bluuebunny/crossref_metadata_2025 huggingface dataset:
Price Discrimination and Public Policy in the US College Market
Authors: Fillmore Ian
Published: July 2022

In the US, the federal government grants colleges access to a student’s Free Application for Federal Student Aid (FAFSA) which facilitates substantial price discrimination. This article is the first to estimate the consequences of allowing colleges to use the FAFSA in their pricing decisions. I build and estimate a structural model of college pricing and simulate counterfactuals wherein some or all of the FAFSA information is restricted. I find that if FAFSA information were restricted, 13$\%$ of students attending elite colleges would be inefficiently priced out of the elite market. Nevertheless, student welfare would rise as colleges charged the majority of students lower prices. Colleges do use the FAFSA to transfer resources from high- to low-income students on average, but this redistribution is highly imprecise: allowing colleges to use the FAFSA harms one-third of low-income students while one in seven high-income students actually benefit.
Malaria diagnosis in an emergency department before and after the COVID-19 pandemic: a retrospective study
Authors: Demotier Sophie , Gornet Marion , Belli Arianna , Huguenin Antoine , N'Guyen Yohan
Published: July 2022

Background

The COVID-19 pandemic impacted access to health facilities.

Methods

We assessed the number of blood smears sampled in the emergency department (ED) among all blood smears performed for malaria in Reims University Hospital before and after 2020.

Results

We showed a decrease in the number of blood smears performed after the onset of the COVID-19 pandemic, but only in 2020. The seasonal increase of cases during summer was preserved. All blood smears positive for malaria in 2020 were sampled in the ED.

Conclusions

The ED played a key role in the diagnosis of malaria with the onset of the COVID-19 pandemic.
Hyperspectral Imaging in the UV Range Allows for Differentiation of Sugar Beet Diseases Based on Changes in Secondary Plant Metabolites
Authors: Brugger Anna , Yamati Facundo Ispizua , Barreto Abel , Paulus Stefan , Schramowsk Patrick , Kersting Kristian , Steiner Ulrike , Neugart Susanne , Mahlein Anne-Katrin
Published: July 2022

Fungal infections trigger defense or signaling responses in plants, leading to various changes in plant metabolites. The changes in metabolites, for example chlorophyll or flavonoids, have long been detectable using time-consuming destructive analytical methods including high-performance liquid chromatography or photometric determination. Recent plant phenotyping studies have revealed that hyperspectral imaging (HSI) in the UV range can be used to link spectral changes with changes in plant metabolites. To compare established destructive analytical methods with new nondestructive hyperspectral measurements, the interaction between sugar beet leaves and the pathogens Cercospora beticola, which causes Cercospora leaf spot disease (CLS), and Uromyces betae, which causes sugar beet rust (BR), was investigated. With the help of destructive analyses, we showed that both diseases have different effects on chlorophylls, carotenoids, flavonoids, and several phenols. Nondestructive hyperspectral measurements in the UV range revealed different effects of CLS and BR on plant metabolites resulting in distinct reflectance patterns. Both diseases resulted in specific spectral changes that allowed differentiation between the two diseases. Machine learning algorithms enabled the differentiation between the symptom classes and recognition of the two sugar beet diseases. Feature importance analysis identified specific wavelengths important to the classification, highlighting the utility of the UV range. The study demonstrates that HSI in the UV range is a promising, nondestructive tool to investigate the influence of plant diseases on plant physiology and biochemistry.
Early Discontinuation, Results Reporting, and Publication of Gynecology Clinical Trials From 2007 to 2020
Authors: Steinberg Jecca R. , Magnani Christopher J. , Turner Brandon E. , Weeks Brannon T. , Young Anna Marie P. , Lu Connie Fei , Zhang Naixin , Richardson Michael Taylor , Fitzgerald Alison Conway , Mekonnen Zesemayat , Redman Tene , Adetunji Modupe , Martin Shanique A. , Anderson Jill N. , Chan Katelyn S. , Milad Magdy P.
Published: July 2022

(Abstracted from Obstet Gynecol 2022;139:821–831)

The aim of this study was to characterize gynecology clinical trials over time, compare trials in various subspecialties, and analyze factors associated with early discontinuation, failure, or inadequacy to report results, as well as to publish and disseminate findings of gynecology clinical trials. The authors performed cross-sectional analysis of all gynecology trials registered on ClinicalTrials.gov between 2007 and 2020 and their resulting publications.
Outcomes of the Second Aqueous Shunt Implant Versus Transscleral Cyclophotocoagulation Treatment Study: A Randomized Comparative Trial
Authors: Feldman Robert M. , Chuang Alice Z. , Mansberger Steve L. , Tanna Angelo P. , Blieden Lauren S. , Bell Nicholas P. , Gross Ronald L. , Pasquale Louis R. , Greenfield David S. , Liebmann Jeffrey M. , Weinreb Robert N. ,   the ASSISTS Group
Published: July 2022

Précis:

Short-term overall success rates were high with either SGDD or CPC. However, SGDD was associated with more clinic visits and an increased risk of additional glaucoma surgery. Both treatments were reasonable options for eyes with inadequately controlled IOP after a single GDD.

Purpose:

The purpose of this study is to compare the implantation of a second glaucoma drainage device (SGDD) and transscleral cyclophotocoagulation (CPC) in eyes with inadequately controlled intraocular pressure (IOP), despite the presence of a preexisting glaucoma drainage device.

