bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Decaffeinated Green Tea Polyphenols on Body Fat and Precocious Puberty in Obese Girls: A Randomized Controlled Trial
Authors: Xie Luyao , Tang Qingya , Yao Die , Gu Qiuyun , Zheng Hao , Wang Xiaodi , Yu Zhiping , Shen Xiuhua
Published: October 2021

Background

Obesity has been reported to be an important contributing factor for precocious puberty, especially in girls. The effect of green tea polyphenols on weight reduction in adult population has been shown, but few related studies have been conducted in children. This study was performed to examine the effectiveness and safety of decaffeinated green tea polyphenols (DGTP) on ameliorating obesity and early sexual development in girls with obesity.

Design

This is a double-blinded randomized controlled trial. Girls with obesity aged 6–10 years old were randomly assigned to receive 400 mg/day DGTP or isodose placebo orally for 12 weeks. During this period, all participants received the same instruction on diet and exercise from trained dietitians. Anthropometric measurements, secondary sexual characteristics, B-scan ultrasonography of uterus, ovaries and breast tissues, and related biochemical parameters were examined and assessed pre- and post-treatment.

Results

Between August 2018 and January 2020, 62 girls with obesity (DGTP group n = 31, control group n = 31) completed the intervention and were included in analysis. After the intervention, body mass index, waist circumference, and waist-to-hip ratio significantly decreased in both groups, but the percentage of body fat (PBF), serum uric acid (UA), and the volumes of ovaries decreased significantly only within the DGTP group. After controlling confounders, DGTP showed a significantly decreased effect on the change of PBF (β = 2.932, 95% CI: 0.214 to 5.650), serum UA (β = 52.601, 95% CI: 2.520 to 102.681), and ovarian volumes (right: β = 1.881, 95% CI: 0.062 to 3.699, left: β = 0.971, 95% CI: 0.019 to 1.923) in girls with obesity. No side effect was reported in both groups during the whole period.

Conclusion

DGTP have shown beneficial effects of ameliorated obesity and postponed early sexual development in girls with obesity without any adverse effects.

Clinical Trial Registration

[https://clinicaltrials.gov/ct2/show/NCT03628937], identifier [NCT03628937].
Energy and Bank Equity Interactions
Authors: Shaiban Mohammed Sharaf , Li Di , Hasanov Akram S.
Published: October 2021

Oil price shocks harm real output and bank and industrial profit in most oil-importing countries, which has motivated us to investigate the impact of these shocks on the equity performance of banking industries. To fulfill the research objectives, we involve a sample of developed and emerging economies for comparison purposes. The objective of employing the Toda and Yamamoto (Journal of econometrics, 1995, 66 (1), 225–250) causality test is to explore the time-variant relationship between oil prices and banking indices to investigate how oil price shocks affect the performance of country-specific banking industries. In addition, an impulse response function and variance decomposition analysis are utilized to, respectively, examine the time-variant relationship between oil price shocks and macroeconomic factors and the performance of the banking sector. Results vary across different economies in our sample, but the magnitude of oil price impact is relatively significant in the US, the UK, Canada, Japan, Mexico, and Brazil. The findings indicate that oil price rises adversely affect equity bank indices in developed and emerging economics except for Mexico. Notably, our findings show that oil prices and interest rates jointly have significant power in explaining the banking equity variation and suggest that international bank portfolio investors should consider hedging oil price risk.
Recycled Paper as a Source of Renewable Jet Fuel in the United States
Authors: Kubic William L. , Moore Cameron M. , Semelsberger Troy A. , Sutton Andrew D.
Published: October 2021

Converting biomass into jet fuel involves more than the core chemical process. The overall process includes the logistics of harvesting and transporting the biomass, handling and preparing the material for processing, and processing and disposal of waste. All of these activities contribute to cost. Controlling cost involves more than developing efficient process chemistry. Choice of feedstock also has a significant impact on process economics. We consider chemical conversion of paper from municipal solid waste as a feedstock for the production of jet fuel and diesel. Paper has a significantly higher cellulose content than raw lignocellulosic biomass such as corn stover, so it requires less pretreatment to convert it into hydrocarbons than lignocellulosic biomass. Our techno-economic analysis showed that the cost of converting paper waste into jet fuel is about $1.00/gal less than jet fuel produced from corn stover. Although the cost of recycling paper into jet fuel is less than producing it from corn stover, the process is not competitive with petroleum. We estimated a minimum selling price of $3.97/gal for paper-derived jet fuel. Our sensitivity studies indicated that the biggest economic obstacle is the cost of cellulose hydrolysis. Direct hydrogenation of paper to sugar alcohols combined with increased economy of scale could make recycling paper jet fuel competitive.
The Particulate Organic Carbon-to-Nitrogen Ratio Varies With Ocean Currents
Authors: Xiao Shengjun , Zhang Linlin , Teng Yuhao , Huang Tao , Luo Wen
Published: October 2021

