bluuebunny/crossref_metadata_2025 huggingface dataset:
The evening light environment in hospitals can be designed to produce less disruptive effects on the circadian system and improve sleep
Authors: Vethe Daniel , Scott Jan , Engstrøm Morten , Salvesen Øyvind , Sand Trond , Olsen Alexander , Morken Gunnar , Heglum Hanne S , Kjørstad Kaia , Faaland Patrick M , Vestergaard Cecilie L , Langsrud Knut , Kallestad Håvard
Published: September 2020

Study Objectives

Blue-depleted lighting reduces the disruptive effects of evening artificial light on the circadian system in laboratory experiments, but this has not yet been shown in naturalistic settings. The aim of the current study was to test the effects of residing in an evening blue-depleted light environment on melatonin levels, sleep, neurocognitive arousal, sleepiness, and potential side effects.

Methods

The study was undertaken in a new psychiatric hospital unit where dynamic light sources were installed. All light sources in all rooms were blue-depleted in one half of the unit between 06:30 pm and 07:00 am (melanopic lux range: 7–21, melanopic equivalent daylight illuminance [M-EDI] range: 6–19, photopic lux range: 55–124), whereas the other had standard lighting (melanopic lux range: 30–70, M-EDI range: 27–63, photopic lux range: 64–136), but was otherwise identical. A total of 12 healthy adults resided for 5 days in each light environment (LE) in a randomized cross-over trial.

Results

Melatonin levels were less suppressed in the blue-depleted LE (15%) compared with the normal LE (45%; p = 0.011). Dim light melatonin onset was phase-advanced more (1:20 h) after residing in the blue-depleted LE than after the normal LE (0:46 h; p = 0.008). Total sleep time was 8.1 min longer (p = 0.032), rapid eye movement sleep 13.9 min longer (p < 0.001), and neurocognitive arousal was lower (p = 0.042) in the blue-depleted LE. There were no significant differences in subjective sleepiness (p = 0.16) or side effects (p = 0.09).

Conclusions

It is possible to create an evening LE that has an impact on the circadian system and sleep without serious side effects. This demonstrates the feasibility and potential benefits of designing buildings or hospital units according to chronobiological principles and provide a basis for studies in both nonclinical and clinical populations.
41st Annual North American Meeting of the Society for Medical Decision Making; October 21, 2019; Portland, Oregon. Keynote Address: The More Who Die, the Less We Care: Confronting the Deadly Arithmetic of Compassion
Authors: Slovic Paul
Published: September 2020

(Abstracted from MDM Policy Pract 2020;5(1):2381468320914310. doi: 10.1177/2381468320914310)

Dr Slovic, a psychologist at the University of Oregon, has devoted his research career to this topic. He is a member of the National Academy of Arts and Sciences.
Neutrophilic Infiltrates in Panniculitis: Comprehensive Review and Diagnostic Algorithm Proposal
Authors: Llamas-Velasco Mar , Fraga Javier , Sánchez-Schmidt Júlia-María , Fernández-Figueras Maite , Gallardo Fernando , Rütten Arno , Kempf Werner
Published: September 2020

Neutrophilic infiltrates in panniculitis can be seen in different clinical–pathological entities. There are a “mostly neutrophilic inflammatory infiltrate” in some entities classically defined as neutrophilic panniculitis and already included in algorithms, such as enzymatic panniculitis, infective and factitial ones, erythema induratum, or subcutaneous Sweet syndrome, but there are also other panniculitis where neutrophils are frequently observed such as panniculitis associated with inflammatory bowel disease or rheumatoid arthritis, or drug-induced panniculitis associated with BRAF inhibitors, and finally, some panniculitis are better classified in other panniculitides groups but may present with neutrophil-rich variants, such as the neutrophil-rich subcutaneous fat necrosis of the newborn. We review the main clinical and histopathological features of most of these panniculitides and construct a diagnostic algorithm including these diseases.
Oseltamivir—Current Dosing Recommendations Reduce the Therapeutic Benefit in Patients With Mild to Moderate Renal Function and/or Large Body Mass: A Review of the Literature With Recommendations to Optimize Dosing, Including the Use of Therapeutic Drug Monitoring
Authors: Jones Terry E.
Published: September 2020

Purpose:

Oseltamivir is indicated for the treatment and prophylaxis of influenza infections. Achieving therapeutic concentrations EARLY in the course of the infection impacts greatly on the magnitude of benefit. Oseltamivir is renally cleared and dose reductions are advised for patients with renal impairment. The purpose of this review was to determine whether these dose reductions facilitate the early attainment of therapeutic concentrations. The review also examined the effect of body mass on the same outcome.

Method:

Oseltamivir is administered as a prodrug and converted to the active carboxylate moiety in the liver. Published articles that included oseltamivir carboxylate (OC) pharmacokinetics in patients with renal impairment and those with large body mass were reviewed. Concentrations of OC achieved in the first 24 hours were compared with those from patients with normal renal function and body mass.

Results:

Studies that informed dosage regimens for patients with mild to moderately impaired renal function focused on attaining steady-state concentrations similar to those observed in patients with normal renal function. They overlooked the importance of achieving therapeutic concentrations EARLY in the course of the infection. As a result, many patients will not attain therapeutic concentrations until too late in the infection. This is also true for patients with a large body mass.