Methods:

Patients with inadequately controlled IOP, despite the medical therapy and a preexisting glaucoma drainage device, were enrolled at 14 clinical centers and randomly assigned to treatment with a SGDD or CPC.

Main Outcome Measures:

Surgical failure was defined as: (1) IOP ≤5 mm Hg or >18 mm Hg or <20% reduction below baseline on maximum tolerated topical ocular hypotensive therapy, (2) reoperation for glaucoma, or (3) loss of light perception. The primary outcome measure was overall success with or without adjunctive medical therapy.

Results:

Forty-two eyes of 42 participants were randomized to SGDD (n=22) or CPC (n=20). Mean duration of follow-up was 18.6 (±12.1; range: 1.1–38.6) months. The cumulative success rate was 79% for SGDD and 88% for CPC at 1 year (P=0.63). Although the study was underpowered, no significant differences in IOP, postoperative number of IOP-lowering medications, or adverse events were observed. The number of additional glaucoma surgeries (P=0.003), office visits during the first 3 months (P<0.001), and office visits per month after month 3 (P<0.001) were greater in the SGDD group.

Conclusions:

Short-term overall success rates were high with either SGDD or CPC. However, SGDD was associated with more clinic visits and an increased risk of additional glaucoma surgery.
Cross-sectional Study of Workers Employed at a Copper Smelter—Effects of Long-term Exposures to Copper on Lung Function and Chronic Inflammation
Authors: Haase Lisa-Marie , Birk Thomas , Poland Craig A. , Holz Olaf , Müller Meike , Bachand Annette M. , Mundt Kenneth A.
Published: July 2022

Objective

The aim of the study was to assess the effect of exposure to copper-containing dust on lung function and inflammatory endpoints among workers of a German copper plant, effects rarely studied before.

Methods

One hundred four copper-exposed smelter workers and 70 referent workers from the precious metal and lead facilities were included, with different metal exposures in both groups due to the different process materials. Body plethysmography, exhaled nitric oxide (FeNO) measurements, and blood sampling were conducted in all workers. Smoking status and the use of respiratory protective equipment were considered. In a subgroup of 40 nonsmoking volunteers (28 copper-exposed and 12 referents), sputum biomarkers were assessed.

Results

Median lung function values of both copper-exposed and the referent groups were within reference ranges of “healthy” individuals, and statistical differences between the groups were mostly not evident. Similarly, differences in blood and sputum biomarkers were too small to be biologically relevant.

Conclusion

The results suggest the absence of the detectable effects of copper-containing dust exposure on lung function or chronic inflammation within the investigated cohort.
A Moderated Mediation Analysis of New Work-Related Stressors, Psychological Distress, and Absenteeism in Health Care During a Pandemic
Authors: Parent-Lamarche Annick , Laforce Sonia
Published: July 2022

Objectives

We aimed to evaluate the effects of new work-related stressors on psychological distress and absenteeism and the role of recognition in these relationships.

Methods

Moderated path analyses were carried out on a sample of 1128 health care workers.

Results

Increased workload related to COVID-19 (coronavirus disease 2019) (β= 1.511,P≤ 0.01) and fear of COVID-19 (β= 0.844,P≤ 0.01) were directly associated with a higher level of psychological distress and indirectly (β= 2.306,P≤ 0.01; andβ= 1.289,P≤ 0.05, respectively) associated with a higher level of absenteeism. Recognition (β= 0.260,P≤ 0.001) moderated the association between teleworking and psychological distress. Furthermore, this significant moderation effect had a significant impact on absenteeism (β= 0.392,P≤ 0.05). Regardless of the workplace (on site or teleworking), high recognition was beneficial for psychological distress. This effect seems more important when working on site.

Conclusions

The results propose that specific new work-related stressors should be addressed in the context of organizational change (eg, a pandemic).
Agreement Between SARS-CoV-2 PCR Test Results Using Nasopharyngeal and Mid-Turbinate Specimens Among Asymptomatic Working-Age Adults
Authors: Wendt Hess Judy , Bhojani Faiyaz , Cameron Derrick , Freire de Carvalho Mary , Momin Fayaz
Published: July 2022

Objective

The aim of this study was to determine whether mid-turbinate specimens reliably detect active infection in asymptomatic adults undergoing regular COVID-19 PCR testing.

Methods

Qualitative agreement between 2481 paired nasopharyngeal and mid-turbinate PCR results was assessed. Mean cycle threshold values for each positive result were evaluated as an indicator of active infection.

Results

Overall agreement between nasopharyngeal and mid-turbinate tests was 98.4%. Positive percent agreement was 37.2%, and negative percent agreement was ~100%. Test pairs with lower cycle thresholds (≤30 and ≤25) reached 67% and 100% positive percent agreement, respectively.

Conclusions

SARS-CoV-2 infections with high viral loads were detected regardless of specimen type. Mid-turbinate swabs reduced staff discomfort and may decrease repeated positive test results weeks or months after initial infection. Discordant pairs generally had high cycle threshold values (>30) indicating low viral load and little risk of transmitting COVID-19.
Fatigue and Pain Severity in Gulf War Illness Is Associated With Changes in Inflammatory Cytokines and Positive Acute Phase Proteins
Authors: Hodgin Kathleen S. , Jones Chloe L. , Younger Jarred W.
Published: July 2022

Objective

The aim of the study is to investigate relationships between inflammatory analytes and symptoms of pain and fatigue in Gulf War illness (GWI).

Methods

In this preliminary study, 12 male veterans meeting GWI criteria provided daily blood samples and symptom ratings over 25 days. Linear mixed models were used to analyze associations between symptoms and sera concentrations of cytokines, acute phase proteins, insulin, and brain-derived neurotropic factor.