Ocean currents could adjust ocean carbon and nitrogen composition which are an important part of the global carbon and nitrogen cycle. We procured global concentrations of particulate carbon and nitrogen in different depths, classified them according to ocean currents (upper 300 m), and analyzed POC-to-PON ratio (particulate organic carbon-to-nitrogen ratio) variations. We found that the regions with currents have a higher ratio than those without currents in the northern hemisphere, except in 50°–60°N (median ratio without currents is 8.38). Warm currents (median ratio ranges from 5.96 to 8.44) have a higher ratio than cold currents (6.19–8.89), except for the East Greenland Current (reach to 8.44) and Labrador Current (reach to 8.89). Meanwhile, we also analyzed the effects of ocean currents’ flowing and found that the distributions of the POC-to-PON ratio vary in different current types (e.g., cause of formation and distance from the shore). Generally speaking, the POC-to-PON ratio of the eolian currents and near-ocean currents change fiercer than that of compensation currents and near-coast currents. Ocean currents also have a buffering effect in the variation between surface and deep water, which prevents the severe change of the POC-to-PON ratio. The high-value anomaly of POC-to-PON caused by the confluence of warm and cold currents was also analyzed. It can be deduced that the high ratio in the high-latitude region was mainly caused by the terrigenous organic matter (especially carbon) and low nitrogen.
The Role of Ion Channel-Related Genes in Autism Spectrum Disorder: A Study Using Next-Generation Sequencing
Authors: Lee Junghan , Ha Sungji , Ahn Jaeun , Lee Seung-Tae , Choi Jong Rak , Cheon Keun-Ah
Published: October 2021

The clinical heterogeneity of autism spectrum disorder (ASD) is closely associated with the diversity of genes related to ASD pathogenesis. With their low effect size, it has been hard to define the role of common variants of genes in ASD phenotype. In this study, we reviewed genetic results and clinical scores widely used for ASD diagnosis to investigate the role of genes in ASD phenotype considering their functions in molecular pathways. Genetic data from next-generation sequencing (NGS) were collected from 94 participants with ASD. We analyzed enrichment of cellular processes and gene ontology using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). We compared clinical characteristics according to genetic functional characteristics. We found 266 genes containing nonsense, frame shift, missense, and splice site mutations. Results from DAVID revealed significant enrichment for “ion channel” with an enrichment score of 8.84. Moreover, ASD participants carrying mutations in ion channel-related genes showed higher total IQ (p = 0.013) and lower repetitive, restricted behavior (RRB)-related scores (p = 0.003) and mannerism subscale of social responsiveness scale scores, compared to other participants. Individuals with variants in ion channel genes showed lower RRB scores, suggesting that ion channel genes might be relatively less associated with RRB pathogenesis. These results contribute to understanding of the role of common variants in ASD and could be important in the development of precision medicine of ASD.
Case Report: Variations in the ALPL Gene in Chinese Patients With Hypophosphatasia
Authors: Zhang Qiang , Qin Zailong , Yi Shang , Wei Hao , Zhou Xun zhao , Shen Fei
Published: October 2021

Background: Hypophosphatasia (HPP) is an autosomal genetic disorder characterized biochemically by abnormal of bone parameters and serum alkaline phosphatase (ALP) activity as well as clinically by deficiency of teeth and bone mineralization. The clinical presentation is a continuum ranging from a prenatal lethal form with no skeletal mineralization to a mild form with late adult onset presenting with non-pathognomonic symptoms. ALP deficiency is the key to the pathogenesis of abnormal metabolism and skeletal system damage in HPP patients.

Methods: We investigated five patients with skeletal dysplasia in the clinic. Whole-exome sequencing was performed in order to aid diagnosis of the patients.

Results: Eight variants in the ALPL gene in the five unrelated Chinese patients (PA-1: c.649_650insC and c.707A > G; PA2: c.98C > T and c.707A > G; PA3: c.407G > A and c.650delTinsCTAA; PA4: c.1247G > T (homozygous); PA5: c.406C > T and c.1178A > G; NM_000478.5) were found. These variations caused two types of HPP: perinatal HPP and Odonto HPP. All cases reported in this study were autosomal recessive. Among the variants, c.1247G > T/p.Gly416Val (PA-4); c.1178A > G/p.Asn393Ser (PA-5) and c.707A > G/p.Tyr236Cys (PA-1, PA-2) have never been reported before.

Conclusion: Clinical phenotypes of perinatal HPP (PA-1,PA-2,PA-3 and PA-4) include skeletal dysplasia, shorter long bones, bowing of long bones, tetraphocomelia, abnormal posturing and abnormal bone ossification. Odonto HPP (PA-5) only presents as dental abnormality with severe dental caries and decreased ALP activity. Our study extends the pool of ALPL variants in different populations.
Genome-Wide Identification and Expression Analysis of AP2/ERF Transcription Factor Related to Drought Stress in Cultivated Peanut (Arachis hypogaea L.)
Authors: Cui Mengjie , Haider Muhammad Salman , Chai Pengpei , Guo Junjia , Du Pei , Li Hongyan , Dong Wenzhao , Huang Bingyan , Zheng Zheng , Shi Lei , Zhang Xinyou , Han Suoyi
Published: October 2021

APETALA2/ethylene response element-binding factor (AP2/ERF) transcription factors (TFs) have been found to regulate plant growth and development and response to various abiotic stresses. However, detailed information of AP2/ERF genes in peanut against drought has not yet been performed. Herein, 185 AP2/ERF TF members were identified from the cultivated peanut (A. hypogaea cv. Tifrunner) genome, clustered into five subfamilies: AP2 (APETALA2), ERF (ethylene-responsive-element-binding), DREB (dehydration-responsive-element-binding), RAV (related to ABI3/VP), and Soloist (few unclassified factors)). Subsequently, the phylogenetic relationship, intron–exon structure, and chromosomal location of AhAP2/ERF were further characterized. All of these AhAP2/ERF genes were distributed unevenly across the 20 chromosomes, and 14 tandem and 85 segmental duplicated gene pairs were identified which originated from ancient duplication events. Gene evolution analysis showed that A. hypogaea cv. Tifrunner were separated 64.07 and 66.44 Mya from Medicago truncatula L. and Glycine max L., respectively. Promoter analysis discovered many cis-acting elements related to light, hormones, tissues, and stress responsiveness process. The protein interaction network predicted the exitance of functional interaction among families or subgroups. Expression profiles showed that genes from AP2, ERF, and dehydration-responsive-element-binding subfamilies were significantly upregulated under drought stress conditions. Our study laid a foundation and provided a panel of candidate AP2/ERF TFs for further functional validation to uplift breeding programs of drought-resistant peanut cultivars.
Identification of miRNA Signature Associated With Erectile Dysfunction in Type 2 Diabetes Mellitus by Support Vector Machine-Recursive Feature Elimination
Authors: Xu Haibo , Zhao Baoyin , Zhong Wei , Teng Peng , Qiao Hong
Published: October 2021

