bluuebunny/crossref_metadata_2025 huggingface dataset:
21-Hydroxylase-Specific CD8+ T Cells in Autoimmune Addison’s Disease Are Restricted by HLA-A2 and HLA-C7 Molecules
Authors: Hellesen Alexander , Aslaksen Sigrid , Breivik Lars , Røyrvik Ellen Christine , Bruserud Øyvind , Edvardsen Kine , Brokstad Karl Albert , Wolff Anette Susanne Bøe , Husebye Eystein Sverre , Bratland Eirik
Published: October 2021

Objectives

CD8+ T cells targeting 21-hydroxylase (21OH) are presumed to play a central role in the destruction of adrenocortical cells in autoimmune Addison’s disease (AAD). Earlier reports have suggested two immunodominant CD8+ T cell epitopes within 21OH: LLNATIAEV (21OH342-350), restricted by HLA-A2, and EPLARLEL (21OH431-438), restricted by HLA-B8. We aimed to characterize polyclonal CD8+ T cell responses to the proposed epitopes in a larger patient cohort with AAD.

Methods

Recombinant fluorescent HLA-peptide multimer reagents were used to quantify antigen-specific CD8+ T cells by flow cytometry. Interferon-gamma (IFNγ) Elispot and biochemical assays were used to functionally investigate the 21OH-specific T cells, and to map the exactly defined epitopes of 21OH.

Results

We found a significantly higher frequency of HLA-A2 restricted LLNATIAEV-specific cells in patients with AAD than in controls. These cells could also be expanded in vitro in an antigen specific manner and displayed a robust antigen-specific IFNγ production. In contrast, only negligible frequencies of EPLARLEL-specific T cells were detected in both patients and controls with limited IFNγ response. However, significant IFNγ production was observed in response to a longer peptide encompassing EPLARLEL, 21OH430-447, suggesting alternative dominant epitopes. Accordingly, we discovered that the slightly offset ARLELFVVL (21OH434-442) peptide is a novel dominant epitope restricted by HLA-C7 and not by HLA-B8 as initially postulated.

Conclusion

We have identified two dominant 21OH epitopes targeted by CD8+ T cells in AAD, restricted by HLA-A2 and HLA-C7, respectively. To our knowledge, this is the first HLA-C7 restricted epitope described for an autoimmune disease.
The Mannose Receptor: From Endocytic Receptor and Biomarker to Regulator of (Meta)Inflammation
Authors: van der Zande Hendrik J. P. , Nitsche Dominik , Schlautmann Laura , Guigas Bruno , Burgdorf Sven
Published: October 2021

The mannose receptor is a member of the C-type lectin (CLEC) family, which can bind and internalize a variety of endogenous and pathogen-associated ligands. Because of these properties, its role in endocytosis as well as antigen processing and presentation has been studied intensively. Recently, it became clear that the mannose receptor can directly influence the activation of various immune cells. Cell-bound mannose receptor expressed by antigen-presenting cells was indeed shown to drive activated T cells towards a tolerogenic phenotype. On the other hand, serum concentrations of a soluble form of the mannose receptor have been reported to be increased in patients suffering from a variety of inflammatory diseases and to correlate with severity of disease. Interestingly, we recently demonstrated that the soluble mannose receptor directly promotes macrophage proinflammatory activation and trigger metaflammation. In this review, we highlight the role of the mannose receptor and other CLECs in regulating the activation of immune cells and in shaping inflammatory responses.
In-situ Detection Method for Microplastics in Water by Polarized Light Scattering
Authors: Liu Tong , Yu Shijun , Zhu Xiaoshan , Liao Ran , Zhuo Zepeng , He Yanping , Ma Hui
Published: October 2021

Microplastics (MPs) have become the widespread contaminants, which raises concerns on their ecological hazards. In-situ detection of MP in water bodies is essential for clear assessment of the ecological risks of MPs. The present study proposes a method based on polarized light scattering which measures the polarization parameters of the scattered light at 120° to detect MP in water. This method takes the advantage of in-situ measurement of the individual particles and the experimental setup in principle is used. By use of the measured polarization parameters equipped by machine learning, the standard polystyrene (PS) spheres, natural water sample, and lab-cultured microalgae are explicitly discriminated, and MP with different physical and chemical properties can be differentiated. It can also characterize the weathering of different MP and identify the specific type from multiple types of MP. This study explores the capability of the proposed method to detect the physical and chemical properties, weathering state and concentration of MP in water which promises the future application in water quality sensing and monitoring.
Extreme Runoff of Chemical Species of Nitrogen and Phosphorus Threatens a Florida Barrier Island Lagoon
Authors: Trefry John H. , Fox Austin L.
Published: October 2021

