bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting NR4A Nuclear Receptors to Control Stromal Cell Inflammation, Metabolism, Angiogenesis, and Tumorigenesis
Authors: Crean Daniel , Murphy Evelyn P.
Published: February 2021

The NR4A1–NR4A3 (Nur77, Nurr1, and Nor-1) subfamily of nuclear receptors is a group of immediate early genes induced by a pleiotropy of stimuli including peptide hormones, growth factors, cytokines, inflammatory, and physiological stimuli, and cellular stress. NR4A receptors function as potent sensors of changes in the cellular microenvironment to control physiological and pathological processes through genomic and non-genomic actions. NR4A receptors control metabolism and cardiovascular and neurological functions and mediate immune cell homeostasis in inflammation and cancer. This receptor subfamily is increasingly recognized as an important molecular connection between chronic inflammation, altered immune cell responses, and cancer development. In this review, we examine how transcriptome analysis identified NR4A1/NR4A2 receptors as transcriptional regulators in mesenchymal stromal cell (MSC) migration, cell cycle progression, and cytokine production to control local immune responses. In chronic inflammatory conditions, such as rheumatoid arthritis, NR4A receptors have been shown to modify the activity of MSC and fibroblast-like stromal cells to regulate synovial tissue hyperplasia, pathological angiogenesis, and cartilage turnover in vivo. Additionally, as NR4A1 has been observed as a major transcriptional regulator in tumor–stromal communication controlling tumorigenesis, we discuss how advances in the pharmacological control of these receptors lead to important new mechanistic insights into understanding the role of the tumor microenvironment in health and disease.
Learning Language and Acoustic Models for Identifying Alzheimer’s Dementia From Speech
Authors: Shah Zehra , Sawalha Jeffrey , Tasnim Mashrura , Qi Shi-ang , Stroulia Eleni , Greiner Russell
Published: February 2021

Alzheimer’s dementia (AD) is a chronic neurodegenerative illness that manifests in a gradual decline of cognitive function. Early identification of AD is essential for managing the ensuing cognitive deficits, which may lead to a better prognostic outcome. Speech data can serve as a window into cognitive functioning and can be used to screen for early signs of AD. This paper describes methods for learning models using speech samples from the DementiaBank database, for identifying which subjects have Alzheimer’s dementia. We consider two machine learning tasks: 1) binary classification to distinguish patients from healthy controls, and 2) regression to estimate each subject’s Mini-Mental State Examination (MMSE) score. To develop models that can use acoustic and/or language features, we explore a variety of dimension reduction techniques, training algorithms, and fusion strategies. Our best performing classification model, using language features with dimension reduction and regularized logistic regression, achieves an accuracy of 85.4% on a held-out test set. On the regression task, a linear regression model trained on a reduced set of language features achieves a root mean square error (RMSE) of 5.62 on the test set. These results demonstrate the promise of using machine learning for detecting cognitive decline from speech in AD patients.
Hemodynamic Modeling of Biological Aortic Valve Replacement Using Preoperative Data Only
Authors: Hellmeier Florian , Brüning Jan , Sündermann Simon , Jarmatz Lina , Schafstedde Marie , Goubergrits Leonid , Kühne Titus , Nordmeyer Sarah
Published: February 2021

Objectives: Prediction of aortic hemodynamics after aortic valve replacement (AVR) could help optimize treatment planning and improve outcomes. This study aims to demonstrate an approach to predict postoperative maximum velocity, maximum pressure gradient, secondary flow degree (SFD), and normalized flow displacement (NFD) in patients receiving biological AVR.

Methods: Virtual AVR was performed for 10 patients, who received actual AVR with a biological prosthesis. The virtual AVRs used only preoperative anatomical and 4D flow MRI data. Subsequently, computational fluid dynamics (CFD) simulations were performed and the abovementioned hemodynamic parameters compared between postoperative 4D flow MRI data and CFD results.

Results: For maximum velocities and pressure gradients, postoperative 4D flow MRI data and CFD results were strongly correlated (R2 = 0.75 and R2 = 0.81) with low root mean square error (0.21 m/s and 3.8 mmHg). SFD and NFD were moderately and weakly correlated at R2 = 0.44 and R2 = 0.20, respectively. Flow visualization through streamlines indicates good qualitative agreement between 4D flow MRI data and CFD results in most cases.

Conclusion: The approach presented here seems suitable to estimate postoperative maximum velocity and pressure gradient in patients receiving biological AVR, using only preoperative MRI data. The workflow can be performed in a reasonable time frame and offers a method to estimate postoperative valve prosthesis performance and to identify patients at risk of patient-prosthesis mismatch preoperatively. Novel parameters, such as SFD and NFD, appear to be more sensitive, and estimation seems harder. Further workflow optimization and validation of results seems warranted.
Systemic Oxidative Stress, Aging and the Risk of Cardiovascular Events in the General Female Population
Authors: Bourgonje Martin F. , Bourgonje Arno R. , Abdulle Amaal E. , Kieneker Lyanne M. , la Bastide-van Gemert Sacha , Gansevoort Ron T. , Bakker Stephan J. L. , Mulder Douwe J. , Pasch Andreas , Saleh Jumana , Gordijn Sanne J. , van Goor Harry
Published: February 2021

Introduction: Menopause is associated with increased cardiovascular risk, in which oxidative stress plays a pivotal role. Systemic oxidative stress is reflected by decreased levels of free thiols (R-SH, sulfhydryl groups), which are key components of the extracellular antioxidant machinery. In this study, we investigated the relation between serum free thiols as marker of oxidative stress and the female cardiovascular phenotype, as well as potential associations with the risk of cardiovascular (CV) events in pre- and postmenopausal women from the general population.