Diabetic mellitus erectile dysfunction (DMED) is one of the most common complications of diabetes mellitus (DM), which seriously affects the self-esteem and quality of life of diabetics. MicroRNAs (miRNAs) are endogenous non-coding RNAs whose expression levels can affect multiple cellular processes. Many pieces of studies have demonstrated that miRNA plays a role in the occurrence and development of DMED. However, the exact mechanism of this process is unclear. Hence, we apply miRNA sequencing from blood samples of 10 DMED patients and 10 DM controls to study the mechanisms of miRNA interactions in DMED patients. Firstly, we found four characteristic miRNAs as signature by the SVM-RFE method (hsa-let-7E-5p, hsa-miR-30 days-5p, hsa-miR-199b-5p, and hsa-miR-342–3p), called DMEDSig-4. Subsequently, we correlated DMEDSig-4 with clinical factors and further verified the ability of these miRNAs to classify samples. Finally, we functionally verified the relationship between DMEDSig-4 and DMED by pathway enrichment analysis of miRNA and its target genes. In brief, our study found four key miRNAs, which may be the key influencing factors of DMED. Meanwhile, the DMEDSig-4 could help in the development of new therapies for DMED.
A Population of M2 Macrophages Associated With Bone Formation
Authors: Olmsted-Davis Elizabeth , Mejia Julio , Salisbury Elizabeth , Gugala Zbigniew , Davis Alan R.
Published: October 2021

We previously identified transient brown adipocyte-like cells associated with heterotopic ossification (HO). These ancillary cells support new vessel synthesis essential to bone formation. Recent studies have shown that the M2 macrophage contributes to tissue regeneration in a similar way. To further define the phenotype of these brown adipocyte-like cells they were isolated and characterized by single-cell RNAseq (scRNAseq). Analysis of the transcriptome and the presence of surface markers specific for macrophages suggest that these cells are M2 macrophages. To validate these findings, clodronate liposomes were delivered to the tissues during HO, and the results showed both a significant reduction in these macrophages as well as bone formation. These cells were isolated and shown in culture to polarize towards either M1 or M2 similar to other macrophages. To confirm that these are M2 macrophages, mice received lipopolysacheride (LPS), which induces proinflammation and M1 macrophages. The results showed a significant decrease in this specific population and bone formation, suggesting an essential role for M2 macrophages in the production of bone. To determine if these macrophages are specific to HO, we isolated these cells using fluorescence-activated cell sorting (FACS) from a bone defect model and subjected them to scRNAseq. Surprisingly, the macrophage populations overlapped between the two groups (HO-derived versus callus) suggesting that they may be essential ancillary cells for bone formation in general and not selective to HO. Of further note, their unique metabolism and lipogenic properties suggest the potential for unique cross talk between these cells and the newly forming bone.
p38 MAP Kinase Signaling in Microglia Plays a Sex-Specific Protective Role in CNS Autoimmunity and Regulates Microglial Transcriptional States
Authors: McGill Mahalia M. , Richman Alyssa R. , Boyd Joseph R. , Sabikunnahar Bristy , Lahue Karolyn G. , Montgomery Theresa L. , Caldwell Sydney , Varnum Stella , Frietze Seth , Krementsov Dimitry N.
Published: October 2021

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system, representing the leading cause of non-traumatic neurologic disease in young adults. This disease is three times more common in women, yet more severe in men, but the mechanisms underlying these sex differences remain largely unknown. MS is initiated by autoreactive T helper cells, but CNS-resident and CNS-infiltrating myeloid cells are the key proximal effector cells regulating disease pathology. We have previously shown that genetic ablation of p38α MAP kinase broadly in the myeloid lineage is protective in the autoimmune model of MS, experimental autoimmune encephalomyelitis (EAE), but only in females, and not males. To precisely define the mechanisms responsible, we used multiple genetic approaches and bone marrow chimeras to ablate p38α in microglial cells, peripheral myeloid cells, or both. Deletion of p38α in both cell types recapitulated the previous sex difference, with reduced EAE severity in females. Unexpectedly, deletion of p38α in the periphery was protective in both sexes. In contrast, deletion of p38α in microglia exacerbated EAE in males only, revealing opposing roles of p38α in microglia vs. periphery. Bulk transcriptional profiling revealed that p38α regulated the expression of distinct gene modules in male vs. female microglia. Single-cell transcriptional analysis of WT and p38α-deficient microglia isolated from the inflamed CNS revealed a diversity of complex microglial states, connected by distinct convergent transcriptional trajectories. In males, microglial p38α deficiency resulted in enhanced transition from homeostatic to disease-associated microglial states, with the downregulation of regulatory genes such as Atf3, Rgs1, Socs3, and Btg2, and increased expression of inflammatory genes such as Cd74, Trem2, and MHC class I and II genes. In females, the effect of p38α deficiency was divergent, exhibiting a unique transcriptional profile that included an upregulation of tissue protective genes, and a small subset of inflammatory genes that were also upregulated in males. Taken together, these results reveal a p38α-dependent sex-specific molecular pathway in microglia that is protective in CNS autoimmunity in males, suggesting that autoimmunity in males and females is driven by distinct cellular and molecular pathways, thus suggesting design of future sex-specific therapeutic approaches.
Effectiveness of Sublingual Immunotherapy in the Treatment of HDM-Induced Nasobronchial Allergies: A 3-Year Randomized Case-Control Study From Kashmir
Authors: Baba Shahid M. , Rasool Roohi , Gull Ayaz , Qureshi Taha A. , Beigh Afaq H. , Qadri Qurteeba , Shah Zafar A.
Published: October 2021