Results

Analyses included 277 days with both blood draws and self-reports. Days with worse fatigue severity were associated with higher C-reactive protein and serum amyloid A, and lower eotaxin 1. Muscle pain and joint pain were associated with leptin, monocyte chemoattractant protein 1, and interferon γ–induced protein. Joint pain was further associated with serum amyloid A and eotaxin 3.

Conclusions

Gulf War illness involves fatigue and pain associated with inflammation. Conventional and novel anti-inflammatories should be further explored for the treatment of GWI.
Do Musculoskeletal Disorders Affect Work Tasks in Farmers
Authors: Friesen Kenzie B. , Lang Angelica E.
Published: July 2022

Objective

Musculoskeletal disorders (MSDs) are common among farmers, yet associated difficulty during work is not well understood. The purpose of this study was to determine the connection between MSDs and work-related task difficulty in rural Saskatchewan.

Methods

Rural Saskatchewan farmers and farm workers with history of MSD in the last 5 years (n= 72) participated via an online survey.

Results

Shoulder MSDs were the most common (75%), followed by neck (65%), knees (61%), and lower back (58%). Many participants reported more than one MSD. Presence of MSDs leads to difficulty in work tasks; for example, difficulty when operating power tools with hands was 8.7 times more likely for those with shoulder MSD.

Conclusions

MSDs in rural Saskatchewan farmers are associated with greater work task difficulty, and future research into risk factors related to those tasks can guide prevention strategies.
Why Am I So Exhausted?
Authors: Allen Joseph A. , Thiese Matt S. , Eden Emilee , Knowles Sarah E.
Published: July 2022

Objective

Ineffective meetings have been well-documented as presenting considerable direct (eg, salary) and indirect costs (eg, employee burnout). We explore the idea that people need meeting recovery, or time to transition from meetings to their next task. Doing so may reduce employee burnout.

Methods

We used a quantitative survey of working adults' last meeting to determine the relationship between meeting outcomes (satisfaction and effectiveness) and meeting recovery.

Results

We found that meeting outcomes are related to meeting recovery and that relationship is moderated by the degree to which the meeting was relevant to the individual. Implications for theory and practice are discussed to provide concrete recommendations for researchers, managers, and consultants.

Conclusions

This study explores virtual meeting fatigue with a focus on meeting quality and explores the need for recovery after workplace meetings.
Safety and Efficacy of Hypofractionated Stereotactic Radiosurgery in Facial Nerve Schwannoma
Authors: Fatima Nida , La Dine Anna K. , Barnard Zachary R. , Ko Katherine , Peng Kevin , Slattery William H. , Lekovic Gregory P.
Published: July 2022

Objective

In the current era of modern neurosurgery, the treatment strategies have been shifted to “nerve-preservation approaches” for achieving a higher facial and hearing function preservation rate following facial nerve tumors. We have conducted this novel report on determining the outcome of patients with facial nerve schwannomas (FNS) treated with hypofractionated stereotactic radiosurgery (hfSRS).

Patients

Retrospective chart review of a prospectively maintained database search was conducted.

Intervention

Patients who underwent hfSRS CyberKnife (Accuray Inc, Sunnyvale, CA, U.S.A.) for FNS were included.

Main Outcome Measures

Outcomes consisted of tumor control, facial and hearing nerve function as graded by House-Brackmann and American Academy of Otolaryngology-Head and Neck Surgery recommendations, and adverse radiation effects.

Results

With an institutional board review approval, we retrospectively identified five patients with FNS (four intracranial [80%] and one extracranial [20%]) treated with hfSRS (2011–2019). Patients received definitive SRS in three patients (60.0%), whereas adjuvant to surgical resection in two patients (40.0%). A median tumor volume of 7.5 cm3 (range, 1.5–19.6 cm3) received a median prescription dose of 23.2 Gy (range, 21–25 Gy) administered in median of three fractions (range, three to five sessions). With a median radiographic follow-up of 31.4 months (range, 13.0–71.0 mo) and clinical follow-up of 32.6 months (range, 15.1–72.0 mo), the local tumor control was 100.0%. At the last clinical follow-up, the facial nerve function improved or remained unchanged House-Brackmann I–II in 80.0% of the patients, whereas the hearing nerve function improved or remained stable in 100.0% of the patients. Temporary clinical toxicity was observed in three patients (60.0%), which resolved. None of the patients developed adverse radiation effect.

Conclusion

From our case series, hfSRS in FNS seems to be safe and efficacious in terms of local tumor control, and improved facial and hearing nerve function.
Unintentional Weight Loss in Adults 65 Years or Older
Authors: Durmuş Nurdan Şentürk , Can Büşra , Tufan Aslı
Published: July 2022

Unintentional weight loss is defined as a more than 5% decrease in body weight within 1 year. Various physical and psychiatric etiologies cause unintentional weight loss, including major depressive disorder (MDD). We present the case of a 69-year-old woman who lost 10 kg in 2 months. She had anhedonia, mobility limitations, and incontinence. Her Mini Nutritional Assessment score indicated malnutrition, whereas her Geriatric Depression Scale score indicated a diagnosis of MDD. Whole-body fluorodeoxyglucose (FDG)–positron emission tomography/computed tomography showed intensely increased FDG uptake in the muscles adjacent to the right and left mandibular rami and the temporal muscle, compatible with jaw clenching associated with the patient's MDD. Subsequent temporal muscle biopsy did not suggest the causes of malignant disorders, dermatomyositis, or polymyositis. Having ruled out all possible organic pathologies, the patient was thus diagnosed with MDD. Escitalopram was prescribed for her MDD, and oral nutritional supplement treatments were initiated for her malnutrition. Patients who present with unintentional weight loss should be assessed first for physical etiologies, and then psychiatric etiologies, particularly as weight loss may be a major symptom of MDD in older adults.
Playing the Role of a Nurse in a Virtual Reality Simulation
Authors: Dubovi Ilana , Itzhaki Michal
Published: July 2022

Background:

Nurses' successful emotional coping with unpleasant emotions triggered by intense clinical situations is associated with better-quality patient care. Nursing students experience significant challenges with managing their emotions in clinical practice.

