bluuebunny/crossref_metadata_2025 huggingface dataset:
Leukotriene A4 Hydrolase Is a Candidate Predictive Biomarker for Successful Allergen Immunotherapy
Authors: Ma Ting-Ting , Cao Meng-Da , Yu Rui-Li , Shi Hai-Yun , Yan Wei-Jun , Liu Jian-Guo , Pan Chen , Sun Jinlyu , Wei Qing-Yu , Wang De-Yun , Wei Ji-Fu , Wang Xue-Yan , Yin Jin-Shu
Published: November 2020

Background

Allergic rhinitis is a common disorder that affects 10% to 40% of the population worldwide. Allergen immunotherapy (AIT) represents the only therapy that has the potential to resolve clinical symptoms of allergic rhinitis. However, up to 30% of patients do not respond to AIT. Biomarkers predicting the clinical efficacy of AIT as early as possible would significantly improve the patient selection and reduce unnecessary societal costs.

Methods

Artemisia pollen allergic patients who received at least 1-year AIT were enrolled. Clinical responses before and after 1-year AIT were evaluated to determine AIT responders. Artemisia specific IgE and IgG4 levels were measured by using ImmunoCAP and enzyme-linked immunosorbent assay (ELISA) separately. Stepwise regression analysis was performed to identify which rhinitis-relevant parameters explained the most variability in AIT results. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics was applied to identify the potential candidate biomarkers in the sera of responders and non-responders collected before and after 1-year therapy. The diagnostic performance of the potential biomarkers was then assessed using enzyme-linked immunosorbent assay (ELISA) in 30 responders and 15 non-responders.

Results

Artemisia specific IgE and IgG4 levels were elevated only in the responders. Regression analysis of allergic rhinitis-relevant parameters provided a robust model that included two most significant variables (sneeze and nasal congestion). Thirteen candidate biomarkers were identified for predicting AIT outcomes. Based on their association with allergy and protein fold change (more than 1.1 or less than 0.9), four proteins were identified to be potential biomarkers for predicting effective AIT. However, further ELISA revealed that only leukotriene A4 hydrolase (LTA4H) was consistent with the proteomics data. The LTA4H level in responders increased significantly (P < 0.001) after 1-year therapy, while that of non-responders remained unchanged. Assessment of LTA4H generated area under curve (AUC) value of 0.844 (95% confidence interval: 0.727 to 0.962; P < 0.05) in distinguishing responders from the non-responders, suggesting that serum LTA4H might be a potential biomarker for predicting the efficiency of AIT.

Conclusion

Serum LTA4H may be a potential biomarker for early prediction of an effective AIT.
Tonsillectomy Improved Therapeutic Response in Anti-SRP Myopathy With Chronic Tonsillitis
Authors: Ikeda Takuya , Takeuchi Hideyuki , Takahashi Keita , Nakamura Haruko , Kunii Misako , Katsumoto Atsuko , Tada Mikiko , Higashiyama Yuichi , Hibiya Takashi , Suzuki Shigeaki , Nishino Ichizo , Koyano Shigeru , Doi Hiroshi , Tanaka Fumiaki
Published: November 2020

Chronic tonsillitis has been attracted attention as a source of abnormal immune responses and a possible trigger of autoimmune diseases such as IgA nephritis, IgA vasculitis, palmoplantar pustulosis, psoriasis, rheumatoid arthritis, Behçet’s disease, and myositis. Here we present the first report of anti–signal recognition particle antibody–associated necrotizing myopathy (anti-SRP myopathy) with IgA nephropathy and chronic tonsillitis in which the therapeutic response to intravenous immunoglobulin (IVIG) treatment was dramatically improved after tonsillectomy and accompanied by a rapid increase in ΔIgG, defined as the change in serum IgG levels 2 weeks after the start of IVIG treatment relative to pre-treatment levels. Moreover, serum anti-SRP antibody titers became undetectable after tonsillectomy even though the resected tonsils did not produce anti-SRP antibodies. Tonsillectomy should be considered when chronic tonsillitis is observed in patients with autoimmune diseases showing poor response to treatment, including anti-SRP myopathy.
Mild SARS-CoV-2 Infection After Gene Therapy in a Child With Wiskott-Aldrich Syndrome: A Case Report
Authors: Cenciarelli Sabina , Calbi Valeria , Barzaghi Federica , Bernardo Maria Ester , Oltolini Chiara , Migliavacca Maddalena , Gallo Vera , Tucci Francesca , Fraschetta Federico , Albertazzi Elena , Fratini Elena Sophia , Consiglieri Giulia , Giannelli Stefania , Dionisio Francesca , Sartirana Claudia , Racca Sara , Camesasca Chiara , Peretto Giovanni , Daverio Rita , Esposito Antonio , De Cobelli Francesco , Silvani Paolo , Rabusin Marco , Cara Andrea , Trabattoni Daria , Dispinseri Stefania , Scarlatti Gabriella , Piemonti Lorenzo , Lampasona Vito , Cicalese Maria Pia , Aiuti Alessandro , Ferrua Francesca
Published: November 2020

In this work we present the case of SARS-CoV-2 infection in a 1.5-year-old boy affected by severe Wiskott-Aldrich Syndrome with previous history of autoinflammatory disease, occurring 5 months after treatment with gene therapy. Before SARS-CoV-2 infection, the patient had obtained engraftment of gene corrected cells, resulting in WASP expression restoration and early immune reconstitution. The patient produced specific immunoglobulins to SARS-CoV-2 at high titer with neutralizing capacity and experienced a mild course of infection, with limited inflammatory complications, despite pre-gene therapy clinical phenotype.
Effects of Heat-Treatment on the Microstructure, Electromagnetic Wave Absorbing Properties, and Mechanical Properties of SiCN Fibers
Authors: Long Xin , Zhang Shuai , Shao Changwei , Wang Bing , Wang Yingde
Published: November 2020