Extreme runoff of stormwater to poorly flushed barrier island lagoons often adds excess nitrogen (N) and phosphorus (P) that can promote subsequent, sometimes intense, harmful algal blooms (HABs). Successful management of such estuaries requires special appreciation of when and how to control concentrations and fluxes of chemical species of N and P during high flow. Toward that end, monthly surveys and episodic rain-event sampling were carried out from December 2015 to March 2018 for two contrasting tributaries of the Indian River Lagoon (IRL), a barrier island lagoon in Florida. One tributary, South Prong Saint Sebastian River, flows through predominantly agricultural, forested and open land, whereas the second tributary, Crane Creek, traverses mainly residential-commercial land. Concentrations of some N and P species in these tributaries increased with increased flow and could be described with statistically significant equations for concentration versus flow rate, thereby supporting flow-rate-dependent flux determinations. Drainage basin yields (fluxes per square km) varied with land cover/use. Calculated annual yields of dissolved organic N (DON) and dissolved inorganic P (DIP) averaged ∼70% greater for South Prong Saint Sebastian River from high flow through thicker, more organic- and P-rich soils. In contrast, yields of nitrate + nitrite were 100% higher for Crane Creek from widespread application of N-fertilizer to thin layers of turfgrass overlying sand, plus runoff of N-rich reclaimed water. Two major weather events highlighted our study and foreshadow impacts from climate change. Seven months of drought from November 2016 to May 2017 were followed in September-October 2017 by excess rain, runoff and flooding from Hurricane Irma. Consequently, >50% of freshwater fluxes and ∼60% of N and P fluxes from South Prong Saint Sebastian River, Crane Creek and other IRL tributaries occurred during 2 months in 2017. Lagoon-wide inputs provided enough bioavailable N and P to help support a nanoeukaryotic bloom for >5 months, with chlorophyll a values >50 μg L–1. The bloom was co-dominated by the brown tide alga, Aureoumbra lagunensis, and an unidentified nanoeukaryotic green alga. Decreased salinity, low concentrations of dissolved inorganic N and P, and decreasing dissolved organic P (DOP), combined with biological factors, diminished the IRL bloom by mid-2018.
Elevated Humoral Immune Response to SARS-CoV-2 at High Altitudes Revealed by an Anti-RBD “In-House” ELISA
Authors: Tomas-Grau Rodrigo Hernán , Ploper Diego , Ávila César Luis , Vera Pingitore Esteban , Maldonado Galdeano Carolina , Chaves Silvina , Socias Sergio Benjamín , Stagnetto Agustín , Navarro Silvia Adriana , Chahla Rossana Elena , Aguilar López Mónica , Llapur Conrado Juan , Aznar Patricia , Alcorta María Elena , Costas Dardo , Flores Isolina , Heinze Dar , Apfelbaum Gabriela , Mostoslavsky Raul , Mostoslavsky Gustavo , Cazorla Silvia Inés , Perdigón Gabriela del Valle , Chehín Rosana
Published: October 2021

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a global pandemic with dramatic health and socioeconomic consequences. The Coronavirus Disease 2019 (COVID-19) challenges health systems to quickly respond by developing new diagnostic strategies that contribute to identify infected individuals, monitor infections, perform contact-tracing, and limit the spread of the virus. In this brief report, we developed a highly sensitive, specific, and precise “In-House” ELISA to correctly discriminate previously SARS-CoV-2-infected and non-infected individuals and study population seroprevalence. Among 758 individuals evaluated for anti-SARS-CoV-2 serology in the province of Tucumán, Argentina, we found a weak correlation between antibodies elicited against the RBD, the receptor-binding domain of the Spike protein, and the nucleocapsid (N) antigens of this virus. Additionally, we detected mild levels of anti-RBD IgG antibodies in 33.6% of individuals diagnosed with COVID-19, while only 19% showed sufficient antibody titers to be considered as plasma donors. No differences in IgG anti-RBD titers were found between women and men, neither in between different age groups ranging from 18 to 60. Surprisingly, individuals from a high altitude village displayed elevated and longer lasting anti-RBD titers compared to those from a lower altitude city. To our knowledge, this is the first report correlating altitude with increased humoral immune response against SARS-CoV-2 infection.
Phenotypic Recovery of a Heterobasidion Isolate Infected by a Debilitation-Associated Virus Is Related to Altered Host Gene Expression and Reduced Virus Titer
Authors: Kashif Muhammad , Jurvansuu Jaana , Hyder Rafiqul , Vainio Eeva J. , Hantula Jarkko
Published: October 2021

The fungal genus Heterobasidion includes forest pathogenic species hosting a diverse group of partitiviruses. They include the host debilitating Heterobasidion partitivirus 13 strain an1 (HetPV13-an1), which was originally observed in a slowly growing H. annosum strain 94233. In this study, a relatively fast-growing sector strain 94233-RC3 was isolated from a highly debilitated mycelial culture of 94233, and its gene expression and virus transcript quantities as well as the genomic sequence of HetPV13-an1 were examined. The sequence of HetPV13-an1 genome in 94233-RC3 was identical to that in the original 94233, and thus not the reason for the partial phenotypic recovery. According to RNA-seq analysis, the HetPV13-an1 infected 94233-RC3 transcribed eight genes differently from the partitivirus-free 94233-32D. Three of these genes were downregulated and five upregulated. The number of differentially expressed genes was considerably lower and the changes in their expression were small compared to those of the highly debilitated original strain 94233 with the exception of the most highly upregulated ones, and therefore viral effects on the host transcriptome correlated with the degree of the virus-caused debilitation. The amounts of RdRp and CP transcripts of HetPV13-an1 were considerably lower in 94233-RC3 and also in 94233 strain infected by a closely related mildly debilitating virus HetPV13-an2, suggesting that the virus titer would have a role in determining the effect of HetPV13 viruses on their hosts.
Comparison of 16S rRNA Gene Based Microbial Profiling Using Five Next-Generation Sequencers and Various Primers
Authors: Park Changwoo , Kim Seung Bum , Choi Sang Ho , Kim Seil
Published: October 2021

