bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost-Utility of Acromegaly Pharmacological Treatments in a French Context
Authors: Brue Thierry , Chanson Philippe , Rodien Patrice , Delemer Brigitte , Drui Delphine , Marié Lucile , Juban Laurène , Salvi Lara , Henocque Robin , Raverot Gérald
Published: October 2021

Objective

Efficacy of pharmacological treatments for acromegaly has been assessed in many clinical or real-world studies but no study was interested in economics evaluation of these treatments in France. Therefore, the objective of this study was to estimate the cost-utility of second-line pharmacological treatments in acromegaly patients.

Methods

A Markov model was developed to follow a cohort of 1,000 patients for a lifetime horizon. First-generation somatostatin analogues (FGSA), pegvisomant, pasireotide and pegvisomant combined with FGSA (off label) were compared. Efficacy was defined as the normalization of insulin-like growth factor-1 (IGF-1) concentration and was obtained from pivotal trials and adjusted by a network meta-analysis. Costs data were obtained from French databases and literature. Utilities from the literature were used to estimate quality-adjusted life year (QALY).

Results

The incremental cost-utility ratios (ICUR) of treatments compared to FGSA were estimated to be 562,463 € per QALY gained for pasireotide, 171,332 € per QALY gained for pegvisomant, and 186,242 € per QALY gained for pegvisomant + FGSA. Pasireotide seems to be the least cost-efficient treatment. Sensitivity analyses showed the robustness of the results.

Conclusion

FGSA, pegvisomant and pegvisomant + FGSA were on the cost-effective frontier, therefore, depending on the willingness-to-pay for an additional QALY, they are the most cost-effective treatments. This medico-economic analysis highlighted the consistency of the efficiency results with the efficacy results assessed in the pivotal trials. However, most recent treatment guidelines recommend an individualized treatment strategy based on the patient and disease profile.
Using Machine Learning to Predict the Fuel Peak Cladding Temperature for a Large Break Loss of Coolant Accident
Authors: Sallehhudin Wazif , Diab Aya
Published: October 2021

In this paper the use of machine learning (ML) is explored as an efficient tool for uncertainty quantification. A machine learning algorithm is developed to predict the peak cladding temperature (PCT) under the conditions of a large break loss of coolant accident given the various underlying uncertainties. The best estimate approach is used to simulate the thermal-hydraulic system of APR1400 large break loss of coolant accident (LBLOCA) scenario using the multidimensional reactor safety analysis code (MARS-KS) lumped parameter system code developed by Korea Atomic Energy Research Institute (KAERI). To generate the database necessary to train the ML model, a set of uncertainty parameters derived from the phenomena identification and ranking table (PIRT) is propagated through the thermal hydraulic model using the Dakota-MARS uncertainty quantification framework. The developed ML model uses the database created by the uncertainty quantification framework along with Keras library and Talos optimization to construct the artificial neural network (ANN). After learning and validation, the ML model can predict the peak cladding temperature (PCT) reasonably well with a mean squared error (MSE) of ∼0.002 and R2 of ∼0.9 with 9 to 11 key uncertain parameters. As a bounding accident scenario analysis of the LBLOCA case paves the way to using machine learning as a decision making tool for design extension conditions as well as severe accidents.
Epibiont Assemblages on Nesting Hawksbill Turtles Show Site-Specificity in the Persian Gulf
Authors: Loghmannia Javad , Nasrolahi Ali , Rezaie-Atagholipour Mohsen , Kiabi Bahram H.
Published: October 2021

Sea turtle epibionts can provide insights into the hosts' habitat use. However, at present, there is a lack of information on sea turtle epibiont communities in many locations worldwide. Here, we describe the epibiont communities of 46 hawksbill turtles (Eretmochelys imbricata) in the Persian Gulf. Specifically, we sampled 28 turtles from the Dayyer-Nakhiloo National Park (DNNP) in the northern Gulf and 18 turtles from Shibderaz beach in the Strait of Hormuz. A total of 54 macro, meio, and micro-epibiont taxa were identified, including 46 taxa from Shibderaz and 29 taxa from DNNP. The barnacles Chelonibia testudinaria and Platylepas hexastylos, as well as harpacticoid copepods and Rotaliid foraminifers, had the highest frequency of occurrence found on almost all turtle individuals. Harpacticoids were the most abundant epizoic taxa (19.55 ± 3.9 ind. per 9 cm2) followed by forams (Quinqueloculina spp.: 6.25 ± 1.5 ind. per 9 cm2 and Rotaliids: 6.02 ± 1.3 ind. per 9 cm2). Our results showed significant differences between the study sites in the composition of micro and macro-epibiont communities found on hawksbill turtles. We speculate that the differences in epibiont communities were largely influenced by local environmental conditions.
Application of Deep Learning in Plant–Microbiota Association Analysis
Authors: Deng Zhiyu , Zhang Jinming , Li Junya , Zhang Xiujun
Published: October 2021

Unraveling the association between microbiome and plant phenotype can illustrate the effect of microbiome on host and then guide the agriculture management. Adequate identification of species and appropriate choice of models are two challenges in microbiome data analysis. Computational models of microbiome data could help in association analysis between the microbiome and plant host. The deep learning methods have been widely used to learn the microbiome data due to their powerful strength of handling the complex, sparse, noisy, and high-dimensional data. Here, we review the analytic strategies in the microbiome data analysis and describe the applications of deep learning models for plant–microbiome correlation studies. We also introduce the application cases of different models in plant–microbiome correlation analysis and discuss how to adapt the models on the critical steps in data processing. From the aspect of data processing manner, model structure, and operating principle, most deep learning models are suitable for the plant microbiome data analysis. The ability of feature representation and pattern recognition is the advantage of deep learning methods in modeling and interpretation for association analysis. Based on published computational experiments, the convolutional neural network and graph neural networks could be recommended for plant microbiome analysis.
Prediction and Identification of Power Performance Using Polygenic Models of Three Single-Nucleotide Polymorphisms in Chinese Elite Athletes
Authors: Yang Ruoyu , Jin Feng , Wang Liyan , Shen Xunzhang , Guo Qi , Song Haihan , Hu Jingyun , Zhao Qiang , Wan Jian , Cai Ming
Published: October 2021

Objective: The manuscript aims to explore the relationship between power performance and SNPs of Chinese elite athletes and to create polygenic models.

