bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolved resistance to a novel cationic peptide antibiotic requires high mutation supply
Authors: Santos-Lopez Alfonso , Fritz Melissa J , Lombardo Jeffrey B , Burr Ansen H P , Heinrich Victoria A , Marshall Christopher W , Cooper Vaughn S
Published: May 2022

Background and Objectives

A key strategy for resolving the antibiotic resistance crisis is the development of new drugs with antimicrobial properties. The engineered cationic antimicrobial peptide WLBU2 (also known as PLG0206) is a promising broad-spectrum antimicrobial compound that has completed Phase I clinical studies. It has activity against Gram-negative and Gram-positive bacteria including infections associated with biofilm. No definitive mechanisms of resistance to WLBU2 have been identified.

Methodology

Here, we used experimental evolution under different levels of mutation supply and whole genome sequencing (WGS) to detect the genetic pathways and probable mechanisms of resistance to this peptide. We propagated populations of wild-type and hypermutator Pseudomonas aeruginosa in the presence of WLBU2 and performed WGS of evolved populations and clones.

Results

Populations that survived WLBU2 treatment acquired a minimum of two mutations, making the acquisition of resistance more difficult than for most antibiotics, which can be tolerated by mutation of a single target. Major targets of resistance to WLBU2 included the orfN and pmrB genes, previously described to confer resistance to other cationic peptides. More surprisingly, mutations that increase aggregation such as the wsp pathway were also selected despite the ability of WLBU2 to kill cells growing in a biofilm.

Conclusions and implications

The results show how experimental evolution and WGS can identify genetic targets and actions of new antimicrobial compounds and predict pathways to resistance of new antibiotics in clinical practice.
Polygenic discrimination of migratory phenotypes in an estuarine forage fish
Authors: Campbell Matthew A , Joslin Shannon E K , Goodbla Alisha M , Willmes Malte , Hobbs James A , Lewis Levi S , Finger Amanda J
Published: May 2022

Migration is a complex phenotypic trait with some species containing migratory and nonmigratory individuals. Such life history variation may be attributed in part to plasticity, epigenetics, or genetics. Although considered semianadromous, recent studies using otolith geochemistry have revealed life history variation within the critically endangered Delta Smelt. Broadly categorizable as migratory or freshwater residents, we examined Restriction site Associated DNA sequencing data to test for a relationship between genetic variation and migratory behaviors. As previously shown, we found no evidence for neutral population genetic structure within Delta Smelt; however, we found significant evidence for associations between genetic variants and life history phenotypes. Furthermore, discriminant analysis of principal components, hierarchical clustering, and machine learning resulted in accurate assignment of fish into the freshwater resident or migratory classes based on their genotypes. These results suggest the presence of adaptive genetic variants relating to life history variation within a panmictic population. Mechanisms that may lead to this observation are genotype dependent habitat choice and spatially variable selection, both of which could operate each generation and are not exclusive. Given that the population of cultured Delta Smelt are being used as a refugial population for conservation, as a supply for wild population supplementation, and currently represent the majority of all living individuals of this species, we recommend that the hatchery management strategy consider the frequencies of life history-associated alleles and how to maintain this important aspect of Delta Smelt biological variation while under captive propagation.
Diagnostic performance of endoscopic ultrasound-guided tissue acquisition of splenic lesions: systematic review with pooled analysis
Authors: Lisotti Andrea , Crinò Stefano Francesco , Mangiavillano Benedetto , Cominardi Anna , Ofosu Andrew , Brighi Nicole , Metelli Flavio , Zagari Rocco Maurizio , Facciorusso Antonio , Fusaroli Pietro
Published: May 2022

Background

Focal splenic lesions are usually incidentally discovered on radiological assessments. Although percutaneous tissue acquisition (TA) under trans-abdominal ultrasound guidance is a well-established technique for obtaining cyto-histological diagnosis of focal splenic lesions, endoscopic ultrasound (EUS)-guided TA has been described in several studies, reporting different safety and outcomes. The aim was to assess the pooled safety, adequacy, and accuracy of EUS-TA of splenic lesions.

Methods

A comprehensive review of available evidence was conducted at the end of November 2021. All studies including more than five patients and reporting about the safety, adequacy, and accuracy of EUS-TA of the spleen were included.

Results

Six studies (62 patients) were identified; all studies have been conducted using fine-needle aspiration (FNA) needles. Pooled specimen adequacy and accuracy of EUS-TA for spleen characterization were 92.8% [95% confidence interval (CI), 86.3%–99.3%] and 88.2% (95% CI, 79.3%–97.1%), respectively. The pooled incidence of adverse events (six studies, 62 patients) was 4.7% (95% CI, 0.4%–9.7%).

