bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolution of Modeled Cortisol Is Prognostic of Death in Hospitalized Patients With COVID-19 Syndrome
Authors: Hedayat Kamyar M. , Chalvet David , Yang Maël , Golshan Shahrokh , Allix-Beguec Caroline , Beneteaud Serge , Schmit Thomas
Published: June 2022

Introduction

Patients hospitalized with SARS-CoV-2 have an elevated risk of mortality related to a severe inflammatory response. We hypothesized that biological modeling with a complete blood count (CBC) would be predictive of mortality.

Method

In 2020, 81 patients were randomly selected from La Rochelle Hospital, France for a simple blinded retrospective study. Demographic, vital signs, CBC and CRP were obtained on admission, at days 2-3 and 3-5. From a CBC, two biological modeling indexes were resulted: the neutrophil-to-lymphocyte ratio (NLR) and cortisol index adjusted (CA).

Results

By ANOVA, in survivors vs. non-survivors there was statistical different at p < 0.01 for age (66.2 vs. 80), CRP (92 vs. 179 mg/dL, normal < 10), cortisol index adjusted (323 vs. 698, normal 3-7) and genito-thyroid indexes (7.5 vs. 18.2, normal 1.5–2.5), and at p = 0.02 creatinine (1.03 vs. 1.48, normal 0.73–1.8 mg/dL). By mixed model analysis, CA and NLR improved in those who survived across all three time points, but worsened again after 3–5 days in non-survivors. CRP continued to improve over time in survivors and non-survivors. Positive vs. Negative predictive value were: CRP (91.1%, 30.4%), NLR (94.5%, 22.7%), CA (100%, 0%).

Discussion

Cortisol modeling and the neutrophil-to-lymphocyte ratio were more accurate in describing the course of non-survivors than CRP.

Conclusion

In patients admitted for SARS CoV-2 infection, biological modeling with a CBC predicted risk of death better than CRP. This approach is inexpensive and easily repeated.
Toward Rapid, Widely Available Autologous CAR-T Cell Therapy – Artificial Intelligence and Automation Enabling the Smart Manufacturing Hospital
Authors: Hort Simon , Herbst Laura , Bäckel Niklas , Erkens Frederik , Niessing Bastian , Frye Maik , König Niels , Papantoniou Ioannis , Hudecek Michael , Jacobs John J. L. , Schmitt Robert H.
Published: June 2022

CAR-T cell therapy is a promising treatment for acute leukemia and lymphoma. CAR-T cell therapies take a pioneering role in autologous gene therapy with three EMA-approved products. However, the chance of clinical success remains relatively low as the applicability of CAR-T cell therapy suffers from long, labor-intensive manufacturing and a lack of comprehensive insight into the bioprocess. This leads to high manufacturing costs and limited clinical success, preventing the widespread use of CAR-T cell therapies. New manufacturing approaches are needed to lower costs to improve manufacturing capacity and shorten provision times. Semi-automated devices such as the Miltenyi Prodigy® were developed to reduce hands-on production time. However, these devices are not equipped with the process analytical technology necessary to fully characterize and control the process. An automated AI-driven CAR-T cell manufacturing platform in smart manufacturing hospitals (SMH) is being developed to address these challenges. Automation will increase the cost-effectiveness and robustness of manufacturing. Using Artificial Intelligence (AI) to interpret the data collected on the platform will provide valuable process insights and drive decisions for process optimization. The smart integration of automated CAR-T cell manufacturing platforms into hospitals enables the independent manufacture of autologous CAR-T cell products. In this perspective, we will be discussing current challenges and opportunities of the patient-specific but highly automated, AI-enabled CAR-T cell manufacturing. A first automation concept will be shown, including a system architecture based on current Industry 4.0 approaches for AI integration.
CpG Island Methylation of Suppressor of Cytokine Signaling-1 Gene Induced by HCV Is Associated With HCV-Related Hepatocellular Carcinoma
Authors: Liu Miao , Du Lingyao , Cheng Xing , Yuan Man , Shang Jin , Shi Ying , Yang Hailing , Tang Hong
Published: June 2022

Suppressor of cytokine signaling 1 (SOCS-1) is implicated in both virus infection and carcinogenesis. This study investigated the role of HCV infection on SOCS-1 in normal and HCV-infected tissues and revealed a possible mechanism underlying HCV-induced hepatocellular carcinoma (HCC) genesis. In total, 10 HCV-HCC tissues, seven adjacent tissues, seven distal tissues, and 16 normal liver tissues were collected. SOCS-1 expression in tissue sections was detected by immunohistochemistry. After viral load was quantified, the correlation between SOCS-1 expression and viral load was analyzed in different tissues. Then, HCV replicon model was used to detect a relationship between HCV and SOCS-1. Subsequently, methylation-specific PCR (MSP) was applied to show the methylation status of SOCS-1 genes in normal tissues and HCV-replicating cell lines. A correlation between gene methylation, SOCS-1 expression, and HCV was analyzed. The lowest expression of SOCS-1 was observed in HCV-HCC tissues. Tissues with a higher HCV viral load showed lower SOCS-1 expression (p = 0.0282). Consistently, SOCS-1 mRNA and protein were lower in HCV-replicating cell lines than in uninfected ones. Furthermore, gene methylation was found in all examined tissues but higher in HCC tissues, and it is positively correlated with HCV viral load (r2 = 0.7309, p < 0.0001). HCV infection would upregulate methylation of the SOCS-1 gene in HCV-replicating cell lines. The downregulation of SOCS-1 in normal and HCV-replicating cell lines may result from HCV infection through epigenetic regulation, in which gene methylation in the CpG island of SOCS-1 promoters upon HCV infection suppresses its expression.
In vitro and in silico Studies Reveal Bacillus cereus AA-18 as a Potential Candidate for Bioremediation of Mercury-Contaminated Wastewater
Authors: Amin Aatif , Naveed Muhammad , Sarwar Arslan , Rasheed Sunbul , Saleem Hafiz Ghulam Murtaza , Latif Zakia , Bechthold Andreas
Published: June 2022

