bluuebunny/crossref_metadata_2025 huggingface dataset:
NOT Gates Based on Protein Degradation as a Case Study for a New Modular Modeling via SBML Level 3—Comp Package
Authors: Abraha Biruck Woldai , Marchisio Mario Andrea
Published: March 2022

In 2008, we were among the first to propose a method for the visual design and modular modeling of synthetic gene circuits, mimicking the way electronic circuits are realized in silico. Basic components were DNA sequences that could be composed, first, into transcription units (TUs) and, then, circuits by exchanging fluxes of molecules, such as PoPS (polymerase per second) and RiPS (ribosomes per seconds) as suggested by Drew Endy. However, it became clear soon that such fluxes were not measurable, which highlighted the limit of using some concepts from electronics to represent biological systems. SBML Level 3 with the comp package permitted us to revise circuit modularity, especially for the modeling of eukaryotic networks. By using the libSBML Python API, TUs—rather than single parts—are encoded in SBML Level 3 files that contain species, reactions, and ports, i.e., the interfaces that permit to wire TUs into circuits. A circuit model consists of a collection of SBML Level 3 files associated with the different TUs plus a “main” file that delineates the circuit structure. Within this framework, there is no more need for any flux of molecules. Here, we present the SBML Level 3-based models and the wet-lab implementations of Boolean NOT gates that make use, in the yeast Saccharomyces cerevisiae, of the bacterial ClpX-ClpP system for protein degradation. This work is the starting point towards a new piece of software for the modular design of eukaryotic gene circuits and shows an alternative way to build genetic Boolean gates.
Streamlining the Characterization of Disulfide Bond Shuffling and Protein Degradation in IgG1 Biopharmaceuticals Under Native and Stressed Conditions
Authors: Coghlan Jill , Benet Alexander , Kumaran Preethi , Ford Michael , Veale Lawrie , Skilton St. John , Saveliev Sergei , Schwendeman Anna A.
Published: March 2022

Post translational modifications (PTMs) have been shown to negatively impact protein efficacy and safety by altering its native conformation, stability, target binding and/or pharmacokinetics. One PTM in particular, shuffled disulfide bonds, has been linked to decreased potency and increased immunogenicity of protein therapeutics. In an effort to gain more insights into the effects of shuffled disulfide bonds on protein therapeutics’ safety and efficacy, we designed and further optimized a semi-automated LC-MS/MS method for disulfide bond characterization on two IgG1 protein therapeutics—rituximab and bevacizumab. We also compared originator vs. biosimilar versions of the two therapeutics to determine if there were notable variations in the disulfide shuffling and overall degradation between originator and biosimilar drug products. From our resulting data, we noticed differences in how the two proteins degraded. Bevacizumab had a general upward trend in shuffled disulfide bond levels over the course of a 4-week incubation (0.58 ± 0.08% to 1.46 ± 1.10% for originator) whereas rituximab maintained similar levels throughout the incubation (0.24 ± 0.21% to 0.51 ± 0.11% for originator). When we measured degradation by SEC and SDS-PAGE, we observed trends that correlated with the LC-MS/MS data. Across all methods, we observed that the originator and biosimilar drugs performed similarly. The results from this study will help provide groundwork for comparative disulfide shuffling analysis by LC-MS/MS and standard analytical methodology implementation for the development and regulatory approval of biosimilars.
Notochordal Cell-Based Treatment Strategies and Their Potential in Intervertebral Disc Regeneration
Authors: Bach Frances C. , Poramba-Liyanage Deepani W. , Riemers Frank M. , Guicheux Jerome , Camus Anne , Iatridis James C. , Chan Danny , Ito Keita , Le Maitre Christine L. , Tryfonidou Marianna A.
Published: March 2022

