bluuebunny/crossref_metadata_2025 huggingface dataset:
Monitoring the Sequential Organ Failure Assessment score in nonocclusive mesenteric ischemia increases the survival rate
Authors: Murata Takaaki , Kawachi Jun , Igarashi Yuto , Suno Yuma , Nishida Tomoki , Miyake Katsunori , Isogai Naoko , Fukai Ryuta , Kashiwagi Hiroyuki , Shimoyama Rai , Hirata Masahiro , Shinozaki Nobuaki
Published: December 2021

Several large-scale studies have assessed the endovascular and surgical treatments for nonocclusive mesenteric ischemia (NOMI); nonetheless, the prognostic factors for NOMI remain unclear.

In this single-center study, we retrospectively reviewed the electronic medical records of 197, 149 patients were retrieved from the inpatient database of our hospital from January 2011 to January 2020; 79 patients with NOMI were observed. A total of 44 patients who underwent laparotomy were statistically analyzed and divided into the survivor and non-survivor groups. Prognostic factors were compared between the 2 groups. Exploratory laparotomy based on a second-look surgery was the first treatment choice.

The overall mortality rate was 61.3%, with a male-to-female ratio of 1.6:1. The median Sequential Organ Failure Assessment (SOFA) score was 11.06 [5.75-17.25]. The median SOFA score was 5 [interquartile range: 3-8] in the survivor group and 14.8 [interquartile range: 10.5-19] in the non-survivor group. The log-rank test showed a significant difference in the presence of diabetes mellitus (P = .025), hypoglycemia (P = .001), SOFA score ≥10 (P < .001), hemoglobin levels ≥11 g/dL (P = .003), platelet count ≥12.9 × 104/μL (P = .01), lactate levels ≥2.6 mmol/L (P = .005), and base excess <-3.0 (P < .023). Multivariate analysis using the factors with significant differences revealed that SOFA score ≥10 (hazard ratio for death, 1.199; 95% confidence interval, 1.101-1.305; P < .001) was an independent prognostic factor.

The SOFA score can be used to assess disease severity. A SOFA score of ≥10 may be associated with increased mortality.
Surgical management of a giant venous aneurysm in an autogenous arteriovenous fistula with the vessel loop shoelace technique for wound closure
Authors: Yoo Young Sun
Published: December 2021

Rationale:

Giant venous aneurysm (GVA) is a complication of chronic arteriovenous fistula (AVF). The risks of thrombosis, rupture, and massive hemorrhage increase with the increasing size of GVA; therefore, GVA requires treatment. However, the optimal timing and treatments are yet to be established.

Patient concerns:

A 51-year-old male patient who had been undergoing hemodialysis for 10 years using a left radio-cephalic AVF presented to the hospital with an enormous venous aneurysm.

Diagnosis:

Physical examination and ultrasound revealed a GVA in the AVF.

Intervention:

The aneurysm was resected, and autogenous AVF was concomitantly formed using the basilic vein. The large wound caused by the removed aneurysm defect was closed using the vessel loop shoelace technique.

Outcomes:

The wound healed completely, and the patient has been undergoing hemodialysis using the autogenous AVF created during the surgery for 15 months since then.

Lessons:

Surgical treatment should be considered for symptomatic GVA. Concomitant aneurysm resection and autogenous AVF formation using the basilic vein may be performed, and the resulting large wound can be closed with the vessel loop shoelace technique to facilitate healing.
Risk factors for anterior communicating artery aneurysm rupture
Authors: Xie Yong , Tian Huan , Xiang Bin , Li Ding , Liu Yu-Zhou , Xiang Hua
Published: December 2021

Background:

Although the research on the risk factors of anterior communicating artery (AComA) aneurysm has made great progress, the independent effect of each risk factor on the rupture of AComA aneurysm is controversial among different studies. We will perform a protocol for systematic review and meta-analysis to investigate risk factors for AComA aneurysm rupture and quantify their independent effects.

Methods:

A systematic search according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols guidelines in PubMed, Embase, and the Cochrane Library databases was conducted from inception to August 31, 2021 for published studies concerning risk factors for AComA aneurysm rupture. In the absence of statistical heterogeneity (ie, P > .10 and I
2 < 50%), we will use a fixed-effects model to pool the results across sufficient studies. Otherwise, we will present the results employing the random-effects model. Quality assessment of the included studies will be evaluated using the Newcastle–Ottawa Scale. Statistical analyses will be performed using Stata16 (Stata Corporation, College Station, TX, USA) software.

Results:

The findings of this study will be submitted to peer-reviewed journals for publication.

Conclusion:

This systematic review will provide evidence to determine the risk factors that affect the rupture of the AComA aneurysm and quantify their independent effects.

Ethics and dissemination:

Since the proposed study uses pre-published data, ethical approval is not required.

Review registration number:

CRD42021284262. (https://www.crd.york.ac.uk/PROSPERO/).
Transient lower extremity lymphedema following COVID-19 vaccination
Authors: Chung Jae-Ho , Sohn Sung-Min , Yoo Hyun-Joon , Yoon Eul-Sik , Park Seung-Ha
Published: December 2021

Rationale:

Complications from COVID-19 vaccines have yet to be sufficiently analyzed because they are rapidly approved without long-term data. In particular, there are no case reports of lymphedema in a healthy patient following vaccination. Herein, we report a patient who underwent transient lymphedema after vaccination with BNT16b2.