Methods: One hundred three Chinese elite athletes were divided into the power group (n = 60) and endurance group (n = 43) by their sports event. Best standing long jump (SLJ) and standing vertical jump (SVJ) were collected. Twenty SNPs were genotyped by SNaPshot. Genotype distribution and allele frequency were compared between groups. Additional genotype data of 125 Chinese elite athletes were used to verify the screened SNPs. Predictive and identifying models were established by multivariate logistic regression analysis.

Results: ACTN3 (rs1815739), ADRB3 (rs4994), CNTFR (rs2070802), and PPARGC1A (rs8192678) were significantly different in genotype distribution or allele frequency between groups (p < 0.05). The predictive model consisted of ACTN3 (rs1815739), ADRB3 (rs4994), and PPARGC1A (rs8192678), the area under curve (AUC) of which was 0.736. The identifying model consisted of body mass index (BMI), standing vertical jump (SVJ), ACTN3, ADRB3, and PPARGC1A, the area under curve (AUC) of which was 0.854. Based on the two models, nomograms were created to visualize the results.

Conclusion: Two models can be used for talent identification in Chinese athletes, among which the predictive model can be used in adolescent athletes to predict development potential of power performance and the identifying one can be used in elite athletes to evaluate power athletic status. These can be applied quickly and visually by using nomograms. When the score is more than the 130 or 148 cutoff, it suggests that the athlete has a good development potential or a high level for power performance.
The Effect of Atypical Nucleic Acids Structures in DNA Double Strand Break Repair: A Tale of R-loops and G-Quadruplexes
Authors: Camarillo Rosa , Jimeno Sonia , Huertas Pablo
Published: October 2021

The fine tuning of the DNA double strand break repair pathway choice relies on different regulatory layers that respond to environmental and local cues. Among them, the presence of non-canonical nucleic acids structures seems to create challenges for the repair of nearby DNA double strand breaks. In this review, we focus on the recently published effects of G-quadruplexes and R-loops on DNA end resection and homologous recombination. Finally, we hypothesized a connection between those two atypical DNA structures in inhibiting the DNA end resection step of HR.
Genome-Wide Association Studies for Growth Curves in Meat Rabbits Through the Single-Step Nonlinear Mixed Model
Authors: Liao Yonglan , Wang Zhicheng , Glória Leonardo S. , Zhang Kai , Zhang Cuixia , Yang Rui , Luo Xinmao , Jia Xianbo , Lai Song-Jia , Chen Shi-Yi
Published: October 2021

Growth is a complex trait with moderate to high heritability in livestock and must be described by the longitudinal data measured over multiple time points. Therefore, the used phenotype in genome-wide association studies (GWAS) of growth traits could be either the measures at the preselected time point or the fitted parameters of whole growth trajectory. A promising alternative approach was recently proposed that combined the fitting of growth curves and estimation of single-nucleotide polymorphism (SNP) effects into single-step nonlinear mixed model (NMM). In this study, we collected the body weights at 35, 42, 49, 56, 63, 70, and 84 days of age for 401 animals in a crossbred population of meat rabbits and compared five fitting models of growth curves (Logistic, Gompertz, Brody, Von Bertalanffy, and Richards). The logistic model was preferably selected and subjected to GWAS using the approach of single-step NMM, which was based on 87,704 genome-wide SNPs. A total of 45 significant SNPs distributed on five chromosomes were found to simultaneously affect the two growth parameters of mature weight (A) and maturity rate (K). However, no SNP was found to be independently associated with either A or K. Seven positional genes, including KCNIP4, GBA3, PPARGC1A, LDB2, SHISA3, GNA13, and FGF10, were suggested to be candidates affecting growth performances in meat rabbits. To the best of our knowledge, this is the first report of GWAS based on single-step NMM for longitudinal traits in rabbits, which also revealed the genetic architecture of growth traits that are helpful in implementing genome selection.
Serum Biomarker Profile Including CCL1, CXCL10, VEGF, and Adenosine Deaminase Activity Distinguishes Active From Remotely Acquired Latent Tuberculosis
Authors: Delemarre Eveline M. , van Hoorn Laura , Bossink Aik W. J. , Drylewicz Julia , Joosten Simone A. , Ottenhoff Tom H. M. , Akkerman Onno W. , Goletti Delia , Petruccioli Elisa , Navarra Assunta , van den Broek Brigitte T. A. , Paardekooper Sanne P. A. , van Haeften Ineke , Koenderman Leo , Lammers Jan-Willem J. , Thijsen Steven F. T. , Hofland Regina W. , Nierkens Stefan
Published: October 2021

Introduction

There is an urgent medical need to differentiate active tuberculosis (ATB) from latent tuberculosis infection (LTBI) and prevent undertreatment and overtreatment. The aim of this study was to identify biomarker profiles that may support the differentiation between ATB and LTBI and to validate these signatures.