Chronic low back pain is the number one cause of years lived with disability. In about 40% of patients, chronic lower back pain is related to intervertebral disc (IVD) degeneration. The standard-of-care focuses on symptomatic relief, while surgery is the last resort. Emerging therapeutic strategies target the underlying cause of IVD degeneration and increasingly focus on the relatively overlooked notochordal cells (NCs). NCs are derived from the notochord and once the notochord regresses they remain in the core of the developing IVD, the nucleus pulposus. The large vacuolated NCs rapidly decline after birth and are replaced by the smaller nucleus pulposus cells with maturation, ageing, and degeneration. Here, we provide an update on the journey of NCs and discuss the cell markers and tools that can be used to study their fate and regenerative capacity. We review the therapeutic potential of NCs for the treatment of IVD-related lower back pain and outline important future directions in this area. Promising studies indicate that NCs and their secretome exerts regenerative effects, via increased proliferation, extracellular matrix production, and anti-inflammatory effects. Reports on NC-like cells derived from embryonic- or induced pluripotent-stem cells claim to have successfully generated NC-like cells but did not compare them with native NCs for phenotypic markers or in terms of their regenerative capacity. Altogether, this is an emerging and active field of research with exciting possibilities. NC-based studies demonstrate that cues from developmental biology can pave the path for future clinical therapies focused on regenerating the diseased IVD.
Selective Retinoic Acid Receptor γ Antagonist 7C is a Potent Enhancer of BMP-Induced Ectopic Endochondral Bone Formation
Authors: Tateiwa Daisuke , Kaito Takashi , Hashimoto Kunihiko , Okada Rintaro , Kodama Joe , Kushioka Junichi , Bal Zeynep , Tsukazaki Hiroyuki , Nakagawa Shinichi , Ukon Yuichiro , Hirai Hiromasa , Tian Hongying , Alferiev Ivan , Chorny Michael , Otsuru Satoru , Okada Seiji , Iwamoto Masahiro
Published: March 2022

Bone morphogenetic proteins (BMPs) have been clinically applied for induction of bone formation in musculoskeletal disorders such as critical-sized bone defects, nonunions, and spinal fusion surgeries. However, the use of supraphysiological doses of BMP caused adverse events, which were sometimes life-threatening. Therefore, safer treatment strategies for bone regeneration have been sought for decades. Systemic administration of a potent selective antagonist of retinoic acid nuclear receptor gamma (RARγ) (7C) stimulated BMP-induced ectopic bone formation. In this study, we developed 7C-loaded poly lactic nanoparticles (7C-NPs) and examined whether local application of 7C enhances BMP-induced bone regeneration. The collagen sponge discs that absorbed recombinant human (rh) BMP-2 were implanted into the dorsal fascia of young adult mice to induce ectopic bone. The combination of rhBMP-2 and 7C-NP markedly increased the total bone volume and thickness of the bone shell of the ectopic bone in a dose-dependent manner compared to those with rhBMP-2 only. 7C stimulated sulfated proteoglycan production, expression of chondrogenic marker genes, and Sox9 reporter activity in both chondrogenic cells and MSCs. The findings suggest that selective RARγ antagonist 7C or the related compounds potentiate the bone inductive ability of rhBMP-2, as well as support any future research to improve the BMP-2 based bone regeneration procedures in a safe and efficient manner.
The MDM2 Single-Nucleotide Polymorphism T309G Is Associated With the Development of Epimacular Membranes
Authors: Jiang Heng , Yan Bin , Meng Zhishang , Zhang Lusi , Lei Hetian , Luo Jing
Published: March 2022

Purpose: To investigate the role of the mouse double minute 2 (MDM2) gene single-nucleotide polymorphism (SNP) T309G in the development of epimacular membranes (EMMs) by analyzing the genotype distribution and consistency of the polymorphism in paired membrane-blood samples.

Methods: This was a cross–sectional genetic association study of patients with proliferative vitreoretinopathy (PVR) or EMMs. PVR membranes (PVRMs), internal limiting membranes (ILMs) (PVR-ILMs) and blood samples (PVR-blood) from patients with PVR, and EMMs, EMM-ILMs and EMM-blood from patients with EMMs were collected. The genotype of all samples was determined by Sanger sequencing. Sex composition, mean age, the genotype distribution of MDM2 T309G, the allelic frequency of the MDM2 SNP309 G allele (% G) and the somatic mutation rate at the MDM2 T309G locus (% M) were analyzed and compared. The PVR and healthy Chinese donor groups were used as controls for different comparisons.