SiCN fibers can not only be used for reinforcement of composites materials but also for electromagnetic wave (EMW) absorbing applications in a high-temperature oxidizing environment above 1,200°C. In this work, the microstructural evolution and EMW absorbing properties of SiCN fibers after annealing at 1,300–1,600°C in N2 atmosphere were investigated. Results showed that the amorphous SiCN fibers presented poor EMW absorbing properties when the annealing temperature was below 1,400°C. As the annealing temperature increased to 1,500°C, the EMW absorbing properties could been largely enhanced with a minimum reflation loss value of -55.8 dB and an effective absorption bandwidth value of 2.5 GHz. The enhanced EMW absorbing properties should contribute to the formation and growth of grain boundaries and defects among the amorphous fiber matrix and turbostratic graphite carbon, which could enhance the space charge polarization at the heterogeneous interfaces and increase the conductivity of the SiCN fibers. Meanwhile, SiCN fibers retained a rather high tensile strength of ∼1.0 GPa after annealing at 1,500°C, which showed it to be a promising candidate for reinforcing the stealth ceramic matrix composites used in harsh environments.
Comparative Study on the Mechanical Strength of SAP Internally Cured Concrete
Authors: Xie Faxiang , Zhang Chuanlong , Cai Dingpeng , Ruan Jing
Published: November 2020

To investigate the relationships between the different mechanical strengths of internally cured concrete with Super Absorbent Polymer (SAP concrete), the uniaxial mechanical properties of SAP concrete with different internal curing water-cement ratios were studied. Various SAP concrete specimens were prepared, and the uniaxial compressive, splitting tensile, as well as four-point bending tests, were carried out using the electro-hydraulic servo testing machine. The cubic compressive strength, splitting tensile strength, and flexural strength of SAP concrete with different internal curing water-cement ratios was obtained. The converting relationships between the internal curing water-cement ratio and different mechanical strengths were analyzed extensively. Based on the conversion formulas of different strength indexes proposed by different national standards and other researchers, the equations among the splitting tensile strength, cubic compressive strength, and flexural strength of SAP concrete were proposed and verified using the experimental data. According to the comparative analysis results, the proposed equations in this study have significant applicability and can be conducted in the practical application of SAP concrete.
Processing of Sr2+ Containing Poly L-Lactic Acid-Based Hybrid Composites for Additive Manufacturing of Bone Scaffolds
Authors: Melo Priscila , Naseem Raasti , Corvaglia Ilaria , Montalbano Giorgia , Pontremoli Carlotta , Azevedo António , Quadros Paulo , Gentile Piergiorgio , Ferreira Ana Marina , Dalgarno Kenneth , Vitale-Brovarone Chiara , Fiorilli Sonia
Published: November 2020

Biodegradable composite materials represent one of the major areas of investigation for bone tissue engineering due to their tuneable compositional and mechanical properties, which can potentially mimic those of bone and potentially avoid the removal of implants, mitigating the risks for the patient and reducing the overall clinical costs. In addition, the introduction of additive manufacturing technologies enables a strict control over the final morphological features of the scaffolds. In this scenario, the optimisation of 3D printable resorbable composites, made of biocompatible polymers and osteoinductive inorganic phases, offers the potential to produce a chemically and structurally biomimetic implant, which will resorb over time. The present work focuses on the development and process optimisation of two hybrid composite filaments, to be used as feedstock for the fused filament fabrication 3D printing process. A Poly L-lactic acid matrix was blended with either rod-like nano-hydroxyapatite (nano-HA) or nanoparticles of mesoporous bioactive glasses, both partially substituted with strontium (Sr2+), due to the well-known pro-osteogenic effect of this ion. Both inorganic phases were incorporated into Poly L-lactic acid using an innovative combination of processes, obtaining a homogeneous distribution throughout the polymer whilst preserving their ability to release Sr2+. The filament mechanical properties were not hindered after the incorporation of the inorganic phases, resulting in tensile strengths and moduli within the range of cancellous bone, 50 ± 10 MPa and 3 ± 1 GPa. Finally, the rheological characterization of the hybrid composites indicated a shear thinning behaviour, ideal for the processing with fused filament fabrication, proving the potential of these materials to be processed into 3D structures aiming bone regeneration.
Oral Treatment With an Engineered Uricase, ALLN-346, Reduces Hyperuricemia, and Uricosuria in Urate Oxidase-Deficient Mice
Authors: Pierzynowska Kateryna , Deshpande Aditi , Mosiichuk Nadiia , Terkeltaub Robert , Szczurek Paulina , Salido Eduardo , Pierzynowski Stefan , Grujic Danica
Published: November 2020