Microbial community analysis based on the 16S rRNA-gene is used to investigate both beneficial and harmful microorganisms in various fields and environments. Recently, the next-generation sequencing (NGS) technology has enabled rapid and accurate microbial community analysis. Despite these advantages of NGS based metagenomics study, sample transport, storage conditions, amplification, library preparation kits, sequencing, and bioinformatics procedures can bias microbial community analysis results. In this study, eight mock communities were pooled from genomic DNA of Lactobacillus acidophilus KCTC 3164T, Limosilactobacillus fermentum KCTC 3112T, Lactobacillus gasseri KCTC 3163T, Lacticaseibacillus paracasei subsp. paracasei KCTC 3510T, Limosilactobacillus reuteri KCTC 3594T, Lactococcus lactis subsp. lactis KCTC 3769T, Bifidobacterium animalis subsp. lactis KCTC 5854T, and Bifidobacterium breve KCTC 3220T. The genomic DNAs were quantified by droplet digital PCR (ddPCR) and were mixed as mock communities. The mock communities were amplified with various 16S rRNA gene universal primer pairs and sequenced by MiSeq, IonTorrent, MGIseq-2000, Sequel II, and MinION NGS platforms. In a comparison of primer-dependent bias, the microbial profiles of V1-V2 and V3 regions were similar to the original ratio of the mock communities, while the microbial profiles of the V1-V3 region were relatively biased. In a comparison of platform-dependent bias, the sequence read from short-read platforms (MiSeq, IonTorrent, and MGIseq-2000) showed lower bias than that of long-read platforms (Sequel II and MinION). Meanwhile, the sequences read from Sequel II and MinION platforms were relatively biased in some mock communities. In the data of all NGS platforms and regions, L. acidophilus was greatly underrepresented while Lactococcus lactis subsp. lactis was generally overrepresented. In all samples of this study, the bias index (BI) was calculated and PCA was performed for comparison. The samples with biased relative abundance showed high BI values and were separated in the PCA results. In particular, analysis of regions rich in AT and GC poses problems for genome assembly, which can lead to sequencing bias. According to this comparative analysis, the development of reference material (RM) material has been proposed to calibrate the bias in microbiome analysis.
The S Protein of Group B Streptococcus Is a Critical Virulence Determinant That Impacts the Cell Surface Virulome
Authors: Campeau Anaamika , Uchiyama Satoshi , Sanchez Concepcion , Sauceda Consuelo , Nizet Victor , Gonzalez David J.
Published: October 2021

Group B Streptococcus (GBS, S. agalactiae) is a human commensal and occasional pathogen that remains a leading cause of neonatal sepsis and meningitis with increasing disease burden in adult populations. Although programs for universal screening in pregnancy to guide intrapartum prophylaxis have reduced GBS invasive disease burden resulting from mother-to-newborn transfer during birth, better knowledge of disease mechanisms may elucidate new strategies to reduce antibiotic exposure. In our efforts to expand the knowledge base required for targeted anti-virulence therapies, we identified a GBS homolog for a recently identified virulence determinant of group A Streptococcus, S protein, and evaluated its role in GBS pathogenesis. A GBS S protein deletion mutant, Δess, showed altered cell-surface properties compared to the WT parent strain, including defective retention of its surface polysaccharide. Quantitative proteome analysis of enzymatically shaved surface epitopes of the GBS Δess mutant revealed a dysregulated cell surface virulome, with reduced abundance of several protein and glycoprotein components. The Δess mutant showed markedly attenuated virulence in a murine model of GBS systemic infection, with increased proteasome activity detected in the spleens of animals infected with the Δess mutant. These results expand the key roles S protein plays in streptococcal pathogenesis and introduces a new GBS virulence determinant and potential target for therapy development.
Dynamic Changes in Endophytic Microorganisms and Metabolites During Natural Drying of Licorice
Authors: Li Ting , Ren Guangxi , Jiang Dan , Liu Chunsheng
Published: October 2021

The method of drying licorice is an important factor affecting the quality of the final product. To determine the best processing method of licorice postharvest, we investigated the interaction of increasing aridity between the endophytic microorganisms and the accumulation of metabolites. Samples from the roots of licorice growing along an aridity gradient during the natural drying process were collected, and the metabolic components, the content of the main active substances and the dynamic changes of the endophytic microbial community were assessed. The glycyrrhizic acid and liquiritin contents decreased slightly or remained flat during natural drying, whereas those of liquiritigenin and isoliquiritigenin increased slightly. Moreover, the Shannon index of endophytic microbial diversity of licorice was the highest in the fresh period and showed a downward trend during the drying process. When the licorice were fresh, Cladosporiaceae and Burkholderiaceae were the dominant family present, but after drying, Nectriaceae and Enterobacteriaceae were the dominant families. A similar trend was also found in which the differential metabolites of licorice were reduced during natural drying. Furthermore, correlation analysis between dominant families and differential metabolites showed that there was a correlation between the two. Therefore, fresh processing is an effective drying method to ensure the quality of licorice. This study revealed the relationship of endophytic microbiota and changes in the licorice metabolites during different stages of drying, which provided a scientific basis for the drying method of licorice.
Lipid Remodeling Reveals the Adaptations of a Marine Diatom to Ocean Acidification
Authors: Jin Peng , Liang Zhe , Lu Hua , Pan Jinmei , Li Peiyuan , Huang Quanting , Guo Yingyan , Zhong Jiahui , Li Futian , Wan Jiaofeng , Overmans Sebastian , Xia Jianrong
Published: October 2021