Mercury (Hg) pollution is a worldwide problem and increasing day by day due to natural and anthropogenic sources. In this study, mercury-resistant (HgR) bacterial isolates were isolated from industrial wastewater of Ittehad Chemicals Ltd., Kala Shah Kaku, Lahore, Pakistan. Out of 65 bacterial isolates, five isolates were screened out based on showing resistance at 30–40 μg/ml against HgCl2. Selected Hg-resistant bacterial isolates were characterized as Bacillus subtilis AA-16 (OK562835), Bacillus cereus AA-18 (OK562834), Bacillus sp. AA-20 (OK562833), Bacillus paramycoides AA-30 (OK562836), and Bacillus thuringiensis AA-35 (OK562837). B. cereus AA-18 showed promising results in the resistance of HgCl2 (40 μg/ml) due to the presence of merA gene. Scanning electron microscopy (SEM) analysis of immobilized B. cereus AA-18 showed the accumulation Hg on the cell surface. The inoculation of immobilized B. cereus AA-18 remediated 86% Hg of industrial wastewater up to 72 h at large scale (p < 0.05). In silico analysis showed structural determination of MerA protein encoded by merA gene of B. cereus AA-18 (OK562598) using ProtParam, Pfam, ConSurf Server, InterPro, STRING, Jpred4, PSIPRED, I-TASSER, COACH server, TrRosetta, ERRAT, VERIFY3D, Ramachandran plot, and AutoDock Vina (PyRx 8.0). These bioinformatics tools predicted the structural-based functional homology of MerA protein (mercuric reductase) associated with mer operon harboring bacteria involved in Hg-bioremediation system.
Bile Salt Hydrolase Degrades β-Lactam Antibiotics and Confers Antibiotic Resistance on Lactobacillus paragasseri
Authors: Kusada Hiroyuki , Arita Masanori , Tohno Masanori , Tamaki Hideyuki
Published: June 2022

Bile salt hydrolase (BSH) is a well-characterized probiotic enzyme associated with bile detoxification and colonization of lactic acid bacteria in the human gastrointestinal tract. Here, we isolated a putative BSH (LpBSH) from the probiotic bacterium Lactobacillus paragasseri JCM 5343T and demonstrated its bifunctional activity that allows it to degrade not only bile salts but also the antibiotic (penicillin). Although antibiotic resistance and bile detoxification have been separately recognized as different microbial functions, our findings suggest that bifunctional BSHs simultaneously confer ecological advantages to host gut bacteria to improve their survival in the mammalian intestine by attaining a high resistance to bile salts and β-lactams. Strain JCM 5343T showed resistance to both bile salts and β-lactam antibiotics, suggesting that LpBSH may be involved in this multi-resistance of the strain. We further verified that such bifunctional enzymes were broadly distributed among the phylogeny, suggesting that the bifunctionality may be conserved in other BSHs of gut bacteria. This study revealed the physiological role and phylogenetic diversity of bifunctional enzymes degrading bile salts and β-lactams in gut bacteria. Furthermore, our findings suggest that the hitherto-overlooked penicillin-degrading activity of penicillin acylase could be a potential new target for the probiotic function of gut bacteria.
Evolutionary Divergence of Marinobacter Strains in Cryopeg Brines as Revealed by Pangenomics
Authors: Cooper Zachary S. , Rapp Josephine Z. , Shoemaker Anna M. D. , Anderson Rika E. , Zhong Zhi-Ping , Deming Jody W.
Published: June 2022

Marinobacter spp. are cosmopolitan in saline environments, displaying a diverse set of metabolisms that allow them to competitively occupy these environments, some of which can be extreme in both salinity and temperature. Here, we introduce a distinct cluster of Marinobacter genomes, composed of novel isolates and in silico assembled genomes obtained from subzero, hypersaline cryopeg brines, relic seawater-derived liquid habitats within permafrost sampled near Utqiaġvik, Alaska. Using these new genomes and 45 representative publicly available genomes of Marinobacter spp. from other settings, we assembled a pangenome to examine how the new extremophile members fit evolutionarily and ecologically, based on genetic potential and environmental source. This first genus-wide genomic analysis revealed that Marinobacter spp. in general encode metabolic pathways that are thermodynamically favored at low temperature, cover a broad range of organic compounds, and optimize protein usage, e.g., the Entner–Doudoroff pathway, the glyoxylate shunt, and amino acid metabolism. The new isolates contributed to a distinct clade of subzero brine-dwelling Marinobacter spp. that diverged genotypically and phylogenetically from all other Marinobacter members. The subzero brine clade displays genomic characteristics that may explain competitive adaptations to the extreme environments they inhabit, including more abundant membrane transport systems (e.g., for organic substrates, compatible solutes, and ions) and stress-induced transcriptional regulatory mechanisms (e.g., for cold and salt stress) than in the other Marinobacter clades. We also identified more abundant signatures of potential horizontal transfer of genes involved in transcription, the mobilome, and a variety of metabolite exchange systems, which led to considering the importance of this evolutionary mechanism in an extreme environment where adaptation via vertical evolution is physiologically rate limited. Assessing these new extremophile genomes in a pangenomic context has provided a unique view into the ecological and evolutionary history of the genus Marinobacter, particularly with regard to its remarkable diversity and its opportunism in extremely cold and saline environments.
Genes Involved in Biofilm Matrix Formation of the Food Spoiler Pseudomonas fluorescens PF07
Authors: Guo Miao , Tan Siqi , Zhu Junli , Sun Aihua , Du Peng , Liu Xiaoxiang
Published: June 2022