Limitations in efficacy and/or tolerance of currently available urate-lowering therapies (ULTs), such as oral xanthine oxidase inhibitors, uricosurics, and intravenous uricase agents contribute to the development of refractory gout. Renal excretion is the major route of uric acid elimination, but the intestinal tract plays an increasingly recognized role in urate homeostasis, particularly in chronic kidney disease (CKD) in which the renal elimination of urate is impaired. We targeted intestinal degradation of urate in vivo with ALLN-346, an orally administered, engineered urate oxidase, optimized for proteolytic stability, and activity in the gut. We tested ALLN-346 in uricase/urate oxidase deficient mice (URKO mice) with severe hyperuricemia, hyperuricosuria, and uric acid crystalline obstructive nephropathy. A total of 55 male and female URKO mice were used in the two consecutive studies. These seminal, proof-of-concept studies aimed to explore both short- (7-day) and long-term (19-day) effects of ALLN-346 on the reduction of plasma and urine urate. In both the 7- and 19-day studies, ALLN-346 oral therapy resulted in the normalization of urine uric acid excretion and a significant reduction of hyperuricemia by 44 and 28% when therapy was given with food over 24 h or was limited for up to 6 h, respectively. Fractional excretion of uric acid (FEUA) was normalized with ALLN-346 therapy. Oral enzyme therapy with engineered urate oxidase (ALLN-346) designed to degrade urate in the intestinal tract has the potential to reduce hyperuricemia and the renal burden of filtered urate in patients with hyperuricemia and gout with and without CKD.
Complete Inactivation of Blood Borne Pathogen Trypanosoma cruzi in Stored Human Platelet Concentrates and Plasma Treated With 405 nm Violet-Blue Light
Authors: Jankowska Katarzyna I. , Nagarkatti Rana , Acharyya Nirmallya , Dahiya Neetu , Stewart Caitlin F. , Macpherson Ruairidh W. , Wilson Mark P. , Anderson John G. , MacGregor Scott J. , Maclean Michelle , Dey Neil , Debrabant Alain , Atreya Chintamani D.
Published: November 2020

The introduction of pathogen reduction technologies (PRTs) to inactivate bacteria, viruses and parasites in donated blood components stored for transfusion adds to the existing arsenal toward reducing the risk of transfusion-transmitted infectious diseases (TTIDs). We have previously demonstrated that 405 nm violet-blue light effectively reduces blood-borne bacteria in stored human plasma and platelet concentrates. In this report, we investigated the microbicidal effect of 405 nm light on one important bloodborne parasite Trypanosoma cruzi that causes Chagas disease in humans. Our results demonstrated that a light irradiance at 15 mWcm−2 for 5 h, equivalent to 270 Jcm−2, effectively inactivated T. cruzi by over 9.0 Log10, in plasma and platelets that were evaluated by a MK2 cell infectivity assay. Giemsa stained T. cruzi infected MK2 cells showed that the light-treated parasites in plasma and platelets were deficient in infecting MK2 cells and did not differentiate further into intracellular amastigotes unlike the untreated parasites. The light-treated and untreated parasite samples were then evaluated for any residual infectivity by injecting the treated parasites into Swiss Webster mice, which did not develop infection even after the animals were immunosuppressed, further demonstrating that the light treatment was completely effective for inactivation of the parasite; the light-treated platelets had similar in vitro metabolic and biochemical indices to that of untreated platelets. Overall, these results provide a proof of concept toward developing 405 nm light treatment as a pathogen reduction technology (PRT) to enhance the safety of stored human plasma and platelet concentrates from bloodborne T. cruzi, which causes Chagas disease.
Enhanced T Cell Responses Induced by a Necrotic Dendritic Cell Vaccine, Expressing HCV NS3
Authors: Mekonnen Zelalem A. , Masavuli Makutiro G. , Yu Wenbo , Gummow Jason , Whelan Dawn M. , Al-Delfi Zahraa , Torresi Joseph , Gowans Eric J. , Grubor-Bauk Branka
Published: November 2020

A vaccine that induces potent, broad and sustained cell-mediated immunity, resulting in effective memory has the potential to restrict hepatitis C (HCV) virus infection. Early, multi-functional CD4+ and CD8+ T cell responses against non-structural protein 3 (NS3) have been associated with HCV clearance. Necrotic cells generate strong immune responses and represent a major antigenic source used by dendritic cells (DC) for processing and presentation, but there is conflicting evidence as to their immunogenicity in vaccination. Immunization with DC loaded with viral antigens has been done in the past, but to date the immunogenicity of live vs. necrotic DC vaccines has not been investigated. We developed a DC2.4 cell line stably expressing HCV NS3, and compared the NS3-specific responses of live vs. necrotic NS3 DC. Vaccination of mice with necrotic NS3 DC increased the breadth of T-cell responses and enhanced the production of IL-2, TNF-α, and IFN-γ by effector memory CD4+ and CD8+T cells, compared to mice vaccinated with live NS3 DC. A single dose of necrotic NS3 DC vaccine induced a greater influx and activation of cross-presenting CD11c+ CD8α+ DC and necrosis-sensing Clec9A+ DC in the draining lymph nodes. Furthermore, using a hydrodynamic challenge model necrotic NS3 DC vaccination resulted in enhanced clearance of NS3-positive hepatocytes from the livers of vaccinated mice. Taken together, the data demonstrate that necrotic DC represent a novel and exciting vaccination strategy capable of inducing broad and multifunctional T cell memory.
A Candidate Secreted Effector Protein of Rubber Tree Powdery Mildew Fungus Contributes to Infection by Regulating Plant ABA Biosynthesis
Authors: Li Xiao , Liu Yuhan , He Qiguang , Li Sipeng , Liu Wenbo , Lin Chunhua , Miao Weiguo
Published: November 2020

Powdery mildew infects a wide range of crops and economic plants, causing substantial losses. Rubber trees (Hevea brasiliensis) are the primary source of natural rubber, and powdery mildew infection causes significant losses to natural rubber yields. How the causal agent, Erysiphe quercicola, establishes successful infection in rubber trees is largely unknown. Previously, 133 candidate secreted effector proteins (CSEPs) were identified in powdery mildew fungus. In this study, we characterize a CSEP named EqCSEP01276 for its function in suppressing host plant defense responses. We show that EqCSEP01276 is a secreted protein and is able to disturb the localization of 9-cis-epoxycarotenoid dioxygenase 5 (HbNCED5), a key enzyme in abscisic acid (ABA) biosynthesis in plant cell chloroplasts of H. brasiliensis. We also show that this effector inhibits ABA biosynthesis, and that in H. brasiliensis ABA is a positive regulator of the plant immune response against powdery mildew. Our study reveals a strategy by which powdery mildew fungus manipulates plant ABA-mediated defense for a successful infection.
A Robust Symbiotic Relationship Between the Ciliate Paramecium multimicronucleatum and the Bacterium Ca. Trichorickettsia Mobilis
Authors: Mironov Timofey , Sabaneyeva Elena
Published: November 2020