Conclusions:

Current dosing advice for oseltamivir in patients with mild to moderate renal impairment and those with a larger body mass are likely to reduce (or even negate) its efficacy. The first dose should be 75 mg for patients with normal body mass and proportionately larger when body mass is larger. Subsequent doses should be reduced in proportion to the degree of renal impairment. Timely therapeutic drug monitoring can provide invaluable dosing (and other) information to the clinician treating patients with influenza and could improve patient outcomes.
Body Dysmorphic Disorder in the Perspective of the Alternative DSM-5 Model for Personality Disorder
Authors: Somma Antonella , Krueger Robert F. , Markon Kristian E. , Gialdi Giulia , Frau Claudia , Boscaro Linda , Liberatore Giada , Fossati Andrea
Published: September 2020

To evaluate the relationships between body dysmorphic disorder (BDD) and Alternative DSM-5 Model for Personality Disorder (AMPD) criterion A and dysfunctional personality trait (i.e., criterion B) measures, 420 Italian community-dwelling women were administered three measures of BDD (i.e., the Body Dysmorphic Disorder Questionnaire, the Body Dysmorphic Disorder–Dimensional Scale, and the Appearance Anxiety Inventory), as well as the Level of Personality Functioning Scale–Brief Form (LPFS-BF) and the Personality Inventory for DSM-5–Short Form (PID-5-SF). The three BDD measures showed substantial convergent validity correlations and could be reliably cumulated to obtain the BDD Cumulative Index (BDDCI). Several significant, nonnegligible correlations were observed between the BDDCI as well as the LPFS-BF scale scores and PID-5-SF personality trait scale scores. Relative importance weight analysis results showed that LPFS-BF scale scores and PID-5-SF trait scale scores were substantial predictors of the BDDCI scores (R
2 = 0.42, f
2 = 0.72). In particular, AMPD criterion A impairment in self-functioning and AMPD criterion B depressivity, anhedonia, perseveration, separation insecurity, and cognitive and perceptual dysregulation were core components of the dysfunctional personality profile associated with BDD.
Screening for Microscopic Hematuria in a Urogynecologic Population
Authors: Dune Tanaka J. , Kliethermes Stephanie , Mueller Elizabeth R. , Fitzgerald Colleen M. , Brubaker Linda , Brincat Cynthia A.
Published: September 2020

(Abstracted from Female Pelvic Med Reconstr Surg 2020;26:382–386)

Microscopic hematuria (MH) is often used in the initial evaluation to determine if urinary cancer is present. Microscopic hematuria is often defined as the finding of greater than or equal to 3 red blood cells per high-power field (RBCs/HPF) on urinalysis with microscopy, but there is no broad consensus.
Opportunistic Salpingectomy at the Time of Urogynecologic Surgery: Why, in Whom, and How?
Authors: Catanzarite Tatiana , Eskander Ramez N.
Published: September 2020

(Abstracted from Female Pelvic Med Reconstr Surg 2020;26:401–406)

Worldwide, ovarian cancer is the most lethal gynecologic malignancy, accounting for more than 184,000 deaths annually. Ninety percent of ovarian cancer cases are epithelial ovarian cancers, and 60% to 80% of epithelial ovarian cancers are high-grade serous carcinoma (HGSC).
Predictors of Opioid Consumption in Immediate, Implant-Based Breast Reconstruction
Authors: Egan Katie G. , De Souza Michelle , Muenks Elizabeth , Nazir Niaman , Korentager Richard
Published: September 2020

Background:

Current rates of opioid prescribing have deleterious consequences on both patient and societal levels. This study aims to evaluate responsible opioid prescribing and predictors of opioid consumption in immediate implant-based breast reconstruction.

Methods:

Patients undergoing consultation for immediate, implant-based breast reconstruction were enrolled in a prospective, cohort survey study. A survey was administered at the preoperative and postoperative appointment to collect data on pain expectations and opioid use. A medical record review was performed.

Results:

Of 100 enrolled patients, 97 (97.0 percent) underwent surgery and 85 (85.0 percent) completed the postoperative survey. Preoperatively, 27 patients (27.0 percent) had a history of a chronic pain syndrome, 34 (34.0 percent) had a history of a mental health comorbidity, and nine (9.0 percent) had a history of active preoperative opioid use. A total of 85 tissue expander (87.6 percent) and 12 direct-to-implant (12.4 percent) reconstructions were completed. Patients were prescribed an average of 36.0 5-mg oxycodone tablets postoperatively. Patients reported consuming an average of 20.6 tablets, or 57.0 percent of the average prescription amount. The majority of patients (75.3 percent) reported taking an opioid less than once per day at the time of survey completion, and 24 patients (28.2 percent) reported that they did not use any opioids postoperatively. Preoperative opioid use (p = 0.004), inpatient opioid consumption (p < 0.0001), and patient-reported anxiety related to pain control (p < 0.05) were predictors of opioid consumption.

Conclusions:

Patients undergoing mastectomy and implant-based breast reconstruction are prescribed nearly twice as many opioid tablets as consumed, and one in three patients report not using any opioids postoperatively. Clinical factors may help guide prescribing practices.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, III.
Safety in Female Genital Plastic Surgery
Authors: Furnas Heather J. , Graw Grace J. , Cho Min-Jeong , Othman Sammy , Graw Bradley , Percec Ivona
Published: September 2020

Learning Objectives:

After studying this article, participants should be able to: (1) Identify the most appropriate type of anesthesia for the female genital plastic surgical patient and minimize risks of nerve injury and thromboembolic event through proper preoperative evaluation and knowledge of positioning. (2) Define the vulvovaginal anatomy, including common variants, and assess vulvovaginal tissues after childbirth and menopause. (3) Apply surgical techniques to minimize complications in female genital plastic surgery. (4) Classify the types of female genital mutilation/cutting and design methods of reconstruction after female genital mutilation/cutting.