Ocean acidification is recognized as a major anthropogenic perturbation of the modern ocean. While extensive studies have been carried out to explore the short-term physiological responses of phytoplankton to ocean acidification, little is known about their lipidomic responses after a long-term ocean acidification adaptation. Here we perform the lipidomic analysis of a marine diatom Phaeodactylum tricornutum following long-term (∼400 days) selection to ocean acidification conditions. We identified a total of 476 lipid metabolites in long-term high CO2 (i.e., ocean acidification condition) and low CO2 (i.e., ambient condition) selected P. tricornutum cells. Our results further show that long-term high CO2 selection triggered substantial changes in lipid metabolites by down- and up-regulating 33 and 42 lipid metabolites. While monogalactosyldiacylglycerol (MGDG) was significantly down-regulated in the long-term high CO2 selected conditions, the majority (∼80%) of phosphatidylglycerol (PG) was up-regulated. The tightly coupled regulations (positively or negatively correlated) of significantly regulated lipid metabolites suggest that the lipid remodeling is an organismal adaptation strategy of marine diatoms to ongoing ocean acidification. Since the composition and content of lipids are crucial for marine food quality, and these changes can be transferred to high trophic levels, our results highlight the importance of determining the long-term adaptation of lipids in marine producers in predicting the ecological consequences of climate change.
Physiology, Taxonomy, and Sulfur Metabolism of the Sulfolobales, an Order of Thermoacidophilic Archaea
Authors: Liu Li-Jun , Jiang Zhen , Wang Pei , Qin Ya-Ling , Xu Wen , Wang Yang , Liu Shuang-Jiang , Jiang Cheng-Ying
Published: October 2021

The order Sulfolobales (phylum Crenarchaeota) is a group of thermoacidophilic archaea. The first member of the Sulfolobales was discovered in 1972, and current 23 species are validly named under the International Code of Nomenclature of Prokaryotes. The majority of members of the Sulfolobales is obligately or facultatively chemolithoautotrophic. When they grow autotrophically, elemental sulfur or reduced inorganic sulfur compounds are their energy sources. Therefore, sulfur metabolism is the most important physiological characteristic of the Sulfolobales. The functions of some enzymes and proteins involved in sulfur reduction, sulfur oxidation, sulfide oxidation, thiosulfate oxidation, sulfite oxidation, tetrathionate hydrolysis, and sulfur trafficking have been determined. In this review, we describe current knowledge about the physiology, taxonomy, and sulfur metabolism of the Sulfolobales, and note future challenges in this field.
Analysis of Genotype-Phenotype Correlations in Patients With Degenerative Dementia Through the Whole Exome Sequencing
Authors: Sun Lin , Zhang Jianye , Su Ning , Zhang Shaowei , Yan Feng , Lin Xiang , Yu Jie , Li Wei , Li Xia , Xiao Shifu
Published: October 2021

Background: Sporadic dementias generally occur in older age and are highly polygenic, which indicates some patients transmitted in a poly-genes hereditary fashion.

Objective: Our study aimed to analyze the correlations of genetic features with clinical symptoms in patients with degenerative dementia.

Methods: We recruited a group of 84 dementia patients and conducted the whole exome sequencing (WES). The data were analyzed focusing on 153 dementia-related causing and susceptible genes.

Results: According to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines, we identified four reported pathogenic variants, namely, PSEN1 c.A344G, APP c.G2149A, MAPT c.G1165A, and MAPT c.G742A, one reported likely pathogenic variant, namely, PSEN2 c.G100A, one novel pathogenic variants, SQSTM1 c.C671A, and three novel likely pathogenic variants, namely, ABCA7 c.C4690T, ATP13A2 c.3135delC, and NOS3 c.2897-2A > G. 21 variants with uncertain significance in PSEN2, C9orf72, NOTCH3, ABCA7, ERBB4, GRN, MPO, SETX, SORL1, NEFH, ADCM10, and SORL1, etc., were also detected in patients with Alzheimer’s disease (AD) and frontotemporal dementia (FTD).

Conclusion: The new variants in dementia-related genes indicated heterogeneity in pathogenesis and phenotype of degenerative dementia. WES could serve as an efficient diagnostic tool for detecting intractable dementia.
Inhibition of Rho Kinase by Fasudil Ameliorates Cognition Impairment in APP/PS1 Transgenic Mice via Modulation of Gut Microbiota and Metabolites
Authors: Yan Yuqing , Gao Ye , Fang Qingli , Zhang Nianping , Kumar Gajendra , Yan Hailong , Song Lijuan , Li Jiehui , Zhang Yuna , Sun Jingxian , Wang Jiawei , Zhao Linhu , Skaggs Keith , Zhang Han-Ting , Ma Cun-Gen
Published: October 2021

Background:Fasudil, a Rho kinase inhibitor, exerts therapeutic effects in a mouse model of Alzheimer's disease (AD), a chronic neurodegenerative disease with progressive loss of memory. However, the mechanisms remain unclear. In addition, the gut microbiota and its metabolites have been implicated in AD.

Methods:We examined the effect of fasudil on learning and memory using the Morris water-maze (MWM) test in APPswe/PSEN1dE9 transgenic (APP/PS1) mice (8 months old) treated (i.p.) with fasudil (25 mg/kg/day; ADF) or saline (ADNS) and in age- and gender-matched wild-type (WT) mice. Fecal metagenomics and metabolites were performed to identify novel biomarkers of AD and elucidate the mechanisms of fasudil induced beneficial effects in AD mice.

Results:The MWM test showed significant improvement of spatial memory in APP/PS1 mice treated with fasudil as compared to ADNS. The metagenomic analysis revealed the abundance of the dominant phyla in all the three groups, includingBacteroidetes(23.7–44%) andFirmicutes(6.4–26.6%), and the increased relative abundance ratio ofFirmicutes/Bacteroidetesin ADNS (59.1%) compared to WT (31.7%). In contrast, theFirmicutes/Bacteroidetesratio was decreased to the WT level in ADF (32.8%). Lefse analysis of metagenomics identifieds_Prevotella_sp_CAG873as an ADF potential biomarker, whiles_Helicobacter_typhloniusands_Helicobacter_sp_MIT_03-1616as ADNS potential biomarkers. Metabolite analysis revealed the increment of various metabolites, including glutamate, hypoxanthine, thymine, hexanoyl-CoA, and leukotriene, which were relative to ADNS or ADF microbiota potential biomarkers and mainly involved in the metabolism of nucleotide, lipids and sugars, and the inflammatory pathway.