Close reciprocal interactions in symbiotic systems have suggested the holobiont concept, in which the host and its microbiota are considered as a single entity. Ciliates are known for their ability to form symbiotic associations with prokaryotes. Relationships between the partners in such systems vary from mutualism to parasitism and differ significantly in their robustness. We assessed the viability of the ciliate Paramecium multimicronucleatum and its ability to maintain its intranuclear endosymbiont Ca. Trichorickettsia mobilis (Rickettsiaceae) after treatment with antibiotics characterized by different mode of action, such as ampicillin, streptomycin, chloramphenicol, tetracycline. The presence of endosymbionts in the host cell was determined by means of living cell observations made using differential interference contrast or fluorescence in situ hybridization with the species-specific oligonucleotide probe (FISH). Administration of antibiotics traditionally used in treatments of rickettsioses, tetracycline and chloramphenicol, depending on the concentration used and the ciliate strain treated, either caused death of both, infected and control cells, or did not affect the ability of the host to maintain the intranuclear endosymbiont. The surviving cells always manifested motile bacteria in the macronucleus. Streptomycin treatment never led to the loss of endosymbionts in any of the four infected strains, and nearly all ciliates remained viable. Ampicillin treatment never caused host cell death, but resulted in formation of filamentous and immobile oval bacterial forms. Under repeated ampicillin treatments, a part of endosymbionts was registered in the host cytoplasm, as evidenced both by FISH and transmission electron microscopy. Endosymbionts located in the host cytoplasm were enclosed in vacuoles, apparently, corresponding to autophagosomes. Nevertheless, the bacteria seemed to persist in this compartment and might cause relapse of the infection. Although the antibiotic sensitivity profile of Trichorickettsia seems to resemble that of other representatives of Rickettsiaceae, causative agents of severe diseases in humans, neither of the antibiotic treatments used in this study resulted in an aposymbiotic cell line, apparently, due to the protists’ sensitivity to tetracyclines, the drugs of preference in rickettsiosis treatment. The observed robustness of this symbiotic system makes it a good model for further elaboration of the holobiont concept.
Computational Investigation of Structural Dynamics of SARS-CoV-2 Methyltransferase-Stimulatory Factor Heterodimer nsp16/nsp10 Bound to the Cofactor SAM
Authors: Sk Md Fulbabu , Jonniya Nisha Amarnath , Roy Rajarshi , Poddar Sayan , Kar Parimal
Published: November 2020

Recently, a highly contagious novel coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has emerged, posing a global threat to public health. Identifying a potential target and developing vaccines or antiviral drugs is an urgent demand in the absence of approved therapeutic agents. The 5′-capping mechanism of eukaryotic mRNA and some viruses such as coronaviruses (CoVs) are essential for maintaining the RNA stability and protein translation in the virus. SARS-CoV-2 encodes S-adenosyl-L-methionine (SAM) dependent methyltransferase (MTase) enzyme characterized by nsp16 (2′-O-MTase) for generating the capped structure. The present study highlights the binding mechanism of nsp16 and nsp10 to identify the role of nsp10 in MTase activity. Furthermore, we investigated the conformational dynamics and energetics behind the binding of SAM to nsp16 and nsp16/nsp10 heterodimer by employing molecular dynamics simulations in conjunction with the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) method. We observed from our simulations that the presence of nsp10 increases the favorable van der Waals and electrostatic interactions between SAM and nsp16. Thus, nsp10 acts as a stimulator for the strong binding of SAM to nsp16. The hydrophobic interactions were predominately identified for the nsp16-nsp10 interactions. Also, the stable hydrogen bonds between Ala83 (nsp16) and Tyr96 (nsp10), and between Gln87 (nsp16) and Leu45 (nsp10) play a vital role in the dimerization of nsp16 and nsp10. Besides, Computational Alanine Scanning (CAS) mutagenesis was performed, which revealed hotspot mutants, namely I40A, V104A, and R86A for the dimer association. Hence, the dimer interface of nsp16/nsp10 could also be a potential target in retarding the 2′-O-MTase activity in SARS-CoV-2. Overall, our study provides a comprehensive understanding of the dynamic and thermodynamic process of binding nsp16 and nsp10 that will contribute to the novel design of peptide inhibitors based on nsp16.
Surprisingly Fast Interface and Elbow Angle Dynamics of Antigen-Binding Fragments
Authors: Fernández-Quintero Monica L. , Kroell Katharina B. , Heiss Martin C. , Loeffler Johannes R. , Quoika Patrick K. , Waibl Franz , Bujotzek Alexander , Moessner Ekkehard , Georges Guy , Liedl Klaus R.
Published: November 2020