Allergen immunotherapy (AIT) is the only disease-modifying treatment for allergic disorders that induces immunological tolerance through administration of specific allergens. Studies on AIT for subcutaneous route are in abundance; however, the efficacy of AIT in tablet form through sublingual route has not been well elucidated. The present prospective, parallel-group, controlled study sought to compare the efficacy of sublingual immunotherapy (SLIT) tablets with pharmacotherapy (PT) in 332 house dust mite (HDM)-specific allergic asthma and/or rhinitis patients over a period of 3 years. Patients were followed up for a 6-month run-in period and then randomly stratified as those who would receive SLIT, SLIT in addition to PT (SLIT+PT), and PT alone. AIT was administered in the form of sublingual tablets. Symptom and medication scores were measured every 3 months. In vitro evaluation of serum total and HDM specific immunoglobulin E (HDM sIgE) levels was carried out every 3 months, whereas in vivo skin prick test was performed annually for 3 years. Our study demonstrated sustained clinical improvement, reduction in inhaled corticosteroid (ICS) dose and duration as well as prevention from development of neosensitization to other aero allergens in HDM-allergic asthmatics and/or rhinitis patients treated with 3 years SLIT. Despite a remarkable clinical improvement with AIT, we observed that SLIT did not significantly change the skin reactivity to HDM at 3 years and there was no significant change in the ratio of serum total and HDM sIgE. Given the immune and disease modifying effects of AIT in allergic diseases, the present study supports the notion of its sublingual mode being an effective long-term immunomodulator in HDM-sensitized nasobronchial allergies.
Drug Repurposing for Atopic Dermatitis by Integration of Gene Networking and Genomic Information
Authors: Adikusuma Wirawan , Irham Lalu Muhammad , Chou Wan-Hsuan , Wong Henry Sung-Ching , Mugiyanto Eko , Ting Jafit , Perwitasari Dyah Aryani , Chang Wei-Pin , Chang Wei-Chiao
Published: October 2021

Atopic Dermatitis (AD) is a chronic and relapsing skin disease. The medications for treating AD are still limited, most of them are topical corticosteroid creams or antibiotics. The current study attempted to discover potential AD treatments by integrating a gene network and genomic analytic approaches. Herein, the Single Nucleotide Polymorphism (SNPs) associated with AD were extracted from the GWAS catalog. We identified 70 AD-associated loci, and then 94 AD risk genes were found by extending to proximal SNPs based on r2 > 0.8 in Asian populations using HaploReg v4.1. Next, we prioritized the AD risk genes using in silico pipelines of bioinformatic analysis based on six functional annotations to identify biological AD risk genes. Finally, we expanded them according to the molecular interactions using the STRING database to find the drug target genes. Our analysis showed 27 biological AD risk genes, and they were mapped to 76 drug target genes. According to DrugBank and Therapeutic Target Database, 25 drug target genes overlapping with 53 drugs were identified. Importantly, dupilumab, which is approved for AD, was successfully identified in this bioinformatic analysis. Furthermore, ten drugs were found to be potentially useful for AD with clinical or preclinical evidence. In particular, we identified filgotinub and fedratinib, targeting gene JAK1, as potential drugs for AD. Furthermore, four monoclonal antibody drugs (lebrikizumab, tralokinumab, tocilizumab, and canakinumab) were successfully identified as promising for AD repurposing. In sum, the results showed the feasibility of gene networking and genomic information as a potential drug discovery resource.
Immune Response in Severe and Non-Severe Coronavirus Disease 2019 (COVID-19) Infection: A Mechanistic Landscape
Authors: Mukund Kavitha , Nayak Priya , Ashokkumar Chethan , Rao Sohail , Almeda Jose , Betancourt-Garcia Monica M. , Sindhi Rakesh , Subramaniam Shankar
Published: October 2021

The mechanisms underlying the immune remodeling and severity response in coronavirus disease 2019 (COVID-19) are yet to be fully elucidated. Our comprehensive integrative analyses of single-cell RNA sequencing (scRNAseq) data from four published studies, in patients with mild/moderate and severe infections, indicate a robust expansion and mobilization of the innate immune response and highlight mechanisms by which low-density neutrophils and megakaryocytes play a crucial role in the cross talk between lymphoid and myeloid lineages. We also document a marked reduction of several lymphoid cell types, particularly natural killer cells, mucosal-associated invariant T (MAIT) cells, and gamma-delta T (γδT) cells, and a robust expansion and extensive heterogeneity within plasmablasts, especially in severe COVID-19 patients. We confirm the changes in cellular abundances for certain immune cell types within a new patient cohort. While the cellular heterogeneity in COVID-19 extends across cells in both lineages, we consistently observe certain subsets respond more potently to interferon type I (IFN-I) and display increased cellular abundances across the spectrum of severity, as compared with healthy subjects. However, we identify these expanded subsets to have a more muted response to IFN-I within severe disease compared to non-severe disease. Our analyses further highlight an increased aggregation potential of the myeloid subsets, particularly monocytes, in COVID-19. Finally, we provide detailed mechanistic insights into the interaction between lymphoid and myeloid lineages, which contributes to the multisystemic phenotype of COVID-19, distinguishing severe from non-severe responses.
Mycoplasma genitalium and M. pneumoniae Regulate a Distinct Set of Protein-Coding Genes in Epithelial Cells
Authors: Ramos Enrique I. , Das Kishore , Harrison Alana L. , Garcia Anissa , Gadad Shrikanth S. , Dhandayuthapani Subramanian
Published: October 2021

