). Individual area under the curve (AUC) estimates were generated as a measure of drug exposure over time. Population PK modeling (nonlinear mixed‐effect modeling) identified serum albumin, antibody to infliximab, erythrocyte sedimentation rate (ESR), and neutrophil CD64 as biomarkers for drug clearance. Week 14 and week 52 biochemical remitters (fecal calprotectin < 250 µg/g) had higher infliximab exposure (AUC) throughout induction. The optimal infliximab AUC target during induction for week 14 biochemical remission was 79,348 µg*h/mL (area under the receiver operating characteristic curve (AUROC) 0.77, [0.63‐0.90], 85.7% sensitive, and 64.3% specific) with those exceeding the AUC target more likely to achieve a surgery‐free week 52 biochemical remission (OR 4.3, [1.2–14.6]). Pretreatment predictors for subtherapeutic week 14 AUC included neutrophil CD64 > 6 (OR 4.5, [1.4–17.8]), ESR > 30 mm/h (OR 3.8, [1.4–11]), age < 10 years old (OR 4.2, [1.2–20]), and weight < 30 kg (OR 6.6, [2.1–25]). We created a decision‐support PK dashboard with an iterative process and embedded the modeling program within the electronic health record. Model‐informed precision dosing guided by real‐world PKs is now available at the bedside in real‐time.
Distributed parallel genetic algorithm for online virtual network embedding
Authors: Nguyen Khoa T. D. , Huang Changcheng 
Published: December 2020

SummaryNetwork virtualization (NV) has emerged as a promising paradigm to address the constraints of implementing new protocols and services in existing network architecture by allowing the simultaneous coexistence of multiple heterogeneous virtual networks on a shared substrate infrastructure. Hence, NV is a critical technology for establishing future network architectures (e.g., 5G network and the smart Internet of Things [IoT]). Virtual network embedding (VNE) is a major challenge in NV since it is acknowledged as
‐hard. Many VNE solutions have been proposed over the past decade. However, the proposed solutions merely centralize VNE node mapping while recommending virtual link embedding for the shortest path method or multicommodity flow (MCF) mechanism. This research paper presents an intelligent virtual network orchestration based on genetic algorithm (GA) for the link mapping stage that implements distributed parallelism to significantly and efficiently reduce the operation time. Our extensive simulations have demonstrated that the proposed algorithm not only outperforms the state‐of‐the‐art VNE algorithm in all performance metrics but also achieves 44.01% faster embedding speed than the most well‐known, fastest link mapping method in VNE.
Risk factors for anorexia nervosa and bulimia nervosa in Japan and compared to a U.S. sample
Authors: Pike Kathleen M. , So Mirai , Hilbert Anja , Maekawa Hiroko , Shimanouchi Tomoko , Wilfley Denise , Dohm Faith‐Anne , Fairburn Christopher G. , Weissman Ruth Striegel 
Published: December 2020

AbstractObjectiveThis study provides the first systematic investigation of environmental exposure to putative psychosocial risk factors for eating disorders in individuals with AN and BN in Japan. It also provides a comparison of risk factors for the development of AN and BN in Japan versus the United States.MethodParticipants in Japan were 96 women with a current DSM‐IV AN or BN primary diagnosis (AN, n = 60; BN, n = 36) and 57 women with no current psychiatric diagnosis (NC group). Participants in the United States were 137 women with a current DSM‐IV AN or BN primary diagnosis (AN‐U.S., n = 71; BN‐U.S., n = 66). A standardized semi‐structured interview retrospectively assessed exposure to risk factors prior to first symptom onset, which were analyzed using General Linear Model analyses.ResultsPerfectionism and negative affectivity, family relationship issues, and, to a lesser degree, parental psychopathology predicted the emergence of AN and BN in Japan. Physical and sexual abuse and family eating and weight concerns were not significant risk factors in Japan. Compared to their respective diagnostic U.S. groups, the Japanese AN group reported higher levels of individual mental health factors and lower levels of family dieting and family overweight, and the Japanese BN group reported higher levels on individual mental health factors, lower exposure to problems with their parents, and lower exposure to family weight and eating concerns.DiscussionThese country‐specific data from Japan contribute to an increasingly nuanced and global understanding of risk factors for eating disorders.
Prevalence and prognostic value of autonomic neuropathy assessed by Sudoscan® in transthyretin wild‐type cardiac amyloidosis
Authors: Kharoubi Mounira , Roche Fréderic , Bézard Mélanie , Hupin David , Silva Sidney , Oghina Silvia , Chalard Coraline , Zaroui Amira , Galat Arnault , Guendouz Soulef , Canoui‐Poitrine Florence , Hittinger Luc , Teiger Emmanuel , Lefaucheur Jean‐Pascal , Damy Thibaud 
Published: December 2020

AbstractAimsThe prevalence of autonomic neuropathy (AN) is high in patients with hereditary transthyretin amyloidosis but remains unknown in transthyretin wild‐type cardiac amyloidosis (ATTRwt‐CA). This study aimed to determine the prevalence of AN in patients with ATTRwt‐CA using Sudoscan®, a non‐invasive method used to provide evidence of AN in clinical practice and based on measurement of electrochemical skin conductance at the hands and feet (fESC).Methods and resultsA series of 62 non‐diabetic patients with ATTRwt‐CA was prospectively included over 2 years and compared with healthy elderly subjects, matched by age, gender, and body mass index. The presence of AN was defined as electrochemical skin conductance at the hands <60 μS and/or fESC <70 μS, and conductances were analysed according to clinical, biological, and echocardiographic data. Mean fESC was significantly lower in patients with ATTRwt‐CA compared with elderly controls: 68.3 (64.1–72.5) vs. 76.9 (75.6–78.1) μS (P < 0.0001), respectively. Prevalence of fESC <70 μS was higher in ATTRwt‐CA patients than in controls: 48.4% vs. 19.9%, P < 0.05. Univariate analysis showed that fESC, N‐terminal pro‐B‐type natriuretic peptide, creatinine plasma levels, and echocardiographic global longitudinal strain were associated with decompensated cardiac failure and death. Multivariate analysis revealed that fESC was an independent prognostic factor, and Kaplan–Meier estimator evidenced a greater occurrence of cardiac decompensation and death in patients with fESC <70 μS, P = 0.046.ConclusionsReduced fESC was observed in almost 50% of patients with ATTRwt‐CA and was associated with a worse prognosis. Sudoscan® could easily be used to screen ATTRwt‐CA patients for the presence of AN and identify patients at higher risk for a poor outcome.