bluuebunny/crossref_metadata_2025_split huggingface dataset:
X-shaped structure of bacterial heterotetrameric tRNA synthetase suggests cryptic prokaryote functions and a rationale for synthetase classifications
Authors: Ju Yingchen , Han Lu , Chen Bingyi , Luo Zhiteng , Gu Qiong , Xu Jun , Yang Xiang-Lei , Schimmel Paul , Zhou Huihao 
Published: August 2021

AbstractAaRSs (aminoacyl-tRNA synthetases) group into two ten-member classes throughout evolution, with unique active site architectures defining each class. Most are monomers or homodimers but, for no apparent reason, many bacterial GlyRSs are heterotetramers consisting of two catalytic α-subunits and two tRNA-binding β-subunits. The heterotetrameric GlyRS from Escherichia coli (EcGlyRS) was historically tested whether its α- and β-polypeptides, which are encoded by a single mRNA with a gap of three in-frame codons, are replaceable by a single chain. Here, an unprecedented X-shaped structure of EcGlyRS shows wide separation of the abutting chain termini seen in the coding sequences, suggesting strong pressure to avoid a single polypeptide format. The structure of the five-domain β-subunit is unique across all aaRSs in current databases, and structural analyses suggest these domains play different functions on α-subunit binding, ATP coordination and tRNA recognition. Moreover, the X-shaped architecture of EcGlyRS largely fits with a model for how two classes of tRNA synthetases arose, according to whether enzymes from opposite classes can simultaneously co-dock onto separate faces of the same tRNA acceptor stem. While heterotetrameric GlyRS remains the last structurally uncharacterized member of aaRSs, our study contributes to a better understanding of this ancient and essential enzyme family.
Defective Severe Acute Respiratory Syndrome Coronavirus 2 Immune Responses in an Immunocompromised Individual With Prolonged Viral Replication
Authors: Gordon Claire L , Smibert Olivia C , Holmes Natasha E , Chua Kyra Y L , Rose Morgan , Drewett George , James Fiona , Mouhtouris Effie , Nguyen Thi H O , Zhang Wuji , Kedzierski Lukasz , Rowntree Louise C , Chua Brendon Y , Caly Leon , Catton Mike G , Druce Julian , Sait Michelle , Seemann Torsten , Sherry Norelle L , Howden Benjamin P , Kedzierska Katherine , Kwong Jason C , Trubiano Jason A 
Published: August 2021

Abstract
We describe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specific immune responses in a patient with lymphoma and recent programmed death 1 (PD-1) inhibitor therapy with late onset of severe coronavirus disease 2019 disease and prolonged SARS-CoV-2 replication, in comparison to age-matched and immunocompromised controls. High levels of HLA-DR+/CD38+ activation, interleukin 6, and interleukin 18 in the absence of B cells and PD-1 expression was observed. SARS-CoV-2–specific antibody responses were absent and SARS-CoV-2–specific T cells were minimally detected. This case highlights challenges in managing immunocompromised hosts who may fail to mount effective virus-specific immune responses.
Association of Physician Orders for Life-Sustaining Treatment With Inpatient Antimicrobial Use at End of Life in Patients With Cancer
Authors: Kates Olivia S , Krantz Elizabeth M , Lee Juhye , Klaassen John , Morris Jessica , Mezheritsky Irina , Sweet Ania , Tverdek Frank , Loggers Elizabeth T , Pergam Steven A , Liu Catherine 
Published: August 2021

Abstract

Background
Antimicrobial utilization at end of life is common, but whether advance directives correlate with usage is unknown. We sought to determine whether Washington State Physician Orders for Life Sustaining Treatment (POLST) form completion or antimicrobial preferences documented therein correlate with subsequent inpatient antimicrobial prescribing at end of life.

Methods
This was a single-center, retrospective cohort study of adult patients at a cancer center who died between January 1, 2016, and June 30, 2019. We used negative binomial models adjusted for age, sex, and malignancy type to test the relationship between POLST form completion ≥30 days before death, antimicrobial preferences, and antimicrobial days of therapy (DOT) per 1000 inpatient-days in the last 30 days of life.