Methods: Female participants (n = 2,980) of the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort study were included. Serum free thiol concentrations were analyzed for associations with demographic, clinical, biochemical, and gynecological parameters, as well as with menopausal status and, prospectively, with the risk of CV events.

Results: Postmenopausal women had significantly reduced levels of serum free thiols (4.8 ± 1.0 vs. 5.2 ± 1.0 μmol/g, P < 0.001) compared to reproductive women. In multivariable analyses, serum free thiols were significantly associated with menopausal status (OR 0.70 [0.49–0.98], P = 0.039), even when adjusted for potential confounding factors, except for age (P = 0.550). Prospectively, serum free thiols were significantly associated with the risk of CV events (HR 0.52 [0.27–0.97], P = 0.040), even with covariate adjustment, although this disappeared when correcting for age.

Conclusion: In this study, we revealed serum free thiols to be strongly associated with the female cardiovascular phenotype as well as with female risk of CV events, where the influence of age itself seemed to outweigh that of female menopause. Future studies are warranted to further unravel the clinical utility of serum free thiol levels in the context of female cardiovascular risk management.
Disclosing Pharmacogenetic Feedback of Caffeine via eHealth Channels, Assessment of the Methods and Effects to Behavior Change: A Pilot Study
Authors: Alev Kerti , Kütt Andres , Viigimaa Margus
Published: February 2021

Background: The integration of genetic testing into eHealth applications holds great promise for the personalization of disease prevention guidelines. However, relatively little is known about the impact of eHealth applications on an individual's behavior.

Aim: The aim of the pilot study was to investigate the effect of the personalized eHealth application approach to behavior change in a 1-month follow-up period on groups with previously known and unknown caffeine impacts.

Method: We created a direct-to-consumer approach that includes providing relevant information and personalized reminders and goals on the digital device regarding the caffeine intake for two groups of individuals: the intervention group (IG) with the genetic raw data available and the control group (CG) to test the impact of the same content (article about caffeine metabolism) on participants without the genetic test. Study participants were all Estonians (n = 160).

Results: The study suggests that eHealth applications work for short-term behavior change. Participants in the genetic IG tended to increase caffeine intake if they were informed about caffeine not being harmful. They reported feeling better physically and/or mentally after their behavioral change decision during the period of the study.

Conclusions: Our pilot study revealed that eHealth applications may have a positive effect for short-term behavior change, regardless of a prior genetic test. Further studies among larger study groups are required to achieve a better understanding about behavior change of individuals in the field of personalized medicine and eHealth interventions.
Evaluation of Ultrasound-Guided Radiofrequency Ablation as a Treatment Option for Papillary Thyroid Microcarcinoma in the Isthmus: A Retrospective Study
Authors: Song Qing , Gao Hanjing , Tian Xiaoqi , Ren Ling , Lan Yu , Yan Lin , Luo Yukun
Published: February 2021

Background

About 3–9.2% of papillary thyroid carcinomas (PTC) are found in the isthmus, which has unique anatomic properties, making treatment more challenging. The aim of this study was to evaluate the treatment and undesirable effects of ultrasound-guided radiofrequency ablation (RFA) for PTC in the isthmus.

Methods

This retrospective case series study assessed 112 patients with single papillary thyroid microcarcinoma in the isthmus, pathologically diagnosed before RFA at the General Hospital of Chinese PLA in 2014–2018. Follow-up was performed by contrast-enhanced ultrasound (CEUS) and ultrasound examinations at 1, 3, and 6 months and every 6 months thereafter. The complete ablation (CAR), disappearance (DR), and volume reduction (VRR) rates of nodules, the incidence of complications, and the rate of lymph-node metastasis were recorded.

Results

The CAR of the tumors was 100%. During follow-up, the volume of coagulation necrosis gradually decreased. DRs at 1, 3, 6, 12, and 18 months after RFA were 0.8% (1/112), 10.7% (12/112), 51.7% (58/112), 91.0% (102/112), and 100% (112/112), respectively. The VRR evaluated by ultrasound and CEUS gradually increased. One recurrent case (0.8%) was found at 7 months after RFA. No complications, lymph node metastasis confirmed by ultrasound, and abnormal thyroid function were observed.

Conclusions

This retrospective study shows that RFA is beneficial for the treatment of PTMC in the isthmus.
The Sex Specific Association Between Maternal Gestational Diabetes and Offspring Metabolic Status at 1 Year of Age
Authors: Du Qinwen , Sompolinsky Yishai , Walfisch Asnat , Zhong Huiping , Liu Yan , Feng Weiwei
Published: February 2021