Mycoplasma genitalium and M. pneumoniae are two significant mycoplasmas that infect the urogenital and respiratory tracts of humans. Despite distinct tissue tropisms, they both have similar pathogenic mechanisms and infect/invade epithelial cells in the respective regions and persist within these cells. However, the pathogenic mechanisms of these species in terms of bacterium-host interactions are poorly understood. To gain insights on this, we infected HeLa cells independently with M. genitalium and M. pneumoniae and assessed gene expression by whole transcriptome sequencing (RNA-seq) approach. The results revealed that HeLa cells respond to M. genitalium and M. pneumoniae differently by regulating various protein-coding genes. Though there is a significant overlap between the genes regulated by these species, many of the differentially expressed genes were specific to each species. KEGG pathway and signaling network analyses revealed that the genes specific to M. genitalium are more related to cellular processes. In contrast, the genes specific to M. pneumoniae infection are correlated with immune response and inflammation, possibly suggesting that M. pneumoniae has some inherent ability to modulate host immune pathways.
Rituximab Immunomonitoring Predicts Remission in Membranous Nephropathy
Authors: Teisseyre Maxime , Cremoni Marion , Boyer-Suavet Sonia , Crepin Thomas , Benzaken Sylvia , Zorzi Kévin , Esnault Vincent , Brglez Vesna , Seitz-Polski Barbara
Published: October 2021

Primary membranous nephropathy (pMN) is an autoimmune kidney disease and a common cause of nephrotic syndrome in adults. Rituximab is becoming a first line therapy for patients with persistent nephrotic syndrome with proven safety and efficacy, achieving remission in 60%–80% of cases. For the remaining 20%–40% of patients there is an urgent need to identify early biomarkers of resistance to rituximab to adapt therapeutic management. In nephrotic patients, rituximab is found in the blood more transiently than in other autoimmune diseases without proteinuria, due to rituximab wasting in the urine. However, rituximab immunomonitoring is not routinely performed. We evaluated the predictive value of serum rituximab levels in patients with pMN three months after rituximab injection (month-3) on clinical remission rates six months (month-6) and 12 months (month-12) after injection and investigated predictive factors for serum rituximab levels at month-3. Sixty-eight patients treated with rituximab between July 2015 and January 2020 from two French nephrology centers were included. We identified residual rituximab levels at month-3 as a novel early predictor of remission at month-6 (p <0.0001) and month-12 (p = 0.001). Reduced likelihood of remission in patients with undetectable rituximab at month-3 was associated with lower serum albumin and higher anti-PLA2R1 titers at baseline and with lower serum albumin, higher proteinuria, higher CD19+ counts and higher anti-PLA2R1 titers during follow-up. In multivariate analysis, high baseline proteinuria and undetectable rituximab levels at month-3 were independent risk factors for treatment failure at month-6 and high baseline weight and undetectable rituximab levels at month-3 were independent risk factors for treatment failure at month-12. We identified serum albumin at baseline as a predictive factor for serum rituximab levels at month-3. Patients with serum albumin below 22.5 g/L at baseline had an 8.66-fold higher risk of having undetectable rituximab levels at month-3. Therefore, rituximab immunomonitoring in pMN patients treated with rituximab would allow the detection of patients at risk of treatment failure as early as month-3. Studies are needed to assess whether patients with low residual rituximab levels at month-3 may benefit from an early additional course of rituximab.
Effect of Immune Checkpoint Blockade on Myeloid-Derived Suppressor Cell Populations in Patients With Melanoma
Authors: Sun Steven H. , Benner Brooke , Savardekar Himanshu , Lapurga Gabriella , Good Logan , Abood David , Nagle Erin , Duggan Megan , Stiff Andrew , DiVincenzo Mallory J. , Suarez-Kelly Lorena P. , Campbell Amanda , Yu Lianbo , Wesolowski Robert , Howard Harrison , Shah Hiral , Kendra Kari , Carson William E.
Published: October 2021

Introduction

Myeloid-derived suppressor cells (MDSC) are a subset of immature myeloid cells that inhibit anti-tumor immunity and contribute to immune therapy resistance. MDSC populations were measured in melanoma patients receiving immune checkpoint inhibitors (ICI).

Methods

Patients with melanoma (n=128) provided blood samples at baseline (BL), and before cycles 2 and 3 (BC2, BC3). Peripheral blood mononuclear cells (PBMC) were analyzed for MDSC (CD33+/CD11b+/HLA- DRlo/-) and MDSC subsets, monocytic (CD14+, M-MDSC), granulocytic (CD15+, PMN-MDSC), and early (CD14-/CD15-, E-MDSC) via flow cytometry. Statistical analysis employed unpaired and paired t-tests across and within patient cohorts.