Female genital plastic surgery is growing in popularity and in numbers performed. This CME article covers several aspects of safety in the performance of these procedures. In choosing the best candidates, the impact of patient motivation, body mass index, parity, menopause and estrogen therapy is discussed. Under anesthesia, consideration for the risks associated with the dorsal lithotomy position and avoidance of compartment syndrome, nerve injury, deep venous thromboses, and pulmonary embolus are covered. Anatomical variations are discussed, as is the impact of childbirth on tissues and muscles. Surgical safety, avoidance of complications, and postoperative care of a variety of vulvovaginal procedures are discussed. Videos showing anatomical variations and surgical techniques of the most common female genital procedures with recommendations to reduce the complication rate are included in the article. Finally, female genital mutilation/cutting is defined, and treatment, avoidance of complications, and postoperative care are discussed.
Differentiating Nonischemic Dilated Cardiomyopathy With Incidental Infarction From Ischemic Cardiomyopathy by Geometric Indices Derived From Cardiovascular Magnetic Resonance
Authors: Wang Xinyu , Costello Benedict T. , Papapostolou Stavroula , O’Brien Jessica , Taylor Andrew , Zhao Shihua
Published: September 2020

Purpose:

The purpose of this study was to differentiate nonischemic dilated cardiomyopathy with incidental myocardial infarction (NICM with incidental MI) from ischemic cardiomyopathy (ICM) by integrating left ventricular (LV) geometric indices and ischemic late gadolinium enhancement (LGE), obtained from cardiac magnetic resonance (CMR) imaging.

Materials and Methods:

All subjects were studied on a 1.5 Tesla magnetic resonance imaging scanner. All patients had an LV ejection fraction (LVEF) <50% with LV dilation. LV end-diastolic volume (LVEDV), LVEDV index (LVEDVi), LVEF, the number and distribution of ischemic LGE segments, and ratios of volumetric and functional indices to ischemic LGE segments were determined. Logistic regression was used to detect the independent predictor of ICM. Receiver operating characteristic analysis differentiated NICM with incidental MI from ICM.

Results:

Of a total of 63 patients enrolled, 45 patients had ICM, and 18 patients had NICM with incidental MI. Both groups had similar LVEF. Compared with ICM, NICM with incidental MI had more LV dilation, whereas ICM had more ischemic LGE segments. A higher number of ischamic LGE segments remained an independent predictor of ICM (odds ratio: 18.2, 95% confidence interval: 1.64-201.34, P=0.018). The optimal cut-off value for detecting NICM with incidental MI is the ratio of LVEDVi to the number of ischemic LGE segments over 25 mL/m2/segment (sensitivity 100%, specificity 91%, P<0.0001).

Conclusion:

Patients with NICM with incidental MI can be reliably distinguished from ICM using the ratio of LVEDVi divided by the number of ischemic LGE segments. This technique may improve diagnosis and help aid management of patients with cardiomyopathy and coexistent coronary artery disease.
Treat or Wait? Natural Perioperative Course of Overactive Bladder Symptoms at the Time of Midurethral Sling Placement
Authors: Heliker Bhumy Davé , Kenton Kimberly , Komar Alix , Mueller Margaret G. , Lewicky-Gaupp Christina , Abernethy Melinda
Published: September 2020

Objective

The aims of this study were to describe the perioperative course of untreated overactive bladder (OAB) (urinary frequency [UF] and urgency urinary incontinence [UUI]) before and after isolated retropubic midurethral sling (MUS) and to identify the time point for spontaneous OAB symptom improvement in the most patients.

Methods

This is a prospective cohort study of women undergoing an isolated MUS. Women completed the Urogenital Distress Inventory 6 and Incontinence Impact Questionnaire 7 preoperatively and weekly for 13 weeks postoperatively. Bothersome UF and UUI were defined as a response of “moderately” or “greatly” bothered on questions 1 and 2 of the Urogenital Distress Inventory. The treatment for OAB was deferred until 13 weeks after surgery.

Results

Fifty-four women were included with a mean ± SD age of 48 ± 9 years. Preoperatively, 41% of women reported both bothersome UF and UUI. Six weeks after surgery, only 15% and 6% reported bothersome UF and UUI (P < 0.001 and P < 0.001, respectively). Between 6 and 13 weeks, percentages of bothersome symptoms remained low (11.7% UF and 5.8% UUI). In addition, the impact of these urinary symptoms on activities, relationships, and feelings became consistently negligible (Incontinence Impact Questionnaire 7 median score <1) at 5 weeks postoperatively. Only 3 women desired treatment for UUI after the study period.

Conclusions

Overactive bladder is common before and immediately after MUS. However, the majority of patients have spontaneous symptom resolution by 6 weeks after surgery; it may be reasonable to discontinue preoperatively initiated overactive bladder treatment or defer starting treatment until this time point.
Foot Problems in Patients in Acute Care
Authors: Abu-Qamar Ma'en Zaid , Whitehead Lisa , Towell-Barnard Amanda , Kemp Vivien
Published: September 2020

PURPOSE:

Determine the prevalence of foot problems in an inpatient population and to describe demographic data, comorbid conditions, and type of footwear worn.