Previous studies showed the association between maternal GDM and long-term effects of overweight in offspring. However, the nature of this association in the early postnatal period is still undetermined. The aim of this prospective cohort study was to evaluate whether maternal GDM is associated with overweight and obesity status in offspring at age 1 year. We studied 1167 infants born at a large obstetrical care hospital including 778 normal glucose tolerance (NGT) and 389 GDM pregnancies, matched in a 1:2 ratio according to offspring’s gender, during the years 2016–2017. Overweight and obesity status in offspring of both groups were evaluated at 1 year of age through questionnaires. Infant outcomes were defined according to the WHO Child Growth Standards based on the length-based BMI-for-age. Female offspring from the GDM group exhibited a higher mean BMI (17.2 vs. 16.6, p < 0.01), a higher rate of obesity (13.9% vs. 7.7%; p < 0.05), and overweight (33.1% vs. 23.5%; p < 0.05) as compared to the NGT female group. In the multivariable regression model, maternal GDM was found to be independently and significantly associated with overweight or obesity in 1-year aged female offspring only (OR 1.61, 95% CI 1.09–2.37, p < 0.05). We found a sex specific association between maternal GDM and the overweight risk only in female offspring at 1 year of age.
The Association Between Leucine and Diabetic Nephropathy in Different Gender: A Cross-Sectional Study in Chinese Patients With Type 2 Diabetes
Authors: Gao Xiaoqian , Hou Ruiqin , Li Xin , Qiu Xing-Hua , Luo Hui-Huan , Liu Sheng-Lin , Fang Zhong-Ze
Published: February 2021

Objective

This study aimed to evaluate how leucine are associated with diabetic nephropathy (DN) in type 2 diabetes (T2D) patients and the gender difference of this association.

Methods

We retrieved 1,031 consecutive patients with T2D who meet the inclusion and exclusion criteria from the same tertiary care center and extracted clinical information from electronic medical record. Plasma leucine was measured by liquid chromatography-mass spectrometer. Restricted cubic spline (RCS) was conducted to examine potential non-linear relationship between leucine and the risk of DN. Logistic regression was used to obtain odds ratio (OR) and confidence interval (CI). Additive interaction was used to estimate the interaction effect between leucine and gender for DN.

Results

We found there was a negative correlation between leucine and the risk of DN. After stratifying all patients by gender, this relationship only remained significant in women (OR:0.57, CI:0.41–0.79).

Conclusions

In conclusion, T2D patients with high levels of leucine have a lower risk of developing DN in female.
The Recovery of Thyroid Function in Low-Risk Papillary Thyroid Cancer After Lobectomy: A 3-Year Follow-Up Study
Authors: Dou Yi , Chen Yingji , Hu Daixing , Su Xinliang
Published: February 2021

Purpose

Management strategies after lobectomy for low-risk papillary thyroid carcinoma (PTC) are controversial. This study aimed to identify the proportion of patients among low-risk PTC patients who do not require hormone replacement therapy and to evaluate the risk factors for postoperative hypothyroidism after lobectomy.

Patients and Methods

The records of 190 PTC patients who underwent thyroid lobectomy from January 2017 to December 2018 were retrospectively reviewed. Clinicopathological characteristics and follow-up data were collected. Univariate and multivariate analyses were performed to identify the risk factors associated with postoperative hypothyroidism and the recovery of thyroid function.

Results

In summary, 74.21% of patients (141/190) had normal thyroid function without levothyroxine supplementation, while 40.53% (77/190) developed temporary or permanent hypothyroidism. Multivariate analysis indicated that higher preoperative thyroid-stimulating hormone (TSH) levels (>2.62 mIU/L), Hashimoto’s thyroiditis (HT), and right lobectomy were associated with hypothyroidism (all P<0.05). The Area Under Curve (AUC) by logistic analysis was 0.829. Twenty-eight (28/77, 36.4%) patients recovered to the euthyroid state in the first year after surgery, and this recovery was significantly associated with preoperative TSH level. Forty-nine (49/77, 63.6%) patients developed persistent hypothyroidism. The thyroid function of most patients (11/28, 39.3%) recovered in the third month after surgery.

Conclusion

Patients with a lower level of preoperative TSH, with left lobectomy and without Hashimoto’s thyroiditis had a higher chance of normal thyroid function within the first year after lobectomy. The recovery of thyroid function was associated with the level of preoperative TSH.
Characterization of the Leucistic Texas Rat Snake Pantherophis obsoletus
Authors: Ullate-Agote Asier , Tzika Athanasia C.
Published: February 2021

Albinism and leucism are phenotypes resulting from impaired melanin pigmentation in the skin and skin appendages. However, melanin pigmentation of eyes remains unaffected in leucism. Here, using transmission electron microscopy, we show that the leucistic morph of the Texas rat snake (Pantherophis obsoletus lindheimeri) lacks both melanophores and xanthophores in its skin and exhibits a uniform ivory white color generated by iridophores and collagen fibers. In addition, we sequenced the full genome of a leucistic individual and obtained a highly-contiguous near-chromosome quality assembly of 1.69 Gb with an N50 of 14.5 Mb and an L50 of 29 sequences. Using a candidate-gene approach, we then identify in the leucistic genome a single-nucleotide deletion that generates a frameshift and a premature termination codon in the melanocyte inducing transcription factor (MITF) gene. This mutation shortens the translated protein from 574 to 286 amino acids, removing the helix-loop-helix DNA-binding domain that is highly conserved among vertebrates. Genotyping leucistic animals of independent lineages showed that not all leucistic individuals carry this single-nucleotide deletion. Subsequent gene expression analyses reveal that all leucistic individuals that we analyzed exhibit a significantly decreased expression of MITF. We thus suggest that mutations affecting the regulation and, in some cases, the coding sequence ofMITF, the former probably predating the latter, could be associated with the leucistic phenotype in Texas rat snakes.MITFis involved in the development and survival of melanophores in vertebrates. In zebrafish, a classical model species for pigmentation that undergoes metamorphosis, larvae and adults of homozygousmitfamutants lack melanophores, show an excess of iridophores and exhibit reduced yellow pigmentation. On the contrary, in the leucistic Texas rat snake, a non-metamorphic species, only iridophores persist. Our results suggest that fate determination of neural-crest derived melanophores and xanthophores, but not of iridophores, could require the expression ofMITFduring snake embryonic development.
Impacts of Tropical Cyclones on Longleaf Pine Ecosystems of Florida: Tropical Cyclogenesis, Landfall Frequencies, and Climate Change
Authors: Gilliam Frank S.
Published: February 2021