Results

Levels of MDSC as a percentage of PBMC increased during ICI (BL: 9.2 ± 1.0% to BC3: 23.6 ± 1.9%, p<0.0001), and patients who developed progressive disease (PD) had higher baseline MDSC. In patients who had a complete or partial response (CR, PR), total MDSC levels rose dramatically and plateaued (BL: 6.4 ± 1.4%, BC2: 26.2 ± 4.2%, BC3: 27.5 ± 4.4%; p<0.0001), whereas MDSC rose less sharply in PD patients (BL: 11.7 ± 2.1%, BC2: 18.3 ± 3.1%, BC3: 19.0 ± 3.2%; p=0.1952). Subset analysis showed that within the expanding MDSC population, PMN-MDSC and E-MDSC levels decreased, while the proportion of M-MDSC remained constant during ICI. In PD patients, the proportion of PMN-MDSC (as a percentage of total MDSC) decreased (BL: 25.1 ± 4.7%, BC2: 16.1 ± 5.2%, BC3: 8.6 ± 1.8%; p=0.0105), whereas a heretofore under-characterized CD14+/CD15+ double positive MDSC subpopulation increased significantly (BL: 8.7 ± 1.4% to BC3: 26.9 ± 4.9%; p=0.0425).

Conclusions

MDSC levels initially increased significantly in responders. PMN-MDSC decreased and CD14+CD15+ MDSC increased significantly in PD patients. Changes in MDSC levels may have prognostic value in ICI.
Molecular Changes in the Adipose Tissue Induced by Rheumatoid Arthritis: Effects of Disease-Modifying Anti-Rheumatic Drugs
Authors: Arias de la Rosa Iván , Escudero-Contreras Alejandro , Ruiz-Ponce Miriam , Román-Rodríguez Cristóbal , Pérez-Sánchez Carlos , Ábalos-Aguilera María del Carmen , Ortega-Castro Rafaela , Alcaide Juan , Murri Mora , Font Pilar , Calvo-Gutiérrez Jerusalem , Luque-Tevar Maria , Patiño-Trives Alejandra Maria , Guzmán-Ruiz Rocío , Malagón Maria del Mar , Tinahones Francisco José , Collantes-Estévez Eduardo , López-Pedrera Chary , Barbarroja Nuria
Published: October 2021

Disease severity, progression and response to therapy might be worse in obese rheumatoid arthritis (RA) patients, but paradoxically, obesity also might protect from radiographic joint damage. Thus, the intricate relationship between obesity and RA needs urgent clarification. The aim of this study was to assess the influence of obesity on the onset and development of RA and to determine whether arthritis could modify the adipose tissue biology and whether conventional Disease Modifying Anti-Rheumatic Drugs (cDMARDs) can modulate these alterations. Two strategies were followed: (1) clinical profiling of two cohorts of RA: non-obese and obese patients; and (2) mechanistic studies carried out in both a collagen-induced arthritis (CIA) in an obese mouse model and 3T3-L1 adipocytes treated with cDMARDs (leflunomide, methotrexate, and hydroxychloroquine). In our cohort of RA patients with low-moderate disease activity, the presence of obesity was not related to a higher activity of the disease; actually, disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR) was reduced in the obese RA patients. However, the induction of arthritis promoted transcriptomic changes in the adipose tissue under obesity condition in the obese CIA model. Treatment with hydroxychloroquine reduced weight and insulin resistance, accompanied by beneficial metabolic effects in the adipose tissue. These molecular changes in adipose tissue were also observed after methotrexate administration. In sum, arthritis might affect directly the inflammatory burden and metabolic alterations associated with obesity in adipose tissue. Clinicians should be cautious measuring the activity of the disease in obesity and managing the best therapeutic options for the metabolic comorbidities of these patients, where the combination of hydroxychloroquine and methotrexate should be considered to improve adipose tissue dysfunction in obese RA.
Inverted CD8 T-Cell Exhaustion and Co-Stimulation Marker Balance Differentiate Aviremic HIV-2-Infected From Seronegative Individuals
Authors: Scharf Lydia , Pedersen Christina B. , Johansson Emil , Lindman Jacob , Olsen Lars R. , Buggert Marcus , Wilhelmson Sten , Månsson Fredrik , Esbjörnsson Joakim , Biague Antonio , Medstrand Patrik , Norrgren Hans , Karlsson Annika C. , Jansson Marianne ,   the SWEGUB CORE Group
Published: October 2021

HIV-2 is less pathogenic compared to HIV-1. Still, disease progression may develop in aviremic HIV-2 infection, but the driving forces and mechanisms behind such development are unclear. Here, we aimed to reveal the immunophenotypic pattern associated with CD8 T-cell pathology in HIV-2 infection, in relation to viremia and markers of disease progression. The relationships between pathological differences of the CD8 T-cell memory population and viremia were analyzed in blood samples obtained from an occupational cohort in Guinea-Bissau, including HIV-2 viremic and aviremic individuals. For comparison, samples from HIV-1- or dually HIV-1/2-infected and seronegative individuals were obtained from the same cohort. CD8 T-cell exhaustion was evaluated by the combined expression patterns of activation, stimulatory and inhibitory immune checkpoint markers analyzed using multicolor flow cytometry and advanced bioinformatics. Unsupervised multidimensional clustering analysis identified a cluster of late differentiated CD8 T-cells expressing activation (CD38+, HLA-DRint/high), co-stimulatory (CD226+/-), and immune inhibitory (2B4+, PD-1high, TIGIThigh) markers that distinguished aviremic from viremic HIV-2, and treated from untreated HIV-1-infected individuals. This CD8 T-cell population displayed close correlations to CD4%, viremia, and plasma levels of IP-10, sCD14 and beta-2 microglobulin in HIV-2 infection. Detailed analysis revealed that aviremic HIV-2-infected individuals had higher frequencies of exhausted TIGIT+ CD8 T-cell populations lacking CD226, while reduced percentage of stimulation-receptive TIGIT-CD226+ CD8 T-cells, compared to seronegative individuals. Our results suggest that HIV-2 infection, independent of viremia, skews CD8 T-cells towards exhaustion and reduced co-stimulation readiness. Further knowledge on CD8 T-cell phenotypes might provide help in therapy monitoring and identification of immunotherapy targets.
Prophylactic Tocilizumab Prior to Anti-CD19 CAR-T Cell Therapy for Non-Hodgkin Lymphoma
Authors: Caimi Paolo F. , Pacheco Sanchez Gabriela , Sharma Ashish , Otegbeye Folashade , Ahmed Nausheen , Rojas Patricio , Patel Seema , Kleinsorge Block Sarah , Schiavone Jennifer , Zamborsky Kayla , Boughan Kirsten , Hillian Antoinette , Reese-Koc Jane , Maschan Mikhail , Dropulic Boro , Sekaly Rafick-Pierre , de Lima Marcos
Published: October 2021