Conclusion

EUS-FNA of the spleen is a safe technique with high diagnostic adequacy and accuracy. The EUS-guided approach could be considered a valid alternative to the percutaneous approach for spleen TA.
Analysis of SARS-CoV-2 known and novel subgenomic mRNAs in cell culture, animal model, and clinical samples using LeTRS, a bioinformatic tool to identify unique sequence identifiers
Authors: Dong Xiaofeng , Penrice-Randal Rebekah , Goldswain Hannah , Prince Tessa , Randle Nadine , Donovan-Banfield I'ah , Salguero Francisco J , Tree Julia , Vamos Ecaterina , Nelson Charlotte , Clark Jordan , Ryan Yan , Stewart James P , Semple Malcolm G , Baillie J Kenneth , Openshaw Peter J M , Turtle Lance , Matthews David A , Carroll Miles W , Darby Alistair C , Hiscox Julian A
Published: May 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a complex strategy for the transcription of viral subgenomic mRNAs (sgmRNAs), which are targets for nucleic acid diagnostics. Each of these sgmRNAs has a unique 5′ sequence, the leader–transcriptional regulatory sequence gene junction (leader–TRS junction), that can be identified using sequencing. High-resolution sequencing has been used to investigate the biology of SARS-CoV-2 and the host response in cell culture and animal models and from clinical samples. LeTRS, a bioinformatics tool, was developed to identify leader–TRS junctions and can be used as a proxy to quantify sgmRNAs for understanding virus biology. LeTRS is readily adaptable for other coronaviruses such as Middle East respiratory syndrome coronavirus or a future newly discovered coronavirus. LeTRS was tested on published data sets and novel clinical samples from patients and longitudinal samples from animal models with coronavirus disease 2019. LeTRS identified known leader–TRS junctions and identified putative novel sgmRNAs that were common across different mammalian species. This may be indicative of an evolutionary mechanism where plasticity in transcription generates novel open reading frames, which can then subject to selection pressure. The data indicated multiphasic abundance of sgmRNAs in two different animal models. This recapitulates the relative sgmRNA abundance observed in cells at early points in infection but not at late points. This pattern is reflected in some human nasopharyngeal samples and therefore has implications for transmission models and nucleic acid–based diagnostics. LeTRS provides a quantitative measure of sgmRNA abundance from sequencing data. This can be used to assess the biology of SARS-CoV-2 (or other coronaviruses) in clinical and nonclinical samples, especially to evaluate different variants and medical countermeasures that may influence viral RNA synthesis.
Genome-wide core sets of SNP markers and Fluidigm assays for rapid and effective genotypic identification of Korean cultivars of lettuce (Lactuca sativa L.)
Authors: Park Jee-Soo , Kang Min-Young , Shim Eun-Jo , Oh JongHee , Seo Kyoung-In , Kim Kyung Seok , Sim Sung-Chur , Chung Sang-Min , Park Younghoon , Lee Gung Pyo , Lee Won-Sik , Kim Minkyung , Jung Jin-Kee
Published: May 2022

Lettuce is one of the economically important leaf vegetables and is cultivated mainly in temperate climate areas. Cultivar identification based on the distinctness, uniformity, and stability (DUS) test is a prerequisite for new cultivar registration. However, DUS testing based on morphological features is time-consuming, labor-intensive, and costly, and can also be influenced by environmental factors. Thus, molecular markers have also been used for the identification of genetic diversity as an effective, accurate, and stable method. Currently, genome-wide single nucleotide polymorphisms (SNPs) using next-generation sequencing technology are commonly applied in genetic research on diverse plant species. This study aimed to establish an effective and high-throughput cultivar identification system for lettuce using core sets of SNP markers developed by genotyping by sequencing (GBS). GBS identified 17 877 high-quality SNPs for 90 commercial lettuce cultivars. Genetic differentiation analyses based on the selected SNPs classified the lettuce cultivars into three main groups. Core sets of 192, 96, 48, and 24 markers were further selected and validated using the Fluidigm platform. Phylogenetic analyses based on all core sets of SNPs successfully discriminated individual cultivars that have been currently recognized. These core sets of SNP markers will support the construction of a DNA database of lettuce that can be useful for cultivar identification and purity testing, as well as DUS testing in the plant variety protection system. Additionally, this work will facilitate genetic research to improve breeding in lettuce.
The reference genome and full-length transcriptome of pakchoi provide insights into cuticle formation and heat adaption
Authors: Xu Huimin , Wang Chunhua , Shao Guirong , Wu Shasha , Liu Peng , Cao Ping , Jiang Peng , Wang Shubin , Zhu Hong , Lin Xiao , Tauqeer Arfa , Lin Yizhang , Chen Wei , Huang Weiqun , Wen Qingfang , Chang Jiang , Zhong Fenglin , Wu Shuang
Published: May 2022