DESIGN:

Observational point-prevalence cross-sectional design.

SUBJECTS AND SETTING:

The study setting was a 722-bed licensed hospital in Western Australia. A convenience sampling was used to include adults hospitalized in the study setting during the period of data collection.

METHODS:

A subset of foot questions, guided by a literature review, and input from foot, wound, diabetes, and psychometric researchers and clinicians, was incorporated into the hospital point-prevalence survey conducted annually for nursing safety and quality. Trained nurses collected data during the 1-day survey. Data were analyzed using descriptive statistics and 2-tailed tests; associations between study variables were analyzed.

RESULTS:

Two hundred twenty-one patients participated in the survey; a majority (n = 193, 87%) self-reported at least 1 foot problem. More than half (n = 124) reported 3 foot problems and nearly one-third (n = 67) had 5 or more foot problems. Thick nails, damaged nails, and calluses and corns were the most frequently occurring foot problems. Older participants were more likely to have certain foot problems such as calluses and thick nails. Eleven (5%) participants were admitted to the hospital for a foot-related condition.

CONCLUSION:

The majority of foot problems in our study were found to be minor and not the primary admitting diagnosis. However, even minor foot problems can pose a risk of worsening, especially in high-risk populations such as those with diabetes. Thus, detection is critical in overall patient assessment, and nurses play a critical role in assessment and management of minor foot problems through the delivery of skin and nail care and through collaboration with other professionals who provide specialized foot care.
Cytokine storm and COVID-19: a chronicle of pro-inflammatory cytokines
Authors: Fara Antonella , Mitrev Zan , Rosalia Rodney Alexander , Assas Bakri M.
Published: September 2020

Coronavirus disease 2019 (COVID-19) has swept the world, unlike any other pandemic in the last 50 years. Our understanding of the disease has evolved rapidly since the outbreak; disease prognosis is influenced mainly by multi-organ involvement. Acute respiratory distress syndrome, heart failure, renal failure, liver damage, shock and multi-organ failure are strongly associated with morbidity and mortality. The COVID-19 disease pathology is plausibly linked to the hyperinflammatory response of the body characterized by pathological cytokine levels. The term ‘cytokine storm syndrome’ is perhaps one of the critical hallmarks of COVID-19 disease severity. In this review, we highlight prominent cytokine families and their potential role in COVID-19, the type I and II interferons, tumour necrosis factor and members of the Interleukin family. We address various changes in cellular components of the immune response corroborating with changes in cytokine levels while discussing cytokine sources and biological functions. Finally, we discuss in brief potential therapies attempting to modulate the cytokine storm.
Molecular mechanisms behind mRNA localization in axons
Authors: Turner-Bridger Benita , Caterino Cinzia , Cioni Jean-Michel
Published: September 2020

Messenger RNA (mRNA) localization allows spatiotemporal regulation of the proteome at the subcellular level. This is observed in the axons of neurons, where mRNA localization is involved in regulating neuronal development and function by orchestrating rapid adaptive responses to extracellular cues and the maintenance of axonal homeostasis through local translation. Here, we provide an overview of the key findings that have broadened our knowledge regarding how specific mRNAs are trafficked and localize to axons. In particular, we review transcriptomic studies investigating mRNA content in axons and the molecular principles underpinning how these mRNAs arrived there, including cis-acting mRNA sequences and trans-acting proteins playing a role. Further, we discuss evidence that links defective axonal mRNA localization and pathological outcomes.
Quantification of lactoyl-CoA (lactyl-CoA) by liquid chromatography mass spectrometry in mammalian cells and tissues
Authors: Varner Erika L. , Trefely Sophie , Bartee David , von Krusenstiern Eliana , Izzo Luke , Bekeova Carmen , O'Connor Roddy S. , Seifert Erin L. , Wellen Kathryn E. , Meier Jordan L. , Snyder Nathaniel W.
Published: September 2020

Lysine lactoylation is a recently described protein post-translational modification (PTM). However, the biochemical pathways responsible for this acylation remain unclear. Two metabolite-dependent mechanisms have been proposed: enzymatic histone lysine lactoylation derived from lactoyl-coenzyme A (lactoyl-CoA, also termed lactyl-CoA), and non-enzymatic lysine lactoylation resulting from acyl-transfer via lactoyl-glutathione. While the former has precedent in the form of enzyme-catalysed lysine acylation, the lactoyl-CoA metabolite has not been previously quantified in mammalian systems. Here, we use liquid chromatography–high-resolution mass spectrometry (LC-HRMS) together with a synthetic standard to detect and validate the presence of lactoyl-CoA in cell and tissue samples. Conducting a retrospective analysis of data from previously analysed samples revealed the presence of lactoyl-CoA in diverse cell and tissue contexts. In addition, we describe a biosynthetic route to generate
13
C
3
15
N
1
-isotopically labelled lactoyl-CoA, providing a co-eluting internal standard for analysis of this metabolite. We estimate lactoyl-CoA concentrations of 1.14 × 10
−8
pmol per cell in cell culture and 0.0172 pmol mg
−1
tissue wet weight in mouse heart. These levels are similar to crotonyl-CoA, but between 20 and 350 times lower than predominant acyl-CoAs such as acetyl-, propionyl- and succinyl-CoA. Overall our studies provide the first quantitative measurements of lactoyl-CoA in metazoans, and provide a methodological foundation for the interrogation of this novel metabolite in biology and disease.
Trends in scientific research on Environmental Education: A scientometric review
Authors: Gomes Leonardo Fernandes , Pereira Hasley Rodrigo
Published: September 2020