Patient concerns:

A 79-year-old woman with pitting edema in both lower legs after administration of a second dose of Pfizer vaccine was referred to our clinic. In the absence of clinical evidence of swelling during the laboratory evaluation, we suspected deep vein thrombosis. However, ultrasonographic findings revealed no evidence of venous thrombosis or varicose veins.

Diagnosis:

On the basis of lymphoscintigraphy, the patient was diagnosed with transient lymphedema with decreased lymphatic transport in both lower extremities.

Intervention:

The patient received intensive physiotherapy, including complex decongestive physiotherapy and pneumatic pump compression, to improve the lymphatic circulation. Furthermore, the patient was trained to apply a multilayer compressive bandage to the lower extremities.

Outcomes:

At 2 months follow-up after rehabilitative treatment, the patient's symptoms improved without recurring lymphedema.

Lessons:

In the absence of clinical evidence of swelling during laboratory evaluation or ultrasonographic investigations suggesting deep vein thrombosis, we should consider the possibility of lymphatic disorders.
Effects of intraocular treatments for Epstein-Barr virus (EBV) retinitis
Authors: Mushiga Yasuaki , Komoto Tatsunori , Nagai Norihiro , Ozawa Yoko
Published: December 2021

Rationale:

Intraocular infection of Epstein–Barr virus (EBV) may cause severe visual loss. However, it is relatively rare, and there is no consensus on its treatment.

Patient concerns:

A 44-year-old woman complained of a right-eye floater and exhibited a unilateral exudative change along the retinal veins at the Department of Ophthalmology, St. Luke's International Hospital.

Diagnosis:

EBV retinitis was diagnosed based on EBV-positive (9.09 × 103 copies/μl) and cytomegalovirus-negative results in the aqueous humor.

Interventions:

Oral prescription of valaciclovir hydrochloride, and an intravitreal injection of foscarnet sodium hydrate was administered. However, the retinal infiltration progressed, and vitreous opacity with cellular infiltration appeared. Intravitreal methotrexate (MTX) injection effectively suppressed retinal and vitreous infiltration. However, she developed optic-nerve papillitis, and central retinal vein occlusion related to the severe swelling of the optic-nerve, and began steroid pulse therapy. Considering the increase in intraocular EBV levels to 6.4 × 104 copies/ml, we restarted intravitreal foscarnet injections replacing MTX. This in turn rapidly reduced the EBV levels to 3.27 × 104 copies/ml, followed by papillitis alleviation.

Outcomes:

The intraocular MTX administration reduced the inflammatory vitreous and retinal infiltration, but not the EBV load, while foscarnet reduced the EBV load and papillitis, but not vitreous infiltration.

Lessons:

The retinal infiltration may have involved EBV infection to the retinal neurons but also EBV-free reactive inflammatory cells. EBV infection to the neurons may have been, at least partially, treated by intravitreal foscarnet treatment, and the reactive inflammatory cells by intravitreal MTX. Further observations are warranted to reach a consensus on treating intraocular EBV infection.
Association between body mass index and survival in Taiwanese heart failure patients with and without diabetes mellitus
Authors: Lu Yu Ying , Wu Victor Chien Chia , Chu Pao-Hsien , Ho Chien-Te , Chang Chieh-Yu
Published: December 2021

Body mass index (BMI) is positively associated with survival in heart failure (HF) patients with reduced ejection fraction (HFrEF). However, emerging evidence shows that this benefit may not exist in diabetic patients with HFrEF. As this relationship has not been investigated in Asian patients, the aim of this study was to examine the association between obesity and outcomes in HrEFF patients with and without diabetes mellitus (DM), and discuss the potential underlying mechanisms.

The analysis included 900 patients with acute decompensated HF from the Taiwan Society of Cardiology-Heart Failure with Reduced Ejection Fraction Registry, of whom 408 had DM (45%). The association between BMI and all-cause mortality was examined using multivariate Cox proportional hazards regression after adjusting for covariates and Kaplan–Meier survival analysis. Echocardiography parameters were also analyzed in patients with different BMI and DM status.

After adjusting for confounding factors, BMI was a significant independent predictive factor for all-cause mortality in the non-diabetic patients (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.81–0.95) and in Kaplan–Meier survival analysis (log-rank test, P = .034). For diabetic patients, BMI was not a significant predictive factor for all-cause mortality (HR, 0.96; 95% CI, 0.90–1.02) and in Kaplan–Meier survival analysis (log-rank test P = .169). Both DM (47.8 vs 45.4 mm, P = .014) and higher BMI (48.6 vs 44.9 mm, P < .001) are independently associated with higher left atrial size. Patients with a higher BMI had a lower proportion of severe mitral regurgitation (10.0% vs 14.1%, P < .001).

In non-diabetic patients with HFrEF, BMI was a significant predictor of survival. However, in diabetic patients with HF, BMI was not a significant predictor of survival. Diastolic dysfunction in patients with DM and obesity may have played a role in this finding.
Mechanism research of Salvia miltiorrhiza on treating myocardial ischemia reperfusion injury according to network pharmacology combined with molecular docking technique
Authors: Jiang Zhiyan
Published: December 2021

Myocardial ischemia reperfusion injury (MIRI) is a kind of complicated disease with an increasing incidence all over the world. Danshen was shown to exert therapeutic effect on MIRI. However, its chemical and pharmacological profiles remain to be elucidated. Network pharmacology was applied to characterize the mechanisms of Danshen on MIRI.