Brassica rapa includes various vegetables with high economic value. Among them, green petiole type pakchoi (B. rapa ssp. chinensis) is one of the major vegetables grown in southern China. Compared with other B. rapa varieties, green petiole type pakchoi shows a higher level of heat resistance, which is partially derived from the rich epicuticular wax. Here we sequence a high-quality genome of green petiole type pakchoi, which has been widely used as the parent in breeding. Our results reveal that long terminal repeat retrotransposon insertion plays critical roles in promoting the genome expansion and transcriptional diversity of pakchoi genes through preferential insertions, particularly in cuticle biosynthetic genes. After whole-genome triplication, over-retained pakchoi genes escape stringent selection pressure, and among them a set of cuticle-related genes are retained. Using bulked-segregant analysis of a heat-resistant pakchoi cultivar, we identify a frame-shift deletion across the third exon and the subsequent intron of BrcCER1 in candidate regions. Using Nanopore long-read sequencing, we analyze the full-length transcriptome of two pakchoi cultivars with opposite sensitivity to high temperature. We find that the heat-resistant pakchoi cultivar can mitigate heat-caused leaf damage by activating an unfolded protein response, as well as by inhibiting chloroplast development and energy metabolism, which are presumably mediated by both transcriptional regulation and splicing factors. Our study provides valuable resources for Brassica functional genomics and breeding research, and deepens our understanding of plant stress resistance.
Exploring the diversity and genetic structure of the U.S. National Cultivated Strawberry Collection
Authors: Zurn Jason D , Hummer Kim E , Bassil Nahla V
Published: May 2022

The cultivated strawberry (Fragaria ×ananassa) arose through a hybridization of two wild American octoploid strawberry species in a French garden in the 1750s. Since then, breeders have developed improved cultivars adapted to different growing regions. Diverse germplasm is crucial to meet the challenges strawberry breeders will continue to address. The USDA-ARS National Clonal Germplasm Repository (NCGR) in Corvallis, Oregon maintains the U.S. strawberry collection. Recent developments in high-throughput genotyping for strawberry can provide new insights about the diversity and structure of the collection, germplasm management, and future breeding strategies. Genotyping was conducted on 539 F. ×ananassa accessions using either the iStraw35 or FanaSNP 50 K Axiom array. Data for markers shared by the two arrays were curated for call quality, missing data, and minor allele frequency resulting in 4033 markers for structure assessment, diversity analysis, pedigree confirmation, core collection development, and the identification of haplotypes associated with desirable traits. The F. ×ananassa collection was equally diverse across the different geographic regions represented. K-means clustering, sNMF, and UPGMA hierarchal clustering revealed seven to nine sub-populations associated with different geographic breeding centers. Two 100 accession core collections were created. Pedigree linkages within the collection were confirmed. Finally, accessions containing disease resistance-associated haplotypes for FaRCa1, FaRCg1, FaRMp1, and FaRPc2 were identified. These new core collections will allow breeders and researchers to more efficiently utilize the F. ×ananassa collection. The core collections and other accessions of interest can be requested for research from the USDA-ARS NCGR via the Germplasm Resources Information Network (https://www.ars-grin.gov/).
Utility of the surgical Apgar score for predicting the short- and long-term outcomes in non-small-cell lung cancer patients who undergo surgery
Authors: Nagoya Akihiro , Kanzaki Ryu , Kimura Kenji , Fukui Eriko , Kanou Takashi , Ose Naoko , Funaki Soichiro , Minami Masato , Fujii Makoto , Shintani Yasushi
Published: May 2022

OBJECTIVES

The surgical Apgar score (SAS) is a simple score that predicts postoperative complications based on 3 intraoperative valuables. The present study evaluated the association between the SAS and postoperative outcomes in non-small-cell lung cancer patients who underwent surgery.

METHODS

A total of 585 patients who underwent lung resection were enrolled in the present study. We calculated the SAS of each patient and investigated its influence on the short- and long-term outcomes.

RESULTS

Postoperative complications of any grade were detected in 164 cases (28%). The morbidity rate increased with decreasing SAS. When all the patients were divided into 2 groups (SAS <7 vs ≥7), postoperative complications were observed more frequently in the SAS <7 group than in the SAS ≥7 group (41% vs 25%, P < 0.001). In the multivariate analysis, the SAS was an independent risk factor for postoperative complications (odds ratio: 1.64 [1.03–2.61], P = 0.036). In terms of long-term outcomes, the 5-year disease-free survival (54.1% vs 73.2%, P < 0.001) and overall survival (73.8% vs 83.0%, P = 0.031) were significantly worse in the SAS <7 group than in the SAS ≥7 group. In a multivariate analysis, however, the SAS was not found to be an independent prognostic factor for either disease-free survival (hazard ratio: 1.39 [0.97–2.00], P = 0.075) or overall survival (hazard ratio: 0.90 [0.57–1.42], P = 0.642).

CONCLUSIONS

The SAS reflected preoperative and intraoperative characteristics and was able to stratify the morbidity rate, suggesting it to be a useful predictor of short-term outcomes in non-small-cell lung cancer patients who undergo surgery.
Clinical significance of postoperative pulmonary complications in elderly patients with lung cancer
Authors: Okada Satoru , Shimomura Masanori , Ishihara Shunta , Ikebe Satoshi , Furuya Tatsuo , Inoue Masayoshi
Published: May 2022

OBJECTIVES

An increasing number of elderly patients with impaired immunity, malnutrition and comorbidities are considered surgical candidates. This study aimed to clarify the predictive factors and prognostic impact of postoperative pulmonary complications in elderly patients with lung cancer.