Given the need to understand the current approaches to Environmental Education (EE) in the world, we answer the following questions: (i) Have the studies directed to EE received attention from the scientific community? (ii) what are the trends in EE publications? In the past years, there has been an increase in the number of publications on EE. Brazil stood out in the number of publications, reflecting the concern of Brazilian researchers to promote sustainability and biodiversity maintenance. As for the approaches, the studies are broad, ranging from the influence of policies on environmental protection to the importance of reflection at a global level, proposing international agreements. However, regarding the EE application, given the multiple existing currents, it is worth emphasizing the importance of the teaching-learning process to take place critically so that there is no favoring of the contents promoted and supported by a hegemonic class.
Force generation by protein-DNA co-condensation
Authors: Quail Thomas , Golfier Stefan , Elsner Maria , Ishihara Keisuke , Murugesan Vasanthanarayan , Renger Roman , Jülicher Frank , Brugués Jan
Published: September 2020

Interactions between liquids and surfaces generate forces1,2that are crucial for many processes in biology, physics, and engineering, including the motion of insects on the surface of water3, modulation of the material properties of spider silk4, and self-assembly of microstructures5. Recent studies have shown that cells assemble biomolecular condensates via phase separation6. In the nucleus, these condensates are thought to drive transcription7, heterochromatin formation8, nucleolus assembly9, and DNA repair10. Here, we show that the interaction between liquid-like condensates and DNA generates forces that might play a role in bringing distant regulatory elements of DNA together, a key step in transcriptional regulation. We combine quantitative microscopy,in vitroreconstitution, optical tweezers, and theory to show that the transcription factor FoxA1 mediates the condensation of a DNA-protein phase via a mesoscopic first- order phase transition. After nucleation, co-condensation forces drive growth of this phase by pulling non-condensed DNA. Altering the tension on the DNA strand enlarges or dissolves the condensates, revealing their mechanosensitive nature. These findings show that DNA condensation mediated by transcription factors could bring distant regions of DNA in close proximity, suggesting that this physical mechanism is a possible general regulatory principle for chromatin organization that may be relevantin vivo.
MetaFusion: A high-confidence metacaller for filtering and prioritizing RNA-seq gene fusion candidates
Authors: Apostolides Michael , Jiang Yue , Husić Mia , Siddaway Robert , Hawkins Cynthia , Turinsky Andrei L. , Brudno Michael , Ramani Arun K.
Published: September 2020

Motivation

Current fusion detection tools use diverse calling approaches and provide varying results, making selection of the appropriate tool challenging. Ensemble fusion calling techniques appear promising; however, current options have limited accessibility and function.

Results

MetaFusion is a flexible meta-calling tool that amalgamates outputs from any number of fusion callers. Individual caller results are standardized by conversion into the new file type Common Fusion Format (CFF). Calls are annotated, merged using graph clustering, filtered, and ranked to provide a final output of high confidence candidates. MetaFusion consistently achieves higher precision and recall than individual callers on real and simulated datasets, and reaches up to 100% precision, indicating that ensemble calling is imperative for high confidence results. MetaFusion uses FusionAnnotator to annotate calls with information from cancer fusion databases, and is provided with a benchmarking toolkit to calibrate new callers.

Availability

MetaFusion is freely available athttps://github.com/ccmbioinfo/MetaFusion

Contact

arun.ramani@sickkids.ca

Supplementary information

Supplementary data are available at Bioinformatics online.
Scalable Models of Antibody Evolution and Benchmarking of Clonal Tree Reconstruction Methods
Authors: Zhang Chao , Bzikadze Andrey V. , Safonova Yana , Mirarab Siavash
Published: September 2020

Abstract

Affinity maturation (AM) of antibodies through somatic hypermutations (SHMs) enables the immune system to evolve to recognize diverse pathogens. The accumulation of SHMs leads to the formation of clonal trees of antibodies produced by B cells that have evolved from a common naive B cell. Recent advances in high-throughput sequencing have enabled deep scans of antibody repertoires, paving the way for reconstructing clonal trees. However, it is not clear if clonal trees, which capture micro-evolutionary time scales, can be reconstructed using traditional phylogenetic reconstruction methods with adequate accuracy. In fact, several clonal tree reconstruction methods have been developed to fix supposed shortcomings of phylogenetic methods. Nevertheless, no consensus has been reached regarding the relative accuracy of these methods, partially because evaluation is challenging. Benchmarking the performance of existing methods and developing better methods would both benefit from realistic models of clonal tree evolution specifically designed for emulating B cell evolution. In this paper, we propose a model for modeling B cell clonal tree evolution and use this model to benchmark several existing clonal tree reconstruction methods. Our model, designed to be extensible, has several features: by evolving the clonal tree and sequences simultaneously, it allows modelling selective pressure due to changes in affinity binding; it enables scalable simulations of millions of cells; it enables several rounds of infection by an evolving pathogen; and, it models building of memory. In addition, we also suggest a set of metrics for comparing clonal trees and for measuring their properties. Our benchmarking results show that while maximum likelihood phylogenetic reconstruction methods can fail to capture key features of clonal tree expansion if applied naively, a very simple postprocessing of their results, where super short branches are contracted, leads to inferences that are better than alternative methods.
Orbitofrontal cortex and learning predictions of state transitions
Authors: Chan Stephanie C.Y. , Schuck Nicolas W. , Lopatina Nina , Schoenbaum Geoffrey , Niv Yael
Published: September 2020