The active compounds were screened from the online database according to their oral bioavailability and drug-likeness. The potential proteins of Danshen were collected from the TCMSP database, whereas the potential genes of MIRI were obtained from Gene Card database. The function of gene and pathways involved were researched by GO and KEGG enrichment analysis. The compounds-targets and protein–protein interaction networks were constructed by Cytoscape software. The affinity between active components and potential targets was detected by molecular docking simulation.

A total of 202 compounds in Danshen were obtained, and 65 were further selected as active components for which conforming to criteria. Combined the network analysis and molecular docking simulation, the results firstly demonstrated that the effect of Danshen on MIRI may be realized through the targeting of vascular endothelial growth factor A, interleukin-6, and AKT1 by its active components tanshinone IIA, cryptotanshinone, and luteolin. The main regulatory pathways involved may include PI3K/ Akt signaling pathway, HIF-1 signaling pathway, and interleukin-17 signaling pathway. The present study firstly researched the mechanism of Danshen on MIRI based on network pharmacology.

The results revealed the multicomponents and multi-targets effects of Danshen in the treatment of MIRI. Importantly, the study provides objective basis for further experimental research.
Intention to quit smoking according to smoking preferences and perceptions of electronic cigarettes among university students in South Korea
Authors: Choi Ryoung , Kang Hyun Goo
Published: December 2021

This study aimed to alleviate unhealthy smoking habits among university students and provide the basic data necessary for public health-oriented approaches such as developing regulations and policies on electronic cigarettes by analyzing the relationship between university students’ smoking preferences, perceptions of electronic cigarettes, and intention to quit smoking.

This study involved 567 college students and conducted frequency and chi-squared analyses of the general characteristics, smoking preferences, and perceptions of electronic cigarettes. This study also performed logistic regression analysis to analyze the relationship between intention to quit smoking stratified by smoking preferences and the perceptions about electronic cigarettes. SPSS version 25.0 was used for data analysis.

This study showed that electronic cigarette smokers were approximately 6.4 to 10.8 times more likely to think that electronic cigarettes positively affect smoking cessation attitude than nonsmokers. This study showed that regular cigarette smokers were approximately 1.7 to 2.2 times and other smoker 3.3 to 3.9 times more likely to think that electronic cigarettes positively affect smoking cessation attitude than nonsmokers. Those who perceived harmless to the human body, capable of reducing the frequency of smoking, and less harmful than tobacco were approximately 2.6 to 2.9, 11.6 to 12.8, and 3.3 to 3.7 times more likely have intention to quit smoking, respectively.

Regular health education, advertising awareness of health hazards, and public health science-oriented approaches and policies for smoking cessation support services are needed to create awareness on electronic cigarettes among university students.
Endoscopic sleeve gastroplasty and postprocedural nutritional deficiencies: results from a single center exploratory study
Authors: Ghoz Hassan , Bryant Mikel , Fritz Haley , Brown Lauren , Ames Gretchen , Ghazanfari Lisa , Lynch Scott A. , Osborne Tina , Gómez Victoria
Published: December 2021

Nutritional deficiencies following endoscopic sleeve gastroplasty (ESG) are unknown. We retrospectively studied nutritional deficiencies in 20 patients who underwent ESG at our institution. No subjects had preprocedural anemia, whereas 22.2% (N = 2/9) developed anemia at 12 months. Vitamin D deficiency developed in one subject post-ESG. Vitamin A, E, C and magnesium deficiencies developed in 8.3% (N = 1/12), 18.2% (N = 2/11), 14.3% (N = 1/7) and 10% (N = 1/10) of subjects, respectively, at 12 months. Vitamin B12 and B6 deficiencies were detected in 12.5 and 14.3% of the subjects at baseline, however, resolved at 12 months. There were no pre- or postprocedural deficiencies in zinc, selenium, copper, folate, thiamine, phosphorus or calcium. In this study, nutritional deficiencies were observed in a very small subset of patients at various time points after ESG.
Functional Gastrointestinal Disorders in Mediterranean Countries According to Rome IV Criteria
Authors: Strisciuglio Caterina , Cenni Sabrina , Serra Maria Rosaria , Dolce Pasquale , Kolacek Sanja , Sila Sara , Trivic Ivana , Lev Michal Rozenfeld Bar , Shamir Raanan , Kostovski Aco , Papadopoulou Alexandra , Roma Elefthería , Katsagoni Christina , Jojkic‐Pavkov Danijela , Salvatore Silvia , Pensabene Licia , Scarpato Elena , Miele Erasmo , Staiano Annamaria ,   Angelo Campanozzi, and Maria Fotoulaki
Published: December 2021

Objectives:

The aim of this study was to assess the prevalence of functional gastrointestinal disorders (FGIDs) in children of Mediterranean area using Rome IV criteria and to compare the prevalence of FGIDs using Rome IV and Rome III criteria.

Methods:

This was a cross‐sectional study enrolling children and adolescents living in Croatia, Greece, Israel, Italy, Macedonia, and Serbia. Subjects were examined in relation to the presence of FGIDs, using the Rome IV criteria. Data were compared with the results of a previous study using Rome III data.