Purpose:

To evaluate a virtual reality (VR)–based simulation as a platform for emotional management training.

Methods:

A pretest-posttest research design was used to study sophomore nursing students (n = 75) while learning with a VR simulation.

Results:

Playing the role of a nurse in a VR hospital triggered an emotional dissonance to uncover students' management strategies, specifically deep cognitive acting and surface acting strategies. Surface acting emphasizes emotions that are displayed but not genuinely experienced and was negatively associated with posttest knowledge scores (r =−0.34, P < .05).

Conclusion:

Learning with VR can provide a safe environment both for acquiring knowledge and for revealing students' emotional management, which, in turn, can be leveraged by educators to redirect the emotion work required in the nursing profession.
The Impact of Adenomyosis on Pregnancy and Pregnancy Outcomes: A Review
Authors: Wendel Michael P. , Magann Everett F.
Published: July 2022

Objective

The aim of this review was to describe the risk factors, diagnosis, and effects on pregnancy of the gynecologic condition adenomyosis.

Methods

A PubMed, Web of Science, and CINAHL search was undertaken. Citations were limited to the past 30 years.

Results

There were 223 articles identified, with 31 articles being the basis of this review. Adenomyosis is a relatively common gynecologic condition that was previously thought to predominantly occur in older women, as it was diagnosed most commonly after a hysterectomy. As imaging techniques have advanced, this condition is now able to be diagnosed much earlier in life and is estimated to affect up to 20% of reproductive aged women. As studies have followed these women through subsequent pregnancies, an increased risk of adverse pregnancy outcomes has been observed. These include miscarriage, preterm birth, preterm prelabor rupture of membranes, small for gestational age, low birthweight, and preeclampsia, among others. This review is to examine the incidence, risk factors, and diagnostic criteria of adenomyosis and to then discuss its role in adverse pregnancy outcomes.

Conclusions

Adenomyosis has been predominately a gynecologic condition, but now has been shown to adversely affect pregnancy outcomes. Diagnosis is made with histology, but may be suspected based on magnetic resonance imaging and ultrasound findings. Despite evidence of adverse pregnancy outcomes, there are no established strategies to risk, stratify, or prevent any of these outcomes.

Target Audience

Obstetricians and gynecologists, family medicine physicians

Learning Objectives

After completion of this article, the reader should be better able to interpret the incidence and diagnostic criteria for adenomyosis; identify patients at risk for adenomyosis; and predict the adverse outcomes of pregnancy related to adenomyosis.
Liquid Nicotine, E-Cigarettes, and Vaping
Authors: Howard Mary Beth , Guse Sabrina
Published: July 2022

E-cigarettes, or electronic cigarettes, are electronic nicotine delivery systems that are marketed as a healthier alternative to tobacco cigarettes. There has been an exponential increase in their use among youth since their introduction to the United States market in 2007. With increased use and popularity, there has been an increase in calls to poison control centers regarding liquid nicotine toxicity in children and adolescents. Recent US Food and Drug Administration and other federal regulations of e-cigarettes have attempted to limit availability to youth. This article reviews trends in e-cigarette use among youth, the background and mechanism of action of e-cigarettes, liquid nicotine toxicity, management of liquid nicotine toxicity, and recent policy updates regarding e-cigarettes.
Preseptal Cellulitis Versus Orbital Cellulitis
Authors: Milo Razel B.
Published: July 2022

Eye infection with or without swelling is a common complaint in pediatric patients. It commonly affects the eyelid, which can be confused with an insect bite, orbital pseudotumor, or panophthalmitis. The article highlights the differences between preseptal and orbital cellulitis. Preseptal and orbital cellulitis originate from other infections because of the thin bone barrier that separates the eye from other facial structures. The clinical manifestations of preseptal and orbital cellulitis may be perplexing, and emergency nurse practitioners must distinguish between the two infections. The incorrect diagnosis may lead to complications. The complications associated with orbital cellulitis are vision loss, brain abscess, vision loss, cavernous sinus thrombophlebitis, orbital cellulitis, subperiosteal abscess, and death. Thus, early diagnosis and treatment will prevent these complications.
Ruling Out a Myocardial Infarction Safely in 30 Minutes
Authors: Bhimani Alisha , Frenkel Tova Safier
Published: July 2022