The extracellular matrix is essential for the biofilm formation of food spoilers.Pseudomonas fluorescensPF07 is a previous isolate from spoiled marine fish; however, the genes involved in the extracellular matrix formation of PF07 biofilms remain poorly defined. In this study, PF07 formed a wrinkled macrocolony biofilm through the high production of extracellular matrix. The genes involved in biofilm matrix formation and regulation were screened and identified by RNA-seq-dependent transcriptomic analysis and gene knock-out analysis. The macrocolony biofilms of PF07 grown for 5 days (PF07_5d) were compared with those grown for 1 day (PF07_1d). A total of 1,403 genes were significantly differentially expressed during biofilm formation. These mainly include the genes related to biofilm matrix proteins, polysaccharides, rhamnolipids, secretion system, biofilm regulation, and metabolism. Among them, functional amyloid genesfapABCDEwere highly upregulated in the mature biofilm, and the operonfapA-Ehad a –24/–12 promoter dependent on the sigma factor RpoN. Moreover, the RNA-seq analyses of therpoNmutant, compared with PF07, revealed 159 genes were differentially expressed in the macrocolony biofilms, andfapA-Egenes were positively regulated by RpoN. In addition, the deletion mutants offapC,rpoN, andbrfA(a novel gene coding for an RpoN-dependent transcriptional regulator) were defective in forming mature macrocolony biofilms, solid surface-associated (SSA) biofilms, and pellicles, and they showed significantly reduced biofilm matrices. Thefapgenes were significantly downregulated in ΔbrfA, as in ΔrpoN. These findings suggest that the functional amyloid Fap is the main component of PF07 biofilm matrices, and RpoN may directly regulate the transcription offapgenes, in conjunction with BrfA. These genes may serve as potential molecular targets for screening new anti-biofilm agents or for biofilm detection in food environments.
Soil Microbial Network Complexity Varies With pH as a Continuum, Not a Threshold, Across the North China Plain
Authors: Yang Ying , Shi Yu , Fang Jie , Chu Haiyan , Adams Jonathan M.
Published: June 2022

There has been little study on the biogeographical patterns of microbial co-occurrence, especially in agricultural soils. Here we investigated the biogeographical patterns and major drivers of co-occurrence network topological structure, and the relative abundance of keystone taxa for soil bacterial and fungal communities using high-throughput sequencing on a set of 90 samples across a 1,092 km transect in wheat fields of the North China Plain (NCP). We found that pH was the most important environmental factor driving network topology and relative abundance of keystone taxa. For the metacommunity composed of both bacteria and fungi, and for the bacterial community alone, lower soil pH was associated with a more complex microbial network. However, the network for fungi showed no strong trend with soil pH. In addition, keystone taxa abundance was positively correlated with ecosystem function and stability, and best explained by pH. Our results present new perspectives on impacts of pH on soil microbial network structure across large scales in agricultural environments. This improved knowledge of community processes provides a step toward understanding of functioning and stability of agricultural ecosystems.
Identification of Crucial Amino Acid Residues for Antimicrobial Activity of Angiogenin 4 and Its Modulation of Gut Microbiota in Mice
Authors: Sultana Mst. Farzana , Suzuki Maki , Yamasaki Fumiya , Kubota Wataru , Takahashi Kohta , Abo Hirohito , Kawashima Hiroto
Published: June 2022

Angiogenin 4 bearing ribonuclease activity is an endogenous antimicrobial protein expressed in small and large intestine. However, the crucial amino acid residues responsible for the antibacterial activity of Ang4 and its impact on gut microbiota remain unknown. Here, we report the contribution of critical amino acid residues in the functional regions of Ang4 to its activity against Salmonella typhimurium LT2 and the effect of Ang4 on gut microbiota in mice. We found that Ang4 binds S. typhimurium LT2 through two consecutive basic amino acid residues, K58 and K59, in the cell-binding segment and disrupts the bacterial membrane integrity at the N-terminal α-helix containing residues K7 and K30, as evidenced by the specific mutations of cationic residues of Ang4. We also found that the RNase activity of Ang4 was not involved in its bactericidal activity, as shown by the H12 mutant, which lacks RNase activity. In vivo administration of Ang4 through the mouse rectum and subsequent bacterial 16S rRNA gene sequencing analyses demonstrated that administration of Ang4 not only increased beneficial bacteria such as Lactobacillus, Akkermansia, Dubosiella, Coriobacteriaceae UCG-002, and Adlercreutzia, but also decreased certain pathogenic bacteria, including Alistipes and Enterohabdus, indicating that Ang4 regulates the shape of gut microbiota composition. We conclude that Ang4 kills bacteria by disrupting bacterial membrane integrity through critical basic amino acid residues with different functionalities rather than overall electrostatic interactions and potentially maintains gut microflora in vivo under physiological and pathophysiological conditions.
Halotolerant Plant Growth-Promoting Rhizobacteria Isolated From Saline Soil Improve Nitrogen Fixation and Alleviate Salt Stress in Rice Plants
Authors: Khumairah Fiqriah Hanum , Setiawati Mieke Rochimi , Fitriatin Betty Natalie , Simarmata Tualar , Alfaraj Saleh , Ansari Mohammad Javed , Enshasy Hesham A. El , Sayyed R. Z. , Najafi Solmaz
Published: June 2022