Tropical storms and hurricanes (collectively hereafter,tropical cyclones) are among the most destructive forces in nature. These threats are of particular concern to human populations and ecosystems of coastal areas of the southeastern United States, most especially in the State of Florida. This review begins with an overview of the effects of tropical cyclones on Florida’s most conspicuous terrestrial ecosystem—longleaf pine. Environmental factors leading to tropical cyclogenesis will also be reviewed, with a specific focus on (1) landfall history in Florida, and (2) the potential relationship between climate change and the frequency/intensity of tropical cyclones in the North Atlantic Ocean. Given its geographical distribution, it is not surprising that longleaf pine has long been impacted by tropical cyclones of the North Atlantic. Tropical cyclones are formed from a complex combination of meteorological conditions, driven initially by the release of excess heat from the surface waters of the ocean, along with an unstable atmosphere comprising air temperatures decreasing and wind speeds increasing with altitude. Among the coastal counties from Texas to Maine, those of Florida have experienced by far the highest frequency of tropical cyclones, especially the southern tip of peninsular Florida, with its most populous county (Miami-Dade) receiving 25 hits from 1900 to 2010, second only to Monroe County (32 hits) during that period. Frequencies of all categories of cyclones have increased significantly from 1850 to the present. Cyclone frequencies were significantly correlated with increases in air and ocean temperatures, both of which have increased over the past, suggesting a causal relationship with anthropogenic climate change. Of future concern is how increases in frequencies and intensities of tropical cyclones will negatively affect the structure and function of these ecologically and economically important longleaf pine ecosystems.
Transcriptome Analysis of Long Noncoding RNAs and mRNAs in Granulosa Cells of Jinghai Yellow Chickens Illuminated With Red Light
Authors: Wang Ying , Shi Huiqiang , Zhang Genxi , Wu Pengfei , Chen Lan , Shen Manman , Li Tingting , Lv Xiaoyang , Gu Yunfei , Wang Jinyu
Published: February 2021

Jinghai Yellow chickens are a new indigenous breed with a dual purpose in China, but their egg laying performance is limited. Compared with white light (WL), exposure to red light (RL) can improve the egg laying performance of hens. Herein, to elucidate the molecular mechanism by which RL affects the egg laying performance, RNA sequencing was used to analyze long noncoding RNAs (lncRNAs) and mRNAs from granulosa cells of small yellow follicles from Jinghai Yellow chickens in RL and WL groups. A total of 12,466 lncRNAs were identified among the assembled transcripts, of which 168 lncRNAs were significantly different between the RL and WL groups (101 downregulated and 67 upregulated). Additionally, 1182 differentially expressed mRNAs were identified (958 downregulated and 224 upregulated). Integrated network analysis demonstrated that numerous differential mRNAs were involved in follicular development through steroid hormone synthesis, oocyte meiosis, and the PI3K-Akt signaling pathway. The impact of lncRNAs on cis and trans target mRNAs indicates that some lncRNAs play important roles in follicular development of small yellow follicles. The results provide a starting point for studies aimed at understanding the molecular mechanisms by which monochromatic light affects follicular development and egg production in hens.
Welfare Genome Project: A Participatory Korean Personal Genome Project With Free Health Check-Up and Genetic Report Followed by Counseling
Authors: Jeon Yeonsu , Jeon Sungwon , Blazyte Asta , Kim Yeo Jin , Lee Jasmin Junseo , Bhak Youngjune , Cho Yun Sung , Park Yeshin , Noh Eui-Kyu , Manica Andrea , Edwards Jeremy S. , Bolser Dan , Kim Sukyeon , Lee Yuji , Yoon Changhan , Lee Semin , Kim Byung Chul , Park Neung Hwa , Bhak Jong
Published: February 2021

The Welfare Genome Project (WGP) provided 1,000 healthy Korean volunteers with detailed genetic and health reports to test the social perception of integrating personal genetic and healthcare data at a large-scale. WGP was launched in 2016 in the Ulsan Metropolitan City as the first large-scale genome project with public participation in Korea. The project produced a set of genetic materials, genotype information, clinical data, and lifestyle survey answers from participants aged 20–96. As compensation, the participants received a free general health check-up on 110 clinical traits, accompanied by a genetic report of their genotypes followed by genetic counseling. In a follow-up survey, 91.0% of the participants indicated that their genetic reports motivated them to improve their health. Overall, WGP expanded not only the general awareness of genomics, DNA sequencing technologies, bioinformatics, and bioethics regulations among all the parties involved, but also the general public’s understanding of how genome projects can indirectly benefit their health and lifestyle management. WGP established a data construction framework for not only scientific research but also the welfare of participants. In the future, the WGP framework can help lay the groundwork for a new personalized healthcare system that is seamlessly integrated with existing public medical infrastructure.
Discordance Between the Predicted Versus the Actually Recognized CD8+ T Cell Epitopes of HCMV pp65 Antigen and Aleatory Epitope Dominance
Authors: Lehmann Alexander A. , Zhang Ting , Reche Pedro A. , Lehmann Paul V.
Published: February 2021