Results
Among 1295 eligible decedents with ≥1 inpatient-day during the last 30 days of life, 318 (24.6%) completed a POLST form. Of 318, 120 (37.7%) were completed ≥30 days before death, 35/120 (29.2%) specified limited antimicrobials, 55/120 (45.8%) specified full antimicrobial use, and 30/120 (25%) omitted antimicrobial preference. Eighty-three percent (1070/1295) received ≥1 inpatient antimicrobial. The median total and intravenous (IV) antimicrobial DOT/1000 inpatient-days were 1077 and 667. Patients specifying limited antimicrobials had significantly lower total antimicrobial DOT (adjusted incidence rate ratio [IRR], 0.68; 95% CI, 0.49–0.95; P = .02) and IV antimicrobial DOT (IRR, 0.57; 95% CI, 0.38–0.86; P = .008) compared with those without a POLST.

Conclusions
Indicating a preference for limited antimicrobials on a POLST form ≥30 days before death may lead to less inpatient antimicrobial use in the last 30 days of life.
Meropenem Versus Piperacillin-Tazobactam for Definitive Treatment of Bloodstream Infections Caused by AmpC β-Lactamase–Producing Enterobacter spp, Citrobacter freundii, Morganella morganii, Providencia spp, or Serratia marcescens: A Pilot Multicenter Randomized Controlled Trial (MERINO-2)
Authors: Stewart Adam G , Paterson David L , Young Barnaby , Lye David C , Davis Joshua S , Schneider Kellie , Yilmaz Mesut , Dinleyici Rumeysa , Runnegar Naomi , Henderson Andrew , Archuleta Sophia , Kalimuddin Shirin , Forde Brian M , Chatfield Mark D , Bauer Michelle J , Lipman Jeffrey , Harris-Brown Tiffany , Harris Patrick N A ,   MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN), Chia Po Ying , Cross Gail , Somani Jyoti , Yan Gabriel 
Published: August 2021

Abstract

Background
Carbapenems are recommended treatment for serious infections caused by AmpC-producing gram-negative bacteria but can select for carbapenem resistance. Piperacillin-tazobactam may be a suitable alternative.

Methods
We enrolled adult patients with bloodstream infection due to chromosomal AmpC producers in a multicenter randomized controlled trial. Patients were assigned 1:1 to receive piperacillin-tazobactam 4.5 g every 6 hours or meropenem 1 g every 8 hours. The primary efficacy outcome was a composite of death, clinical failure, microbiological failure, and microbiological relapse at 30 days.

Results
Seventy-two patients underwent randomization and were included in the primary analysis population. Eleven of 38 patients (29%) randomized to piperacillin-tazobactam met the primary outcome compared with 7 of 34 patients (21%) in the meropenem group (risk difference, 8% [95% confidence interval {CI}, –12% to 28%]). Effects were consistent in an analysis of the per-protocol population. Within the subcomponents of the primary outcome, 5 of 38 (13%) experienced microbiological failure in the piperacillin-tazobactam group compared to 0 of 34 patients (0%) in the meropenem group (risk difference, 13% [95% CI, 2% to 24%]). In contrast, 0% vs 9% of microbiological relapses were seen in the piperacillin-tazobactam and meropenem arms, respectively. Susceptibility to piperacillin-tazobactam and meropenem using broth microdilution was found in 96.5% and 100% of isolates, respectively. The most common AmpC β-lactamase genes identified were blaCMY-2, blaDHA-17, blaCMH-3, and blaACT-17. No ESBL, OXA, or other carbapenemase genes were identified.

Conclusions
Among patients with bloodstream infection due to AmpC producers, piperacillin-tazobactam may lead to more microbiological failures, although fewer microbiological relapses were seen.

Clinical Trials Registration
NCT02437045.
Two γ-zeins induce the unfolded protein response
Authors: Brocca Lorenzo , Zuccaro Melania , Frugis Giovanna , Mainieri Davide , Marrano Claudia , Ragni Laura , Klein Eva Maria , Vitale Alessandro , Pedrazzini Emanuela 
Published: August 2021