This Research to Practice column assists to provide emergency advanced practice registered nurses an exploration of current evidence to establish implications for practice change within emergency care settings. The article, “Rapid Rule-Out of Myocardial Infarction After 30 Minutes as an Alternative to 1 Hour: The RACING-MI Cohort Study” by Bang et al. (2022), seeks to examine whether non-ST-segment elevation myocardial infarction identified on an electrocardiogram can be safely ruled out among a population of low-risk patients who present to the emergency department (ED) with undifferentiated acute chest pain. The study uses an accelerated 30-min testing algorithm of high-sensitivity troponin I markers as opposed to a traditional 1-hr high-sensitivity troponin I testing algorithm. The study results are presented to understand the factors of managing myocardial infarction (MI) and reducing patient length of stay surrounding MI care among ED providers at an emergency care center.
Functional connectivity between interoceptive brain regions is associated with distinct health-related domains - a population-based neuroimaging study
Authors: Luettich A , Sievers C , Alfaro Almagro F , Allen M , Jbabdi S , Smith SM , Pattinson KTS
Published: July 2022

Interoception is the sensation, perception, and control of signals from within the body. It has been associated with a broad range of physiological and psychological processes. Further, interoceptive variables are related to specific regions and networks in the human brain. However, it is not clear whether or how these networks relate empirically to different domains of physiological and psychological health at the population level.

We analysed a dataset of 19 020 individuals (10 055 females, 8 965 males; mean age: 63 years, age range: 45 – 81 years), who have participated in the UK Biobank Study, a very large scale prospective epidemiological health study. Using canonical correlation analysis (CCA), allowing for the examination of associations between two sets of variables, we related the functional connectome of brain regions implicated in interoception to a selection of non-imaging health and lifestyle related phenotypes, exploring their relationship within modes of population co-variation.

In one integrated and data driven analysis, we obtained four statistically significant modes. Modes could be categorised into domains of affect and cardiovascular health, breathing, obesity, and subjective health (all p < 0.0001) and were meaningfully associated with distinct neural circuits.

Circuits represent specific neural “fingerprints” of functional domains and set the scope for future studies on the neurobiology of interoceptive involvement in different lifestyle and health related phenotypes. Therefore, our research contributes to the conceptualisation of interoception and may lead to a better understanding of co-morbid conditions in the light of shared interoceptive structures.
Characterizing the shared signals of face familiarity: long-term acquaintance, voluntary control, and concealed knowledge
Authors: Dalski Alexia , Kovács Gyula , Wiese Holger , Ambrus Géza Gergely
Published: July 2022

Using cross-experiment multivariate classification of EEG patterns, in a recent study we found evidence for a shared familiarity signal for faces, patterns of neural activity that successfully separate trials for familiar and unfamiliar faces across participants and modes of familiarization. Here, our aim was to expand upon this research to further characterize the spatio-temporal properties of this signal. By utilizing the information content present for incidental exposure to personally familiar and unfamiliar faces, we tested how the information content in the neural signal unfolds over time under different task demands – giving truthful or deceptive responses to photographs of genuinely familiar and unfamiliar individuals. For this goal, we re-analyzed data from two previously published experiments using within-experiment leave-one-subject-out and cross-experiment classification of face familiarity. We observed that the general face familiarity signal, consistent with its previously described spatio-temporal properties, is present for long-term personally familiar faces under passive viewing, as well as for acknowledged and concealed familiarity responses. Also, central-posterior regions contain information related to deception. We propose that signals in the 200-400 ms window are modulated by top-down task-related anticipation, while the patterns in the 400-600 ms window are influenced by conscious effort to deceive. To our knowledge, this is the first report describing the representational dynamics of concealed knowledge for faces.

Highlights

Previous studies found a robust EEG effect for face-familiarity in the 200-600 ms post-stimulus range.

This neural pattern was found to be shared across participants and modes of familiarization.

We used incidental exposure as a template to probe information content for acknowledged and concealed familiarity

The shared familiarity signal is modulated differentially in early (200-400 ms) and late (post-400 ms) windows

Cross-experiment classification is a promising tool to investigate how cognitive processes unfold under different conditions
Patient-derived xenograft studies of fumarate hydratase (FH)-deficient uterine leiomyoma subtype
Authors: Kajimura Takuya , Serna Vanida Ann , Amurgis Emma , Blumenfeld Michael , Kurita Takeshi
Published: July 2022

Uterine leiomyoma (LM) is the most common benign gynecological tumor in premenopausal women. Our previous patient-derived xenograft (PDX) studies established that 17ß-estradiol (E2) and progesterone (P4) stimulate the growth of the two most prevalent subtypes, MED12 mutant (MED12-LM) and HMGA2 overexpressing LMs (HMGA2-LM), via proliferation and hypertrophy of smooth muscle tumor cells (SMTCs). In addition, tumor-associated fibroblasts (TAFs) that do not carry MED12 mutations also contribute to the growth of MED12-LM by secreting extracellular matrix (ECM) proteins. In this study, we investigated the growth control of the fumarate hydratase (FH) deficient LM (FH-LM) subtype, utilizing the PDX model. We identified an FH-negative case with conventional leiomyoma histology. The overexpression of aldo-keto reductase family 1 member B10 (AKR1B10) confirmed the FH deficiency. Like MED12-LM, FH-LM comprised two major cell types: 54.4% SMTCs and 43.3% TAFs. Furthermore, the TAFs expressed FH. The FH-LM PDXs grew in response to E2 and P4 via proliferation and hypertrophy of SMTCs, similar to MED12-LM and HMGA2-LM. While E2 alone did not stimulate growth, E2 was essential for sensitizing FH-deficient SMTCs to P4 by upregulating progesterone receptor (PGR). Our current study established that the growth of the three most prevalent LM subtypes, MED12-LM, HMGA2-LM, and FH-LM, depends on E2 and P4. Thus, selective progesterone receptor modulators (SPRMs) should be an effective treatment option for most symptomatic LM patients.
Sequential in vitro enzymatic N-glycoprotein modification reveals site-specific rates of glycoenzyme processing
Authors: Adams Trevor M. , Zhao Peng , Chapla Digantkumar , Moremen Kelley W. , Wells Lance
Published: July 2022