CD8+ T cell immune monitoring aims at measuring the size and functions of antigen-specific CD8+ T cell populations, thereby providing insights into cell-mediated immunity operational in a test subject. The selection of peptides forex vivoCD8+ T cell detection is critical because within a complex antigen exists a multitude of potential epitopes that can be presented by HLA class I molecules. Further complicating this task, there is HLA class I polygenism and polymorphism which predisposes CD8+ T cell responses towards individualized epitope recognition profiles. In this study, we compare the actual CD8+ T cell recognition of a well-characterized model antigen, human cytomegalovirus (HCMV) pp65 protein, with its anticipated epitope coverage. Due to the abundance of experimentally defined HLA-A*02:01-restricted pp65 epitopes, and becausein silicoepitope predictions are most advanced for HLA-A*02:01, we elected to focus on subjects expressing this allele. In each test subject, every possible CD8+ T cell epitope was systematically covered testing 553 individual peptides that walk the sequence of pp65 in steps of single amino acids. Highly individualized CD8+ T cell response profiles with aleatory epitope recognition patterns were observed. No correlation was found between epitopes’ ranking on the prediction scale and their actual immune dominance. Collectively, these data suggest that accurate CD8+ T cell immune monitoring may necessitate reliance on agnostic mega peptide pools, or brute force mapping, rather than electing individual peptides as representative epitopes for tetramer and other multimer labeling of surface antigen receptors.
VAR2CSA-Mediated Host Defense Evasion of Plasmodium falciparum Infected Erythrocytes in Placental Malaria
Authors: Tomlinson Alice , Semblat Jean-Philippe , Gamain Benoît , Chêne Arnaud
Published: February 2021

Over 30 million women living inP. falciparumendemic areas are at risk of developing malaria during pregnancy every year. Placental malaria is characterized by massive accumulation of infected erythrocytes in the intervillous space of the placenta, accompanied by infiltration of immune cells, particularly monocytes. The consequent local inflammation and the obstruction of the maternofetal exchanges can lead to severe clinical outcomes for both mother and child. Even if protection against the disease can gradually be acquired following successive pregnancies, the malaria parasite has developed a large panel of evasion mechanisms to escape from host defense mechanisms and manipulate the immune system to its advantage. Infected erythrocytes isolated from placentas of women suffering from placental malaria present a unique phenotype and express the pregnancy-specific variant VAR2CSA of thePlasmodium falciparumErythrocyte Membrane Protein (PfEMP1) family at their surface. The polymorphic VAR2CSA protein is able to mediate the interaction of infected erythrocytes with a variety of host cells including placental syncytiotrophoblasts and leukocytes but also with components of the immune system such as non-specific IgM. This review summarizes the described VAR2CSA-mediated host defense evasion mechanisms employed by the parasite during placental malaria to ensure its survival and persistence.
Alterations in the HLA-B*57:01 Immunopeptidome by Flucloxacillin and Immunogenicity of Drug-Haptenated Peptides
Authors: Puig Montserrat , Ananthula Suryatheja , Venna Ramesh , Kumar Polumuri Swamy , Mattson Elliot , Walker Lacey M. , Cardone Marco , Takahashi Mayumi , Su Shan , Boyd Lisa F. , Natarajan Kannan , Abdoulaeva Galina , Wu Wells W. , Roderiquez Gregory , Hildebrand William H. , Beaucage Serge L. , Li Zhihua , Margulies David H. , Norcross Michael A.
Published: February 2021

Neoantigen formation due to the interaction of drug molecules with human leukocyte antigen (HLA)-peptide complexes can lead to severe hypersensitivity reactions. Flucloxacillin (FLX), a β-lactam antibiotic for narrow-spectrum gram-positive bacterial infections, has been associated with severe immune-mediated drug-induced liver injury caused by an influx of T-lymphocytes targeting liver cells potentially recognizing drug-haptenated peptides in the context of HLA-B*57:01. To identify immunopeptidome changes that could lead to drug-driven immunogenicity, we used mass spectrometry to characterize the proteome and immunopeptidome of B-lymphoblastoid cells solely expressing HLA-B*57:01 as MHC-I molecules. Selected drug-conjugated peptides identified in these cells were synthesized and tested for their immunogenicity in HLA-B*57:01-transgenic mice. T cell responses were evaluated in vitro by immune assays. The immunopeptidome of FLX-treated cells was more diverse than that of untreated cells, enriched with peptides containing carboxy-terminal tryptophan and FLX-haptenated lysine residues on peptides. Selected FLX-modified peptides with drug on P4 and P6 induced drug-specific CD8+ T cells in vivo. FLX was also found directly linked to the HLA K146 that could interfere with KIR-3DL or peptide interactions. These studies identify a novel effect of antibiotics to alter anchor residue frequencies in HLA-presented peptides which may impact drug-induced inflammation. Covalent FLX-modified lysines on peptides mapped drug-specific immunogenicity primarily at P4 and P6 suggesting these peptide sites as drivers of off-target adverse reactions mediated by FLX. FLX modifications on HLA-B*57:01-exposed lysines may also impact interactions with KIR or TCR and subsequent NK and T cell function.
Recommendations for the Standardisation of Open Taxonomic Nomenclature for Image-Based Identifications
Authors: Horton Tammy , Marsh Leigh , Bett Brian J. , Gates Andrew R. , Jones Daniel O. B. , Benoist Noëlie M. A. , Pfeifer Simone , Simon-Lledó Erik , Durden Jennifer M. , Vandepitte Leen , Appeltans Ward
Published: February 2021