Fab consist of a heavy and light chain and can be subdivided into a variable (VHand VL) and a constant region (CH1 and CL). The variable region contains the complementarity-determining region (CDR), which is formed by six hypervariable loops, shaping the antigen binding site, the paratope. Apart from the CDR loops, both the elbow angle and the relative interdomain orientations of the VH–VLand the CH1–CLdomains influence the shape of the paratope. Thus, characterization of the interface and elbow angle dynamics is essential to antigen specificity. We studied nine antigen-binding fragments (Fab) to investigate the influence of affinity maturation, antibody humanization, and different light-chain types on the interface and elbow angle dynamics. While the CDR loops reveal conformational transitions in the micro-to-millisecond timescale, both the interface and elbow angle dynamics occur on the low nanosecond timescale. Upon affinity maturation, we observe a substantial rigidification of the VHand VLinterdomain and elbow-angle flexibility, reflected in a narrower and more distinct distribution. Antibody humanization describes the process of grafting non-human CDR loops onto a representative human framework. As the antibody framework changes upon humanization, we investigated if both the interface and the elbow angle distributions are changed or shifted. The results clearly showed a substantial shift in the relative VH–VLdistributions upon antibody humanization, indicating that different frameworks favor distinct interface orientations. Additionally, the interface and elbow angle dynamics of five antibody fragments with different light-chain types are included, because of their strong differences in elbow angles. For these five examples, we clearly see a high variability and flexibility in both interface and elbow angle dynamics, highlighting the fact that Fab interface orientations and elbow angles interconvert between each other in the low nanosecond timescale. Understanding how the relative interdomain orientations and the elbow angle influence antigen specificity, affinity, and stability has broad implications in the field of antibody modeling and engineering.
Glutamate in Male and Female Sexual Behavior: Receptors, Transporters, and Steroid Independence
Authors: Chiang Vic Shao-Chih , Park Jin Ho
Published: November 2020

The survival of animal species predicates on the success of sexual reproduction. Neurotransmitters play an integral role in the expression of these sexual behaviors in the brain. Here, we review the role of glutamate in sexual behavior in rodents and non-rodent species for both males and females. These encompass the release of glutamate and correlations with glutamate receptor expression during sexual behavior. We then present the effects of glutamate on sexual behavior, as well as the effects of antagonists and agonists on different glutamate transporters and receptors. Following that, we discuss the potential role of glutamate on steroid-independent sexual behavior. Finally, we demonstrate the interaction of glutamate with other neurotransmitters to impact sexual behavior. These sexual behavior studies are crucial in the development of novel treatments of sexual dysfunction and in furthering our understanding of the complexity of sexual diversity. In the past decade, we have witnessed the burgeoning of novel techniques to study and manipulate neuron activity, to decode molecular events at the single-cell level, and to analyze behavioral data. They pose exciting avenues to gain further insight into future sexual behavior research. Taken together, this work conveys the essential role of glutamate in sexual behavior.
Nomogram for Acute Bilirubin Encephalopathy Risk in Newborns With Extreme Hyperbilirubinemia
Authors: Qu Yangming , Huang Shuhan , Fu Xin , Wang Youping , Wu Hui
Published: November 2020

Background and Objectives: This work aimed to develop a predictive model of neonatal acute bilirubin encephalopathy.

Methods: We retrospectively analyzed the data on extreme hyperbilirubinemia (EHB) newborns hospitalized in the First Hospital of Jilin University from January 1, 2012 to December 31, 2019. The demographic characteristics, pathological information, and admission examination results of newborns were collected to analyze the factors affecting acute bilirubin encephalopathy and to establish a predictive model.

Results: A total of 517 newborns were included in this study, of which 102 (19.7%) had acute bilirubin encephalopathy. T1WI hyperintensity [18.819 (8.838–40.069)], mother's age > 35 years [2.618 (1.096–6.2530)], abnormal white blood cell (WBC) [6.503 (0.226–18.994)], TSB level [1.340 (1.242–1.445)], and albumin level [0.812 (0.726–0.907)] were independently associated with neonatal acute bilirubin encephalopathy (ABE). All independently associated risk factors were used to form an ABE risk estimation nomogram. The bootstrap validation method was used to internally validate the resulting model. The nomogram demonstrated good accuracy in predicting the risk of ABE, with an unadjusted C index of 0.943 (95% CI, 0.919–0.962) and a bootstrap-corrected C index of 0.900.

Conclusion: A nomogram was constructed using five risk factors of ABE. This model can help clinicians determine the best treatment for neonatal hyperbilirubinemia.
Increases in Bdnf DNA Methylation in the Prefrontal Cortex Following Aversive Caregiving Are Reflected in Blood Tissue
Authors: Duffy Hannah B. D. , Roth Tania L.
Published: November 2020

Child maltreatment not only leads to epigenetic changes, but also increases the risk of related behavioral deficits and mental disorders. These issues presumably are most closely associated with epigenetic changes in the brain, but epigenetic changes in peripheral tissues like blood are often examined instead, due to their accessibility. As such, the reliability of using the peripheral epigenome as a proxy for that of the brain is imperative. Previously, our lab has found aberrant methylation at the Brain-derived neurotrophic factor (Bdnf) gene in the prefrontal cortex of rats following aversive caregiving. The current study examined whether aversive caregiving alters Bdnf DNA methylation in the blood compared to the prefrontal cortex. It was revealed that DNA methylation associated with adversity increased in both tissues, but this methylation was not correlated between tissues. These findings indicate that group trends in Bdnf methylation between blood and the brain are comparable, but variation exists among individual subjects.
Bifidobacterium infantis Metabolizes 2′Fucosyllactose-Derived and Free Fucose Through a Common Catabolic Pathway Resulting in 1,2-Propanediol Secretion
Authors: Dedon Liv R. , Özcan Ezgi , Rani Asha , Sela David A.
Published: November 2020