Anti-CD19 chimeric antigen receptor T (CAR-T) cells have demonstrated activity against relapsed/refractory lymphomas. Cytokine release syndrome (CRS) and immune effector cell – associated neurotoxicity syndrome (ICANS) are well-known complications. Tocilizumab, a monoclonal antibody targeting the interleukin-6 (IL-6) receptor was administered 1 hour prior to infusion of anti-CD19 CAR-T cells with CD3ζ/4-1BB costimulatory signaling used to treat non-Hodgkin lymphoma patients. Relapsed/refractory lymphoma patients treated with anti-CD19 CAR-T cells were included in this analysis. Cytokine plasma levels were measured by electrochemiluminescence before lymphodepleting chemotherapy, prior to infusion and then on days 2, 4,6, and 14 days after treatment. Twenty patients were treated. Cell products included locally manufactured anti-CD19 CAR-T (n=18) and tisagenlecleucel (n=2). There were no adverse events attributed to tocilizumab. Ten patients had grade 1–2 CRS at a median of 4 (range 3-7) days. There were no cases of grade ≥3 CRS. Five patients had ICANS, grade 1 (n=4) and grade 4 (n=1). Laboratory studies obtained prior to lymphodepleting chemotherapy were comparable between patients with and without CRS, except for interleukin (IL)-15 plasma concentrations. patients with CRS had higher post-infusion ferritin and C reactive protein, with more marked increases in inflammatory cytokines, including IL-6, IL-15, IFN-γ, fractalkine and MCP-1. Fifteen patients (75%) achieved CR and 2 (10%), PR. One-year OS and PFS estimates were 83% and 73%. Prophylactic tocilizumab was associated with low CRS incidence and severity. There were no adverse events associated with tocilizumab, no increase in frequency or severity of ICANS and excellent disease control and overall survival.
Bacteriophage T4 Vaccine Platform for Next-Generation Influenza Vaccine Development
Authors: Li Mengling , Guo Pengju , Chen Cen , Feng Helong , Zhang Wanpo , Gu Changqin , Wen Guoyuan , Rao Venigalla B. , Tao Pan
Published: October 2021

Developing influenza vaccines that protect against a broad range of viruses is a global health priority. Several conserved viral proteins or domains have been identified as promising targets for such vaccine development. However, none of the targets is sufficiently immunogenic to elicit complete protection, and vaccine platforms that can enhance immunogenicity and deliver multiple antigens are desperately needed. Here, we report proof-of-concept studies for the development of next-generation influenza vaccines using the bacteriophage T4 virus-like particle (VLP) platform. Using the extracellular domain of influenza matrix protein 2 (M2e) as a readout, we demonstrate that up to ~1,281 M2e molecules can be assembled on a 120 x 86 nanometer phage capsid to generate M2e-T4 VLPs. These M2e-decorated nanoparticles, without any adjuvant, are highly immunogenic, stimulate robust humoral as well as cellular immune responses, and conferred complete protection against lethal influenza virus challenge. Potentially, additional conserved antigens could be incorporated into the M2e-T4 VLPs and mass-produced in E. coli in a short amount of time to deal with an emerging influenza pandemic.
Improved Accuracy for Automated Counting of a Fish in Baited Underwater Videos for Stock Assessment
Authors: Connolly Rod M. , Fairclough David V. , Jinks Eric L. , Ditria Ellen M. , Jackson Gary , Lopez-Marcano Sebastian , Olds Andrew D. , Jinks Kristin I.
Published: October 2021

The ongoing need to sustainably manage fishery resources can benefit from fishery-independent monitoring of fish stocks. Camera systems, particularly baited remote underwater video system (BRUVS), are a widely used and repeatable method for monitoring relative abundance, required for building stock assessment models. The potential for BRUVS-based monitoring is restricted, however, by the substantial costs of manual data extraction from videos. Computer vision, in particular deep learning (DL) models, are increasingly being used to automatically detect and count fish at low abundances in videos. One of the advantages of BRUVS is that bait attractants help to reliably detect species in relatively short deployments (e.g., 1 h). The high abundances of fish attracted to BRUVS, however, make computer vision more difficult, because fish often obscure other fish. We build upon existing DL methods for identifying and counting a target fisheries species across a wide range of fish abundances. Using BRUVS imagery targeting a recovering fishery species, Australasian snapper (Chrysophrys auratus), we tested combinations of three further mathematical steps likely to generate accurate, efficient automation: (1) varying confidence thresholds (CTs), (2) on/off use of sequential non-maximum suppression (Seq-NMS), and (3) statistical correction equations. Output from the DL model was more accurate at low abundances of snapper than at higher abundances (>15 fish per frame) where the model over-predicted counts by as much as 50%. The procedure providing the most accurate counts across all fish abundances, with counts either correct or within 1–2 of manual counts (R2 = 88%), used Seq-NMS, a 45% CT, and a cubic polynomial corrective equation. The optimised modelling provides an automated procedure offering an effective and efficient method for accurately identifying and counting snapper in the BRUV footage on which it was tested. Additional evaluation will be required to test and refine the procedure so that automated counts of snapper are accurate in the survey region over time, and to determine the applicability to other regions within the distributional range of this species. For monitoring stocks of fishery species more generally, the specific equations will differ but the procedure demonstrated here could help to increase the usefulness of BRUVS.
The Extent of Seasonally Suitable Habitats May Limit Forage Fish Production in a Temperate Estuary
Authors: Fabrizio Mary C. , Tuckey Troy D. , Bever Aaron J. , MacWilliams Michael L.
Published: October 2021