Salinity is one of the most damaging abiotic stresses due to climate change impacts that affect the growth and yield of crops, especially in lowland rice fields and coastal areas. This research aimed to isolate potential halotolerant plant growth-promoting rhizobacteria from different rhizo-microbiome and use them as effective bioinoculants to improve rice growth under salinity stress conditions. Bioassay using rice seedlings was performed in a randomized block design consisting of 16 treatments (control and 15 bacterial isolates) with three replications. Results revealed that isolates S3, S5, and S6 gave higher shoot height, root length, and plant dry weight compared with control (without isolates). Based on molecular characteristics, isolates S3 and S5 were identified as Pseudomonas stutzeri and Klebsiella pneumonia. These isolates were able to promote rice growth under salinity stress conditions as halotolerant plant growth-promoting rhizobacteria. These three potent isolates were found to produce indole-3-acetic acid and nitrogenase.
A Rapid, Whole Genome Sequencing Assay for Detection and Characterization of Novel Coronavirus (SARS-CoV-2) Clinical Specimens Using Nanopore Sequencing
Authors: Arévalo Maria T. , Karavis Mark A. , Katoski Sarah E. , Harris Jacquelyn V. , Hill Jessica M. , Deshpande Samir V. , Roth Pierce A. , Liem Alvin T. , Bernhards R. Cory
Published: June 2022

A new human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged at the end of 2019 in Wuhan, China that caused a range of disease severities; including fever, shortness of breath, and coughing. This disease, now known as coronavirus disease 2019 (COVID-19), quickly spread throughout the world, and was declared a pandemic by the World Health Organization in March of 2020. As the disease continues to spread, providing rapid characterization has proven crucial to better inform the design and execution of control measures, such as decontamination methods, diagnostic tests, antiviral drugs, and prophylactic vaccines for long-term control. Our work at the United States Army’s Combat Capabilities Development Command Chemical Biological Center (DEVCOM CBC) is focused on engineering workflows to efficiently identify, characterize, and evaluate the threat level of any potential biological threat in the field and more remote, lower resource settings, such as forward operating bases. While we have successfully established untargeted sequencing approaches for detection of pathogens for rapid identification, our current work entails a more in-depth sequencing analysis for use in evolutionary monitoring. We are developing and validating a SARS-CoV-2 nanopore sequencing assay, based on the ARTIC protocol. The standard ARTIC, Illumina, and nanopore sequencing protocols for SARS-CoV-2 are elaborate and time consuming. The new protocol integrates Oxford Nanopore Technology’s Rapid Sequencing Kit following targeted RT-PCR of RNA extracted from human clinical specimens. This approach decreases sample manipulations and preparation times. Our current bioinformatics pipeline utilizes Centrifuge as the classifier for quick identification of SARS-CoV-2 and RAMPART software for verification and mapping of reads to the full SARS-CoV-2 genome. ARTIC rapid sequencing results, of previous RT-PCR confirmed patient samples, showed that the modified protocol produces high quality data, with up to 98.9% genome coverage at >1,000x depth for samples with presumably higher viral loads. Furthermore, whole genome assembly and subsequent mutational analysis of six of these sequences identified existing and unique mutations to this cluster, including three in the Spike protein: V308L, P521R, and D614G. This work suggests that an accessible, portable, and relatively fast sample-to-sequence process to characterize viral outbreaks is feasible and effective.
Characterization and Value Assignment of a Monoclonal Antibody Reference Material, NMIJ RM 6208a, AIST-MAB
Authors: Kinumi Tomoya , Saikusa Kazumi , Kato Megumi , Kojima Reiko , Igarashi Chieko , Noda Naohiro , Honda Shinya
Published: June 2022

Monoclonal antibodies have been established as the largest product class of biopharmaceuticals. Since extensive characterization is required for development and quality control of monoclonal antibody, a widely available reference material (RM) is needed. Herein, a humanized IgG1κ monoclonal antibody reference material, RM 6208-a, AIST-MAB, was established by the National Metrology Institute of Japan, National Institute of Advanced Industrial Science and Technology (NMIJ/AIST). The monoclonal antibody solution was produced as a pharmaceutical grade using a Chinese hamster ovary-derived cell line. The assigned indicative value represents the concentration of the antibody with a heterotetrameric structure including oligomeric forms, determined by an amino acid analysis using isotope dilution mass spectrometry, and their homogeneity and stability were assessed. In addition to antibody concentration, various physicochemical properties, including peptide mapping data, charge variants, and aggregates, were examined. This RM is intended for use in validation of analytical procedures and instruments such as a system suitability test for quantification of antibody. It is also intended for comparing and evaluating the results of antibody analyses across analytical methods and analytical laboratories such as inter-laboratory comparison. Both the material and the set of data from our study provide a tool for an accurate and reliable characterization of product quality attributes of monoclonal antibodies in biopharmaceutical and metrology communities.
Artificial Visual Information Produced by Retinal Prostheses
Authors: Kim Sein , Roh Hyeonhee , Im Maesoon
Published: June 2022