Human milk oligosaccharides (HMOs) enrich beneficial bifidobacteria in the infant gut microbiome which produce molecules that impact development and physiology. 2′fucosyllactose (2′FL) is a highly abundant fucosylated HMO which is utilized by Bifidobacterium longum subsp. infantis, despite limited scientific understanding of the underlying mechanism. Moreover, there is not a current consensus on whether free fucose could be metabolized when not incorporated in a larger oligosaccharide structure. Based on metabolic and genomic analyses, we hypothesize that B. infantis catabolizes both free fucose and fucosyl oligosaccharide residues to produce 1,2-propanediol (1,2-PD). Accordingly, systems-level approaches including transcriptomics and proteomics support this metabolic path. Co-fermentation of fucose and limiting lactose or glucose was found to promote significantly higher biomass and 1,2-PD concentrations than individual substrates, suggesting a synergistic effect. In addition, and during growth on 2′FL, B. infantis achieves significantly higher biomass corresponding to increased 1,2-PD. These findings support a singular fucose catabolic pathway in B. infantis that is active on both free and HMO-derived fucose and intimately linked with central metabolism. The impact of fucose and 2′FL metabolism on B. infantis physiology provides insight into the role of fucosylated HMOs in influencing host- and microbe-microbe interactions within the infant gut microbiome.
Health Effects of Alternate-Day Fasting in Adults: A Systematic Review and Meta-Analysis
Authors: Cui Yuanshan , Cai Tong , Zhou Zhongbao , Mu Yingmei , Lu Youyi , Gao Zhenli , Wu Jitao , Zhang Yong
Published: November 2020

Background: Alternate-day fasting (ADF) method is becoming more and more popular among adults. This meta-analysis aims to evaluate the effects of ADF on adults.

Methods: Randomized controlled trials (RCTs) of ADF were searched using PubMed (1988 to March 2020), EMBASE (1995 to March 2020), and the Cochrane Controlled Trials Register. A systematic review was carried out using the Preferred Reporting Items for Systematic Reviews and Meta-analyses. The datum was calculated by RevMan version 5.3.0. The original references for relating articles were also reviewed.

Results: Seven randomized controlled trials involving 269 participants (152 in the ADF group and 117 in the control group) were studied. In this meta-analysis, compared with the control group, the ADF group showed statistically significant reductions in weight (p < 0.00001) and body mass index (p < 0.00001). Besides, the ADF group showed significant differences in terms of total cholesterol (p = 0.001), low-density lipoprotein (p = 0.01), triglycerides (p = 0.02), fat mass (p = 0.002), lean mass (p = 0.002), systolic blood pressure (p = 0.003), diastolic blood pressure (p = 0.007), and total calorie intake (p = 0.007). At the same time, the analysis demonstrated that the ADF group had a same effect compared with control group in aspects of high-density lipoprotein (p = 0.27), homeostasis model assessment-insulin resistance (p = 0.55), and fasting blood sugar (p = 0.09).

Conclusions: This meta-analysis suggests that ADF is a viable diet strategy for weight loss, and it has a substantial improvement in risk indicators for diseases in obese or normal people.
Brainstem NTCP and Dose Constraints for Carbon Ion RT—Application and Translation From Japanese to European RBE-Weighted Dose
Authors: Dale Jon Espen , Molinelli Silvia , Vischioni Barbara , Vitolo Viviana , Bonora Maria , Magro Giuseppe , Mairani Andrea , Hasegawa Azusa , Ohno Tatsuya , Dahl Olav , Valvo Francesca , Fossati Piero
Published: November 2020

Background and Purpose

The Italian National Center of Oncological Hadrontherapy (CNAO) has applied dose constraints for carbon ion RT (CIRT) as defined by Japan’s National Institute of Radiological Sciences (NIRS). However, these institutions use different models to predict the relative biological effectiveness (RBE). CNAO applies the Local Effect Model I (LEM I), which in most clinical situations predicts higher RBE than NIRS’s Microdosimetric Kinetic Model (MKM). Equal constraints therefore become more restrictive at CNAO. Tolerance doses for the brainstem have not been validated for LEM I-weighted dose (DLEM I). However, brainstem constraints and a Normal Tissue Complication Probability (NTCP) model were recently reported for MKM-weighted dose (DMKM), showing that a constraint relaxation to DMKM|0.7 cm3 <30 Gy (RBE) and DMKM|0.1 cm3 <40 Gy (RBE) was feasible. The aim of this work was to evaluate the brainstem NTCP associated with CNAO’s current clinical practice and to propose new brainstem constraints for LEM I-optimized CIRT at CNAO.

Material and Methods

We reproduced the absorbed dose of 30 representative patient treatment plans from CNAO. Subsequently, we calculated both DLEM I and DMKM, and the relationship between DMKM and DLEM I for various brainstem dose metrics was analyzed. Furthermore, the NTCP model developed for DMKM was applied to estimate the NTCPs of the delivered plans.

Results

The translation of CNAO treatment plans to DMKM confirmed that the former CNAO constraints were conservative compared with DMKM constraints. Estimated NTCPs were 0% for all but one case, in which the NTCP was 2%. The relationship DMKM/DLEM I could be described by a quadratic regression model which revealed that the validated DMKM constraints corresponded to DLEM I|0.7 cm3 <41 Gy (RBE) (95% CI, 38–44 Gy (RBE)) and DLEM I|0.1 cm3 <49 Gy (RBE) (95% CI, 46–52 Gy (RBE)).

Conclusion

Our study demonstrates that RBE-weighted dose translation is of crucial importance in order to exchange experience and thus harmonize CIRT treatments globally. To mitigate uncertainties involved, we propose to use the lower bound of the 95% CI of the translation estimates, i.e., DLEM I|0.7 cm3 <38 Gy (RBE) and DLEM I|0.1 cm3 <46 Gy (RBE) as brainstem dose constraints for 16 fraction CIRT treatments optimized with LEM I.
Cost-Effectiveness Analysis of Prostate Health Index in Decision Making for Initial Prostate Biopsy
Authors: Huang Da , Yang Xiaoqun , Wu Yishuo , Lin Xiaoling , Xu Danfeng , Na Rong , Xu Jianfeng
Published: November 2020

Background

Clinical studies have suggested that prostate health index (phi) outperforms prostate-specific antigen (PSA) tests in prostate cancer detection. The cost-effectiveness of phi with different cutoffs is poorly understood in the context of decision making for prostate biopsy.