METHODS

This retrospective study included 188 patients (≥75 years) who underwent complete anatomical lung resection for non-small cell lung cancer between 2005 and 2019. Postoperative pulmonary complications graded ≥II in the Clavien-Dindo classification, occurring within 30-day post-surgery were evaluated. Multivariate logistic regression analyses and Cox proportional hazard models were used to analyse predictors and prognostic impact of complications.

RESULTS

Video-assisted thoracoscopic surgery was performed in 154 patients (81.9%). The 90-day mortality rate was 0.5%. Postoperative pulmonary complications including air leak, pneumonia, sputum retention, atelectasis, bronchopleural fistula and empyema occurred in 29 patients (15.4%). A lower prognostic nutritional index (<45) and longer operative time were independent predictive factors of pulmonary complications, with 33.3% of patients experiencing both factors. Following a median follow-up of 48 months, the 5-year overall and relapse-free survival rates were significantly worse in patients with pulmonary complications than in those without them (54.4% vs 81.5% and 41.2% vs 74.9%). Pulmonary complications were significantly associated with worse overall and relapse-free survival [hazard ratio (95% confidence interval): 1.97 (1.01–3.66), P = 0.047 and 2.35 (1.28–4.12), P = 0.007, respectively] along with pathologic stage and carcinoembryonic antigen levels.

CONCLUSIONS

Postoperative pulmonary complications are associated with a lower prognostic nutritional index and prolonged operative time; the complications are independent adverse prognostic factors in elderly patients.
Time to review reflective practice?
Authors: Quilty Terry , Murphy Lyn
Published: May 2022

Background

Reflective practice is an integral part of modern healthcare. If done well, it can significantly improve the individual skills of health care practitioners. However, we hypothesize that extrapolating individual reflective practice into broader organization applications undermines its fundamental nature and inhibits objective benchmarking within the health sector.

Methods

We reflect on the nature and use of the reflective practice in healthcare.

Results

An organization that practices reflective practice may, in effect, create an environment where reflective practice is promoted but operates to homogenize thinking to a point where it turns into dysfunctional institutional navel-gazing. Homogenized thinking may inhibit the ability to move beyond practice to explore ideas that lead to change.

Conclusions

The collective approach to reflective practice can subvert the underlying process of self-analysis, which allows the critical examination of individual values, priorities, and evaluations. It can inhibit individual growth, favouring a homogenizing effect which is the antithesis of an innovative organization when measured against the original intent and must therefore be used with care.
Automatic anomaly detection and processing for long-term tension monitoring of stay cables based on vibration measurements
Authors: Wu Wen-Hwa , Chen Chien-Chou , Lin Shang-Li , Lai Gwolong
Published: May 2022

Stay cables are the crucial force-transmitting components of cable-stayed bridges. Consequently, effective cable tension monitoring is typically regarded as the most important issue in structural health monitoring for this type of bridge. In the long-term monitoring of structures, the occurrence of abnormal signals due to a variety of reasons such as sensor faults, a system malfunction, data loss in transmission, or the instability of power supply, are almost unavoidable and are highly likely to lead to a deterioration in the quality of subsequent analyses. The current paper presents the first phase of a project to develop an automatic monitoring system for cable tension based on ambient vibration signals for the Mao-Luo-Hsi Bridge. The results demonstrate that automatic anomaly detection and processing for cable vibration measurements can be achieved with a relatively simple algorithm using an appropriate threshold of maximum response value. In addition, the paper also reports the elimination of anomalies during testing of the monitoring system installation.
Update on Urine Adulterants and Synthetic Urine Samples to Subvert Urine Drug Testing
Authors: Vikingsson Svante , Krauss Shannon T , Winecker Ruth E , Flegel Ronald R , Hayes Eugene D
Published: May 2022

To avoid a positive urine drug test, donors might try to subvert the test, either by adulterating the specimen with a product designed to interfere with testing or by substituting the specimen for a synthetic urine. A market search conducted in December of 2020 identified 3 adulterants and 32 synthetic urines, and a selection was procured based on specific criteria. Samples prepared with the 3 adulterants and 10 synthetic urines were submitted for testing at five forensic drug testing laboratories to perform immunoassay screening, chromatographic confirmation analysis and specimen validity testing (SVT). One adulterant determined to contain iodate reduced THC-COOH concentrations by 65% and the concentrations of 6-acetylmorphine, morphine, oxycodone, oxymorphone, hydrocodone and hydromorphone by 6–27%. Another adulterant determined to contain nitrite reduced THC-COOH concentrations by 22%, while the third did not affect drug screening or confirmatory testing. Both active adulterants could be identified through positive oxidant screens as well as through signal suppression in cloned enzyme donor immunoassay (CEDIA). The synthetic urines could not be identified either through traditional SVT or by the AdultaCheck10 dipstick. The Synthetic UrineCheck dipstick produced a difference in response between the authentic urine specimen and the synthetic urine samples, but the difference was small and difficult to observe. While most synthetic urines now contain uric acid, magnesium and caffeine, the results indicated that a biomarker panel including endogenous and exogenous markers of authentic urine performed well and clearly demonstrated the absence of biomarkers in the synthetic urines. The SVT assay also offers potential targets for future screening assays.
A Comparison of High Drug Concentrations in Impaired Driving and Postmortem Casework in Harris County, TX
Authors: Dempsey Sara K , Gray Teresa R , Kelly Anna T , Stout Peter , Lee Dayong
Published: May 2022