Conclusions:Memory deficit in APP/PS1 mice was correlated with the gut microbiome and metabolite status. Fasudil reversed the abnormal gut microbiota and subsequently regulated the related metabolisms to normal in the AD mice. It is believed that fasudil can be a novel strategy for the treatment of AD via remodeling of the gut microbiota and metabolites. The novel results also provide valuable references for the use of gut microbiota and metabolites as diagnostic biomarkers and/or therapeutic targets in clinical studies of AD.
Networks Are Associated With Acupuncture Treatment in Patients With Diarrhea-Predominant Irritable Bowel Syndrome: A Resting-State Imaging Study
Authors: Zhao Tingting , Pei Lixia , Ning Houxu , Guo Jing , Song Yafang , Zhou Junling , Chen Lu , Sun Jianhua , Mi Zhongping
Published: October 2021

Background: Irritable Bowel Syndrome (IBS), as a functional gastrointestinal disorder, is characterized by abdominal pain and distension. Recent studies have shown that acupuncture treatment improves symptoms of diarrhea-predominant irritable bowel syndrome (IBS-D) by altering networks in certain brain regions. However, few studies have used resting-state functional magnetic resonance imaging (fMRI) to compare altered resting-state inter-network functional connectivity in IBS-D patients before and after acupuncture treatment.

Objective: To analyze altered resting-state inter-network functional connectivity in IBS-D patients before and after acupuncture treatment.

Methods: A total of 74 patients with IBS-D and 31 healthy controls (HCs) were recruited for this study. fMRI examination was performed in patients with IBS-D before and after acupuncture treatment, but only at baseline in HCs. Data on the left frontoparietal network (LFPN), default mode network (DMN), salience network (SN), ventral attention network (VAN), auditory network (AN), visual network (VN), sensorimotor network (SMN), dorsal attention network (DAN), and right frontoparietal network (RFPN) were subjected to independent component analysis (ICA). The functional connectivity values of inter-network were explored.

Results: Acupuncture decreased irritable bowel syndrome symptom severity score (IBS-SSS) and Hamilton Anxiety Scale (HAMA). It also ameliorated symptoms related to IBS-D. Notably, functional connectivity between AN and VAN, SMN and DMN, RFPN and VAN in IBS-D patients after acupuncture treatment was different from that in HCs. Furthermore, there were differences in functional connectivity between DMN and DAN, DAN and LFPN, DMN and VAN before and after acupuncture treatment. The inter-network changes in DMN-VAN were positively correlated with changes in HAMA, life influence degree, and IBS-SSS in IBS-D.

Conclusion: Altered inter-network functional connectivity is involved in several important hubs in large-scale networks. These networks are altered by acupuncture stimulation in patients with IBS-D.
Dietary Supplementation With Lactobacillus plantarum Ameliorates Compromise of Growth Performance by Modulating Short-Chain Fatty Acids and Intestinal Dysbiosis in Broilers Under Clostridium perfringens Challenge
Authors: Wang Baikui , Zhou Yuanhao , Mao Yulong , Gong Li , Li Xiang , Xu Shujie , Wang Fei , Guo Qianpeng , Zhang Huihua , Li Weifen
Published: October 2021

Clostridium perfringens is an important zoonotic pathogen associated with food contamination and poisoning, gas gangrene, necrotizing enterocolitis or necrotic enteritis in humans and animals. Dysbacteriosis is supposedly associated with the development of C. perfringens infection induced necrotic enteritis, but the detailed relationship between intestinal health, microbiome, and C. perfringens infection-induced necrotic enteritis remains poorly understood. This research investigated the effect of probiotics on the growth performance and intestinal health of broilers, and the involved roles of intestinal microbiota and microbial metabolic functions under C. perfringens infection. Results showed that subclinical necrotic enteritis was successfully induced as evidenced by the significant lower body weight (BW), suppressed feed conversion ratio (FCR), decreased ileal villus height and mucosal barrier function, and increased ileal histopathological score and bursal weight index. Lactobacillus plantarum or Paenibacillus polymyxa significantly attenuated C. perfringens-induced compromise of growth performance (BW, FCR) and ileal mucosa damage as illustrated by the increased ileal villus height and villus/crypt ratio, the decreased ileal histopathological score and the enhanced ileal mucosal barrier function. L. plantarum also significantly alleviated C. perfringens-induced enlarged bursa of fabricius and the decreased levels of ileal total SCFAs, acetate, lactate, and butyrate. Furthermore, dietary L. plantarum improved C. perfringens infection-induced intestinal dysbiosis as evidenced by significantly enriched short-chain fatty acids-producing bacteria (Lachnospiraceae, Ruminococcaceae, Oscillospira, Faecalibacterium, Blautia), reduced drug-resistant bacteria (Bacteroides, Alistipes) and enteric pathogens (Escherichia coli, Bacteroides fragilis) and bacterial metabolic dysfunctions as illustrated by significantly increased bacterial fatty acid biosynthesis, decreased bacterial lipopolysaccharide biosynthesis, and antibiotic biosynthesis (streptomycin and vancomycin). Additionally, the BW and intestinal SCFAs were the principal factors affecting the bacterial communities and microbial metabolic functions. The above findings indicate that dietary with L. plantarum attenuates C. perfringens-induced compromise of growth performance and intestinal dysbiosis by increasing SCFAs and improving intestinal health in broilers.
Predicting Axillary Lymph Node Metastasis in Early Breast Cancer Using Deep Learning on Primary Tumor Biopsy Slides
Authors: Xu Feng , Zhu Chuang , Tang Wenqi , Wang Ying , Zhang Yu , Li Jie , Jiang Hongchuan , Shi Zhongyue , Liu Jun , Jin Mulan
Published: October 2021

Objectives

To develop and validate a deep learning (DL)-based primary tumor biopsy signature for predicting axillary lymph node (ALN) metastasis preoperatively in early breast cancer (EBC) patients with clinically negative ALN.