Numerous retinal prosthetic systems have demonstrated somewhat useful vision can be restored to individuals who had lost their sight due to outer retinal degenerative diseases. Earlier prosthetic studies have mostly focused on the confinement of electrical stimulation for improved spatial resolution and/or the biased stimulation of specific retinal ganglion cell (RGC) types for selective activation of retinal ON/OFF pathway for enhanced visual percepts. To better replicate normal vision, it would be also crucial to consider information transmission by spiking activities arising in the RGC population since an incredible amount of visual information is transferred from the eye to the brain. In previous studies, however, it has not been well explored how much artificial visual information is created in response to electrical stimuli delivered by microelectrodes. In the present work, we discuss the importance of the neural information for high-quality artificial vision. First, we summarize the previous literatures which have computed information transmission rates from spiking activities of RGCs in response to visual stimuli. Second, we exemplify a couple of studies which computed the neural information from electrically evoked responses. Third, we briefly introduce how information rates can be computed in the representative two ways – direct method and reconstruction method. Fourth, we introduce in silico approaches modeling artificial retinal neural networks to explore the relationship between amount of information and the spiking patterns. Lastly, we conclude our review with clinical implications to emphasize the necessity of considering visual information transmission for further improvement of retinal prosthetics.
The Efficacy of V. odorata Extract in the Treatment of Insomnia: A Systematic Review and Meta-Analysis
Authors: Huang Shuangfeng , Huang Qianqian , Zhou Zhongbao , Zhang Junliang , Zhan Yan , Liang Zhigang
Published: June 2022

Aim

This systematic review and meta-analysis was performed to assess the effect of Viola odorata (V. odorata) extract in the treatment of insomnia.

Methods

PubMed, EMBASE, and Cochrane Library databases, as well as references of related articles, were searched. Finally, four articles with five clinical trials including 224 patients were included in the analysis.

Results

The obtained results indicated a greater improvement in total PSQI scores (MD,−4.67; P = 0.0002), subjective sleep quality score (MD,−0.91; P = 0.003), sleep duration score (MD,−0.77; P < 0.00001), and ISI score (MD,−6.30; P = 0.009) in the Viola extract group compared with the placebo group. However, the Viola extract group did not significantly differ in sleep latency (MD,−0.85; P = 0.08), habitual sleep efficiency (MD,−0.61; P = 0.21), sleep disturbances (MD,−0.36; P = 0.11), and daytime dysfunction (MD,−0.94; P = 0.12) from the placebo group.

Conclusions

Viola extract supplement led to a greater improvement in total PSQI scores, subjective sleep quality score, sleep duration score, and ISI score compared with the placebo group of patients with chronic insomnia.
Peptidylarginine Deiminase 2 Autoantibodies Are Linked to Less Severe Disease in Multiple Sclerosis and Post-treatment Lyme Disease
Authors: Kim Yaewon , Rebman Alison W. , Johnson Tory P. , Wang Hong , Yang Ting , Colantuoni Carlo , Bhargava Pavan , Levy Michael , Calabresi Peter A. , Aucott John N. , Soloski Mark J. , Darrah Erika
Published: June 2022

Background

Peptidylarginine deiminase 2 (PAD2) mediates the post-translational conversion of arginine residues in proteins to citrullines and is highly expressed in the central nervous system (CNS). Dysregulated PAD2 activity has been implicated in the pathogenesis of several neurologic diseases, including multiple sclerosis (MS). In this study, we sought to define the cellular and regional expression of the gene encoding for PAD2 (i.e. PADI2) in the human CNS using publicly available datasets and evaluate whether anti-PAD2 antibodies were present in patients with various neurologic diseases.

Methods

A total of 491 study participants were included in this study: 91 people with MS, 32 people with neuromyelitis optica (NMO), 281 people with post-treatment Lyme disease (PTLD), and 87 healthy controls. To measure PADI2 expression in the CNS from healthy individuals, publicly available tissue and single cell RNA sequencing data was analyzed. Anti-PAD2 antibodies were measured in the serum of study participants using anti-PAD2 ELISA. Clinical and demographic variables were compared according to anti-PAD2 antibody positivity for the MS and PTLD groups and correlations between anti-PAD2 levels and disease severity were examined.

Results

PADI2 expression was highest in oligodendrocytes (mean ± SD; 6.4 ± 2.2), followed closely by astrocytes (5.5 ± 2.6), microglia/macrophages (4.5 ± 3.5), and oligodendrocyte precursor cells (3.2 ± 3.3). There was an increased proportion of anti-PAD2 positivity in the MS (19.8%; p = 0.007) and PTLD groups (13.9%; p = 0.057) relative to the healthy controls (5.7%), and these antibodies were not detected in NMO patients. There was a modest inverse correlation between anti-PAD2 levels and disease severity in people with MS (τ = −0.145, p = 0.02), with levels being the highest in those with relapsing-remitting disease. Similarly, there was a modest inverse correlation between anti-PAD2 levels and neurocognitive score (τ = −0.10, p = 0.027) in people with PTLD, with difficulty focusing, memory changes, fatigue, and difficulty finding words contributing most strongly to the effect.

Conclusion

PADI2 expression was observed in diverse regions and cells of the CNS, and anti-PAD2 autoantibodies were associated with less severe symptoms in subsets of patients with MS and PTLD. These data suggest that anti-PAD2 antibodies may attenuate inflammation in diseases of different etiologies, which are united by high PADI2 expression in the target tissue.
Technical Performance Evaluation of Olink Proximity Extension Assay for Blood-Based Biomarker Discovery in Longitudinal Studies of Alzheimer's Disease
Authors: Carlyle Becky C. , Kitchen Robert R. , Mattingly Zoe , Celia Amanda M. , Trombetta Bianca A. , Das Sudeshna , Hyman Bradley T. , Kivisäkk Pia , Arnold Steven E.
Published: June 2022