Drug-impaired driving is a growing public safety issue. Addressing impairment due to drugs other than ethanol can be challenging for forensic toxicologists as many factors need to be considered including the type of drug(s), drug−drug interaction, the dose(s) and the individual’s physiological condition and drug use history. Interpretation of blood drug test results is additionally difficult as drug concentrations in impaired driving cases may overlap levels typically viewed as toxic. This study compares blood concentrations of drugs in impaired driving cases to those in postmortem cases in Houston, TX, from 2014 to 2020. Blood drug concentrations from driving while intoxicated (DWI) or driving under the influence of drugs (DUID) cases submitted to Houston Forensic Science Center (HFSC) and Harris County Institute of Forensic Sciences (HCIFS) were compared to postmortem blood test results from HCIFS. Eight DWI/DUID cases had drugs that exceeded impaired driving concentrations reported in the literature. These drugs included fentanyl (220 ng/mL), oxycodone (680 ng/mL), hydrocodone (310 and 490 ng/mL), clonazepam (330 ng/mL), methamphetamine (3,500 and 7,100 ng/mL) and tetrahydrocannabinol (THC) (160 ng/mL). For oxycodone and hydrocodone, the presented DWI/DUID cases exceeded 91% and 96% of postmortem concentrations, respectively. The 7,100 ng/mL methamphetamine DWI/DUID result was greater than 98% of postmortem cases. The presented DWI/DUID concentrations were higher than all but one postmortem case for clonazepam and higher than all postmortem cases for THC. This study demonstrates that extremely high drug concentrations in DWI/DUID casework blur the line between therapeutic/recreational and toxic concentrations.
Palliative Care and Burn Care: Empirically Derived Referral Criteria
Authors: Grossoehme Daniel H , Shaner Valerie , Friebert Sarah , Brown Miraides , Steiner Stephanie , Khandelwal Anjay , Eickmeyer Shari W , Teo Esther , Brown Carrie , Lou Richard
Published: May 2022

Burns frequently require complex interdisciplinary care. Specialist palliative care (PC) minimizes suffering, aids in decision making, and provides family support in addition to end-of-life care. Specialist PC is a limited resource, best conserved by identifying persons most likely to benefit from a PC referral. Little guidance is available for clinicians on whether and when to refer to PC. This study’s purpose was to identify referral criteria using a mixed-methods approach. Data were examined for between-group differences using Fisher’s exact, chi-square, or Wilcoxon Rank Sum tests. Qualitative thematic analysis was used to analyze PC provider notes to describe interventions provided. These data formed initial referral criteria, which were reviewed by an expert panel. Significant between-group differences included dying in the burn center; whether multiple patients were transported to the burn center from one event; and ventilator days. Four themes emerged from qualitative analysis. These included managing physical aspects of care; clarifying goals of care; managing end-of-life care; and managing patient/family psychosocial distress. Expert panel input clarified referral criteria language and supplemented the proposed criteria. We present empirically derived referral criteria to guide burn providers in referring persons for specialist PC. Subsequent testing is required to determine their efficacy in improving patient/family outcomes.
Current treatment status of older patients with gynecological cancers
Authors: Yunokawa Mayu , Onda Takashi , Ishikawa Mitsuya , Yaegashi Nobuo , Kanao Hiroyuki
Published: May 2022

The percentage of older patients with gynecological malignancies has recently been on the rise. Although prospective studies focusing on the treatment of older patients have been conducted for ovarian cancer, mainly in Europe, there have been scarce literature on cervical and endometrial cancers, and information on their treatment is currently lacking. One of the characteristics of older patients is that not only their performance status but also other factors, such as physical, mental and social factors, cause a large variability, and individual differences in their response to treatments. One of the major issues in the treatment of older patients is how to objectively measure these individual differences and link them to the appropriate treatment selection. In this review, clinical evidence for the guided treatment of older patients with gynecological cancer will be reviewed.
Recurrent chylopericardium in a patient with history of left leg sarcoma
Authors: Aboukheir-Aboukheir Aihab , Lugo-Perez Paloma M , Colon-Melendez Eduardo , Gonzalez-Cancel Ivan , Boodoodingh-Casiano Dev R
Published: May 2022