Methods

A total of 1,058 EBC patients with pathologically confirmed ALN status were enrolled from May 2010 to August 2020. A DL core-needle biopsy (DL-CNB) model was built on the attention-based multiple instance-learning (AMIL) framework to predict ALN status utilizing the DL features, which were extracted from the cancer areas of digitized whole-slide images (WSIs) of breast CNB specimens annotated by two pathologists. Accuracy, sensitivity, specificity, receiver operating characteristic (ROC) curves, and areas under the ROC curve (AUCs) were analyzed to evaluate our model.

Results

The best-performing DL-CNB model with VGG16_BN as the feature extractor achieved an AUC of 0.816 (95% confidence interval (CI): 0.758, 0.865) in predicting positive ALN metastasis in the independent test cohort. Furthermore, our model incorporating the clinical data, which was called DL-CNB+C, yielded the best accuracy of 0.831 (95%CI: 0.775, 0.878), especially for patients younger than 50 years (AUC: 0.918, 95%CI: 0.825, 0.971). The interpretation of DL-CNB model showed that the top signatures most predictive of ALN metastasis were characterized by the nucleus features including density (p= 0.015), circumference (p= 0.009), circularity (p= 0.010), and orientation (p= 0.012).

Conclusion

Our study provides a novel DL-based biomarker on primary tumor CNB slides to predict the metastatic status of ALN preoperatively for patients with EBC.
Path4Drug: Data Science Workflow for Identification of Tissue-Specific Biological Pathways Modulated by Toxic Drugs
Authors: Füzi Barbara , Gurinova Jana , Hermjakob Henning , Ecker Gerhard F. , Sheriff Rahuman
Published: October 2021

The early prediction of drug adverse effects is of great interest to pharmaceutical research, as toxicity is one of the leading reasons for drug attrition. Understanding the cell signaling and regulatory pathways affected by a drug candidate is crucial to the study of drug toxicity. In this study, we present a computational technique that employs the propagation of drug-protein interactions to connect compounds to biological pathways. Target profiles for drugs were built by retrieving drug target proteins from public repositories such as ChEMBL, DrugBank, IUPHAR, PharmGKB, and TTD. Subsequent enrichment test of the protein pool using Reactome revealed potential pathways affected by the drugs. Furthermore, an optional tissue filter utilizing the Human Protein Atlas was applied to identify tissue-specific pathways. The analysis pipeline was implemented in an open-source KNIME workflow called Path4Drug to allow automated data retrieval and reconstruction for any given drug present in ChEMBL. The pipeline was applied to withdrawn drugs and cardio- and hepatotoxic drugs with black box warnings to identify biochemical pathways they affect and to find pathways that can be potentially connected to the toxic events. To complement this approach, drugs used in cardiac therapy without any record of toxicity were also analyzed. The results provide already known associations as well as a large amount of additional potential connections. Consequently, our approach can link drugs to biological pathways by leveraging big data available in public resources. The developed tool is openly available and modifiable to support other systems biology analyses.
Dexmedetomidine Versus Propofol for Patients With Sepsis Requiring Mechanical Ventilation: A Systematic Review and Meta-Analysis
Authors: Huang Po , Zheng Xiangchun , Liu Zhi , Fang Xiaolei
Published: October 2021

Purpose: This meta-analysis was performed to access the influence of dexmedetomidine versus propofol for adult patients with sepsis undergoing mechanical ventilation.

Materials and Methods: NCBI PUBMED, Cochrane Library, Embase, China National Knowledge Internet (CNKI), and China Biological Medicine (CBM) were searched. Revman 5.3 and Stata software (version 12.0, Stata Corp LP, College Station, TX, United States) were used for meta-analysis.

Results: Fifteen studies were included, and the data from the included studies were incorporated into the meta-analysis. Also, the result shows that compared with propofol, dexmedetomidine does not reduce 28-day mortality [risk ratios (RR) =0.97, 95% confidence interval (CI) =0.83–1.13, p = 0.70]. However, our analysis found that dexmedetomidine could reduce intensive care unit (ICU) stays {standard mean difference (SMD): −0.15; 95% CI: [−0.30–(−0.01)], p = 0.03}, duration of mechanical ventilation {SMD: −0.22; 95% CI: [−0.44–(−0.01)], p = 0.043}, sequential organ failure assessment (SOFA) {SMD: −0.41; 95% CI: [−0.73–(−0.09)], p = 0.013}, levels of interleukin-6 (IL-6) at 24 h (SMD: −2.53; 95% CI: −5.30-0.24, p = 0.074), and levels of CK-MB at 72 h {SMD: −0.45; 95% CI: [−0.83–(−0.08)], p = 0.017}.

Conclusions: This meta-analysis (MA) suggests that in terms of 28-day mortality, sepsis patients with the treatment of dexmedetomidine did not differ from those who received propofol. In addition, more high-quality trials are needed to confirm these findings.