Materials and Methods

The discovery cohort included adult individuals classified in four groups: ATB (n = 20), LTBI without prophylaxis (untreated LTBI; n = 20), LTBI after completion of prophylaxis (treated LTBI; n = 20), and healthy controls (HC; n = 20). Their sera were analyzed for 40 cytokines/chemokines and activity of adenosine deaminase (ADA) isozymes. A prediction model was designed to differentiate ATB from untreated LTBI using sparse partial least squares (sPLS) and logistic regression analyses. Serum samples of two independent cohorts (national and international) were used for validation.

Results

sPLS regression analyses identified C-C motif chemokine ligand 1 (CCL1), C-reactive protein (CRP), C-X-C motif chemokine ligand 10 (CXCL10), and vascular endothelial growth factor (VEGF) as the most discriminating biomarkers. These markers and ADA(2) activity were significantly increased in ATB compared to untreated LTBI (p ≤ 0.007). Combining CCL1, CXCL10, VEGF, and ADA2 activity yielded a sensitivity and specificity of 95% and 90%, respectively, in differentiating ATB from untreated LTBI. These findings were confirmed in the validation cohort including remotely acquired untreated LTBI participants.

Conclusion

The biomarker signature of CCL1, CXCL10, VEGF, and ADA2 activity provides a promising tool for differentiating patients with ATB from non-treated LTBI individuals.
Functionally Mature CD1c+ Dendritic Cells Preferentially Accumulate in the Inflammatory Arthritis Synovium
Authors: Canavan Mary , Marzaioli Viviana , Bhargava Vipul , Nagpal Sunil , Gallagher Phil , Hurson Conor , Mullan Ronan , Veale Douglas J. , Fearon Ursula
Published: October 2021

Objective

To examine the role of synovial CD1c+DCs in patients with Inflammatory Arthritis (IA) with a specific focus on the transcriptional and maturation signatures that govern their function.

Methods

RNA sequencing was performed on healthy control (HC) peripheral blood (PB), IA PB, and IA synovial fluid (SF) CD1c+DCs. Multiparametric flow-cytometry and SPICE analysis were used to examine site [SF and Synovial Tissue (ST) CD1c+DCs] and disease specific characteristics of CD1c+DCs, while functional assays such as antigen processing, activation, and MMP production were also performed.

Results

Increased frequency of CD1c+DCs (p<0.01) with a concomitant increase in CD80, CCR7 (p<0.01), and CXCR3 (p<0.05) expression was identified in IA PB compared to HC PB. Enrichment of CD1c+DCs was identified in IA synovial tissue (ST) (p<0.01) and IA SF (p<0.0001) compared to IA PB, while RNAseq revealed distinct transcriptional variation between PB and SF CD1c+DCs. Flow cytometry revealed increased expression of CD83, CD80, PD-L1, and BTLA (all p<0.05) in IA SF CD1c+DCs compared to PB, while SPICE identified synovial cells with unique co-expression patterns, expressing multiple DC maturation markers simultaneously. Functionally, synovial CD1c+DCs are hyper-responsive to TLR7/8 ligation (p<0.05), have decreased antigen processing capacity (p=0.07), and display dysregulated production of MMPs. Finally, examination of both synovial CD1c+DCs and synovial CD141+DCs revealed distinct maturation and transcriptomic profiles.

Conclusion

Synovial CD1c+DCs accumulate in the inflamed IA synovium in a variety of distinct poly-maturational states, distinguishing them transcriptionally and functionally from CD1c+DCs in the periphery and synovial CD141+DCs.
Usefulness of Interleukin-18 as a Diagnostic Biomarker to Differentiate Adult-Onset Still’s Disease With/Without Macrophage Activation Syndrome From Other Secondary Hemophagocytic Lymphohistiocytosis in Adults
Authors: Shiga Toshihiko , Nozaki Yuji , Tomita Daisuke , Kishimoto Kazuya , Hirooka Yasuaki , Kinoshita Koji , Funauchi Masanori , Matsumura Itaru
Published: October 2021

Background

Interleukin (IL)-18 is markedly elevated in systemic inflammatory diseases that cause the ‘cytokine storm’ such as adult-onset Still’s disease (AOSD) and hemophagocytic lymphohistiocytosis (HLH). The differences in IL-18 between AOSD and HLH, especially in adults, is uncertain. Macrophage activation syndrome (MAS), a form of secondary HLH, is often difficult to differentiate cases of AOSD that include MAS from other secondary HLH. In this case-control study, we investigated whether serum IL-18 levels could be a useful biomarker for the differential diagnosis of AOSD with or without MAS (AOSD group) and other secondary HLH in adults (adult HLH group).

Patients and Methods

We enrolled 46 patients diagnosed with AOSD including 9 patients with MAS and 31 patients in the adult HLH group, which excluded AOSD-associated MAS. The clinical features and laboratory data were compared between the AOSD and adult HLH groups. In addition, we subdivided the AOSD group (with or without MAS) and the adult HLH group (whether lymphoma-associated or not) and compared the four groups. A logistic regression analysis was used to identify factors with high efficacy in differentiating the two groups, followed by a receiver operating characteristic (ROC) curve analysis to evaluate the differential diagnostic ability of IL-18. We analyzed the correlation between IL-18 and various laboratory parameters in the AOSD group.

Results

Serum IL-18 levels of patients in the AOSD groups were significantly higher than those of the adult HLH groups, and were closely correlated with ferritin, soluble interleukin-2 receptor (sIL-2R), and other laboratory data. Univariate and multivariate logistic regression analyses revealed that IL-18, sIL-2R, and ‘arthralgia or arthritis’ are independent factors useful in the differential diagnosis of AOSD from adult HLH. In the differential diagnosis of both groups, the area under the curve obtained from the ROC curve of IL-18 with a cutoff value of 18,550 pg/mL was 0.91 (95% confidence interval 0.83–1.00; sensitivity 90.3%, specificity 93.5%), and the differential diagnosis ability of IL-18 was superior to that of other laboratory data.