Chylopericardium is a rare condition that is characterized by the presence of chyle in the pericardial space due to idiopathic (primary) or secondary causes. We present a 43-year-old female with hypothyroidism and left lower extremity sarcoma which were treated with resection and adjuvant chemoradiotherapy that was found with moderate pericardial effusion in surveillance tests. The patient was initially treated with tube thoracostomy and conservative management but presented with recurrence. Eventually, she was treated with left thoracotomy, ligation of the thoracic duct and pericardiectomy.
Functions and mechanisms of the Ubc13-UEV complex and lysine 63-linked polyubiquitination in plants
Authors: Yang Kun , Xiao Wei
Published: May 2022

Ubiquitination is one of the best-known post-translational modifications in eukaryotes, in which different linkage types of polyubiquitination result in different outputs of the target proteins. Distinct from the well-characterized K48-linked polyubiquitination that usually serves as a signal for degradation of the target protein, K63-linked polyubiquitination often requires a unique E2 heterodimer Ubc13-UEV and alters the target protein activity instead of marking it for degradation. This review focuses on recent advances on the roles of Ubc13-UEV-mediated K63-linked polyubiquitination in plant growth, development, and response to environmental stresses.
Relevance of Deployment Experience and Clinical Practice Characteristics on Military Critical Care Air Transport Team Readiness: A Study of Simulation Construct Validity
Authors: Brown Daniel J , Frasier Lane , Robinson F Eric , Cheney Mark , Davis William T , Salvator Ann , Andresen Mark , Proctor Melissa , Earnest Ryan , Pritts Timothy , Strilka Richard
Published: May 2022

Introduction

The Critical Care Air Transport Team (CCATT) Advanced course utilizes fully immersive high-fidelity simulations to train CCATT personnel and assess their readiness for deployment. This study aims to (1) determine whether these simulations correctly discriminate between students with previous deployment experience (“experienced”) and no deployment experience (“novices”) and (2) examine the effects of students’ clinical practice environment on their performance during training simulations.

Materials and Methods

Critical Care Air Transport Team Advanced student survey data and course status (pass/no pass) between March 2006 and April 2020 were analyzed. The data included students’ specialty, previous exposure to the CCATT Advanced course, previous CCATT deployment experience, years in clinical practice (<5, 5–15, and >15 years), and daily practice of critical care (yes/no), as well as a description of the students’ hospital to include the total number of hospital (<100, 100–200, 201–400, and >400) and intensive care unit (0, 1–10, 11–20, and >20) beds. Following descriptive analysis and comparative tests, multivariable regression was used to identify the predictors of passing the CCATT Advanced course.

Results

A total of 2,723 surveys were analyzed: 841 (31%) were physicians (MDs), 1,035 (38%) were registered nurses, and 847 (31%) were respiratory therapists (RTs); 641 (24%) of the students were repeating the course for sustainment training and 664 (24%) had previous deployment experience. Grouped by student specialty, the MDs’, registered nurses’, and RTs’ pass rates were 92.7%, 90.6%, and 85.6%, respectively. Multivariable regression results demonstrated that deployment experience was a robust predictor of passing. In addition, the >15 years in practice group had a 47% decrease in the odds of passing as compared to the 5 to 15 years in practice group. Finally, using MDs as the reference, the RTs had a 61% decrease in their odds of passing. The daily practice of critical care provided a borderline but nonsignificant passing advantage, whereas previous CCATT course exposure had no effect.

Conclusion

Our primary result was that the CCATT Advanced simulations that are used to evaluate whether the students are mission ready successfully differentiated “novice” from “experienced” students; this is consistent with valid simulation constructs. Finally, novice CCATT students do not sustain their readiness skills during the period between mandated refresher training.
Shiitake Dermatitis and Potential Implications for Military Readiness
Authors: Eubanks Bianca N , Linabury John F , Kumetz Erik A
Published: May 2022

Shiitake flagellate dermatitis is an intensely pruritic erythematous or violaceous eruption marked by “whip-like” linear streaks consisting of papules or plaques following the ingestion of undercooked shiitake mushrooms (Lentinula edodes). Most commonly localized on the trunk and upper limbs, the characteristic pattern of the rash is associated with the consumption of lentinan, a thermolabile toxin found within the mushroom, as well as a broad range of other dermatological conditions, including dermatomyositis, adult-onset Still’s disease, and reactions to medications such as bleomycin. In this case report, we present a 24year-old active duty service member who presented to the clinic for the evaluation of a flagellate erythematous eruption on his abdomen, back, and extremities. As U.S. forces pivot to operating in austere and resource-limited settings in the Pacific, recognizing the spectrum of diagnoses encompassed by flagellate erythema is important for maintaining operational readiness and differentiating self-limited cutaneous manifestations from more serious underlying conditions associated with this finding.
tRForest: a novel random forest-based algorithm for tRNA-derived fragment target prediction
Authors: Parikh Rohan , Wilson Briana , Marrah Laine , Su Zhangli , Saha Shekhar , Kumar Pankaj , Huang Fenix , Dutta Anindya
Published: May 2022