The core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers; amyloid-β (Aß), total tau (t-tau), and phosphorylated tau (p-tau181), are strong indicators of the presence of AD pathology, but do not correlate well with disease progression, and can be difficult to implement in longitudinal studies where repeat biofluid sampling is required. As a result, blood-based biomarkers are increasingly being sought as alternatives. In this study, we aimed to evaluate a promising blood biomarker discovery technology, Olink Proximity Extension Assays for technical reproducibility characteristics in order to highlight the advantages and disadvantages of using this technology in biomarker discovery in AD. We evaluated the performance of five Olink Proteomic multiplex proximity extension assays (PEA) in plasma samples. Three technical control samples included on each plate allowed calculation of technical variability. Biotemporal stability was measured in three sequential annual samples from 54 individuals with and without AD. Coefficients of variation (CVs), analysis of variance (ANOVA), and variance component analyses were used to quantify technical and individual variation over time. We show that overall, Olink assays are technically robust, with the largest experimental variation stemming from biological differences between individuals for most analytes. As a powerful illustration of one of the potential pitfalls of using a multi-plexed technology for discovery, we performed power calculations using the baseline samples to demonstrate the size of study required to overcome the need for multiple test correction with this technology. We show that the power of moderate effect size proteins was strongly reduced, and as a result investigators should strongly consider pooling resources to perform larger studies using this multiplexed technique where possible.
Comparison of Slides and Video Clips as Different Methods for Inducing Emotions: An Electroencephalographic Alpha Modulation Study
Authors: Romeo Zaira , Fusina Francesca , Semenzato Luca , Bonato Mario , Angrilli Alessandro , Spironelli Chiara
Published: June 2022

Films, compared with emotional static pictures, represent true-to-life dynamic stimuli that are both ecological and effective in inducing an emotional response given the involvement of multimodal stimulation (i.e., visual and auditory systems). We hypothesized that a direct comparison between the two methods would have shown greater efficacy of movies, compared to standardized slides, in eliciting emotions at both subjective and neurophysiological levels. To this end, we compared these two methods of emotional stimulation in a group of 40 young adults (20 females). Electroencephalographic (EEG) Alpha rhythm (8–12 Hz) was recorded from 64 scalp sites while participants watched (in counterbalanced order across participants) two separate blocks of 45 slides and 45 clips. Each block included three groups of 15 validated stimuli classified as Erotic, Neutral and Fear content. Greater self-perceived arousal was found after the presentation of Fear and Erotic video clips compared with the same slide categories. sLORETA analysis showed a different lateralization pattern: slides induced decreased Alpha power (greater activation) in the left secondary visual area (Brodmann Area, BA, 18) to Erotic and Fear compared with the Neutral stimuli. Instead, video clips elicited reduced Alpha in the homologous right secondary visual area (BA 18) again to both Erotic and Fear contents compared with Neutral ones. Comparison of emotional stimuli showed smaller Alpha power to Erotic than to Fear stimuli in the left precuneus/posterior cingulate cortex (BA 7/31) for the slide condition, and in the left superior parietal lobule (BA 7) for the clip condition. This result matched the parallel analysis of the overlapped Mu rhythm (corresponding to the upper Alpha band) and can be interpreted as Mu/Alpha EEG suppression elicited by greater motor action tendency to Erotic (approach motivation) compared to Fear (withdrawal motivation) stimuli. Correlation analysis found lower Alpha in the left middle temporal gyrus (BA 21) associated with greater pleasantness to Erotic slides (r38= –0.62,p= 0.009), whereas lower Alpha in the right supramarginal/angular gyrus (BA 40/39) was associated with greater pleasantness to Neutral clips (r38= –0.69,p= 0.012). Results point to stronger emotion elicitation of movies vs. slides, but also to a specific involvement of the two hemispheres during emotional processing of slides vs. video clips, with a shift from the left to the right associative visual areas.
Whole-Brain Monosynaptic Afferents to Rostromedial Tegmental Nucleus Gamma-Aminobutyric Acid-Releasing Neurons in Mice
Authors: Zhao Ya-Nan , Zhang Yang , Tao Shi-Yuan , Huang Zhi-Li , Qu Wei-Min , Yang Su-Rong
Published: June 2022

Increasing evidence has revealed that the rostromedial tegmental area (RMTg) mediates many behaviors, including sleep and addiction. However, presynaptic patterns governing the activity of γ-aminobutyric acid-releasing (GABAergic) neurons, the main neuronal type in the RMTg, have not been defined. Here, we used cell-type-specific retrograde trans-synaptic rabies viruses to map and quantify the monosynaptic afferents to RMTg GABAergic neurons in mouse whole brains. We identified 71 ascending projection brain regions. Sixty-eight percent of the input neurons arise from the ipsilateral and 32% from the contralateral areas of the brain. The first three strongest projection regions were the ipsilateral lateral hypothalamus, zone incerta, and contralateral pontine reticular nucleus. Immunohistochemistry imaging showed that the input neurons in the dorsal raphe, laterodorsal tegmentum, and dorsal part of zone incerta were colocalized with serotoninergic, cholinergic, and neuronal nitric oxide synthetase-expressing neurons, respectively. However, in the lateral hypothalamus, a few input neurons innervating RMTg GABAergic neurons colocalized orexinergic neurons but lacked colocalization of melanin-concentrating hormone neurons. Our findings provide anatomical evidence to understand how RMTg GABAergic neurons integrate diverse information to exert varied functions.
Nutraceuticals for the Treatment of IBD: Current Progress and Future Directions
Authors: Ban Quan-Yao , Liu Mei , Ding Ning , Chen Ying , Lin Qiong , Zha Juan-Min , He Wei-Qi
Published: June 2022