Conclusions

IL-18 could be a useful biomarker for the differential diagnosis of AOSD and adult HLH.
Case Report: Post-CAR-T Infusion HBV Reactivation in Two Lymphoma Patients Despite Entecavir Preventive Therapy
Authors: Ma Yaxian , Yang Li , Bao Yuhan , Yang Yang , Chen Liting , Zheng Miao
Published: October 2021

Hepatitis B virus (HBV) reactivation is a common complication in chronic or resolved HBV infection patients undergoing immunosuppressive chemotherapy. Furthermore, few articles have been published regarding the risk of HBV reactivation in lymphoma patients receiving chimeric antigen receptor (CAR) T-cell therapy and anti-HBV prophylaxis. Few guidelines or clear optimal strategies are available for managing these patients. Here, we present two cases of patients who underwent CAR-T-cell cocktail therapy with anti-CD19 and anti-CD22 CAR (CAR19/22) T cell for lymphoma. Patients had previous history of HBV infection, and blood tests on initial admission indicated positive results for hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), and antibody to hepatitis B e antigen (anti-HBe), while serum HBV DNA level was undetectable. Therefore, two patients received entecavir as antiviral prophylactic therapy during their entire treatment. They were diagnosed with HBV reactivation based on positive serum HBV DNA test results, 2 weeks after CAR-T-cell infusion. Liver function assay indicated elevated levels of alanine transaminase (ALT) and aspartate transaminase (AST), combined with increased levels of total bilirubin (TBIL) and direct bilirubin (DBIL). Subsequently, they received anti-HBV treatment with entecavir and tenofovir. As a result, their serum HBV DNA copies and AST/ALT levels returned to normal after 1 week. These cases show that there is a risk of HBV reactivation in lymphoma patients with CAR-T-cell therapy despite entecavir preventive therapy, and combination treatment of entecavir and tenofovir may be an effective treatment option for such patients with HBV reactivation.
COVID-19 Is a Multi-Organ Aggressor: Epigenetic and Clinical Marks
Authors: Kgatle Mankgopo Magdeline , Lawal Ismaheel Opeyemi , Mashabela Gabriel , Boshomane Tebatso Moshoeu Gillian , Koatale Palesa Caroline , Mahasha Phetole Walter , Ndlovu Honest , Vorster Mariza , Rodrigues Hosana Gomes , Zeevaart Jan Rijn , Gordon Siamon , Moura-Alves Pedro , Sathekge Mike Machaba
Published: October 2021

The progression of coronavirus disease 2019 (COVID-19), resulting from a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, may be influenced by both genetic and environmental factors. Several viruses hijack the host genome machinery for their own advantage and survival, and similar phenomena might occur upon SARS-CoV-2 infection. Severe cases of COVID-19 may be driven by metabolic and epigenetic driven mechanisms, including DNA methylation and histone/chromatin alterations. These epigenetic phenomena may respond to enhanced viral replication and mediate persistent long-term infection and clinical phenotypes associated with severe COVID-19 cases and fatalities. Understanding the epigenetic events involved, and their clinical significance, may provide novel insights valuable for the therapeutic control and management of the COVID-19 pandemic. This review highlights different epigenetic marks potentially associated with COVID-19 development, clinical manifestation, and progression.
Insights on Lymphedema Self-Care Knowledge and Practice in Filariasis and Podoconiosis-Endemic Communities in Bangladesh and Ethiopia
Authors: Douglass Janet , Martindale Sarah , Mableson Hayley , Jhara Sanya Tahmina , Karim Mohammad Jahirul , Rahman Muhammad Mujibur , Kawsar Abdullah Al , Khair Abul , Mahmood A. S. M. Sultan , Rahman A. K. M. Fazlur , Chowdhury Salim Mahmud , Hailekiros Fikre , Tamiru Mossie , Seife Fikre , Bishaw Tesfahun , Nigussie Mekdes , Meribo Kadu , Agidew Getnet , Betts Hannah , Taylor Mark J. , Kelly-Hope Louise A.
Published: October 2021

Lymphedema is a life-long sequelae to several neglected tropical diseases (NTD). In Bangladesh the main cause is lymphatic filariasis (LF) and Ethiopia is endemic for both LF and podoconiosis. The World Health Organization (WHO) recommends daily self-care including meticulous washing and drying of affected skin and attention to entry lesions, limb exercises and elevation. Adherence to this regime reduces secondary infections which cause disabling episodes of acute dermato-lymphangitis (ADL). Self-care practices must be integrated into family life, supported by community and monitored by health staff; however, little is known about the influence of personal and socio-demographic factors on adherence. People affected by lymphedema (n=272), adult caregivers (n=272), and health workers (n=68) in Bangladesh and Ethiopia were trained in lymphedema management according to WHO recommendations. Surveys on the causes and management of lymphedema were collected at baseline and 24-weeks, and patients completed a daily journal of self-care activities and symptoms. At baseline knowledge on causes and management of lymphedema was greater among health workers (>70%) than patients and caregivers (<20%) in both countries, and there were significant between-country differences in patient reported use of limb washing (Bangladesh = 7.7%. Ethiopia = 51.1%, p = 0.001). At 24-weeks knowledge on lymphedema causes and management had increased significantly among patients and caregivers, there was <70% adherence to limb washing and exercises, but lesser use of limb elevation in both countries. A range of patient characteristics were associated with significant variation in self-care, except for limb washing. Performance of fewer leg exercises was significantly associated with increased age or severe lymphedema in Bangladesh, and with being female or in paid work in Ethiopia. Patient journals recorded ADL symptoms and working days lost due to lymphedema more frequently than were reported by recall during the 24-week survey. Core elements of lymphedema self-care education, training and monitoring are the same for multiple etiologies. This creates opportunities for cross-cutting implementation of integrated service delivery across several skin NTDs. Sustainability will depend on community level ownership and research on factors affecting adherence to lymphedema self-care are urgently needed.
Physiological Responses of Pocillopora acuta and Porites lutea Under Plastic and Fishing Net Stress
Authors: Ying Long , Sinutok Sutinee , Pramneechote Pathompong , Aiyarak Pattara , Ralph Peter J. , Chotikarn Ponlachart
Published: October 2021