tRNA fragments (tRFs) are small RNAs comparable to the size and function of miRNAs. tRFs are generally Dicer independent, are found associated with Ago, and can repress expression of genes post-transcriptionally. Given that this expands the repertoire of small RNAs capable of post-transcriptional gene expression, it is important to predict tRF targets with confidence. Some attempts have been made to predict tRF targets, but are limited in the scope of tRF classes used in prediction or limited in feature selection. We hypothesized that established miRNA target prediction features applied to tRFs through a random forest machine learning algorithm will immensely improve tRF target prediction. Using this approach, we show significant improvements in tRF target prediction for all classes of tRFs and validate our predictions in two independent cell lines. Finally, Gene Ontology analysis suggests that among the tRFs conserved between mice and humans, the predicted targets are enriched significantly in neuronal function, and we show this specifically for tRF-3009a. These improvements to tRF target prediction further our understanding of tRF function broadly across species and provide avenues for testing novel roles for tRFs in biology. We have created a publicly available website for the targets of tRFs predicted by tRForest.
The Ramp Atlas: facilitating tissue and cell-specific ramp sequence analyses through an intuitive web interface
Authors: Miller Justin B , Meurs Taylor E , Hodgman Matthew W , Song Benjamin , Miller Kyle N , Ebbert Mark T W , Kauwe John S K , Ridge Perry G
Published: May 2022

Ramp sequences occur when the average translational efficiency of codons near the 5′ end of highly expressed genes is significantly lower than the rest of the gene sequence, which counterintuitively increases translational efficiency by decreasing downstream ribosomal collisions. Here, we show that the relative codon adaptiveness within different tissues changes the existence of a ramp sequence without altering the underlying genetic code. We present the first comprehensive analysis of tissue and cell type-specific ramp sequences and report 3108 genes with ramp sequences that change between tissues and cell types, which corresponds with increased gene expression within those tissues and cells. The Ramp Atlas (https://ramps.byu.edu/) allows researchers to query precomputed ramp sequences in 18 388 genes across 62 tissues and 66 cell types and calculate tissue-specific ramp sequences from user-uploaded FASTA files through an intuitive web interface. We used The Ramp Atlas to identify seven SARS-CoV-2 genes and seven human SARS-CoV-2 entry factor genes with tissue-specific ramp sequences that may help explain viral proliferation within those tissues. We anticipate that The Ramp Atlas will facilitate personalized and creative tissue-specific ramp sequence analyses for both human and viral genes that will increase our ability to utilize this often-overlooked regulatory region.
Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: A multicenter, open-label, phase Ib/II trial
Authors: de la Fuente Macarena I , Colman Howard , Rosenthal Mark , Van Tine Brian A , Levacic Danijela , Walbert Tobias , Gan Hui K , Vieito Maria , Milhem Mohammed M , Lipford Kathryn , Forsyth Sanjeev , Guichard Sylvie M , Mikhailov Yelena , Sedkov Alexander , Brevard Julie , Kelly Patrick F , Mohamed Hesham , Monga Varun
Published: May 2022

Background

Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation.

Methods

This was an open-label, multicenter, nonrandomized, phase Ib/II clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1R132X-mutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase I and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase II.

Results

Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase II dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each).

Conclusions

Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population.
Comparative single-cell RNA-sequencing profiling of BMP4-treated primary glioma cultures reveals therapeutic markers
Authors: Verploegh Iris S C , Conidi Andrea , Brouwer Rutger W W , Balcioglu Hayri E , Karras Panagiotis , Makhzami Samira , Korporaal Anne , Marine Jean-Christophe , Lamfers Martine , Van IJcken Wilfred F J , Leenstra Sieger , Huylebroeck Danny
Published: May 2022

Background

Glioblastoma (GBM) is the most aggressive primary brain tumor. Its cellular composition is very heterogeneous, with cells exhibiting stem-cell characteristics (GSCs) that co-determine therapy resistance and tumor recurrence. Bone Morphogenetic Protein (BMP)-4 promotes astroglial and suppresses oligodendrocyte differentiation in GSCs, processes associated with superior patient prognosis. We characterized variability in cell viability of patient-derived GBM cultures in response to BMP4 and, based on single-cell transcriptome profiling, propose predictive positive and early-response markers for sensitivity to BMP4.

Methods

Cell viability was assessed in 17 BMP4-treated patient-derived GBM cultures. In two cultures, one highly-sensitive to BMP4 (high therapeutic efficacy) and one with low-sensitivity, response to treatment with BMP4 was characterized. We applied single-cell RNA-sequencing, analyzed the relative abundance of cell clusters, searched for and identified the aforementioned two marker types, and validated these results in all 17 cultures.