Inflammatory bowel disease (IBD) is a chronic relapsing-remitting inflammatory disease of the gastrointestinal tract. Patients are usually diagnosed in adolescence and early adulthood and need lifelong treatment. In recent years, it has been found that diet plays an important role in the pathogenesis of IBD. Diet can change intestinal barrier function, affect the structure and function of intestinal flora, and promote immune disorder, thus promoting inflammation. Many patients believe that diet plays a role in the onset and treatment of the disease and changes their diet spontaneously. This review provides some insights into how nutraceuticals regulate intestinal immune homeostasis and improve intestinal barrier function. We reviewed the research results of dietary fiber, polyphenols, bioactive peptides, and other nutraceuticals in the prevention and treatment of IBD and sought better alternative or supplementary treatment methods for IBD patients.
A Black Raspberry-Rich Diet Protects From Dextran Sulfate Sodium-Induced Intestinal Inflammation and Host Metabolic Perturbation in Association With Increased Aryl Hydrocarbon Receptor Ligands in the Gut Microbiota of Mice
Authors: Tu Pengcheng , Chi Liang , Bian Xiaoming , Gao Bei , Ru Hongyu , Lu Kun
Published: June 2022

Dietary modulation of the gut microbiota recently received considerable attention, and ligand activation of aryl hydrocarbon receptor (AHR) plays a pivotal role in intestinal immunity. Importantly, black raspberry (BRB, Rubus occidentalis) is associated with a variety of beneficial health effects. We aim to investigate effects of a BRB-rich diet on dextran sulfate sodium (DSS)-induced intestinal inflammation and to determine whether its consequent anti-inflammatory effects are relevant to modulation of the gut microbiota, especially its production of AHR ligands. A mouse model of DSS-induced intestinal inflammation was used in the present study. C57BL/6J mice were fed either AIN-76A or BRB diet. Composition and functions of the gut microbiota were assessed by 16S rRNA sequencing and comparative metagenome analysis. Metabolic profiles of host and the gut microbiome were assessed by serum and fecal metabolomic profiling and identification. BRB diet was found to ameliorate DSS-induced intestinal inflammation and host metabolic perturbation. BRB diet also protected from DSS-induced perturbation in diversity and composition in the gut microbiota. BRB diet promoted AHR ligand production by the gut microbiota, as revealed by increased levels of fecal AHR activity in addition to increased levels of two known AHR ligands, hemin and biliverdin. Accordingly, enrichment of bacterial genes and pathways responsible for production of hemin and biliverdin were found, specific gut bacteria that are highly correlated with abundances of hemin and biliverdin were also identified. BRB dietary intervention ameliorated intestinal inflammation in mice in association with promotion of AHR ligand production by the gut microbiota.
The Composition and Functional Capacities of Saliva Microbiota Differ Between Children With Low and High Sweet Treat Consumption
Authors: Lommi Sohvi , Manzoor Muhammed , Engberg Elina , Agrawal Nitin , Lakka Timo A. , Leinonen Jukka , Kolho Kaija-Leena , Viljakainen Heli
Published: June 2022

Excess sugar consumption—common in youth—is associated with poor health. Evidence on the relationship between sugar consumption and the oral microbiome, however, remains scarce and inconclusive. We explored whether the diversity, composition, and functional capacities of saliva microbiota differ based on the consumption of select sugary foods and drinks (“sweet treats”). Using 16S rRNA gene sequencing, we characterized saliva microbiota from 11 to 13-year-old children who participated in the Finnish Health in Teens (Fin-HIT) cohort study. The sample comprised children in the lowest (n = 227) and highest (n = 226) tertiles of sweet treat consumption. We compared differences in the alpha diversity (Shannon, inverse Simpson, and Chao1 indices), beta diversity (principal coordinates analysis based on Bray–Curtis dissimilarity), and abundance (differentially abundant operational taxonomic units (OTUs) at the genus level) between these low and high consumption groups. We performed PICRUSt2 to predict the metabolic pathways of microbial communities. No differences emerged in the alpha diversity between low and high sweet treat consumption, whereas the beta diversity differed between groups (p = 0.001). The abundance of several genera such as Streptococcus, Prevotella, Veillonella, and Selenomonas was higher in the high consumption group compared with the low consumption group following false discovery rate correction (p < 0.05). Children with high sweet treat consumption exhibited higher proportions of nitrate reduction IV and gondoate biosynthesis pathways compared with the low consumption group (p < 0.05). To conclude, sweet treat consumption shapes saliva microbiota. Children who consume a high level of sweet treats exhibited different compositions and metabolic pathways compared with children who consume low levels of sweet treats. Our findings reveal novel insights into the relationship between sugary diets and oral microbiota.
Cost-Effectiveness of 12 First-Line Treatments for Patients With Advanced EGFR Mutated NSCLC in the United Kingdom and China
Authors: Guan Haijing , Wang Chunping , Chen Chen , Han Sheng , Zhao Zhigang
Published: June 2022

Background

Lung cancer is imposing significant pressure on the national health insurance system worldwide, especially under the COVID-19 pandemic. However, the cost-effectiveness of all available first-line treatments for patients with advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) is still uncertain. The aim of this study was to evaluate the cost-effectiveness of 12 first-line treatments for patients with advanced EGFR mutated NSCLC from the perspective of the United Kingdom (UK) National Health Service and Chinese health care system.

Methods

We used a Markov model to estimate the cost-effectiveness of 12 treatments, including 6 EGFR tyrosine kinase inhibitors, 4 combination treatments and 2 chemotherapies. The key clinical efficacy and safety data were from a network meta-analysis. The cost and health preference were mainly collected from the literature. The most cost-effective treatment was inferred through a sequential analysis. Uncertainty was tested with one-way sensitivity analyses, scenario analyses, and probabilistic sensitivity analyses. Quality-adjusted life years (QALYs), direct medical costs, and incremental cost-effectiveness ratio (ICER) were estimated, at willingness-to-pay thresholds of £20000 to £50000 and £8000 to £24000 per QALY in the UK and China respectively.