Learning the transition structure of the environment – the probabilities of transitioning from one environmental state to another – is a key prerequisite for goal-directed planning and model-based decision making. To investigate the role of the orbitofrontal cortex (OFC) in goal-directed planning and decision making, we used fMRI to assess univariate and multivariate activity in the OFC while humans experienced state transitions that varied in degree of surprise. Converging with recent evidence, we found that OFC activity was related to greater learning about transition structure. However, the observed relationship was inconsistent with a straightforward interpretation of OFC activity as representing a state prediction error that would facilitate learning of transitions via error-correcting mechanisms. The state prediction error hypothesis predicts that OFC activity at the time of observing an outcome should increase expectation of that same observed outcome on subsequent trials. Instead, our results showed that OFC activity was associated with increased expectation of themore probableoutcome; that is, with more optimal predictions. These results suggest that the OFC is involved in updating or reinforcing a learned transition model on a trial-by-trial basis, specifically for the currently observed cue-outcome associations. Our findings add to the evidence of OFC involvement in learning state-to-state transition structure, while providing new constraints for algorithmic hypotheses regarding how these transitions are learned.

Significance Statement

The orbitofrontal cortex (OFC) has been implicated in model-based decision making—the kind of decisions that result from planning using an “environment model” of how current actions affect our future states. However, the widely suggested role of the OFC in representing expected values of future states is not sufficient to explain why the OFC would be critical for planning in particular. A new line of evidence implicates the OFC in learning about transition structure of the environment – a key component of the “environment model” used for planning. We investigate this function, adding to the growing literature on the role of the OFC in learning and decision making, while unveiling new questions about the algorithmic role of OFC in goal-directed planning.
Wheat transcriptome profiling reveals abscisic and gibberellic acid treatments regulate early-stage phytohormone defense signaling, cell wall fortification, and metabolic switches followingFusarium graminearum-challenge
Authors: Buhrow Leann M. , Liu Ziying , Cram Dustin , Sharma Tanya , Foroud Nora A. , Pan Youlian , Loewen Michele C.
Published: September 2020

Background

Application of the wheat phytohormones abscisic acid (ABA) or gibberellic acid (GA) affect Fusarium head blight (FHB) disease severity; however, the molecular underpinnings of the elicited phenotypes remain unclear. Herein, the transcriptomic responses of an FHB-susceptible wheat cultivar ‘Fielder’ were characterized upon treatment with ABA, an ABA receptor antagonist (AS6), or GA in the presence or absence ofFusarium graminearum(Fg) challenge.

Results

A total of 30,876 differentially expressed genes (DEGs) where identified in ‘Fielder’ (26,004) andFg(4,872).Fgchallenge alone resulted in the most substantial wheat DEGs contributing to 57.2% of the total transcriptomic variation. Using a combination of topology overlap and correlation analyses, 9,689Fg-related wheat DEGs were defined. Further enrichment analysis of the top 1% networked wheat DEGs identified critical expression changes within defense responses, cell structural metabolism, molecular transport, and membrane/lipid metabolism.Fg-challenged conditions also included the expression of a putativeFgABA-biosynthetic cytochrome P450 and repression of wheatFUS3for dysregulating ABA and GA crosstalk. ABA treatment alone elicited 4536 (32%) wheat DEGs common to those of theFg-challenge, andFg+ABA further enhanced 888 (12.5%) of them. These ABA elicited DEGs are involved in defense through both classical and non-classical phytohormone signaling and regulating cell wall structures including polyphenolic metabolism. Conversely,Fg+GA opposed 2239 (33%)Fg-elicited wheat DEGs, including modulating primary and secondary metabolism, defense responses, and flowering genes. ABA and jointly ABA⍰Fg⍰[Fg+ABA] treatments repressed, whileFg+GA induced an over-representation of wheat DEGs mapping to chromosome 6BL. Finally, compared toFg+ABA, co-application ofFg+AS6 did not antagonize ABA biosynthesis or signal but rather elicited antagonisticFg(557) and wheat (11) DEGs responses directly tied to stress responses, phytohormone transport, and FHB.

Conclusions

Comparative transcriptomics highlight the effects of wheat phytohormones on individual pathway and global metabolism simultaneously. Application of ABA may reduce FHB severity through misregulating defense mechanisms and cell wall fortification pathways. GA application may alter primary and secondary metabolism, creating a metabolic shift to ultimately reduce FHB severity. By comparing these findings to those previously reported for four additional plant genotypes, an additive model of the wheat-Fginteraction is proposed.
Individual Ants Do Not Show Active-rest Rhythms in Natural Nest Conditions
Authors: Fujioka Haruna , Abe Masato S. , Okada Yasukazu
Published: September 2020