Methods

In a multicenter cohort, 3,348 men with elevated total PSA (tPSA) underwent initial prostate biopsy from August 2013 to May 2019. We constructed a decision model to evaluate the incremental cost-effectiveness ratios of different phi cutoffs. Total costs and reimbursement payments were based on the fee schedule of Shanghai Basic Medical Insurance and converted into United States dollars ($). Two willingness-to-pay thresholds were estimated as one or three times the average gross domestic product per capita of China ($7,760 or $23,279, respectively).

Results

The total costs of prostate biopsy and PSA tests were estimated at $315 and $19, respectively. The cost of phi test varied between $72 to $130 in different medical centers. Under different phi cutoffs (from 23 to 35), phi test predicted reductions of 420 (21.7%) to 972 (50.2%) in unnecessary biopsies, with a total gain of 23.77–57.58 quality adjusted life-years compared to PSA tests. All the cutoffs would be cost-effective for patients with tPSA levels of 2–10 ng/ml. Applying 27 as the cutoff was cost-effective for each tPSA range, with missing positive cases ranging from 11 (3.4%) to 33 (11.5%).

Conclusions

Using phi test was cost-effective in the decision-making process for initial prostate biopsy, especially for patients with tPSA values between 2–10 ng/ml. The phi cutoff of 27 was cost-effective regardless of tPSA ranges and should be recommended from a health-economic perspective.
Antioxidant Effect of Propofol in Gliomas and Its Association With Divalent Metal Transporter 1
Authors: Yang Chenyi , Xia Zhengyuan , Li Tang , Chen Yimeng , Zhao Mingshu , Sun Yi , Ma Ji , Wu Yi , Wang Xinyue , Wang Peng , Wang Haiyun
Published: November 2020

Background

Oxidative stress enhances tumor invasion and metastasis in brain cancer. The activation of divalent metal transporter 1 (DMT1), which is regulated by glutamate receptors, can result in the increase of oxidative stress and risk of cancer development. Propofol, an anesthetic with antioxidant capacity, has been shown to decrease oxidative stress in several different types of cancer. However, the underlying mechanism remains unclear. Therefore, the present study aimed to elucidate the mechanism underlying the suppression of oxidative stress in glioma cells by propofol. It was hypothesized that propofol may inhibit oxidative stress in gliomas via suppressing Ca2+-permeable α-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA) receptor (CPAR)-DMT1 signaling.

Methods

Male Wistar rats with C6 gliomas, which were established by intracranial injection of C6 glioma cells, were either treated with propofol or not for 6 h before being sacrificed. The levels of AMPA receptor subunit GluR2 and DMT1 protein expression were assessed using western blotting. The association between CPARs and DMT1 was confirmed in vitro using the AMPA receptor activator (R, S)-AMPA. Glutathione and reactive oxygen species assay kits were used to evaluate tumor oxidative stress. The effect of propofol on glioma proliferation was evaluated by determining tumor weight, cell cycles and a growth curve.

Results

Propofol infusion at either 20 or 40 mg/kg-1/h-1 increased GluR2 levels and downregulated DMT1 expression as well as glutathione content markedly in the periphery compared with that in the glioma core. The in vitro results revealed that (R, S)-AMPA increased DMT1 expression and reactive oxygen species levels, which were partly reversed by propofol treatment.

Conclusion

Propofol regulated DMT1 expression by modulating CPARs, resulting in the inhibition of tumor oxidative stress and glioma growth. The present study provides evidence for optimizing the selection of anesthetic drugs in perioperative management and prognosis of patients with glioma.
LncRNA SNHG7 Mediates the Chemoresistance and Stemness of Breast Cancer by Sponging miR-34a
Authors: Li Zhi-hua , Yu Ni-si , Deng Qing , Zhang Yulu , Hu Yang-yang , Liu Gang , Huang Kedi
Published: November 2020

Chemoresistance is considered to be a major cause of the recurrence and metastasis of breast cancer (BC). LncRNA SNHG7 has been reported to be upregulated in breast cancer and to promote tumor progression and metastasis. Nevertheless, the function and potential regulatory mechanism of SNHG7 in BC drug resistance are still largely unclear. This study indicated that SNHG7 was highly expressed in chemoresistant BC tissues and cells. Upregulated SNHG7 might predict a low pCR rate and poor clinical outcome in BC patients. Knockdown of SNHG7 enhanced drug sensitivity and drug-induced apoptosis in chemoresistant BC cells. In terms of the mechanism, miR-34a was found to be a target of SNHG7 and its expression in breast cancer tissues and chemoresistant cell lines was negatively correlated with SNHG7 expression. Importantly, sh-SNHG7 upregulated miR-34a expression, reduced the percentages of CD44+/CD24−cells, and inhibited sphere-formation and stem cell factor (Oct4, Nanog, SOX2) expression. Functional loss experiments showed that the repressive effect of SNHG7 knockdown on BC cell stemness was partially reversed by transfection with miR-34a inhibitors. In summary, this study indicated that SNHG7 contributed to the chemoresistance of BC and mediated chemoresistance and cancer stemness by sponging miR-34a.
Association of Protein and Vitamin D Intake With Biochemical Markers in Premature Osteopenic Infants: A Case-Control Study
Authors: Mohamed Mohamed , Kamleh May , Muzzy Julia , Groh-Wargo Sharon , Abu-Shaweesh Jalal
Published: November 2020