Results

For clinical effectiveness, osimertinib and gefitinib plus pemetrexed based chemotherapy (PbCT) yielded the highest QALYs, while two chemotherapy treatments gained the lowest QALYs. For costs, gefitinib treatment was the cheapest option in both countries (£24529 in the UK and £12961 in China). For cost-effectiveness, 4 treatments including gefitinib, gefitinib plus pemetrexed, gefitinib plus PbCT, and osimertinib formed the cost-effectiveness frontier in both countries. Gefitinib alone (70.7% and 80.0% under the threshold of £20000 and £8000 per QALY in the UK and China, respectively) and gefitinib plus PbCT (62.3% and 71.2% under the threshold of £50000 and £24000 per QALY in the UK and China, respectively) were most likely to be cost-effective compared with other first-line treatments.

Conclusions

Gefitinib and gefitinib plus PbCT were likely to be cost-effective for patients with advanced EGFR mutated NSCLC in both countries.
Germline Mutations in Patients With Early-Onset Prostate Cancer
Authors: Tang Tang , Tan Xintao , Wang Ze , Wang Shuo , Wang Yapeng , Xu Jing , Wei Xiajie , Zhang Dianzheng , Liu Qiuli , Jiang Jun
Published: June 2022

Objective

To investigate the inherited mutations and their association with clinical features and treatment response in young-onset prostate cancer patients.

Method

Targeted gene sequencing on 139 tumor susceptibility genes was conducted with a total of 24 patients diagnosed with PCa under the age of 63 years old. Meanwhile, the related clinical information of those patients is collected and analyzed.

Results

Sixty-two germline mutations in 45 genes were verified in 22 patients. BRCA2 (20.8%) and GJB2 (20.8%) were found to be the most frequently mutated, followed by CHEK2, BRCA1, PALB2, CDKN2A, HOXB13, PPM1D, and RECQL (8.3% of each, 2/24). Of note, 58.3% (14/24) patients carry germline mutations in DNA repair genes (DRGs). Four families with HRR (homologous recombination repair)-related gene mutations were described and analyzed in detail. Two patients with BRCA2 mutation responded well to the combined treatment of androgen deprivation therapy (ADT) and radiotherapy/chemotherapy.

Conclusion

Mutations in DRGs are more prevalent in early-onset PCa with advanced clinical stages, and these patients had shorter progression-free survival. ADT Combined with either radiotherapy or chemotherapy may be effective in treating PCa caused by HRR-related gene mutations.
Establishment of Prognostic Signatures of N6-Methyladenosine-Related lncRNAs and Their Potential Functions in Hepatocellular Carcinoma Patients
Authors: Wu Xianbin , Deng Zhejun , Liao Xiaomin , Ruan Xianxian , Qu Nanfang , Pang Lixing , Shi Xiaoyan , Qin Shanyu , Jiang Haixing
Published: June 2022

N6-methyladenosine (m6a)-related mRNAs and lncRNAs have been explored for their functions in several cancers. The present study aimed to identify potential signatures of m6a-related lncRNAs in hepatocellular carcinoma (HCC). We downloaded the expression and clinical data from The Cancer Genome Atlas (TCGA) database. The interacted mRNAs and lncRNAs, prognosis-related lncRNAs, potential metabolic pathways of lncRNAs, immune infiltration of various cells, and CD274 (PD-L1) -related lncRNAs were analyzed. Then, in vitro experiments explored the role of AC012073.1 (LOC105377626) in HCC cell lines. We found that candidate 14 lncRNA signatures play functions in HCC maybe by affecting immune infiltration, cell cycle, Notch signaling pathway, etc. LncRNA AC012073.1 (LOC105377626) functions as oncogenic roles in affecting HCC prognosis.
Impact of Limb Salvage on Prognosis of Patients Diagnosed With Extremity Bone and Soft Tissue Sarcomas
Authors: Yu Kaixu , Chen Ying , Song Kehan , Xiong Fanxiu , Tian Yahao , Guan Hanfeng , Li Feng
Published: June 2022

Background

Although clinicians and patients with extremity bone and soft tissue (EBST) are increasingly interested in limb salvage surgery (LSS), because of the minimal damage to physical appearance and function, however, there is still a lack of large-scale population studies on whether LSS improves the prognosis of patients.

Purpose

The aim of this study was to compare the survival of patients with EBST sarcomas after receiving LSS and amputation.

Methods

To conduct the population-based study, we identified 6,717 patients with a histologically diagnosed bone sarcoma and 24,378 patients with a histologically diagnosed soft tissue sarcoma from the Surveillance, Epidemiology, and End Results database. We analyzed overall survival (OS), cancer-specific survival (CSS), and non-sarcoma survival (NSS) using the Kaplan–Meier method, log-rank test or Gray test, Cox regression model, propensity score-matched analysis, and landmark analysis.

Results

LSS could improve the prognosis in patients with most EBST subtypes, except for Ewing sarcomas and MPNST. However, in the subgroup without distant metastases, limb salvage increased CSS only for patients with osteosarcoma, Ewing sarcoma, and leiomyosarcoma, as well as NSS for patients with chondrosarcoma and synovial sarcoma. Landmark analysis further demonstrated that sarcoma survivors surviving <10 years could benefit from LSS but not for long-term survivors ≥10 years. Moreover, for patients with distant metastases, LSS could improve survival of osteosarcoma patients but worsen CSS among patients with MPNST. Landmark analysis further demonstrated that LSS improved survival among osteosarcomas patients with distant metastases only within 1 year after surgery. Moreover, patients receiving LSS and those receiving amputation had a high risk of dying from different non-sarcoma diseases during the postoperative follow-up.

Conclusions

The impact of limb salvage on the prognosis of patients depends on the pathological subtype and stage of EBST sarcomas.