Abstract
The rapid, massive synthesis of storage proteins that occurs during seed development stresses endoplasmic reticulum (ER) homeostasis, which activates the ER unfolded protein response (UPR). However, how different storage proteins contribute to UPR is not clear. We analyzed vegetative tissues of transgenic Arabidopsis (Arabidopsis thaliana) plants constitutively expressing the common bean (Phaseolus vulgaris) soluble vacuolar storage protein PHASEOLIN (PHSL) or maize (Zea mays) prolamins (27-kDa γ-zein or 16-kDa γ-zein) that participate in forming insoluble protein bodies in the ER. We show that 16-kDa γ-zein significantly activates the INOSITOL REQUIRING ENZYME1/BASIC LEUCINE ZIPPER 60 (bZIP60) UPR branch—but not the bZIP28 branch or autophagy—leading to induction of major UPR-controlled genes that encode folding helpers that function inside the ER. Protein blot analysis of IMMUNOGLOBULIN-BINDING PROTEIN (BIP) 1 and 2, BIP3, GLUCOSE REGULATED PROTEIN 94 (GRP94), and ER-localized DNAJ family 3A (ERDJ3A) polypeptides confirmed their higher accumulation in the plant expressing 16-kDa γ-zein. Expression of 27-kDa γ-zein significantly induced only BIP3 and ERDJ3A transcription even though an increase in GRP94 and BIP1/2 polypeptides also occurred in this plant. These results indicate a significant but weaker effect of 27-kDa γ-zein compared to 16-kDa γ-zein, which corresponds with the higher availability of 16-kDa γ-zein for BIP binding, and indicates subtle protein-specific modulations of plant UPR. None of the analyzed genes was significantly induced by PHSL or by a mutated, soluble form of 27-kDa γ-zein that traffics along the secretory pathway. Such variability in UPR induction may have influenced the evolution of storage proteins with different tissue and subcellular localization.
Beyond the Binary: Intraracial Diversity in Family Organization and Black Adolescents’ Educational Performance
Authors: Cross Christina J 
Published: August 2021

Abstract
Using a nationally representative sample of African American adolescents from the National Survey of American Life Adolescent supplement (NSAL-A), this study examines intraracial diversity in two key dimensions of family organization—family structure and family integration—and assesses their relationship with youths’ educational performance, namely, grades, grade repetition, and number of suspensions. Results show that there is substantial within-group heterogeneity in family organization among African Americans, and that patterns of organization vary systematically by level of household resources, specifically household income. Results also indicate that the relationship between family structure and family integration and Black adolescents’ educational performance differs by resource level. These factors are generally unrelated to the grades, grade repetition, and number of suspensions of adolescents from low-income households, but they are associated with these outcomes for adolescents from the most economically advantaged households. Irrespective of household income, findings demonstrate that the substantive impact of family organization on Black youths’ educational outcomes is small, which suggests that family organization has a more limited relationship with Black Americans’ life chances than previously theorized.
Toxicity and biochemical responses induced by phosmet in rainbow trout (Oncorhynchus mykiss)
Authors: Muhammed Firas , Dogan Demet 
Published: August 2021

Abstract
Phosmet is a non-systemic organophosphorus insecticide exerting its toxicity by inhibiting acetylcholinesterase upon entering the body via contact, ingestion and inhalation. Data regarding its sublethal effects on fish are limited, and therefore, with this study it was aimed to investigate the effects of phosmet on liver and brain tissues of juvenile Oncorhynchus mykiss following 24, 48, 72 and 96 h of exposure to 5, 25 and 50 μg/l concentrations. Pesticide treatment caused notable decrease in the levels of serum glucose, protein and cholesterol, whereas there was prominent elevation in the activities of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. Anticholinesterase activity of phosmet was observed in brain tissue reaching maximum of 46%. In both tissues, increase in the activities of superoxide dismutase, catalase and glutathione peroxidase and level of glutathione was accompanied by elevated thiobarbituric acid reactive substances level. Our results clearly indicate the modulatory effect of phosmet on acetylcholinesterase activity and its potency to provoke oxidative stress condition. The determined alteration in alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase activities indicates hepatotoxic potential of pesticide; meanwhile, obtained hypoglycaemia and hypoproteinaemia are evaluated as adaptive responses to handle the stress to survive.
The Liminal European: Subject to the EU Legal Order
Authors: de Witte Floris 
Published: August 2021

Abstract
This contribution suggests that recent changes to EU free movement law have led to the emergence of a new type of subject: the liminal European. This subject is deemed to deserve the protection of EU law, in terms of the rights of residence and equal treatment in the host state, only when she is economically productive and socially adaptive. These changes pose a fundamental challenge to the authority of the EU, whose legal order is premised on its ability to challenge domestic processes of subjugation, exclusion, and precarity, which it is now, instead, starting to perpetuate. Being European is increasingly a status that is deeply precarious and conditional: a transitory state that is bestowed on rather than inhabited by the European. This notion of liminality is not only a useful descriptive category with which to analyse recent changes in EU free movement law. It also comes with significant normative implications for the EU and its legal order.
Developmental lineage of human pluripotent stem cell‐derived cardiac fibroblasts affects their functional phenotype
Authors: Floy Martha E. , Givens Sophie E. , Matthys Oriane B. , Mateyka Taylor D. , Kerr Charles M. , Steinberg Alexandra B. , Silva Ana C. , Zhang Jianhua , Mei Ying , Ogle Brenda M. , McDevitt Todd C. , Kamp Timothy J. , Palecek Sean P. 
Published: August 2021