N-glycosylation is an essential eukaryotic post-translational modification that affects various glycoprotein properties, including folding, solubility, protein-protein interactions, and half-life. N-glycans are processed in the secretory pathway to form varied ensembles of structures, and diversity at a single site on a glycoprotein is termed ‘microheterogeneity’. To understand the factors that influence glycan microheterogeneity, we hypothesized that local steric and electrostatic factors surrounding each site influences glycan availability to enzymatic modification. We tested this hypothesis by expression of a panel of reporter N-linked glycoproteins in MGAT1- null HEK293 cells to produce immature Man5GlcNAc2 glycoforms (38 glycan sites total). These glycoproteins were then sequentially modified in vitro from high-mannose to hybrid and on to biantennary, core fucosylated, complex structures by a panel of N-glycosylation enzymes and each reaction time-course was quantified by LC-MS/MS. Substantial differences in rates of in vitro enzymatic modification were observed between glycan sites on the same protein and differences in modification rates varied depending on the glycoenzyme being evaluated. By comparison, proteolytic digestion of the reporters prior to N-glycan processing eliminated differences in in vitro enzymatic modification. Comparison of in vitro rates of enzymatic modification with the glycan structures found on the mature reporters expressed in wild type cells correlate well with the enzymatic bottlenecks found in vitro. These data suggest that higher-order local structures surrounding each glycosylation site contribute to the efficiency of modification both in vitro and in vivo to establish the spectrum of site-specific microheterogeneity found on N-linked glycoproteins.
An Evidence-based Cognitive Model of Uncertainty during Indoor Multi-level Human Wayfinding
Authors: Yang Qi , Dubey Rohit K. , Kalantari Saleh
Published: July 2022

Existing computational models lack adequate representation of the uncertainty experienced in human wayfinding tasks. They overly rely on optimized pathing algorithms, which reduces realism and limits insights on human responses to architectural designs. To address this, we developed an empirically grounded model that predicts human wayfinding uncertainty experience. Using data from 28 participants navigating an educational building with varying signage, we constructed the model (Study 1), and validated it with data from 11 other participants (Study 2). We found the wayfinding uncertainty correlated with the time elapsed since seeing the last helpful sign. The cognitive agent based on this model closely replicated human-reported uncertainty levels during wayfinding tasks under different signage conditions. Although the model more closely resembled human behavior compared to a shortest-route algorithm, additional environmental variables and heuristics are needed for better human outcome alignment. Our study showcases that evidence-based cognitive agent modeling can provide nuanced, human-like wayfinding behavior, enhancing the potential for effective computational design evaluation.
Three Distinct Annotation Platforms Differ in Detection of Antimicrobial Resistance Genes in Long-Read, Short-Read, and Hybrid Sequences Derived from Total Genomic DNA or from Purified Plasmid DNA
Authors: Maboni Grazieli , de Paula Baptista Rodrigo , Wireman Joy , Framst Isaac , Summers Anne O. , Sanchez Susan
Published: July 2022

Recent advances and lower costs in rapid high-throughput sequencing have engendered hope that whole genome sequencing (WGS) might afford complete resistome characterization in clinical bacterial isolates. Despite its potential, several challenges should be addressed before adopting WGS to detect antimicrobial resistance (AMR) genes in the clinical laboratory. Here, with three distinct ESKAPE bacteria, we compared different approaches to identify best practices for detection of AMR genes, including: total genomic DNA and plasmid DNA extractions, solo assembly of Illumina short-reads and of ONT long-reads, two hybrid assembly pipelines, and three in silico AMR databases. We also determined the susceptibility of each strain to 21 antimicrobials. We found that all AMR genes detected in pure plasmid DNA were also detectable in total genomic DNA indicating that, at least in these three enterobacterial genera, purification of plasmid DNA was not necessary to detect plasmid-borne AMR genes. We also found that Illumina short-reads used with ONT long-reads in either hybrid or polished assemblies of total genomic DNA enhanced sensitivity and accuracy of AMR gene detection. Phenotypic susceptibility corresponded well with genotypes identified by sequencing, but the three AMR databases differed significantly in distinguishing mobile dedicated AMR genes from non-mobile chromosomal housekeeping genes in which rare spontaneous resistance mutations might occur. This study reveals the need for standardized biochemical and informatic procedures and database resources for consistent, reliable AMR genotyping to take full advantage of WGS to expedite patient treatment and to track AMR genes within the hospital and community.
Characterization of the NSE6 subunit of thePhyscomitrium patensPpSMC5/6 complex
Authors: Lelkes E. , Holá M. , Jemelková J. , Štefanovie B. , Kolesár P. , Vágnerová R. , Angelis K.J. , Paleček J.J.
Published: July 2022