Marine debris has become a global problem affecting coral health around the globe. However, the photophysiological responses of corals to marine debris stress remain unclear. Therefore, this study firstly investigated transparent and opaque plastic bag shading and fishing nets directly contacting the coral. Photosynthetic performance, pigment content, symbiont density, and calcification rate of a branching coral Pocillopora acuta and a massive coral Porites lutea were investigated after 4 weeks of exposure to marine debris. The results show that the maximum quantum yield of PSII significantly decreased in P. lutea with all treatments, while P. acuta showed no effect on the maximum quantum yield of PSII from any treatments. Transparent plastic bag shading does not affect P. acuta, but significantly affected the maximum photochemical efficiency of P. lutea. Photoacclimation of cellular pigment content was also observed under opaque plastic bag shading for both species at week 2. Fishing nets had the strongest effect and resulted in P. acuta bleaching and P. lutea partial mortality as well as a decline in zooxanthellae density. Calcification rate of P. acuta significantly decreased with treatments using opaque plastic bag and fishing net, but for P. lutea only the treatment with fishing net gave any observable effects. This study suggests that the sensitivities of corals to marine debris differ strongly by species and morphology of the coral.
Bone Morphogenetic Protein 2 Is Involved in Oocyte Maturation Through an Autocrine/Paracrine Pathway in Scylla paramamosain
Authors: Yang Yanan , Zhang Peng , Cui Zhaoxia , Bao Chenchang
Published: October 2021

Ovary-secreted autocrine/paracrine factors play important roles in regulating oocyte maturation via the autocrine/paracrine pathway. This study aimed to evaluate the functions of bone morphogenetic protein 2 (BMP2) in oocyte maturation and communication between follicle cells and oocytes. In our study, we first identified BMP2 from the mud crab Scylla paramamosain. Quantitative real-time PCR showed that BMP2 was detected in diverse tissues, notably in the ovary, stomach and gill. The expression levels of BMP2 transcripts increased during vitellogenesis. Spatial expression of BMP2 and receptors in the ovary revealed that BMP2 was exclusively detected in oocytes, whereas the receptors were expressed in both follicle cells and oocytes. RNAi tests revealed that the expression of cyclin B first decreased at 2 h and then increased at 4 h after BMP2 knockdown. These combined findings suggest that BMP2 may promote oocyte maturation through an autocrine/paracrine pathway in S. paramamosain.
Construction of Hierarchical Porous Architecture on Ni Foam for Efficient Oxygen Evolution Reaction Electrode
Authors: Ao Guang-Hong , Zhao Pei-Zhi , Peng Zhi-Gang , Wang Shuo , Guo Ying-Shuang , Chen Chun-Tian , Wang Zhi-Hong
Published: October 2021

Nickel foam (NF) with a three-dimensional porous structure plays an important role in a wide variety of applications such as energy storage and conversion, catalysis, and sensor due to its high porosity, low density, and excellent conductivity. However, the main drawback of NF is that its ligaments are very smooth, and thus the surface area is relatively low. In this work, we propose a novel strategy, oxidization and reduction process, in situ to construct micron/nano pores on the ligaments of commercial NF to fabricate a typical hierarchical porous architecture. This process is simple and green, avoiding the use of sacrificial materials. Furthermore, MnO2 is coated on the micron/nano-porous Ni foam (MPNF) to construct an oxygen evolution reaction (OER) electrode through pulse electrodeposition. The designed MPNF-MnO2 electrode presents enhanced OER electrocatalysis activity with a low overpotential of 363.5 mV at the current density of 10 mA cm−2 in an alkaline solution, which is 66.4 mV lower than that of the NF-MnO2 electrode in the same operating conditions. Furthermore, the porous and wrinkled structures of the MPNF also improve the mechanical integrity of the electrode, resulting in super-long stability.
Mycobacterium leprae Induces Neutrophilic Degranulation and Low-Density Neutrophil Generation During Erythema Nodosum Leprosum
Authors: Tavares Isabella Forasteiro , dos Santos Jessica Brandão , Pacheco Fabiana dos Santos , Gandini Mariana , Mariante Rafael M. , Rodrigues Thais Fernanda , Sales Anna Maria , Moraes Milton Ozório , Sarno Euzenir Nunes , Schmitz Veronica
Published: October 2021