Results

High variation in cell viability was observed after treatment with BMP4. In three cultures with highest sensitivity for BMP4, a substantial new cell subpopulation formed. These cells displayed decreased cell proliferation and increased apoptosis. Neuronal differentiation was reduced most in cultures with little sensitivity for BMP4. OLIG1/2 levels were found predictive for high sensitivity to BMP4. Activation of ribosomal translation (RPL27A, RPS27) was up-regulated within one day in cultures that were very sensitive to BMP4.

Conclusion

The changes in composition of patient-derived GBM cultures obtained after treatment with BMP4 correlate with treatment efficacy. OLIG1/2 expression can predict this efficacy, and upregulation of RPL27A and RPS27 are useful early-response markers.
Sexual dimorphism of the immune system predicts clinical outcomes in glioblastoma immunotherapy: A systematic review and meta-analysis
Authors: Shireman Jack M , Ammanuel Simon , Eickhoff Jens C , Dey Mahua
Published: May 2022

Background

Biological differences based on sex have been documented throughout the scientific literature. Glioblastoma (GBM), the most common primary malignant brain tumor in adults, has a male sex incidence bias, however, no clinical trial data examining differential effects of treatment between sexes currently exists.

Method

We analyzed genomic data, as well as clinical trials, to delineate the effect of sex on the immune system and GBM outcome following immunotherapy.

Results

We found that in general females possess enriched immunological signatures on gene set enrichment analysis, which also stratified patient survival when delineated by sex. Female GBM patients treated with immunotherapy had a statistically significant survival advantage at the 1-year compared to males (relative risk [RR] = 1.15; P = .0241). This effect was even more pronounced in vaccine-based immunotherapy (RR = 1.29; P = .0158).

Conclusions

Our study shows a meaningful difference in the immunobiology between males and females that also influences the overall response to immunotherapy in the setting of GBM.
Coordination of hydraulic thresholds across roots, stems, and leaves of two co-occurring mangrove species
Authors: Jiang (蒋国凤) Guo-Feng , Li (李溯源) Su-Yuan , Li (李艺蝉) Yi-Chan , Roddy Adam B
Published: May 2022

Mangroves are frequently inundated with saline water and have evolved different anatomical and physiological mechanisms to filter and, in some species, excrete excess salt from the water they take up. Because salts impose osmotic stress, interspecific differences in salt tolerance and salt management strategy may influence physiological responses to drought throughout the entire plant hydraulic pathway, from roots to leaves. Here, we characterized embolism vulnerability simultaneously in leaves, stems, and roots of seedlings of two mangrove species (Avicennia marina and Bruguiera gymnorrhiza) along with turgor-loss points in roots and leaves and xylem anatomical traits. In both species, the water potentials causing 50% of total embolism were less negative in roots and leaves than they were in stems, but the water potentials causing incipient embolism (5%) were similar in roots, stems, and leaves. Stomatal closure in leaves and turgor loss in both leaves and roots occurred at water potentials only slightly less negative than the water potentials causing 5% of total embolism. Xylem anatomical traits were unrelated to vulnerability to embolism. Vulnerability segmentation may be important in limiting embolism spread into stems from more vulnerable roots and leaves. Interspecific differences in salt tolerance affected hydraulic traits from roots to leaves: the salt-secretor A. marina lost turgor at more negative water potentials and had more embolism-resistant xylem than the salt-excluder B. gymnorrhiza. Characterizing physiological thresholds of roots may help to explain recent mangrove mortality after drought and extended saltwater inundation.
Regulating Family Law in Federations: The Impact of De/Centralization, Religion, and International Treaties on Abortion and Child Marriage Policies
Authors: Vickers Jill
Published: May 2022

There has been little study of the effects of federalism on the regulation and reform of family law (FL). This article addresses that gap by identifying variables that affect two aspects of FL: child marriage and abortion. The underlying research question is what conditions make it easier to reform discriminatory FL in one federation compared to another. FL involves multiple rules governing marriage, divorce, custody, adoption, and often inheritance and family property use. Many gender scholars also include reproductive self-determination, specifically abortion. FL rules also have multiple elements: e.g., marriage regulations govern age, “race,” sex, domicile, etc., that often differ across constituent units. The main variable examined is the extent of centralization, because the dominant pattern of regulation in these cases is centralized legislation and decentralized implementation. The other two variables explored are religion and international norms-building and their effects on FL regulation and reform.
Bank Bonus Pay as a Risk Sharing Contract
Authors: Efing Matthias , Hau Harald , Kampkötter Patrick , Rochet Jean-Charles
Published: May 2022

We argue that risk sharing motivates the bankwide structure of bonus pay. In the presence of financial frictions that make external financing costly, the optimal contract between shareholders and employees involves some degree of risk sharing whereby bonus pay partially absorbs negative earnings shocks. Using payroll data for $1.26$ million employee-years in all functional divisions of Austrian, German, and Swiss banks, we uncover several empirical patterns in bonus pay that are difficult to rationalize exclusively with incentive theories of bonus pay but that support an important risk sharing motive.

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.