Results:

We analyzed 1972 children ages 4 to 9 years (group A), and 2450 adolescents 10 to 18 years old (group B). The overall prevalence of FGIDs was 16% in group A and 26% in group B, with statistical differences among countries in both groups (P < 0.001). In group A, the prevalence of FGIDs and of functional constipation (FC) was significantly lower than in the previous study (P < 0.001), whereas in group B no significant difference was found. In both groups of age, the prevalence of abdominal migraine and irritable bowel syndrome decreased significantly (P < 0.001 and P < 0.001, respectively) using Rome IV versus Rome III criteria, conversely functional dyspepsia increased (P < 0.001).

Conclusions:

FGIDs are common in children and adolescents, their frequency increases with age, and there is a significant variation in the prevalence of some FGIDs among different European countries. The application of the Rome IV criteria resulted in a significantly lower prevalence of FGIDs in children compared with Rome III criteria.
Celiac Disease
Authors: Habash Nawras , Choung Rok Seon , Jacobson Robert M. , Murray Joseph A. , Absah Imad
Published: December 2021

Objective:

The aim of our study was to assess the response to hepatitis B virus (HBV) vaccination and the risk of HBV infection in patients with celiac disease (CD).

Patients and Methods:

We performed a cross‐sectional study using the National Health and Nutrition Examination Survey (NHANES) database (2009–2014) to assess the rate of HBV vaccination, immune response, and HBV infection risk in patients with and without CD. We also determined the rate of HBV infection via retrospective analysis of two cohorts: patients seen at Mayo Clinic (1998–2021), and a stable longitudinally observed cohort, the Rochester Epidemiology Project (REP; 2010–2020).

Results:

Based on the NHANES data, the rate of HBV infection in the United States was 0.33% (95% confidence interval 0.25–0.41). Of 93 patients with CD, 46 (49%) were vaccinated for HBV and of the remaining 19,422 without CD, 10,228 (53%) were vaccinated. Twenty‐two (48%) vaccinated patients with CD had HBV immunity and 4405 (43.07%) vaccinated patients without CD had HBV immunity, which was not statistically different. In NHANES data, there were no cases of HBV infection in patients with CD. During the study period, 3568 patients with CD were seen at Mayo Clinic and 3918 patients with CD were identified using the REP database. Of those patients with CD, only four (0.11%) at Mayo Clinic and nine (0.23%) of the REP patients had HBV infection.

Conclusion:

The rate of HBV vaccination and immunity was similar in individuals with and without CD. Predictably, no increased risk of HBV infection was detected in CD patients. These results do not support screening and revaccination practice for HBV immunity in patients with CD within the United States.
The Use of Hyperbaric Oxygen Therapy in the Management of Severe Radiation-Induced Hemorrhagic Gastritis in a Pediatric Patient
Authors: Rabinovich Erica , Johnson-Arbor Kelly , Serrano Mariastella , Chao Catherine , Eblan Michael J. , Rao Avani D. , Terao Michael , Toretsky Jeffrey , Sarangi Susmita , Varela Carly , Hong Dahye
Published: December 2021

Radiation-induced hemorrhagic gastritis is a serious and rare complication of radiation therapy. Optimal therapies in the pediatric population are not well established. We report a 2-year-old female diagnosed with rhabdomyosarcoma who developed hemorrhagic gastritis following chemotherapy and radiation therapy. The patient presented with acute onset anemia, hematemesis, and melena. Endoscopies revealed circumferential ulceration at the pylorus with spontaneous oozing that failed to respond effectively with multimodal medical and endoscopic therapies. Following hemodynamic stabilization, the patient was treated with hyperbaric oxygen therapy with excellent clinical response of the bleeding. Further research on the benefit of hyperbaric oxygen therapy is warranted to determine if this treatment can reduce the incidence of gastrointestinal complications in patients who have received radiation therapy.
ECTyper: in silico Escherichia coli serotype and species prediction from raw and assembled whole-genome sequence data
Authors: Bessonov Kyrylo , Laing Chad , Robertson James , Yong Irene , Ziebell Kim , Gannon Victor P. J. , Nichani Anil , Arya Gitanjali , Nash John H. E. , Christianson Sara
Published: December 2021

Escherichia coli

is a priority foodborne pathogen of public health concern and phenotypic serotyping provides critical information for surveillance and outbreak detection activities. Public health and food safety laboratories are increasingly adopting whole-genome sequencing (WGS) for characterizing pathogens, but it is imperative to maintain serotype designations in order to minimize disruptions to existing public health workflows. Multiple in silico tools have been developed for predicting serotypes from WGS data, including SRST2, SerotypeFinder and EToKi EBEis, but these tools were not designed with the specific requirements of diagnostic laboratories, which include: speciation, input data flexibility (fasta/fastq), quality control information and easily interpretable results. To address these specific requirements, we developed ECTyper (https://github.com/phac-nml/ecoli_serotyping) for performing both speciation within

Escherichia

and

Shigella

, and in silico serotype prediction. We compared the serotype prediction performance of each tool on a newly sequenced panel of 185 isolates with confirmed phenotypic serotype information. We found that all tools were highly concordant, with 92–97 % for O-antigens and 98–100 % for H-antigens, and ECTyper having the highest rate of concordance. We extended the benchmarking to a large panel of 6954 publicly available