Erythema Nodosum Leprosum (ENL) is a recurrent acute inflammatory complication of leprosy affecting up to 50% of all Borderline Lepromatous and Lepromatous Leprosy (BL/LL) patients. Although ENL is described as an immune reaction mediated by neutrophils, studies demonstrating the direct role of neutrophils in ENL are still rare. One subpopulation of low-density neutrophils (LDNs), present within the fraction of peripheral blood mononuclear cells (PBMC), has been associated with the pathogenesis and severity of diseases like sepsis, lupus, and tuberculosis. We herein analyzed LDNs and high-density neutrophils (HDNs) in terms of frequency, phenotype, and morphology. Serum levels of MMP-9 (a neutrophilic degranulation marker) were evaluated by ELISA; and LDNs were generated in vitro by stimulating healthy-donor, whole-blood cultures. PBMC layers of ENL patients presented segmented/hypersegmented cells that were morphologically compatible with neutrophils. Immunofluorescence analyses identified LDNs in ENL. Flow cytometry confirmed the elevated frequency of circulating LDNs (CD14−CD15+) in ENL patients compared to healthy donors and nonreactional Borderline Tuberculoid (BT) patients. Moreover, flow cytometry analyses revealed that ENL LDNs had a neutrophilic-activated phenotype. ENL patients under thalidomide treatment presented similar frequency of LDNs as observed before treatment but its activation status was lower. In addition, Mycobacterium leprae induced in vitro generation of LDNs in whole blood in a dose-dependent fashion; and TGF-β, an inhibitor of neutrophilic degranulation, prevented LDNs generation. MMP-9 serum levels of BL/LL patients with or without ENL correlated with LDNs frequency at the same time that ultrastructural observations of ENL LDNs showed suggestive signs of degranulation. Together, our data provide new insights into the knowledge and understanding of the pathogenesis of ENL while enriching the role of neutrophils in leprosy.
Inflammatory Foot Involvement in Spondyloarthritis: From Tarsitis to Ankylosing Tarsitis
Authors: Romero-López José Pablo , Elewaut Dirk , Pacheco-Tena César , Burgos-Vargas Rubén
Published: October 2021

Spondyloarthritis (SpA) is a group that includes a wide spectrum of clinically similar diseases manifested by oligoarticular arthritis and axial or peripheral ankylosis. Although axial SpA is predominant in Caucasians and adult-onset patients, juvenile-onset and Latin American patients are characterized by severe peripheral arthritis and particularly foot involvement. The peripheral involvement of SpA can vary from tarsal arthritis to the most severe form named ankylosing tarsitis (AT). Although the cause and etiopathogenesis of axSpA are often studied, the specific characteristics of pSpA are unknown. Several animal models of SpA develop initial tarsitis and foot ankylosis as the main signs, emphasizing the role of foot inflammation in the overall SpA spectrum. In this review, we attempt to highlight the clinical characteristics of foot involvement in SpA and update the knowledge regarding its pathogenesis, focusing on animal models and the role of mechanical forces in inflammation.
PNPLA3, TM6SF2, and MBOAT7 Influence on Nutraceutical Therapy Response for Non-alcoholic Fatty Liver Disease: A Randomized Controlled Trial
Authors: Dallio Marcello , Masarone Mario , Romeo Mario , Tuccillo Concetta , Morisco Filomena , Persico Marcello , Loguercio Carmelina , Federico Alessandro
Published: October 2021

Introduction: PNPLA3, TM6SF2, and MBOAT7 genes play a crucial role in non-alcoholic fatty liver disease (NAFLD) development and worsening. However, few data are available on their treatment response influence. The aim of this trial is to explore the effect derived from silybin-phospholipids complex (303 mg of silybin-phospholipids complex, 10 μg of vitamin D, and 15 mg of vitamin E twice a day for 6 months) oral administration in NAFLD patients carrying PNPLA3-rs738409, TM6SF2-rs58542926, or MBOAT7-rs641738 genetic variants.

Materials and Methods: In all, 92 biopsy-proven NAFLD patients were grouped in 30 NAFLD wild type controls, 30 wild type treated patients, and 32 mutated treated ones. We assessed glycemia (FPG), insulinemia, HOMA-IR, aspartate and alanine aminotransferases (AST, ALT), C-reactive protein (CRP), thiobarbituric acid reactive substance (TBARS), stiffness, controlled attenuation parameter (CAP), dietary daily intake, and physical activity at baseline and end of treatment.

Results: The wild-type treated group showed a significant improvement of FPG, insulinemia, HOMA-IR, ALT, CRP, and TBARS (p < 0.05), whereas no improvements were recorded in the other two study groups. NAFLD wild type treated patients showed higher possibilities of useful therapeutic outcome (p < 0.01), obtained from the prescribed therapeutic regimen, independently from age, sex, comorbidities, medications, CAP, and stiffness in comparison to the mutated group.

Discussion: The assessed mutations are independently associated with no response to a silybin-based therapeutic regimen and could be considered as useful predictive markers in this context.

Clinical Trial Registry Number:www.ClinicalTrials.gov, identifier: NCT04640324.
First Attempt at Using Electrical Impedance Tomography to Predict High Flow Nasal Cannula Therapy Outcomes at an Early Phase
Authors: Li Zhe , Zhang Zhiyun , Xia Qian , Xu Danling , Qin Shaojie , Dai Meng , Fu Feng , Gao Yuan , Zhao Zhanqi
Published: October 2021

Objective: Spatial and temporal ventilation distributions in patients with acute respiratory failure during high flow nasal cannula (HFNC) therapy were previously studied with electrical impedance tomography (EIT). The aim of the study was to explore the possibility of predicting HFNC failure based on various EIT-derived parameters.

Methods: High flow nasal cannula failure was defined reintubation within 48 h after HFNC. EIT was performed with the patients spontaneously breathing in the supine position at the start of HFNC. EIT-based indices (comprising the global inhomogeneity index, center of ventilation, ventilation delay, rapid shallow breathing index, minute volume, and inspiration to expiration time) were explored and evaluated at three time points (prior to HFNC, T1; 30 min after HFNC started, T2; and 1 h after, T3).