This paper recommends best practice for the use of open nomenclature (ON) signs applicable to image-based faunal analyses. It is one of numerous initiatives to improve biodiversity data input to improve the reliability of biological datasets and their utility in informing policy and management. Image-based faunal analyses are increasingly common but have limitations in the level of taxonomic precision that can be achieved, which varies among groups and imaging methods. This is particularly critical for deep-sea studies owing to the difficulties in reaching confident species-level identifications of unknown taxa. ON signs indicate a standard level of identification and improve clarity, precision and comparability of biodiversity data. Here we provide examples of recommended usage of these terms for input to online databases and preparation of morphospecies catalogues. Because the processes of identification differ when working with physical specimens and with images of the taxa, we build upon previously provided recommendations for specific use with image-based identifications.
Development and Multi-Data Set Verification of an RNA Binding Protein Signature for Prognosis Prediction in Glioma
Authors: Sheng Chunpeng , Chen Zhihua , Lei Jianwei , Zhu Jianming , Song Shuxin
Published: February 2021

Objective: Increasing evidence emphasizes the clinical implications of RNA binding proteins (RBPs) in cancers. This study aimed to develop a RBP signature for predicting prognosis in glioma.

Methods: Two glioma datasets as training (n = 693) and validation (n = 325) sets were retrieved from the CGGA database. In the training set, univariate Cox regression analysis was conducted to screen prognosis-related RBPs based on differentially expressed RBPs between WHO grade II and IV. A ten-RBP signature was then established. The predictive efficacy was evaluated by ROCs. The applicability was verified in the validation set. The pathways involving the risk scores were analyzed by ssGSEA. scRNA-seq was utilized for evaluating their expression in different glioma cell types. Moreover, their expression was externally validated between glioma and control samples.

Results: Based on 39 prognosis-related RBPs, a ten RBP signature was constructed. High risk score distinctly indicated a poorer prognosis than low risk score. AUCs were separately 0.838 and 0.822 in the training and validation sets, suggesting its well performance for prognosis prediction. Following adjustment of other clinicopathological characteristics, the signature was an independent risk factor. Various cancer-related pathways were significantly activated in samples with high risk score. The scRNA-seq identified that risk RBPs were mainly expressed in glioma malignant cells. Their high expression was also found in glioma than control samples.

Conclusion: This study developed a novel RBP signature for robustly predicting prognosis of glioma following multi-data set verification. These RBPs may affect the progression of glioma.
Case Report: Intrapulmonary Arteriovenous Anastomoses in COVID-19-Related Pulmonary Vascular Changes: A New Player in the Arena?
Authors: Qanadli Salah D. , Rocha Ana Carolina , Rotzinger David C.
Published: February 2021

Up to now, COVID-19-related vascular changes were mainly described as thrombo-embolic events. A handful of researchers reported another type of vascular abnormality referred to as “vascular thickening” or “vascular enlargement,” without specifying whether the dilated vessels are arteries or veins nor providing a physiopathological hypothesis. Our observations indicate that the vascular dilatation occurs in the venous compartment, and underlying mechanisms might include increased blood flow due to inflammation and the activation of arteriovenous anastomoses.
Synergistic Combination of Linezolid and Fosfomycin Closing Each Other’s Mutant Selection Window to Prevent Enterococcal Resistance
Authors: Jiang Lifang , Xie Na , Chen Mingtao , Liu Yanyan , Wang Shuaishuai , Mao Jun , Li Jiabin , Huang Xiaohui
Published: February 2021

Enterococci, the main pathogens associated with nosocomial infections, are resistant to many common antibacterial drugs including β-lactams, aminoglycosides, etc. Combination therapy is considered an effective way to prevent bacterial resistance. Preliminary studies in our group have shown that linezolid combined with fosfomycin has synergistic or additive antibacterial activity against enterococci, while the ability of the combination to prevent resistance remains unknown. In this study, we determined mutant prevention concentration (MPC) and mutant selection window (MSW) of linezolid, fosfomycin alone and in combination including different proportions for five clinical isolates of Enterococcus and characterized the resistance mechanism for resistant mutants. The results indicated that different proportions of linezolid combined with fosfomycin had presented different MPCs and MSWs. Compared with linezolid or fosfomycin alone, the combination can restrict the enrichment of resistant mutants at a lower concentration. A rough positive correlation between the selection index (SI) of the two agents in combination and the fractional inhibitory concentration index (FICI) of the combination displayed that the smaller FICI of linezolid and fosfomycin, the more probable their MSWs were to close each other. Mutations in ribosomal proteins (L3 and L4) were the mechanisms for linezolid resistant mutants. Among the fosfomycin-resistant mutants, only two strains have detected the MurA gene mutation related to fosfomycin resistance. In conclusion, the synergistic combination of linezolid and fosfomycin closing each other’s MSW could effectively suppress the selection of enterococcus resistant mutants, suggesting that the combination may be an alternative for preventing enterococcal resistance. In this study, the resistance mechanism of fosfomycin remains to be further studied.
Metagenomic Analysis of the Microbial Communities and Resistomes of Veal Calf Feces
Authors: Salaheen Serajus , Kim Seon Woo , Hovingh Ernest , Van Kessel Jo Ann S. , Haley Bradd J.
Published: February 2021