E. coli

genomes to assess the performance of the tools on a more diverse dataset. On the public data, there was a considerable drop in concordance, with 75–91 % for O-antigens and 62–90 % for H-antigens, and ECTyper and SerotypeFinder being the most concordant. This study highlights that in silico predictions show high concordance with phenotypic serotyping results, but there are notable differences in tool performance. ECTyper provides highly accurate and sensitive in silico serotype predictions, in addition to speciation, and is designed to be easily incorporated into bioinformatic workflows.
Graph Neural Network Modelling as a potentially effective Method for predicting and analyzing Procedures based on Patient Diagnoses
Authors: Ochoa Juan G. Diaz , Mustafa Faizan
Published: December 2021

Abstract

Background

Currently, the healthcare sector strives to increase the quality of patient management and improve the economic performance of healthcare providers. The data contained in electronic health records (EHRs) offer the potential to discover relevant patterns that aim to relate diseases and therapies, and thus discover patterns that could help identify empirical medical guidelines that reflect best practices in the healthcare system. Based on this pattern identification, it is then possible to implement recommendation systems based on the idea that a higher volume of procedures is associated with high-quality models.

Methods

Although there are several applications that use machine learning methods to identify these patterns, this identification is still a challenge, in part because these methods often ignore the basic structure of the population, considering the similarity of diagnoses and patient typology. To this end, we have developed graph methods that aim to cluster similar patients. In such models, patients are linked when the same or similar patterns can be observed for these patients, a concept that enables the construction of a network-like structure. This structure can then be analyzed with Graph Neural Networks (GNN) to identify relevant labels, in this case the appropriate medical procedures.

Results

We report the construction of a patient Graph structure based on basic patient’s information like age and gender as well as the diagnoses and trained GNNs models to identify the corresponding patient’s therapies using a synthetic patient database. We compared our GNN models against different baseline models (using the SCIKIT-learn library of python) and compared the performance of the different model methods. We have found that GNNs are superior, with an average improvement of thef1score of 6.48% respect to the baseline models. In addition, the GNNs are useful for performing additional clustering analyses that allow specific identification of specific therapeutic clusters related to a particular combination of diagnoses.

Conclusions

We found that GNNs are a promising way to model the distribution of diagnoses in a patient population and thus better model how similar patients can be identified based on the combination of morbidities and comorbidities. Nevertheless, network building is still challenging and prone to prejudice, as it depends on how ICD distribution affects the patient network embedding space. This network setup requires not only a high quality of the underlying diagnostic ecosystem, but also a good understanding of how to identify related patients by disease. For this reason, additional work is needed to improve and better standardize patient embedding in graph structures for future investigations and applications of services based on this technology, and therefore is not yet an interventional study.
A public antibody class recognizes a novel S2 epitope exposed on open conformations of SARS-CoV-2 spike
Authors: Claireaux Mathieu , Caniels Tom G , de Gast Marlon , Han Julianna , Guerra Denise , Kerster Gius , van Schaik Barbera DC , Jongejan Aldo , Schriek Angela I. , Grobben Marloes , Brouwer Philip JM , van der Straten Karlijn , Aldon Yoann , Capella-Pujol Joan , Snitselaar Jonne L , Olijhoek Wouter , Aartse Aafke , Brinkkemper Mitch , Bontjer Ilja , Burger Judith A , Poniman Meliawati , Bijl Tom PL , Torres Jonathan L , Copps Jeffrey , Martin Isabel Cuella , de Taeye Steven W , de Bree Godelieve J , Ward Andrew B , Sliepen Kwinten , van Kampen Antoine HC , Moerland Perry D , Sanders Rogier W , van Gils Marit J
Published: December 2021

Delineating the origins and properties of antibodies elicited by SARS-CoV-2 infection and vaccination is critical for understanding their benefits and potential shortcomings. Therefore, we investigated the SARS-CoV-2 spike (S)-reactive B cell repertoire in unexposed individuals by flow cytometry and single-cell sequencing. We found that ∼82% of SARS-CoV-2 S-reactive B cells show a naive phenotype, which represents an unusually high fraction of total human naive B cells (∼0.1%). Approximately 10% of these naive S-reactive B cells shared an IGHV1-69/IGKV3-11 B cell receptor pairing, an enrichment of 18-fold compared to the complete naive repertoire. A proportion of memory B cells, comprising switched (∼0.05%) and unswitched B cells (∼0.04%), was also reactive with S and some of these cells were reactive with ADAMTS13, which is associated with thrombotic thrombocytopenia. Following SARS-CoV-2 infection, we report an average 37-fold enrichment of IGHV1-69/IGKV3-11 B cell receptor pairing in the S-reactive memory B cells compared to the unselected memory repertoire. This class of B cells targets a previously undefined non-neutralizing epitope on the S2 subunit that becomes exposed on S proteins used in approved vaccines when they transition away from the native pre-fusion state because of instability. These findings can help guide the improvement of SARS-CoV-2 vaccines.
Fitness and mating consequences of variation in male allocation in a wind pollinated plant
Authors: Aljiboury Abrar A. , Friedman Jannice
Published: December 2021