Circadian rhythms, which respond to the day/night cycle on the earth, arise from the endogenous timekeeping system within organisms, called the biological clock. For accurate circadian rhythms, endogenous oscillations are synchronized to light and temperature. In social insects, both abiotic and biotic factors (i.e., social interactions) play a significant role in active/rest rhythm regulation. However, it is challenging to monitor individual active-rest rhythms in a colony because of the large group size and small body size. Therefore, it is unclear how social interactions coordinate each individual’s active/rest rhythms. This study developed an image-based tracking system using 2D barcodes for Diacamma sp. (a monomorphic ant) and measured the locomotor activities of all colony members under laboratory colony conditions. We also investigated the effect of broods on active/rest rhythms by removing all broods under colony conditions. Active/rest rhythms appeared only in solitary ants, not under colony conditions. In addition, arrhythmic active-rest rhythms were retained after brood removal. Therefore, a mixture of social interactions, not abiotic factors, induces the loss of active/rest rhythms. These results contribute to the knowledge of the diversity pattern of circadian rhythms in social insects.
Report 32: Age groups that sustain resurging COVID-19 epidemics in the United States
Authors: Monod Mélodie , Blenkinsop Alexandra , Xi Xiaoyue , Hebert Daniel , Bershan Sivan , Tietze Simon , Bradley Valerie C , Chen Yu , Coupland Helen , Filippi Sarah , Ish-Horowicz Jonathan , McManus Martin , Mellan Thomas , Gandy Axel , Hutchinson Michael , T Unwin H Juliette , C Vollmer Michaela A , Weber Sebastian , Zhu Harrison , Bezancon Anne , Ferguson Neil M , Mishra Swapnil , Flaxman Seth , Bhatt Samir , Ratmann Oliver
Published: September 2020

Following initial declines, in mid 2020, a resurgence in transmission of novel coronavirus disease (COVID-19) has occurred in the United States and parts of Europe. Despite the wide implementation of non-pharmaceutical interventions, it is still not known how they are impacted by changing contact patterns, age and other demographics. As COVID-19 disease control becomes more localised, understanding the age demographics driving transmission and how these impacts the loosening of interventions such as school reopening is crucial. Considering dynamics for the United States, we analyse aggregated, age-specific mobility trends from more than 10 million individuals and link these mechanistically to age-specific COVID-19 mortality data. In contrast to previous approaches, we link mobility to mortality via age specific contact patterns and use this rich relationship to reconstruct accurate transmission dynamics. Contrary to anecdotal evidence, we find little support for age-shifts in contact and transmission dynamics over time. We estimate that, until August, 63.4% [60.9%-65.5%] of SARS-CoV-2 infections in the United States originated from adults aged 20-49, while 1.2% [0.8%-1.8%] originated from children aged 0-9. In areas with continued, community-wide transmission, our transmission model predicts that re-opening kindergartens and elementary schools could facilitate spread and lead to additional COVID-19 attributable deaths over a 90-day period. These findings indicate that targeting interventions to adults aged 20-49 are an important consideration in halting resurgent epidemics and preventing COVID-19-attributable deaths when kindergartens and elementary schools reopen.

One sentence summary

Adults aged 20-49 are a main driver of the COVID-19 epidemic in the United States; yet, in areas with resurging epidemics, opening schools will lead to more COVID-19-attributable deaths, so more targeted interventions in the 20-49 age group could bring epidemics under control, avert deaths, and facilitate the safe reopening of schools.
Dimerization mechanism and structural features of human LI-cadherin
Authors: Yui Anna , Caaveiro Jose M. M. , Kuroda Daisuke , Nakakido Makoto , Nagatoishi Satoru , Goda Shuichiro , Maruno Takahiro , Uchiyama Susumu , Tsumoto Kouhei
Published: September 2020

LI-cadherin is a member of the cadherin superfamily, which encompasses a group of Ca2+-dependent cell adhesion proteins. The expression of LI-cadherin is observed on various types of cells in the human body, such as normal small intestine and colon cells, and gastric cancer cells. Because its expression is not observed on normal gastric cells, LI-cadherin is a promising target for gastric cancer imaging. However, since the cell adhesion mechanism of LI-cadherin has remained unknown, rational design of therapeutic molecules targeting this cadherin has been hampered. Here, we have studied the homodimerization mechanism of LI-cadherin. We report the crystal structure of the LI-cadherin EC1-4 homodimer. The EC1-4 homodimer exhibited a unique architecture different from that of other cadherins reported so far. The crystal structure also revealed that LI-cadherin possesses a noncanonical calcium ion-free linker between EC2 and EC3. Various biochemical techniques and molecular dynamics (MD) simulations were employed to elucidate the mechanism of homodimerization. We also showed that the formation of the homodimer observed by the crystal structure is necessary for LI-cadherin-dependent cell adhesion by performing cell aggregation assay.
Periplasmic Expression of SpyTagged Antibody Fragments Enables Rapid Modular Antibody Assembly
Authors: Hentrich Christian , Kellmann Sarah-Jane , Putyrski Mateusz , Cavada Manuel , Hanuschka Hanh , Knappik Achim , Ylera Francisco
Published: September 2020

Antibodies are essential tools in research and diagnostics. While antibody fragments can be rapidly produced inEscherichia coli, full-length antibodies with an Fc region or antibodies modified with probes are time and labor intensive in production.

SpyTag/SpyCatcher protein ligation technology could covalently attach such functionalities to antibody fragments equipped with a SpyTag. However, we found that the necessarily periplasmic expression of such antibody fragments inE. coliled to rapid cleavage of the SpyTag by proteases.