Results: A total of 46 subjects were included in the final analysis. Eleven subjects had failed HFNC. The time to failure was 27.8 ± 12.4 h. The ROX index (defined as SpO2/FiO2/respiratory rate) for HFNC success patients was 8.3 ± 2.7 and for HFNC failure patients, 6.2 ± 1.8 (p = 0.23). None of the investigated EIT-based parameters showed significant differences between subjects with HFNC failure and success. Further subgroup analysis indicated that a significant difference in ventilation inhomogeneity was found between ARDS and non-ARDS [0.54 (0.37) vs. 0.46 (0.28) as evaluated with GI, p < 0.01]. Ventilation homogeneity significantly improved in ARDS after 60-min HFNC treatment [0.59 (0.20) vs 0.57 (0.19), T1 vs. T3, p < 0.05].

Conclusion: Spatial and temporal ventilation distributions were slightly but insignificantly different between the HFNC success and failure groups. HFNC failure could not be predicted by changes in EIT temporal and spatial indexes of ventilation distribution within the first hour. Further studies are required to predict the outcomes of HFNC.
Update on Cardiovascular Risk and Obesity in Psoriatic Arthritis
Authors: Ramírez Julio , Azuaga-Piñango Ana Belén , Celis Raquel , Cañete Juan D.
Published: October 2021

PsA is characterized by a high prevalence of cardiovascular (CV) comorbidities. Recognizing these comorbidities is critical due to their influence on the quality of life and the choice of therapy. Imaging techniques also play an important role in the evaluation of the CV risk in psoriatic disease, improving the prediction of CV events when combined with clinical scores as a predictive tool. Meta-analyses point to a significant reduction in the incidence of CV events associated with the suppression of inflammatory activity when using systemic therapies. Consequently, the mortality rate in PsA patients has fallen in the last 40 years and is now similar to that of the general population, including cardiovascular causes. Obesity is an especially relevant CV comorbidity in patients with psoriatic disease, most of whom are overweight/obese. Body mass index (BMI) is a risk factor for PsA and a causal relationship with psoriasis has been demonstrated by Mendelian randomized studies. The study of fat distribution shows that patients with psoriasis are characterized by visceral fat accumulation, which correlates with CV risk measurements. These findings suggest that approaches to the prevention and treatment of psoriatic disease might come from targeting adiposity levels, in addition to the immune pathways. Weight loss treatment with low energy diets in patients with PsA has been associated with significant improvements in disease activity. Novel strategies using a multimorbidity approach, focused more on patients outcomes, are necessary to better address comorbidities, improve clinical outcomes and the quality of life of patients with psoriatic disease.
Removal of COVID-19 Spike Protein, Whole Virus, Exosomes, and Exosomal MicroRNAs by the Hemopurifier® Lectin-Affinity Cartridge in Critically Ill Patients With COVID-19 Infection
Authors: Amundson Dennis E. , Shah Usman S. , de Necochea-Campion Rosalia , Jacobs Michael , LaRosa Steven P. , Fisher Charles J.
Published: October 2021

Coronavirus−19 (COVID-19) has rapidly spread throughout the world resulting in a significant amount of morbidity and mortality. Despite advances in therapy, social distancing, masks, and vaccination many places in the world continue to see an increase in the number of cases and deaths. Viremia is commonly present in severely ill patients with COVID-19 infections and is associated with organ dysfunction and poor outcomes. Exosomes released by activated cells have been implicated in the pathogenesis of COVID-19 infection. We report the experience of two cases of critically ill COVID-19 patients treated with the Hemopurifier; a lectin affinity cartridge designed to remove mannosylated viruses and exosomes. Both patients tolerated the Hemopurifier sessions without adverse effects. In the first patient removal of exosomes and exosomal microRNAs was associated with improved coagulopathy, oxygenation, and clinical recovery, while in a second patient removal of COVID-19 by the Hemopurifier cartridge was observed. The Hemopurifier is currently under further investigation in up to 40-patients in a safety and feasibility study in ICU patients with COVID-19 infection.
Engineered Remolding and Application of Bacterial Membrane Vesicles
Authors: Qiao Li , Rao Yifan , Zhu Keting , Rao Xiancai , Zhou Renjie
Published: October 2021

Bacterial membrane vesicles (MVs) are produced by both Gram-positive and Gram-negative bacteria during growth in vitro and in vivo. MVs are nanoscale vesicular structures with diameters ranging from 20 to 400 nm. MVs incorporate bacterial lipids, proteins, and often nucleic acids, and can effectively stimulate host immune response against bacterial infections. As vaccine candidates and drug delivery systems, MVs possess high biosafety owing to the lack of self-replication ability. However, wild-type bacterial strains have poor MV yield, and MVs from the wild-type strains may be harmful due to the carriage of toxic components, such as lipopolysaccharides, hemolysins, enzymes, etc. In this review, we summarize the genetic modification of vesicle-producing bacteria to reduce MV toxicity, enhance vesicle immunogenicity, and increase vesicle production. The engineered MVs exhibit broad applications in vaccine designs, vaccine delivery vesicles, and drug delivery systems.
A Novel Antimicrobial Peptide Sparamosin26–54 From the Mud Crab Scylla paramamosain Showing Potent Antifungal Activity Against Cryptococcus neoformans
Authors: Chen Yan-Chao , Yang Ying , Zhang Chang , Chen Hui-Yun , Chen Fangyi , Wang Ke-Jian
Published: October 2021