In hermaphrodites, the allocation of resources to each sex function can influence fitness through reproductive success and mating success. In wind pollinated plants, sex allocation theory predicts that male fitness increases linearly with investment of resources into male function. However, there have been few empirical tests of this prediction. We experimentally manipulated allocation to male function inAmbrosia artemisiifolia(common ragweed) in a field experiment and measured mating success using genetic assays. We investigated the effects of various morphological traits and flowering phenology on male fitness, and on male and female mate diversity. Our results provide evidence for a linear relation between allocation to male function and fitness. We find earlier onset of male flowering time increases reproductive success, while later onset flowering time increases the probability of mating with diverse individuals. This research is among the first empirical studies testing the prediction of linear male fitness returns in wind pollinated plants. Our results provide insight into the large investment into male function by wind pollinated plants and temporal variation in sex allocation.
Dietary and serum tyrosine, white matter microstructure and inter-individual variability in executive functions in overweight adults: relation to sex/gender and age
Authors: A-K Brecht , Medawar E , Thieleking R , Sacher J , Beyer F , Villringer A , Witte AV
Published: December 2021

Tyrosine (tyr), the precursor of the neurotransmitter dopamine, is known to modulate cognitive functions including executive attention. Tyr supplementation is suggested to influence dopamine-modulated cognitive performance. However, results are inconclusive, regarding the presence or strength and also the direction of the association between tyr and cognitive function. This pre-registered cross-sectional analysis investigates whether diet-associated serum tyr relates to executive attention performance, and whether this relationship is moderated by differences in white matter microstructure. 59 healthy, overweight, young to middle-aged adults (20F, 28.3 ± 6.6 years, BMI: 27.3 ± 1.5 kg/m2) drawn from a longitudinal study reported dietary habits, donated blood and completed diffusion-weighted brain magnetic resonance imaging and the attention network test. Main analyses were performed using linear regressions and non-parametric voxel-wise inference testing.

Confirmatory analyses did neither support an association between dietary and serum tyr nor a relationship between relative serum tyr/large neutral amino acids (LNAA) levels or white matter microstructure and executive attention performance. However, exploratory analyses revealed higher tyr intake, higher serum tyr and better executive attention performance in the male sex/gender group. In addition, older age was associated with higher dietary tyr intake and lower fractional anisotropy in a widespread cluster across the brain. Finally, a positive association between relative serum tyr/LNAA and executive attention performance was found in the male sex/gender group when accounting for age effects.

Our analysis advances the field of dopamine-modulated cognitive functions by revealing sex/gender and age differences which might be diet-related. Longitudinal or intervention studies and larger sample sizes are needed to provide more reliable evidence for links between tyr and executive attention.
Information flow across the cortical timescales hierarchy during narrative construction
Authors: Chang Claire H. C. , Nastase Samuel A. , Hasson Uri
Published: December 2021

When listening to spoken narratives, we must integrate information over multiple, concurrent timescales, building up from words to sentences to paragraphs to a coherent narrative. Recent evidence suggests that the brain relies on a chain of hierarchically organized areas with increasing temporal receptive windows to process naturalistic narratives. We hypothesized that the structure of this cortical processing hierarchy should result in an observable sequence of response lags between networks comprising the hierarchy during narrative comprehension. This study uses functional MRI to estimate the response lags between functional networks during narrative comprehension. We use inter-subject cross-correlation analysis to capture network connectivity driven by the shared stimulus. We found a fixed temporal sequence of response lags—on the scale of several seconds—starting in early auditory areas, followed by language areas, the attention network, and lastly the default mode network. This gradient is consistent across eight distinct stories but absent in data acquired during rest or using a scrambled story stimulus, supporting our hypothesis that narrative construction gives rise to inter-network lags. Finally, we build a simple computational model for the neural dynamics underlying the construction of nested narrative features. Our simulations illustrate how the gradual accumulation of information within the boundaries of nested linguistic events, accompanied by increased activity at each level of the processing hierarchy, can give rise to the observed lag gradient.

Significance Statement

Our findings reveal a consistent, stimulus-driven gradient of lags in connectivity along the cortical processing hierarchy—from early auditory cortex to the language network, then to the default mode network—during the comprehension of naturalistic, spoken narratives. We provide a simple computational model for the neural dynamics underlying the construction of nested narrative features, allowing us to systematically explore the conditions under which the lag gradient emerges and synthesize our results with previous findings based on simple well-controlled language stimuli. Our results illustrate the isomorphism between hierarchically structured neural dynamics and hierarchically structured, real-world narrative inputs.
Neutralization Fingerprinting Technology for Characterizing Polyclonal Antibody Responses to Dengue Vaccines
Authors: Raju Nagarajan , Zhan Xiaoyan , Das Subash , Karwal Lovkesh , Dean Hansi J. , Crowe James E. , Carnahan Robert H. , Georgiev Ivelin S.
Published: December 2021