Here we show how this cleavage can be prevented, making the SpyTag technology accessible forE. coliproduced antibodies. We demonstrate a modular toolbox for rapid creation of synthetic IgGs, oligomerized antibodies, and antibodies with different tags or enzymatic functionalities and measure their performance in a variety of immunoassays. Furthermore, we demonstrate surface immobilization, high-throughput screening of antibody libraries, and rapid prototyping of antibodies based on modular antibody assembly.
MBG: Minimizer-based Sparse de Bruijn Graph Construction
Authors: Rautiainen Mikko , Marschall Tobias
Published: September 2020

Motivation

De Bruijn graphs can be constructed from short reads efficiently and have been used for many purposes. Traditionally long read sequencing technologies have had too high error rates for de Bruijn graph-based methods. Recently, HiFi reads have provided a combination of long read length and low error rate, which enables de Bruijn graphs to be used with HiFi reads.

Results

We have implemented MBG, a tool for building sparse de Bruijn graphs from HiFi reads. MBG outperforms existing tools for building dense de Bruijn graphs, and can build a graph of 50x coverage whole human genome HiFi reads in four hours on a single core. MBG also assembles the bacterialE. coligenome into a single contig in 8 seconds.

Availability

Package manager:https://anaconda.org/bioconda/mbgand source code:https://github.com/maickrau/MBG
Slow rhythmic eye motion predicts periodic alternation of bistable perception
Authors: Choi Woochul , Lee Hyeonsu , Paik Se-Bum
Published: September 2020

Bistable perception is characterized by periodic alternation between two different perceptual interpretations, the mechanism of which is poorly understood. Herein, we show that perceptual decisions in bistable perception are strongly correlated with slow rhythmic eye motion, the frequency of which varies across individuals. From eye gaze trajectory measurements during three types of bistable tasks, we found that each subject’s gaze position oscillates slowly(less than 1Hz), and that this frequency matches that of bistable perceptual alternation. Notably, the motion of the eye apparently moves in opposite directions before two opposite perceptual decisions, and this enables the prediction of the timing and direction of perceptual alternation from eye motion. We also found that the correlation between eye movement and a perceptual decision is maintained during variations of the alternation frequency by the intentional switching or retaining of perceived states. This result suggests that periodic bistable perception is phase-locked with rhythmic eye motion.
Adaptation of a microfluidic qPCR system for enzyme kinetics studies
Authors: Rembeza Elzbieta , Engqvist Martin KM
Published: September 2020

Microfluidic platforms offer a drastic increase in throughput while minimizing sample usage and hands-on time, which makes them important tools for large-scale biological studies. A range of such systems have been developed for enzyme activity studies, although their complexity largely hinders their application by a wider scientific community. Here we present adaptation of an easy-to-use commercial microfluidic qPCR system for performing enzyme kinetics studies. We demonstrate functionality of the Fluidigm Biomark HD system (the Fluidigm system) by determining kinetic properties of three oxidases in a resorufin-based fluorescent assay. The results obtained in the microfluidic system proved reproducible and comparable to the ones obtained in a standard microplate-based assay. With a wide range of easy-to-use, off-the-shelf components, the microfluidic system presents itself as a simple and customizable platform for high-throughput enzyme activity studies.

Graphical abstract
Selective metal ion utilization contributes to the transformation of the activity of yeast polymerase η from DNA polymerization toward RNA polymerization
Authors: Balint Eva , Unk Ildiko
Published: September 2020

Polymerase eta (Polη) is a translesion synthesis DNA polymerase directly linked to cancer development. It can bypass several DNA lesions thereby rescuing DNA damage-stalled replication complexes. We previously presented evidence implicatingSaccharomyces cerevisiaePolη in transcription elongation, and identified its specific RNA extension and translesion RNA synthetic activities. However, RNA synthesis by Polη proved rather inefficient under conditions optimal for DNA synthesis. Searching for factors that could enhance its RNA synthetic activity, we have identified the divalent cation of manganese. Here we show, that manganese triggers drastic changes in the activity of Polη. It increases the efficiency of ribonucleoside incorporation into RNA by ∼400-2000-fold opposite undamaged DNA, and ∼3000 and ∼6000-fold opposite TT dimer and 8oxoG, respectively. Importantly, preference for the correct base is maintained with manganese during RNA synthesis. In contrast, activity is strongly impaired, and base discrimination almost lost during DNA synthesis by Polη with manganese. Moreover, Polη shows strong preference for manganese during RNA synthesis even at 25-fold excess magnesium concentration. Based on these, we suggest that selective metal cofactor usage plays an important role in determining the specificity of Polη during synthesis enabling it to function at both replication and transcription.
Women born to older mothers have reduced fertility: Evidence from a natural fertility population
Authors: van den Berg Niels , van Dijk Ingrid , Mourits Rick
Published: September 2020

Are daughters of older mothers less fertile? The human mutation rate is high and increases with chronological age. As female oocytes age, they become less functional, reducing female chances at successful reproduction. Increased oocyte mutation loads at advanced age may be passed on to offspring, decreasing fertility among daughters born to older mothers. In this paper we study the effects of maternal ageing on her daughter’s fertility, including total number of children, age at last birth, and neonatal mortality among her children. We study fertility histories of two generations of women from disjoint families from a pre-transitional historical population in the Dutch province of Zeeland. Using mixed effect Poisson models to take within family (sibling) relations into account, we show that fertility is reduced among married daughters who were born at advanced maternal age, with fewer children ever born and earlier ages at last birth. We do not find consistent evidence for effects on neonatal mortality. These results may indicate that women born to older mothers are negatively affected by their mothers’ increased oocyte mutation load.