Systematic Review Registration:https://www.crd.york.ac.uk/prospero/#recordDetails, identifier CRD42021249780.
Comparison of Safety and Efficacy Between Clopidogrel and Ticagrelor in Elderly Patients With Acute Coronary Syndrome: A Systematic Review and Meta-Analysis
Authors: Zhao Xiangkai , Zhang Jian , Guo Jialin , Wang Jinxin , Pan Yuhui , Zhao Xue , Sang Wentao , Yang Kehui , Xu Fengyang , Xu Feng , Chen Yuguo
Published: October 2021

Background: Dual antiplatelet therapy combining aspirin with a P2Y12 adenosine diphosphate receptor inhibitor is a therapeutic mainstay for acute coronary syndrome (ACS). However, the optimal choice of P2Y12 adenosine diphosphate receptor inhibitor in elderly (aged ≥65 years) patients remains controversial. We conducted a meta-analysis to compare the efficacy and safety of ticagrelor and clopidogrel in elderly patients with ACS. Methods: We comprehensively searched in Web of Science, EMBASE, PubMed, and Cochrane databases through 29th March, 2021 for eligible randomized controlled trials (RCTs) comparing the efficacy and safety of ticagrelor or clopidogrel plus aspirin in elderly patients with ACS. Four studies were included in the final analysis. A fixed effects model or random effects model was applied to analyze risk ratios (RRs) and hazard ratios (HRs) across studies, and I2 to assess heterogeneity.

Results: A total number of 4429 elderly patients with ACS were included in this analysis, of whom 2170 (49.0%) patients received aspirin plus ticagrelor and 2259 (51.0%) received aspirin plus clopidogrel. The ticagrelor group showed a significant advantage over the clopidogrel group concerning all-cause mortality (HR 0.78, 95% CI 0.63–0.96, I2 = 0%; RR 0.79, 95% CI 0.66–0.95, I2 = 0%) and cardiovascular death (HR 0.71, 95% CI 0.56–0.91, I2 = 0%; RR 0.76, 95% CI 0.62–0.94, I2 = 5%) but owned a higher risk of PLATO major or minor bleeding (HR 1.46, 95% CI 1.13–1.89, I2 = 0%; RR 1.40, 95% CI 1.11–1.76, I2 = 0%). Both the groups showed no significant difference regarding major adverse cardiovascular events (MACEs) (HR 1.06, 95% CI 0.68–1.65, I2 = 77%; RR 1.04, 95% CI 0.69–1.58, I2 = 77%).

Conclusion: For elderly ACS patients, aspirin plus ticagrelor reduces cardiovascular death and all-cause mortality but increases the risk of bleeding. Herein, aspirin plus ticagrelor may extend lifetime for elderly ACS patients compared with aspirin plus clopidogrel. The optimal DAPT for elderly ACS patients may be a valuable direction for future research studies.
The Use of Artificial Neural Networks to Forecast the Behavior of Agent-Based Models of Pathophysiology: An Example Utilizing an Agent-Based Model of Sepsis
Authors: Larie Dale , An Gary , Cockrell R. Chase
Published: October 2021

Introduction: Disease states are being characterized at finer and finer levels of resolution via biomarker or gene expression profiles, while at the same time. Machine learning (ML) is increasingly used to analyze and potentially classify or predict the behavior of biological systems based on such characterization. As ML applications are extremely data-intensive, given the relative sparsity of biomedical data sets ML training of artificial neural networks (ANNs) often require the use of synthetic training data. Agent-based models (ABMs) that incorporate known biological mechanisms and their associated stochastic properties are a potential means of generating synthetic data. Herein we present an example of ML used to train an artificial neural network (ANN) as a surrogate system used to predict the time evolution of an ABM focusing on the clinical condition of sepsis.

Methods: The disease trajectories for clinical sepsis, in terms of temporal cytokine and phenotypic dynamics, can be interpreted as a random dynamical system. The Innate Immune Response Agent-based Model (IIRABM) is a well-established model that utilizes known cellular and molecular rules to simulate disease trajectories corresponding to clinical sepsis. We have utilized two distinct neural network architectures, Long Short-Term Memory and Multi-Layer Perceptron, to take a time sequence of five measurements of eleven IIRABM simulated serum cytokine concentrations as input and to return both the future cytokine trajectories as well as an aggregate metric representing the patient’s state of health.

Results: The ANNs predicted model trajectories with the expected amount of error, due to stochasticity in the simulation, and recognizing that the mapping from a specific cytokine profile to a state-of-health is not unique. The Multi-Layer Perceptron neural network, generated predictions with a more accurate forecasted trajectory cone.

Discussion: This work serves as a proof-of-concept for the use of ANNs to predict disease progression in sepsis as represented by an ABM. The findings demonstrate that multicellular systems with intrinsic stochasticity can be approximated with an ANN, but that forecasting a specific trajectory of the system requires sequential updating of the system state to provide a rolling forecast horizon.
Effects of Low and High Aneurysmal Wall Shear Stress on Endothelial Cell Behavior: Differences and Similarities
Authors: Morel Sandrine , Schilling Sabine , Diagbouga Mannekomba R. , Delucchi Matteo , Bochaton-Piallat Marie-Luce , Lemeille Sylvain , Hirsch Sven , Kwak Brenda R.
Published: October 2021

Background: Intracranial aneurysms (IAs) result from abnormal enlargement of the arterial lumen. IAs are mostly quiescent and asymptomatic, but their rupture leads to severe brain damage or death. As the evolution of IAs is hard to predict and intricates medical decision, it is essential to improve our understanding of their pathophysiology. Wall shear stress (WSS) is proposed to influence IA growth and rupture. In this study, we investigated the effects of low and supra-high aneurysmal WSS on endothelial cells (ECs).