Dengue is a major public health threat. There are four serotypes of dengue virus (DENV), therefore efforts are focused on development of safe and effective tetravalent DENV vaccines. While neutralizing antibodies contribute to protective immunity, there are still important gaps in understanding of immune responses elicited by dengue infection and vaccination, including defining immune correlates of protection. To that end, here we present a computational modeling framework for evaluating the specificities of neutralizing antibodies elicited to tetravalent DENV vaccines, based on the concept of antibody-virus neutralization fingerprints. We developed and applied this framework to samples from clinical studies of TAK-003, a tetravalent vaccine candidate currently in phase 3 trials, to characterize the effect of prior dengue infection (baseline) on the specificities of vaccine-elicited antibody responses. Our results suggested a similarity of neutralizing antibody specificities in baseline-seronegative individuals. In contrast, amplification of pre-existing neutralizing antibody specificities was predicted for baseline-seropositive individuals, thus quantifying the role of immunologic imprinting in driving antibody responses to DENV vaccines. The analysis framework proposed here can apply to studies of sequential dengue infections and other tetravalent DENV vaccines and can contribute to understanding dengue immune correlates of protection to help guide further vaccine development and optimization.
A versatile new ubiquitin detection and purification tool derived from a bacterial deubiquitylase
Authors: Zhang Mengwen , Berk Jason M. , Mehrtash Adrian B. , Kanyo Jean , Hochstrasser Mark
Published: December 2021

Protein ubiquitylation is an important post-translational modification affecting an wide range of cellular processes. Due to the low abundance of ubiquitylated species in biological samples, considerable effort has been spent on developing methods to purify and detect ubiquitylated proteins. We have developed and characterized a novel tool for ubiquitin detection and purification based on OtUBD, a high-affinity ubiquitin-binding domain derived from anOrientia tsutsugamushideubiquitylase. We demonstrate that OtUBD can be used to purify both monoubiquitylated and polyubiquitylated substrates from yeast and human tissue culture samples and compare their performance with existing methods. Importantly, we found conditions for either selective purification of covalently ubiquitylated proteins or co-isolation of both ubiquitylated proteins and their interacting proteins. As a proof-of-principle for these newly developed methods, we profiled the ubiquitylome and ubiquitin-associated proteome of the yeastSaccharomyces cerevisiae. Combining OtUBD affinity purification with quantitative proteomics, we identified potential substrates for E3 ligases Bre1 and Pib1. OtUBD provides a versatile, efficient, and economical tool for ubiquitin researchers with specific advantages over other methods, such as in detecting monoubiquitylation or ubiquitin linkages to noncanonical sites.
Predicting the functional effects of voltage-gated potassium channel missense variants with multi-task learning
Authors: Boßelmann Christian Malte , Hedrich Ulrike B.S. , Müller Peter , Sonnenberg Lukas , Parthasarathy Shridhar , Helbig Ingo , Lerche Holger , Pfeifer Nico
Published: December 2021

Purpose

Variants in genes encoding voltage-gated potassium channels are associated with a broad spectrum of neurological diseases including epilepsy, ataxia, and intellectual disability. Knowledge of the resulting functional changes, characterized as overall ion channel gain- or loss-of-function, is essential to guide clinical management including precision medicine therapies. However, for an increasing number of variants, little to no experimental data is available. New tools are needed to evaluate variant functional effects.

Methods

We catalogued a comprehensive dataset of 959 functional experiments across 19 voltage-gated potassium channels, leveraging data from 782 unique disease-associated and synthetic variants. We used these data to train a taxonomy-based multi-task learning support vector machine (MTL-SVM), and compared performance to a baseline of standard SVMs.

Results

MTL-SVM maintains channel family structure during model training, improving overall predictive performance (mean balanced accuracy 0.729 ± 0.029, AU-ROC 0.757 ± 0.039) over baseline (mean balanced accuracy 0.645 ± 0.041, AU-ROC 0.710 ± 0.074). We can obtain meaningful predictions even for channels with few known variants (KCNC1, KCNQ5).

Conclusion

Our model enables functional variant prediction for voltage-gated potassium channels. It may assist in tailoring current and future precision therapies for the increasing number of patients with ion channel disorders.
A 3’-end capture sequencing method for high-throughput targeted gene expression profiling
Authors: de Bony Eric , Gysens Fien , Yigit Nurten , Anckaert Jasper , Everaert Celine , Eynde Eveline Vanden , Verniers Kimberly , Van Snippenberg Willem , Trypsteen Wim , Mestdagh Pieter
Published: December 2021

Molecular phenotyping through shallow 3’-end RNA-sequencing workflows is increasingly applied in the context of large-scale chemical or genetic perturbation screens to study disease biology or support drug discovery. While these workflows enable accurate quantification of the most abundant genes, they are less effective for applications that require expression profiling of low abundant transcripts, like long non-coding RNAs (lncRNAs), or selected gene panels. To tackle these issues, we describe a workflow combining 3’-end library preparation with 3’-end hybrid capture probes and shallow RNA-sequencing for cost-effective, targeted quantification of subsets of (low abundant) genes across hundreds to thousands of samples. To assess the performance of the method, we designed a capture probe set for more than 100 mRNA and lncRNA target genes and applied the workflow to a cohort of 360 samples. When compared to standard 3’-end RNA-sequencing, 3’-end capture sequencing resulted in a more than 100-fold enrichment of target gene abundance while conserving relative inter-gene and inter-sample abundances. 3’-end RNA capture sequencing enables accurate targeted gene expression profiling at extremely shallow sequencing depth.
Attracting pollinators vs escaping herbivores: eco-evolutionary dynamics of plants confronted with an ecological trade-off
Authors: Yacine Youssef , Loeuille Nicolas
Published: December 2021