Structural Maintenance of Chromosome (SMC) complexes are molecular machines ensuring chromatin organization at higher levels. They play direct roles in cohesion, condensation, replication, transcription and DNA repair. Their cores are composed of long-armed SMC, kleisin, and kleisin-associated KITE or HAWK subunits. Additional factors, like NSE6 within SMC5/6, bind to SMC core complexes and regulate their activities. To characterize the NSE6 subunit of mossPhyscomitrium patens, we analyzed its protein-protein interactions andPpnse6mutant phenotypes. We identified a previously unrecognized sequence motif conserved from yeast to humans within the NSE6 CANIN domain that is required for interaction with its NSE5 partner. In addition, the CANIN domain and its preceding sequences bind and link SMC5 and SMC6 arms, suggesting its role in SMC5/6 dynamics. BothPpnse6dCas9_3andPpnse6KO1_47mutant lines exhibited reduced growth and developmental aberrations. These mutants were also sensitive to DNA-damaging drug bleomycin and lost a significant portion of rDNA copies, suggesting conserved architecture and functions of SMC5/6 complexes across species.
Endothelial Dnmt3a controls placenta vascularization and function to support fetal growth
Authors: Gehrs Stephanie , Jakab Moritz , Gutjahr Ewgenija , Gu Zuguang , Weichenhan Dieter , Mogler Carolin , Schlesner Matthias , Plass Christoph , Augustin Hellmut G. , Schlereth Katharina
Published: July 2022

The fetoplacental capillary network is of vital importance for proper nourishment during early development. Inadequate maternal-fetal circulation has emerged as one of the main pathophysiological features of placental insufficiency. Meta-analysis of human placental endothelial cells (EC) revealed that downregulation of the de novo DNA methyltransferase 3A (DNMT3A) is associated with preeclampsia. However, mechanistic insights into functional consequences of altered DNA methylation patterns during placental vascular development remain elusive. Here, we investigated the role of Dnmt3a in the vasculature during murine placenta development. Spatial and temporal expression analyses revealed an induction of Dnmt3a in the mature labyrinth layer. The global and endothelium-specific loss (ECKO) of Dnmt3a resulted in reduced placental vascularization and fetal growth restriction. EC deleted for Dnmt3a demonstrated extensive loss of DNA methylation, particularly close to angiogenesis related genes. Loss of DNA methylation decreased the angiogenic capacity of EC in vitro and in vivo. Collectively, these data identify DNMT3A as the main DNA methyltransferase in the human and murine placental vasculature and characterize its importance for physiological endothelial function. The Dnmt3a-dependent regulation of genes related to placenta insufficiency validates Dnmt3a ECKO mice as an epigenetically driven mouse model of placenta insufficiency with potential translational relevance.
PEPseq Quantifies Transcriptome-Wide Changes in Protein Occupancy and Reveals Selective Translational Repression After Translational Stress
Authors: Trendel Jakob , Boileau Etienne , Jochem Marco , Dieterich Christoph , Krijgsveld Jeroen
Published: July 2022

Post-transcriptional gene regulation is accomplished by the interplay of the transcriptome with RNA-binding proteins, which occurs in a dynamic manner in response to altered cellular conditions. Recording the combined occupancy of all proteins binding to the transcriptome offers the opportunity to interrogate if a particular treatment leads to any interaction changes, pointing to sites in RNA that undergo post-transcriptional regulation. Here, we establish a method to monitor protein occupancy in a transcriptome-wide fashion by RNA sequencing. To this end, peptide-enhanced pull-down for RNA sequencing (or PEPseq) uses metabolic RNA labelling with 4-thiouridine (4SU) for light-induced protein-RNA crosslinking, and N-hydroxysuccinimide (NHS) chemistry to isolate protein-crosslinked RNA fragments across all long RNA biotypes. We use PEPseq to investigate changes in protein occupancy during the onset of arsenite-induced translational stress in human cells and reveal evidence for ribosome stalling and depletion from stress granules for a distinct set of mRNAs, many coding for ribosomal proteins. We use quantitative proteomics to demonstrate that translation of these mRNAs remains repressed during the initial hours of recovery after arsenite stress. Thus, we present PEPseq as a discovery platform for the unbiased investigation of post-transcriptional regulation.
Targeting triple-negative breast cancer with β1-integrin binding aptamer
Authors: Pleiko Karlis , Haugas Maarja , Parfejevs Vadims , Pantelejevs Teodors , Parisini Emilio , Teesalu Tambet , Riekstina Una
Published: July 2022

Targeted therapies have increased the treatment options for triple-negative breast cancer patients. However, the paucity of targetable biomarkers and tumour heterogeneity have limited the ability of precision-guided interventions to live up to their full potential. As affinity targeting ligands, aptamers show high selectivity towards target molecules. Compared to antibodies, aptamers have lower molecular weight, increased stability during transportation, reduced immunogenicity, and increased tissue uptake. Recently, we reported the discovery of GreenB1 aptamer that is internalized in cultured triple-negative MDA-MB-231 human breast cancer cells. We show that the GreenB1 aptamer specifically targets β1-integrin, a protein previously linked to breast cancer cell invasiveness and migration. Aptamer binds to β1-integrin with low nanomolar affinity. GreenB1 homes in the orthotopic 4T1 triple-negative breast cancer lesions modelled in mice. Our findings suggest potential applications for the GreenB1-guided precision agents for the diagnosis and therapy of triple-negative breast cancer.
A unique peptide recognition mechanism by the human relaxin family peptide receptor 4 (RXFP4)
Authors: Chen Yan , Zhou Qingtong , Wang Jiang , Xu Youwei , Wang Yun , Yan Jiahui , Wang Yibing , Zhu Qi , Zhao Fenghui , Li Chenghao , Chen Chuan-Wei , Cai Xiaoqing , Bathgate Ross A.D. , Shen Chun , Xu H. Eric , Yang Dehua , Liu Hong , Wang Ming-Wei
Published: July 2022