Osteopenia in preterm infants (OP) remains an important challenge and is largely dependent on nutritional post-natal intake of factors influencing bone mineralization. We conducted a prospective case-control study to evaluate the importance of protein and vitamin D intake in OP among neonates with birth weight <1,250 g. Simultaneous serum parathyroid hormone (PTH), alkaline phosphatase (ALP), calcium (Ca), phosphorus (P), vitamin D and protein levels were measured during the first six post-natal weeks. At 6 weeks of age, OP was evaluated using wrist radiographs. Comparisons were analyzed using multivariate linear regression, receiver operating characteristic curves, χ2 and Wilcoxon Rank Sum. Of the 26 premature infants enrolled, 13 developed radiographic OP. Daily protein intake (coef = −0.40, p = 0.001) and vitamin D concentrations (21 ± 5.7 ng/ml) were significantly lower in the OP group compared to non-OP subjects. ALP concentration exceeding 619 IU/L, sensitivity of 76.9% and specificity of 75%, was predictive of OP at 6 weeks post-natally. PTH levels were higher at 6 weeks in OP subjects (193 ± 102.5 pg/ml, p < 0.001) compared to non-OP subjects. The findings in this study support the role of vitamin D and protein intake in the development of OP in VLBW infants and inform future practice and research on best practices for OP management.
Structural Characterization and Immune Activity Screening of Polysaccharides With Different Molecular Weights From Astragali Radix
Authors: Li Ke , Cao Y-x , Jiao S-m , Du G-h , Du Y-g , Qin X-m
Published: November 2020

Saccharides are the most abundant substance with the strongest immunological activity in Astragali Radix (AR). However, systematic structure study and immunoactivity screening of polysaccharides with different molecular weights (Mw) in AR have yet to be conducted. In this study, Astragalus polysaccharides (APSs) were divided into three fragments of different Mw values, >2,000 kDa (APS-Ⅰ), about 10 kDa (APS-Ⅱ), and about 300 Da (APS-Ⅲ), by using ultrafiltration for the first time. The structural differences of the three products were determined on the basis of monosaccharide composition, FT-IR spectrum, linkage analysis, and nuclear magnetic resonance analysis. Cellular immune activity experiments in vitro and cyclophosphamide immunosuppression animal model experiments in vivo for nonspecific and specific immunoactivity screening were applied to identify the most immunogenic fragment in APSs. Linkage analysis results showed that APS-Ⅰ, APS-Ⅱ, and APS-Ⅲ have different attachment sites of monosaccharide residues. Immune screening experiments indicated that the Mw of the APSs influenced their activity, and APS-Ⅱ had the strongest immunoenhancing activity among the products. This research may serve as a reference for further study on APSs with different structures and immune activities, and as a guidance for the quality control of APSs and the development of new APS products.
Bruceine D inhibits Cell Proliferation Through Downregulating LINC01667/MicroRNA-138-5p/Cyclin E1 Axis in Gastric Cancer
Authors: Li Lin , Dong Zhen , Shi Pengfei , Tan Li , Xu Jie , Huang Pan , Wang Zhongze , Cui Hongjuan , Yang Liqun
Published: November 2020

Objective: Gastric cancer is one of the most common malignant tumors. Bruceine D (BD) is one of the extracts of Brucea javanica. In recent years, it has been reported that BD has anti-tumor activity in some human cancers through different mechanisms. Here, this study try to explore the effect of BD on gastric cancer and its regulatory mechanism.

Methods: Cell proliferation ability was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays, 5-bromo-2-deoxyuridine (BrdU) staining and soft agar colony formation assay, respectively. The tumor xenograft model was used to verify the effect of BD on the tumorigenicity of gastric cancer cells in vivo. Flow cytometry analysis and Western blot assay were performed to detect cell cycle and apoptosis. Gastric cancer cells were analyzed by transcriptome sequencing. The interaction between LINC01667, microRNA-138-5p (miR-138-5p) and Cyclin E1 was verified by dual luciferase experiment and RT-PCR assays.

Results: We found that BD significantly inhibited cell proliferation and induced cell cycle arrest at S phase in gastric cancer cells. Transcriptome analysis found that the expression of a long non-coding RNA, LINC01667, were significantly down-regulated after BD treatment. Mechanically, it was discovered that LINC01667 upregulated the expression of Cyclin E1 by sponging miR-138-5p. Furthermore, BD enhanced the chemosensitivity of gastric cancer cells to doxorubicin, a clinically used anti-cancer agent.

Conclusion: BD inhibit the growth of gastric cancer cells by downregulating the LINC01667/miR-138-5p/Cyclin E1 axis. In addition, BD enhances the chemosensitivity of gastric cancer cells to doxorubicin. This study indicates that BD may be used as a candidate drug for the treatment of patients with gastric cancer.
Entropy Optimization of Third-Grade Nanofluid Slip Flow Embedded in a Porous Sheet With Zero Mass Flux and a Non-Fourier Heat Flux Model
Authors: Loganathan K. , Muhiuddin G. , Alanazi A. M. , Alshammari Fehaid S. , Alqurashi Bader M. , Rajan S.
Published: November 2020

The prime objective of this article is to explore the entropy analysis of third-order nanofluid fluid slip flow caused by a stretchable sheet implanted in a porous plate along with thermal radiation, convective surface boundary, non-Fourier heat flux applications, and nanoparticle concentration on zero mass flux conditions. The governing physical systems are modified into non-linear ordinary systems with the aid of similarity variables, and the outcomes are solved by a homotopy analysis scheme. The impression of certain governing flow parameters on the nanoparticle concentration, temperature, and velocity is illustrated through graphs, while the alteration of many valuable engineering parameters viz. the Nusselt number and Sherwood number are depicted in graphs. Entropy generation with various parameters is obtained and discussed in detail. The estimation of entropy generation using the Bejan number find robust application in power engineering and aeronautical propulsion to forecast the smartness of entire system.