AbstractCardiac fibroblasts (CFBs) support heart function by secreting extracellular matrix (ECM) and paracrine factors, respond to stress associated with injury and disease, and therefore are an increasingly important therapeutic target. We describe how developmental lineage of human pluripotent stem cell‐derived CFBs, epicardial (EpiC‐FB), and second heart field (SHF‐FB) impacts transcriptional and functional properties. Both EpiC‐FBs and SHF‐FBs exhibited CFB transcriptional programs and improved calcium handling in human pluripotent stem cell‐derived cardiac tissues. We identified differences including in composition of ECM synthesized, secretion of growth and differentiation factors, and myofibroblast activation potential, with EpiC‐FBs exhibiting higher stress‐induced activation potential akin to myofibroblasts and SHF‐FBs demonstrating higher calcification and mineralization potential. These phenotypic differences suggest that EpiC‐FBs have utility in modeling fibrotic diseases while SHF‐FBs are a promising source of cells for regenerative therapies. This work directly contrasts regional and developmental specificity of CFBs and informs CFB in vitro model selection.
S100A8 may govern hyper‐inflammation in severe COVID‐19
Authors: Deguchi Atsuko , Yamamoto Tomoko , Shibata Noriyuki , Maru Yoshiro 
Published: August 2021

AbstractThe coronavirus disease 2019 (COVID‐19) pandemic threatens human species with mortality rate of roughly 2%. We can hardly predict the time of herd immunity against and end of COVID‐19 with or without success of vaccine. One way to overcome the situation is to define what delineates disease severity and serves as a molecular target. The most successful analogy is found in BCR‐ABL in chronic myeloid leukemia, which is the golden biomarker, and simultaneously, the most effective molecular target. We hypothesize that S100 calcium‐binding protein A8 (S100A8) is one such molecule. The underlying evidence includes accumulating clinical information that S100A8 is upregulated in severe forms of COVID‐19, pathological similarities of the affected lungs between COVID‐19 and S100A8‐induced acute respiratory distress syndrome (ARDS) model, homeostatic inflammation theory in which S100A8 is an endogenous ligand for endotoxin sensor Toll‐like receptor 4/Myeloid differentiation protein‐2 (TLR4/MD‐2) and mediates hyper‐inflammation even after elimination of endotoxin‐producing extrinsic pathogens, analogous findings between COVID‐19‐associated ARDS and pre‐metastatic lungs such as S100A8 upregulation, pulmonary recruitment of myeloid cells, increased vascular permeability, and activation coagulation cascade. A successful treatment in an animal COVID‐19 model is given with a reagent capable of abrogating interaction between S100A8/S100A9 and TLR4. In this paper, we try to verify our hypothesis that S100A8 governs COVID‐19‐associated ARDS.
Development of a Novel Assessment Tool and Code Sepsis Checklist for Neonatal Late-Onset Sepsis
Authors: Perkins Beckett S. , Brandon Debra H. , Kahn Doron J. 
Published: August 2021

Background:
Accurate diagnosis and timely management of neonatal late-onset sepsis (nLOS) have been less well-studied than those of early-onset sepsis. We noticed a delay in nLOS detection and management in our neonatal intensive care unit.

Purpose:
To develop an assessment tool to aid in the recognition and reporting of nLOS and to standardize the management process once sepsis is recognized.

Methods:
The Plan-Do-Study-Act (PDSA) improvement model provided the framework for interventions for our antibiotic stewardship program, including the aims of this project. A literature review was performed to evaluate tools and other literature available to guide the evaluation and management of suspected sepsis. A quality improvement project was initiated to develop tools for the detection and management of nLOS.

Results:
An nLOS assessment tool to help identify neonates at risk for nLOS and a Code Sepsis checklist to standardize the process of evaluation and management of nLOS were developed. The guiding principles of this tool development were empowerment of nurses to initiate the assessment process, clarification of team roles, and removal of barriers to appropriate antibiotic administration.