Methods: Porcine arterial ECs were exposed for 48 h to defined levels of shear stress (2, 30, or 80 dyne/cm2) using an Ibidi flow apparatus. Immunostaining for CD31 or γ-cytoplasmic actin was performed to outline cell borders or to determine cell architecture. Geometry measurements (cell orientation, area, circularity and aspect ratio) were performed on confocal microscopy images. mRNA was extracted for RNAseq analysis.

Results: ECs exposed to low or supra-high aneurysmal WSS were more circular and had a lower aspect ratio than cells exposed to physiological flow. Furthermore, they lost the alignment in the direction of flow observed under physiological conditions. The effects of low WSS on differential gene expression were stronger than those of supra-high WSS. Gene set enrichment analysis highlighted that extracellular matrix proteins, cytoskeletal proteins and more particularly the actin protein family were among the protein classes the most affected by shear stress. Interestingly, most genes showed an opposite regulation under both types of aneurysmal WSS. Immunostainings for γ-cytoplasmic actin suggested a different organization of this cytoskeletal protein between ECs exposed to physiological and both types of aneurysmal WSS.

Conclusion: Under both aneurysmal low and supra-high WSS the typical arterial EC morphology molds to a more spherical shape. Whereas low WSS down-regulates the expression of cytoskeletal-related proteins and up-regulates extracellular matrix proteins, supra-high WSS induces opposite changes in gene expression of these protein classes. The differential regulation in EC gene expression observed under various WSS translate into a different organization of the ECs’ architecture. This adaptation of ECs to different aneurysmal WSS conditions may affect vascular remodeling in IAs.
Hip Abductor and Adductor Rate of Torque Development and Muscle Activation, but Not Muscle Size, Are Associated With Functional Performance
Authors: Lanza Marcel Bahia , Rock Kelly , Marchese Victoria , Addison Odessa , Gray Vicki L.
Published: October 2021

Understanding the physiological variables that contribute to a functional task provides important information for trainers and clinicians to improve functional performance. The hip abductors and adductors muscles appear to be important in determining the performance of some functional tasks; however, little is known about the relationship of the hip abductor/adductors muscle strength, activation, and size with functional performance. This study aimed to investigate the relationship of maximum torque, rate of torque development (RTD), rate of activation (RoA), and muscle thickness of the hip abductors [tensor fascia latae (TFL) and gluteus medius (GM)] and adductor magnus muscle with the Four Square Step Test (FSST) and the two-leg hop test in healthy young adults. Twenty participants (five males) attended one testing session that involved ultrasound image acquisition, maximal isometric voluntary contractions (hip abduction and hip adduction) while surface electromyography (EMG) was recorded, and two functional tests (FSST and two-leg side hop test). Bivariate correlations were performed between maximum voluntary torque (MVT), RTD at 50, 100, 200, and 300ms, RoA at 0–50, 0–100, 0–200, and 0–300, and muscle thickness with the dynamic stability tests. For the hip abduction, MVT (r=−0.455,p=0.044) and RTD300(r=−0.494,p=0.027) was correlated with the FSST. GM RoA50(r=−0.481,p=0.032) and RoA100(r=−0.459,p=0.042) were significantly correlated with the two-leg side hop test. For the hip adduction, there was a significant correlation between the FSST and RTD300(r=−0.500,p=0.025), while the two-leg side hop test was correlated with RTD200(r=0.446,p=0.049) and RTD300(r=0.594,p=0.006). Overall, the ability of the hip abductor and adductor muscles to produce torque quickly, GM rapid activation, and hip abductor MVT is important for better performance on the FSST and two-leg hop tests. However, muscle size appears not to influence the same tests.
Pathogenesis of Children’s Allergic Diseases: Refocusing the Role of the Gut Microbiota
Authors: Hu Tingting , Dong Yinmiao , Yang Chenghao , Zhao Mingyi , He Qingnan
Published: October 2021

Allergic diseases comprise a genetically heterogeneous cluster of immunologically mediated diseases, including asthma, food allergy (FA), allergic rhinitis (AR) and eczema, that have become major worldwide health problems. Over the past few decades, the spread of allergic diseases has displayed an increasing trend, and it has been reported that 22% of 1.39 billion people in 30 countries have a type of allergic disease. Undoubtedly, allergic diseases, which can be chronic, with significant morbidity, mortality and dynamic progression, impose major economic burdens on society and families; thus, exploring the cause of allergic diseases and reducing their prevalence is a top priority. Recently, it has been reported that the gastrointestinal (GI) microbiota can provide vital signals for the development, function, and regulation of the immune system, and the above-mentioned contributions make the GI microbiota a key player in allergic diseases. Notably, the GI microbiota is highly influenced by the mode of delivery, infant diet, environment, antibiotic use and so on. Specifically, changes in the environment can result in the dysbiosis of the GI microbiota. The proper function of the GI microbiota depends on a stable cellular composition which in the case of the human microbiota consists mainly of bacteria. Large shifts in the ratio between these phyla or the expansion of new bacterial groups lead to a disease-promoting imbalance, which is often referred to as dysbiosis. And the dysbiosis can lead to alterations of the composition of the microbiota and subsequent changes in metabolism. Further, the GI microbiota can affect the physiological characteristics of the human host and modulate the immune response of the host. The objectives of this review are to evaluate the development of the GI microbiota, the main drivers of the colonization of the GI tract, and the potential role of the GI microbiota in allergic diseases and provide a theoretical basis as well as molecular strategies for clinical practice.