Antimicrobial resistance (AMR) is a major public health concern, and dairy calves, including veal calves, are known reservoirs of resistant bacteria. To investigate AMR in the fecal microbial communities of veal calves, we conducted metagenomic sequencing of feces collected from individual animals on four commercial veal operations in Pennsylvania. Fecal samples from three randomly selected calves on each farm were collected soon after the calves were brought onto the farms (n= 12), and again, just before the calves from the same cohorts were ready for slaughter (n= 12). Results indicated that the most frequently identified phyla were Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Fecal microbial communities in samples collected from the calves at the early and late stages of production were significantly different at the genus level (analysis of similarities [ANOSIM] on Bray-Curtis distances,R= 0.37,p< 0.05), but not at the phylum level. Variances among microbial communities in the feces of the younger calves were significantly higher than those from the feces of calves at the late stage of production (betadisperF= 8.25,p< 0.05). Additionally, our analyses identified a diverse set of mobile antimicrobial resistance genes (ARGs) in the veal calf feces. The fecal resistomes mostly consisted of ARGs that confer resistance to aminoglycosides, tetracyclines, and macrolide-lincosamide-streptogramin B (MLS), and these ARGs represented more than 70% of the fecal resistomes. Factors that are responsible for selection and persistence of resistant bacteria in the veal calf gut need to be identified to implement novel control points and interrupt detrimental AMR occurrence and shedding.
Changes in Gastric Corpus Microbiota With Age and After Helicobacter pylori Eradication: A Long-Term Follow-Up Study
Authors: Shin Cheol Min , Kim Nayoung , Park Ji Hyun , Lee Dong Ho
Published: February 2021

Helicobacter pyloriinfection changes gastric microbiota profiles. However, it is not clear whetherH. pylorieradication can restore the healthy gastric microbiota. Moreover, there has been no study regarding the changes in gastric microbiota with aging. The objective of this study was to investigate the changes in gastric corpus microbiota with age and followingH. pylorieradication. Changes in corpus mucosa-associated microbiota were evaluated in 43 individuals with endoscopic follow-up > 1 year, including 8H. pylori-uninfected and 15H. pylori-infected subjects with no atrophy/metaplasia by histology and pepsinogen I/II ratio > 4.0; 17H. pylori-infected subjects with atrophy/metaplasia and pepsinogen I/II ratio < 2.5; and 3 subjects with atrophy/metaplasia, no evidence of activeH. pyloriinfection, negative for anti-H. pyloriimmunoglobulin G (IgG) antibody testing, and no previous history ofH. pylorieradication. SuccessfulH. pylorieradication was achieved in 21 patients. The gastric microbiota was characterized using an Illumina MiSeq platform targeting 16S ribosomal DNA (rDNA). The mean follow-up duration was 57.4 months (range, 12–145 months), and median follow-up visit was 1 (range, 1–3). Relative abundance of Lactobacillales andStreptococcuswas increased with atrophy/metaplasia. InH. pylori-uninfected subjects (n= 8), an increase in Proteobacteria (Enhydrobacter, Comamonadaceae,Sphingobium); a decrease in Firmicutes (Streptococcus,Veillonella), Fusobacteria (Fusobacterium), Nocardioidaceae,Rothia, and Prevotella; and a decrease in microbial diversity were observed during the follow-up (ptrend < 0.05). In 10 of 21 subjects (47.6%),H. pylorieradication induced restoration of microbial diversity; however, a predominance ofAcinetobacterwith a decrease in microbial diversity occurred in 11 subjects (52.3%). The presence of atrophy/metaplasia at baseline and higher neutrophil infiltration in the corpus were associated with the restoration of gastric microbiota after successful eradication, whereas a higher relative abundance ofAcinetobacterat baseline was associated with the predominance ofAcinetobacterafterH. pylorieradication (p< 0.05). To conclude, inH. pylori-uninfected stomach, relative abundance of Proteobacteria increases, relative abundance of Firmicutes and Fusobacteria decreases, and microbial diversity decreases with aging.H. pylorieradication does not always restore gastric microbiota; in some individuals, gastric colonization byAcinetobacterspecies occurs after anti-Helicobactertreatment.
Genetics, Structure, and Function of Group A Streptococcal Pili
Authors: Nakata Masanobu , Kreikemeyer Bernd
Published: February 2021