Implications for Practice:
Useful and practical tools valued by nursing and the multidisciplinary team may facilitate timely identification and treatment of infants with nLOS.

Implications for Research:
Future directions include validation of the nLOS assessment tool and the Code Sepsis checklist as well as ensuring the reliability of the tool to improve detection of nLOS and to reduce time to administer antibiotics in cases of nLOS.
The Impact of Cast Immobilization on Return to Daycare
Authors: Heffernan Michael J. , Barnett Scott A. , Nungesser Matthew E. , Song Bryant M. , Leonardi Claudia , Gonzales Joseph 
Published: August 2021

Background:
Children who are prohibited from returning to daycare (RTD) after treatment with cast immobilization place an increased burden on parents and caregivers. The purpose of this study was to assess the impact of cast immobilization on RTD. Specifically, we sought to determine the prevalence of RTD after orthopaedic immobilization based on daycare facility policy.

Methods:
This was a survey study of randomly selected daycare facilities servicing a total of 6662 children within 10 miles of a major metropolitan city center. The 40-question survey included information on daycare policies and experience caring for children treated with orthopaedic immobilization. The survey also included questions about daycare type, enrollment, and geographic location. Photographs of the types of immobilization were embedded in the survey to facilitate understanding. Daycare facilities were randomly selected based on a power analysis to estimate a 50% prevalence of RTD after spica casting within 10% margin of error.

Results:
Seventy-three daycare facilities completed the survey study. The average child-staff ratio was 5:1 and most daycare facilities (78%) did not have a nurse on staff. Predetermined policies regarding RTD after injury were available at 81% of daycares. Twenty-eight (38.5%) facilities had encountered a child with a cast in the previous year. The rate of RTD for children with upper limb injuries was 90.5% compared with 79% for lower limb injuries (P=0.003). Spica casts showed the lowest RTD rate: single leg (22.5%), 1 and a half leg (18%), and 2 leg (16%) (P<0.0001). Experienced daycare facilities (>5 y) had a higher RTD rate compared with less experienced facilities (P=0.026).

Conclusions:
The ability to RTD is dependent on immobilization type. Children with long leg and spica casts are disproportionately restricted when compared with other cast types. At minimum, surgeons should consider the socioeconomic implications of orthopaedic immobilization. There is also a need for orthopaedic involvement in policy formation at the local level to provide standardized guidelines for re-entry into childcare facilities following orthopaedic immobilization.

Level of Evidence:
Level IV.
Calculating Utilities From the Spine Oncology Study Group Outcomes Questionnaire
Authors: Pahuta Markian A. , Fisk Felicity , Versteeg Anne L. , Fisher Charles G. , Sahgal Arjun , Gokaslan Ziya L. , Reynolds Jeremy J. , Laufer Ilya , Lazary Aron , Rhines Laurence D. , Boriani Stefano , Bettegowda Chetan , Dea Nicolas 
Published: August 2021

Study Design.
General population utility valuation study.

Objective.
The aim of this study was to develop a technique for calculating utilities from the Spine Oncology Study Group Outcomes Questionnaire v2.0 (SOSGOQ2.0).

Summary of Background Data.
The ability to calculate quality-adjusted life-years (QALYs) for metastatic spine disease would enhance treatment decision-making and facilitate economic analysis. QALYs are calculated using utilities.

Methods.
Using a hybrid concept-retention and factorial analysis shortening approach, we first shortened the SOSGOQ2.0 to eight items (SOSGOQ-8D). This was done to lessen the cognitive burden of the utility valuation exercise. A general population sample of 2730 adults was then asked to evaluate 12 choice sets based on SOSGOQ-8D health states in a Discrete Choice Experiment. A utility scoring rubric was then developed using a mixed multinomial-logit regression model.

Results.
We were able to reduce the SOSGOQ2.0 to an SOSGOQ-8D with a mean error of 0.003 and mean absolute error of 3.078 compared to the full questionnaire. The regression model demonstrated good predictive performance and was used to develop a utility scoring rubric. Regression results revealed that participants did not regard all SOSGOQ-8D items as equally important.

Conclusion.
We provide a simple technique for converting the SOSGOQ2.0 to utilities. The ability to evaluate QALYs in metastatic spine disease will facilitate economic analysis and patient counseling. We also quantify the importance of individual SOSGOQ-8D items. Clinicians should heed these findings and offer treatments that maximize function in the most important items.

Level of Evidence: 3