The sustained production of sufficient forage is critical to advancing ecosystem-based management, yet factors that affect local abundances and habitat conditions necessary to support aggregate forage production remain largely unexplored. We quantified suitable habitat in the Chesapeake Bay and its tidal tributaries for four key forage fishes: juvenile spotted hake Urophycis regia, juvenile spot Leiostomus xanthurus, juvenile weakfish Cynoscion regalis, and bay anchovy Anchoa mitchilli. We used information from monthly fisheries surveys from 2000 to 2016 coupled with hindcasts from a spatially interpolated model of dissolved oxygen and a 3-D hydrodynamic model of the Chesapeake Bay to identify influential covariates and construct habitat suitability models for each species. Suitable habitat conditions resulted from a complex interplay between water quality and geophysical properties of the environment and varied among species. Habitat suitability indices ranging between 0 (poor) and 1 (superior) were used to estimate seasonal and annual extents of suitable habitats. Seasonal variations in suitable habitat extents in Chesapeake Bay, which were more pronounced than annual variations during 2000–2016, reflected the phenology of estuarine use by these species. Areas near shorelines served as suitable habitats in spring for juvenile spot and in summer for juvenile weakfish, indicating the importance of these shallow areas for production. Tributaries were more suitable for bay anchovy in spring than during other seasons. The relative baywide abundances of juvenile spot and bay anchovy were significantly related to the extent of suitable habitats in summer and winter, respectively, indicating that Chesapeake Bay habitats may be limiting for these species. In contrast, the relative baywide abundances of juvenile weakfish and juvenile spotted hake varied independently of the spatial extent of suitable habitats. In an ecosystem-based approach, areas that persistently provide suitable conditions for forage species such as shoreline and tributary habitats may be targeted for protection or restoration, thereby promoting sufficient production of forage for predators. Further, quantitative habitat targets or spatial thresholds may be developed for habitat-limited species using estimates of the minimum habitat area required to produce a desired abundance or biomass; such targets or thresholds may serve as spatial reference points for management.
Deep Learning for Simulating Harmful Algal Blooms Using Ocean Numerical Model
Authors: Baek Sang-Soo , Pyo JongCheol , Kwon Yong Sung , Chun Seong-Jun , Baek Seung Ho , Ahn Chi-Yong , Oh Hee-Mock , Kim Young Ok , Cho Kyung Hwa
Published: October 2021

In several countries, the public health and fishery industries have suffered from harmful algal blooms (HABs) that have escalated to become a global issue. Though computational modeling offers an effective means to understand and mitigate the adverse effects of HABs, it is challenging to design models that adequately reflect the complexity of HAB dynamics. This paper presents a method involving the application of deep learning to an ocean model for simulating blooms of Alexandrium catenella. The classification and regression convolutional neural network (CNN) models are used for simulating the blooms. The classification CNN determines the bloom initiation while the regression CNN estimates the bloom density. GoogleNet and Resnet 101 are identified as the best structures for the classification and regression CNNs, respectively. The corresponding accuracy and root means square error values are determined as 96.8% and 1.20 [log(cells L–1)], respectively. The results obtained in this study reveal the simulated distribution to follow the Alexandrium catenella bloom. Moreover, Grad-CAM identifies that the salinity and temperature contributed to the initiation of the bloom whereas NH4-N influenced the growth of the bloom.
State of Shark and Ray Genomics in an Era of Extinction
Authors: Pearce Jessica , Fraser Matthew W. , Sequeira Ana M. M. , Kaur Parwinder
Published: October 2021

Chondrichthyan species (sharks, rays, skates, and chimeras) are a class of high ecological, economic, and cultural significance, and yet they are the most threatened taxa in the marine environment. The creation of reference chromosome-length genome assemblies allows for conservation genomics methods, such as population and ecological genomics, to be utilized. Despite being greatly threatened and of great importance in maintaining ecosystem function, chondrichthyan species have been repeatedly absent from conservation-based genome sequencing projects. Less than 1% of these species have a genome sequence, despite their almost 50% either threatened or Data Deficient conservation status. Most notably, there are seven orders within this class without any genome representation. In this review, we identify gaps in chondrichthyan genomic resources and demonstrate how the lack of genomic resources for this major taxonomic class is limiting the conservation of these already difficult to conserve species. We highlight other applications for chondrichthyans genomics, such as evolutionary and developmental biology. Likely, the mismatching sampling protocols and limited computational skills and communication between fields have been preventing the integration of marine and molecular sciences. Here, we propose that this field is in dire need to move forward quickly to increase protection for marine species and ecosystems through improved collaboration between marine, molecular, and computer sciences.