Streptococcus pyogenes (Group A Streptococcus; GAS) is an exclusively human pathogen. This bacterial species is responsible for a large variety of infections, ranging from purulent but mostly self-limiting oropharynx/skin diseases to streptococcal sequelae, including glomerulonephritis and rheumatic fever, as well as life-threatening streptococcal toxic-shock syndrome. GAS displays a wide array of surface proteins, with antigenicity of the M protein and pili utilized for M- and T-serotyping, respectively. Since the discovery of GAS pili in 2005, their genetic features, including regulation of expression, and structural features, including assembly mechanisms and protein conformation, as well as their functional role in GAS pathogenesis have been intensively examined. Moreover, their potential as vaccine antigens has been studied in detail. Pilus biogenesis-related genes are located in a discrete section of the GAS genome encoding fibronectin and collagen binding proteins and trypsin-resistant antigens (FCT region). Based on the heterogeneity of genetic composition and DNA sequences, this region is currently classified into nine distinguishable forms. Pili and fibronectin-binding proteins encoded in the FCT region are known to be correlated with infection sites, such as the skin and throat, possibly contributing to tissue tropism. As also found for pili of other Gram-positive bacterial pathogens, GAS pilin proteins polymerize via isopeptide bonds, while intramolecular isopeptide bonds present in the pilin provide increased resistance to degradation by proteases. As supported by findings showing that the main subunit is primarily responsible for T-serotyping antigenicity, pilus functions and gene expression modes are divergent. GAS pili serve as adhesins for tonsillar tissues and keratinocyte cell lines. Of note, a minor subunit is considered to have a harpoon function by which covalent thioester bonds with host ligands are formed. Additionally, GAS pili participate in biofilm formation and evasion of the immune system in a serotype/strain-specific manner. These multiple functions highlight crucial roles of pili during the onset of GAS infection. This review summarizes the current state of the art regarding GAS pili, including a new mode of host-GAS interaction mediated by pili, along with insights into pilus expression in terms of tissue tropism.
High Prevalence of Drug Resistance and Class 1 Integrons in Escherichia coli Isolated From River Yamuna, India: A Serious Public Health Risk
Authors: Singh Nambram Somendro , Singhal Neelja , Kumar Manish , Virdi Jugsharan Singh
Published: February 2021

Globally, urban water bodies have emerged as an environmental reservoir of antimicrobial resistance (AMR) genes because resistant bacteria residing here might easily disseminate these traits to other waterborne pathogens. In the present study, we have investigated the AMR phenotypes, prevalent plasmid-mediated AMR genes, and integrons in commensal strains ofEscherichia coli, the predominant fecal indicator bacteria isolated from a major urban river of northern India Yamuna. The genetic environment ofblaCTX–M–15was also investigated. Our results indicated that 57.5% of theE. colistrains were resistant to at least two antibiotic classes and 20% strains were multidrug resistant, i.e., resistant to three or more antibiotic classes. The multiple antibiotic resistance index of about one-third of theE. colistrains was quite high (>0.2), reflecting high contamination of river Yamuna with antibiotics. With regard to plasmid-mediated AMR genes,blaTEM–1was present in 95% of the strains, followed by qnrS1 andarmA (17% each),blaCTX–M–15(15%),strA-strB (12%), andtetA (7%). Contrary to the earlier reports whereblaCTX–M–15was mostly associated with pathogenic phylogroup B2, our study revealed that the CTX-M-15 type extended-spectrum β-lactamases (ESBLs) were present in the commensal phylogroups A and B1, also. The genetic organization ofblaCTX–M–15was similar to that reported forE. coli, isolated from other parts of the world; and ISEcp1was present upstream ofblaCTX–M–15. The integrons of classes 2 and 3 were absent, but class 1 integron geneintI1was present in 75% of the isolates, denoting its high prevalence inE. coliof river Yamuna. These evidences indicate that due to high prevalence of plasmid-mediated AMR genes andintI1, commensalE. colican become vehicles for widespread dissemination of AMR in the environment. Thus, regular surveillance and management of urban rivers is necessary to curtail the spread of AMR and associated health risks.
Different Modular Organization Between Early Onset and Late Onset Depression: A Study Base on Granger Causality Analysis
Authors: Mai Naikeng , Wu Yujie , Zhong Xiaomei , Chen Ben , Zhang Min , Peng Qi , Ning Yuping
Published: February 2021

Background: Modular organization reflects the activity patterns of our brain. Different disease states may lead to different activity patterns and clinical features. Early onset depression (EOD) and late onset depression (LOD) share the same clinical symptoms, but have different treatment strategies and prognosis. Thus, explored the modular organization of EOD and LOD might help us understand their pathogenesis.

Method: The study included 82 patients with late life depression (EOD 40, LOD 42) and 90 healthy controls. We evaluated the memory, executive function and processing speed and performed resting-stage functional MRI for all participants. We constructed a functional network based on Granger causality analysis and carried out modularity, normalized mutual information (NMI), Phi coefficient, within module degree z-score, and participation coefficient analyses for all the participants.

Result: The Granger function network analysis suggested that the functional modularity was different among the three groups (Pauc = 0.0300), and NMI analysis confirmed that the partition of EOD was different from that of LOD (Pauc = 0.0190). Rh.10d.ROI (polar frontal cortex) and Rh.IPS1.ROI (dorsal stream visual cortex) were shown to be the potential specific nodes in the modular assignment according to the Phi coefficient (P = 0.0002, Pfdr = 0.0744 & P = 0.0004, Pfdr = 0.0744).

Conclusion: This study reveal that the functional modularity and partition were different between EOD and LOD in Granger function network. These findings support the hypothesis that different pathological changes might exist in EOD and LOD.