Due to the increasing prevalence of drug-resistant fungi and the limitations of current treatment strategies to fungal infections, exploration and development of new antifungal drugs or substituents are necessary. In the study, a novel antimicrobial peptide, named Sparamosin, was identified in the mud crab Scylla paramamosain, which contains a signal peptide of 22 amino acids and a mature peptide of 54 amino acids. The antimicrobial activity of its synthetic mature peptide and two truncated peptides (Sparamosin1–25 and Sparamosin26–54) were determined. The results showed that Sparamosin26–54 had the strongest activity against a variety of Gram-negative bacteria, Gram-positive bacteria and fungi, in particular had rapid fungicidal kinetics (killed 99% Cryptococcus neoformans within 10 min) and had potent anti-biofilm activity against C. neoformans, but had no cytotoxic effect on mammalian cells. The RNA-seq results showed that after Sparamosin26–54 treatment, the expression of genes involved in cell wall component biosynthesis, cell wall integrity signaling pathway, anti-oxidative stress, apoptosis and DNA repair were significantly up-regulated, indicating that Sparamosin26–54 might disrupt the cell wall of C. neoformans, causing oxidative stress, DNA damage and cell apoptosis. The underlying mechanism was further confirmed. Sparamosin26–54 could bind to several phospholipids in the cell membrane and effectively killed C. neoformans through disrupting the integrity of the cell wall and cell membrane observed by electron microscope and staining assay. In addition, it was found that the accumulation of reactive oxygen species (ROS) increased, the mitochondrial membrane potential (MMP) was disrupted, and DNA fragmentation was induced after Sparamosin26–54 treatment, which are all hallmarks of apoptosis. Taken together, Sparamosin26–54 has a good application prospect as an effective antimicrobial agent, especially for C. neoformans infections.
Biosynthetic Pathway and the Potential Role of Melatonin at Different Abiotic Stressors and Developmental Stages in Tolypocladium guangdongense
Authors: Wang Gangzheng , Chen Xianglian , Zhang Chenghua , Li Min , Sun Chengyuan , Zhan Ning , Huang Xueshuang , Li Taihui , Deng Wangqiu
Published: October 2021

Melatonin, a bioactive compound and an important signaling molecule produced in plants and animals, is involved in many biological processes. However, its function and synthetic pathways in fungi are poorly understood. Here, the samples from Tolypocladium guangdongense, a highly valued edible fungus with functional food properties, were collected under different experimental conditions to quantify the levels of melatonin and its intermediates. The results showed that the intracellular melatonin content was markedly improved by Congo red (CR), cold, and heat stresses; the levels of intracellular melatonin and its intermediates increased at the primordial (P) and fruiting body (FB) stages. However, the levels of most intermediates exhibited a notable decrease under CR stress. Several genes related to melatonin synthesis, excluding AADC (aromatic-L-amino-acid decarboxylase), were markedly upregulated at an early stage of CR stress but downregulated later. Compared to the mycelial stage, those genes were significantly upregulated at the P and FB stages. Additionally, exogenous melatonin promoted resistance to several abiotic stressors and P formation in T. guangdongense. This study is the first to report melatonin biosynthesis pathway in macro-fungi. Our results should help in studying the diversity of melatonin function and melatonin-synthesis pathways and provide a new viewpoint for melatonin applications in the edible-medicinal fungus.
Mechanistic Effects of Aerobic Exercise in Alzheimer's Disease: Imaging Findings From the Pilot FIT-AD Trial
Authors: Yu Fang , Mathiason Michelle A. , Han SeungYong , Gunter Jeffrey L. , Jones David , Botha Hugo , Jack Clifford
Published: October 2021

Despite strong evidence from animal models of Alzheimer's disease (AD) supporting aerobic exercise as a disease-modifying treatment for AD, human mechanistic studies are limited with mixed findings. The objective of this pilot randomized controlled trial was to examine the effects of 6-month aerobic exercise on hippocampal volume, temporal meta-regions of interest (ROI) cortical thickness, white matter hyperintensity (WMH) volume, and network failure quotient (NFQ), measured with MRI, in community-dwelling older adults with AD dementia. Additionally, the relationships between 6- and 12-month changes in MRI biomarkers and the AD Assessment Scale-Cognition (ADAS-Cog) were examined. Sixty participants were randomized, but one was excluded because baseline MRI failed quality control: 38 randomized to cycling and 21 to stretching. The intervention was moderate-intensity cycling for 20–50 mins, three times a week for 6 months. Control was low-intensity stretching. The study outcomes include hippocampal volume, temporal meta-ROI cortical thickness, WMH volume, and NFQ. Outcomes were measured at baseline, 6 months, and 12 months. The sample averaged 77.3 ± 6.3 years old with 15.6 ± 2.9 years of education and 53% men. Both groups experienced significant declines over 6 months in hippocampal volume (2.64% in cycling vs. 2.89% in stretching) and temporal meta-ROI cortical thickness (0.94 vs. 1.54%), and over 12 months in hippocampal volume (4.47 vs. 3.84%) and temporal meta-ROI cortical thickness (2.27 vs. 1.79%). These declines did not differ between groups. WMH volume increased significantly with the cycling group increasing less (10.9%) than stretching (24.5%) over 6 months (f = 4.47, p = 0.04) and over 12 months (12.1 vs. 27.6%, f = 5.88, p = 0.02). NFQ did not change significantly over time. Pairwise correlational analyses showed a significant negative correlation between 6-month changes in hippocampal volume and ADAS-Cog (r = −0.34, p < 0.05). To conclude, aerobic exercise may reduce the decline in hippocampal volume and temporal meta-ROI cortical thickness during the intervention period, but the effect sizes are likely to be very small and dose-dependent and reverse once the intervention stops. Aerobic exercise is effective on slowing down WMH progression but has no effect on NFQ. Hippocampal atrophy was associated with cognitive decline during the intervention period.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT01954550.