Many plant traits are subject to an ecological trade-off between attracting pollinators and escaping herbivores. The interplay of both plant-animal interaction types determines their evolution. As most studies focus on either pollination or herbivory, how they jointly affect the eco-evolutionary dynamics of plant-animal communities is often left unknown. Within a plant-pollinator-herbivore community where interaction strengths depend on trait matching, we consider the evolution of a plant trait involved in both plant-animal interactions. Using adaptive dynamics, we uncover when stabilizing, runaway (i.e. directional) or disruptive selection emerges and its consequences for multispecies coexistence. We find that strong pollination relative to herbivory favors stabilizing selection and coexistence. Strong herbivory relative to pollination fosters runaway selection and threatens coexistence. Importantly, given balanced interactions, joint effects may lead to disruptive selection, allowing the emergence of plant dimorphism. The strength of the ecological trade-off largely explains the occurrence of these contrasting eco-evolutionary dynamics. In particular, plant diversification requires strong trade-offs, with the strongest trade-offs allowing long-term polymorphism. We discuss how our results relate to various empirical cases where the interplay of pollination and herbivory maintains plant polymorphism. Beyond maintenance, our work suggests that it might also have fueled the diversification process itself.

Graphical Abstract

Eco-evolutionary dynamics resulting from the evolution of plant phenotype under ecological trade-off

A. Typical eco-evolutionary landscape. The type of selection and the ecological outcome depend on the dissimilarity between animal phenotypes (i.e. preferences for plant phenotype), which is a proxy for the strength of the ecological trade-off.B. The long-term community compositiondepends on the type of selection.(1)Runaway selection leads to the extinction of a first animal species as the plant phenotype is diverging.(a)Pollinators are lost first so that runway selection continues until herbivores are also lost.(b)Herbivores are lost first so that selection turns stabilizing over time, leading to a perfect plant-pollinator matching.(2)Stabilizing selection can enable the maintenance of coexistence.(3)Disruptive selection leads to the emergence of plant dimorphism.
MDR1 Drug Efflux Pump Promotes Intrinsic and Acquired Resistance to PROTACs in Cancer Cells
Authors: Kurimchak Alison M. , Herrera-Montávez Carlos , Montserrat Sara , Araiza Daniela , Hu Jianping , Jin Jian , Duncan James S.
Published: December 2021

PROTACs (Proteolysis-Targeting Chimeras) represent a promising new class of drugs that selectively degrade proteins of interest from cells. PROTACs targeting oncogenes are avidly being explored for cancer therapies, with several currently in clinical trials. Drug resistance represents a significant challenge in cancer therapies, and the mechanism by which cancer cells acquire resistance to PROTACs remains poorly understood. Using proteomics, we discovered acquired and intrinsic resistance to PROTACs in cancer cells can be mediated by upregulation of the drug efflux pump MDR1. PROTAC-resistant cells could be re-sensitized to PROTACs through co-administering MDR1 inhibitors. Notably, co-treatment of MDR1-overexpressing colorectal cancer cells with MEK1/2 or KRASG12C degraders and the dual ErbB receptor/MDR1 inhibitor lapatinib exhibited potent drug synergy due to simultaneous blockade of MDR1 and ErbB receptor activity. Together, our findings suggest that concurrent blockade of MDR1 will likely be required in combination with PROTACs to achieve durable protein degradation and therapeutic response in cancer.
Comparison of subjective peripheral sensation, F-waves, and somatosensory evoked potentials in response to a unilateral pinch task measured on the contractile and non-contractile sides
Authors: Takahara Terumasa , Yamaguchi Hidetaka , Seki Kazutoshi , Onodera Sho
Published: December 2021

Depression of sensory input during voluntary muscle contractions has been demonstrated using electrophysiological methods in both animals and humans. However, the association between electrophysiological responses of the sensory system and subjective peripheral sensation (SPS) during a voluntary muscle contraction remains unclear. Our aim in this study was to describe the changes in SPS, spinal α-motoneuron excitability (F-wave to M-wave amplitude), and somatosensory evoked potentials (SEPs) during a unilateral pinch-grip task. Outcome variables were measured on the side ipsilateral and contralateral to the muscle contraction, and at rest (control). Participants were 8 healthy men, 20.9±0.8 years of age. The isometric pinch-grip task was performed at 30% of the maximum voluntary isometric force measured for the right and left hand separately. The appearance rate of the F-wave during the task was significantly higher for the ipsilateral (right) hand than for the contralateral (left) hand and control condition. Although there was no difference in F-wave latency between hands and the control condition, the amplitude of the F-wave was significantly higher for the ipsilateral (right) hand than for the contralateral (left) hand and the control condition. There was no difference in the amplitude of the SEP at N20. However, the amplitude at P25 was significantly lower for the ipsilateral (right) hand than for the contralateral (left) hand and the control condition. The accuracy rate of detecting tactile stimulation, evaluated for 20 repetitions using a Semmes–Weinstein monofilament at the sensory threshold for each participant, was significantly lower during the pinch-grip task for both the ipsilateral (right) and contralateral (left) hand compared to the control condition. Overall, our findings show that SPS and neurophysiological parameters were not modulated in parallel during the task, with changes in subjective sensation preceding changes in electrophysiological indices during the motor task. Our findings provide basic information on sensory-motor coordination.