Results: The EMM group of 62 patients was older than the PVR group of 61 patients by an average of 8.87 years (p < 0.0001), but the two groups were statistically similar in the sex composition (p = 0.1754). Importantly, G allele carriers were at a higher risk of developing EMMs than non-G allele carriers (p = 0.0479; OR = 2.047). Moreover, EMM-blood exhibited a significantly higher % G than blood samples from healthy Chinese donors (EMM-blood: 56.78%, donors: 45.61%; p = 0.0256; OR = 1.567). Regarding membrane-blood consistency, % M was significantly different between PVRMs and EMMs (PVRMs: 2.63%, EMMs: 21.57%; p = 0.0097; OR = 10.18) but not between different types of ILMs (PVR-ILMs: 18.18%, EMM-ILMs: 29.17%; p = 0.6855). Furthermore, EMMs (p = 0.0053; OR = 8.250) and EMM-ILMs (p = 0.0233; OR = 14.40) from patients with preoperative macular holes were more predisposed toward somatic mutations at the MDM2 T309G locus than those from patients without preoperative macular holes.

Conclusions:MDM2 T309G is associated with the development of EMMs. Herein, the MDM2 SNP309 G allele is first reported as an associated factor of EMMs in a Chinese population. In addition, EMMs and ILMs are genetically unstable at the MDM2 T309G locus, especially when complicated with preoperative macular holes.
Reduced Retinoic Acid Signaling During Gastrulation Induces Developmental Microcephaly
Authors: Gur Michal , Bendelac-Kapon Liat , Shabtai Yehuda , Pillemer Graciela , Fainsod Abraham
Published: March 2022

Retinoic acid (RA) is a central signaling molecule regulating multiple developmental decisions during embryogenesis. Excess RA induces head malformations, primarily by expansion of posterior brain structures at the expense of anterior head regions, i.e., hindbrain expansion. Despite this extensively studied RA teratogenic effect, a number of syndromes exhibiting microcephaly, such as DiGeorge, Vitamin A Deficiency, Fetal Alcohol Syndrome, and others, have been attributed to reduced RA signaling. This causative link suggests a requirement for RA signaling during normal head development in all these syndromes. To characterize this novel RA function, we studied the involvement of RA in the early events leading to head formation inXenopusembryos. This effect was mapped to the earliest RA biosynthesis in the embryo within the gastrula Spemann-Mangold organizer. Head malformations were observed when reduced RA signaling was induced in the endogenous Spemann-Mangold organizer and in the ectopic organizer of twinned embryos. Two embryonic retinaldehyde dehydrogenases, ALDH1A2 (RALDH2) and ALDH1A3 (RALDH3) are initially expressed in the organizer and subsequently mark the trunk and the migrating leading edge mesendoderm, respectively. Gene-specific knockdowns and CRISPR/Cas9 targeting show that RALDH3 is a key enzyme involved in RA production required for head formation. These observations indicate that in addition to the teratogenic effect of excess RA on head development, RA signaling also has a positive and required regulatory role in the early formation of the head during gastrula stages. These results identify a novel RA activity that concurs with its proposed reduction in syndromes exhibiting microcephaly.
Structure-Property Relationship for Different Mesoporous Silica Nanoparticles and its Drug Delivery Applications: A Review
Authors: Kazemzadeh Parya , Sayadi Khalil , Toolabi Ali , Sayadi Jalil , Zeraati Malihe , Chauhan Narendra Pal Singh , Sargazi Ghasem
Published: March 2022