Members of the insulin superfamily regulate a variety of biological processes through two types of target-specific but structurally conserved peptides, insulin/insulin-like growth factors and relaxin/insulin-like peptides. The latter bind to the human relaxin family peptide receptors (RXFPs), which are class A G protein-coupled receptors (GPCRs), to exert pleiotropic actions. Here, we report three cryo-electron microscopy structures of RXFP4–Giprotein complexes in the presence of the endogenous ligand insulin-like peptide 5 (INSL5) or one of the two small molecule agonists, compound 4 and DC591053, both were discovered through medicinal chemistry efforts. The B chain of INSL5 adopts a single α-helix that penetrates into the orthostatic pocket, while the A chain sits above the orthosteric pocket to interact with the extracellular surface of RXFP4, revealing a unique peptide-binding mode previously unknown. Together with mutagenesis and functional analyses, the key determinants responsible for the peptidomimetic agonism and subtype selectivity were identified. DC591053 selectively mimicked the action of INSL5 at RXFP4 whereas compound 4 activated both RXFP3 and RXFP4. Comparison of peptide binding modes within the insulin superfamily displayed diverse interaction mechanisms distinct to each type of the peptides. Our findings not only provide valuable insights into ligand recognition and subtype selectivity among class A GPCRs, but also expand the knowledge of signaling mechanisms in the insulin superfamily.
A clade of RHH proteins ubiquitous in Sulfolobales and their viruses regulates cell cycle progression
Authors: Li X , Lozano-Madueño C , Martínez-Alvarez L , Peng X
Published: July 2022

Cell cycle regulation is crucial for all living organisms and is often targeted by viruses to facilitate their own propagation, yet cell cycle progression control is largely underexplored in archaea. In this work, we reveal a cell cycle regulator (aCcr1) carrying a ribbon-helix-helix (RHH) domain and ubiquitous in the crenarchaeal order Sulfolobales and their viruses. Overexpression of several aCcr1 members including gp21 of rudivirus SIRV2 and its host homolog SiL_0190 of S. islandicus LAL14/1 results in impairment of cell division, evidenced by growth retardation, cell enlargement and an increase in cellular DNA content. Additionally, both gp21 and SiL_0190 can bind to the motif AGTATTA conserved in the promoter of several genes involved in cell division, DNA replication and cellular metabolism thereby repressing or inducing their transcription. Our results suggest that aCcr1 silences cell division and drives progression to the S-phase in Sulfolobales, a function exploited by viruses to facilitate viral propagation.
A multispecific antibody prevents immune escape and confers pan-SARS-CoV-2 neutralization
Authors: Misasi John , Wei Ronnie R. , Wang Lingshu , Pegu Amarendra , Wei Chih-Jen , Oloniniyi Olamide K. , Zhou Tongqing , Moliva Juan I. , Zhao Bingchun , Choe Misook , Yang Eun Sung , Zhang Yi , Boruszczak Marika , Chen Man , Leung Kwan , Li Juan , Yang Zhi-Yong , Andersen Hanne , Carlton Kevin , Godbole Sucheta , Harris Darcy R. , Henry Amy R. , Ivleva Vera B. , Lei Paula , Liu Cuiping , Longobardi Lindsay , Merriam Jonah S. , Nase Danielle , Olia Adam S. , Pessaint Laurent , Porto Maciel , Shi Wei , Wolff Jeremy J. , Douek Daniel C. , Suthar Mehul S. , Gall Jason , Koup Richard A. , Kwong Peter D. , Mascola John R. , Nabel Gary J. , Sullivan Nancy J.
Published: July 2022

Summary Paragraph

Despite effective countermeasures, SARS-CoV-2 persists worldwide due to its ability to diversify and evade human immunity1. This evasion stems from amino-acid substitutions, particularly in the receptor-binding domain of the spike, that confer resistance to vaccines and antibodies2–16. To constrain viral escape through resistance mutations, we combined antibody variable regions that recognize different receptor binding domain (RBD) sites17,18into multispecific antibodies. Here, we describe multispecific antibodies, including a trispecific that prevented virus escape >3000-fold more potently than the most effective clinical antibody or mixtures of the parental antibodies. Despite being generated before the evolution of Omicron, this trispecific antibody potently neutralized all previous variants of concern and major Omicron variants, including the most recent BA.4/BA.5 strains at nanomolar concentrations. Negative stain electron microscopy revealed that synergistic neutralization was achieved by engaging different epitopes in specific orientations that facilitated inter-spike binding. An optimized trispecific antibody also protected Syrian hamsters against Omicron variants BA.1, BA.2 and BA.5, each of which uses different amino acid substitutions to mediate escape from therapeutic antibodies. Such multispecific antibodies decrease the likelihood of SARS-CoV-2 escape, simplify treatment, and maximize coverage, providing a strategy for universal antibody therapies that could help eliminate pandemic spread for this and other pathogens.
Crystal structure and Hirshfeld surface analysis of 2-azido-N-(4-fluorophenyl)acetamide
Authors: Missioui Mohcine , Guerrab Walid , Alsubari Abdulsalam , Mague Joel T. , Ramli Youssef
Published: July 2022

The asymmetric unit of the title compound, C8H7FN4O, consists of two independent molecules differing in the orientation of the azido group. Each molecule forms N—H...O hydrogen-bonded chains along along the c-axis direction with its symmetry-related counterparts and the chains are connected by C—F...π(ring), C=O...π(ring) and slipped π-stacking interactions. A Hirshfeld surface analysis of these interactions was performed.