Mesoporous silica nanoparticles (MSNs) are widely used as a promising candidate for drug delivery applications due to silica’s favorable biocompatibility, thermal stability, and chemical properties. Silica’s unique mesoporous structure allows for effective drug loading and controlled release at the target site. In this review, we have discussed various methods of MSNs’ mechanism, properties, and its drug delivery applications. As a result, we came to the conclusion that more in vivo biocompatibility studies, toxicity studies, bio-distribution studies and clinical research are essential for MSN advancement.
NanoSIMS Analysis of Rare Earth Elements in Silicate Glass and Zircon: Implications for Partition Coefficients
Authors: Shi Lanlan , Sano Yuji , Takahata Naoto , Koike Mizuho , Morita Takuya , Koyama Yuta , Kagoshima Takanori , Li Yuan , Xu Sheng , Liu Congqiang
Published: March 2022

We have developed a method to analyze all rare earth elements in silicate glasses and zircon minerals using a high lateral resolution secondary ion mass spectrometer (NanoSIMS). A 2nA O− primary beam was used to sputter a 7–8-μm diameter crater on the sample surface, and secondary positive ions were extracted for mass analysis using an accelerating voltage of 8 kV. A high mass resolving power of 9,400 at 10% peak height was attained to separate heavy REE from oxide of light REE. A multi-collector system combined with peak-jumping by magnetic field was adjusted to detect REEs and silicon-30 for calibration. Based on results of NIST SRM610 glass, sensitivities of REEs vary from 3 cps/ppm/nA of Lu to 13 cps/ppm/nA of Eu. Reproducibility of REE/Si ratios is better than 18% at 2σ. Secondary ion yields of REEs show positive relationships with their ionization potential of second valence. REEs of AS3, QGNG, and Torihama zircons were measured and calibrated against those of 91500 standard zircon. SIYs of REEs of zircon are identical to those of the glass standard. AS3 and QGNG data are generally consistent with those of previous work. Torihama REE data combined with the whole rock data provide partition coefficients of REEs between silicate melt and zircon. The relationship between these coefficients and ionic radius is explained by an elastic moduli model.
EhVps23, an ESCRT-I Member, Is a Key Factor in Secretion, Motility, Phagocytosis and Tissue Invasion by Entamoeba histolytica
Authors: Galindo Ausencio , Javier-Reyna Rosario , García-Rivera Guillermina , Bañuelos Cecilia , Chávez-Munguía Bibiana , Salazar-Villatoro Lizbeth , Orozco Esther
Published: March 2022

The EhVps23 protein, an orthologue of the yeast Vps23 and the mammalian TSG101 proteins, is the single member of the ESCRT-I complex of Entamoeba histolytica identified and characterized until now. EhVps23 actively participates in vesicular trafficking and phagocytosis, which influence several cellular events. In this paper, we investigated the role of EhVps23 in virulence-related functions, including the invasive capacity of trophozoites, using transfected trophozoites. Trophozoites overexpressing the EhVps23 protein (Neo-EhVps23) presented helical arrangements in the cytoplasm, similar to the ones formed by EhVps32 for scission of vesicles. By confocal and transmission electron microscopy, EhVps23 was detected in multivesicular bodies, vesicles, and the extracellular space. It was secreted in vesicles together with other proteins, including the EhADH adhesin. Probably, these vesicles carry molecules that participate in the prey capture or in cell-cell communication. Mass spectrometry of precipitates obtained using α-EhVps23 antibodies, evidenced the presence of proteins involved in motility, phagocytosis, vesicular trafficking and secretion. The study of cellular functions, revealed that Neo-EhVps23 trophozoites exhibit characteristics similar to those described for mammalian transformed cells: they grew 50% faster than the control; presented a significant higher rate of phagocytosis, and migrated five-fold faster than the control, in concordance with the low rate of migration exhibited by Ehvps23-knocked down trophozoites. In addition, Neo-EhVps23 trophozoites produced dramatic liver abscesses in experimental animals. In conclusion, our results showed that EhVps23 overexpression gave to the trophozoites characteristics that resemble cancer cells, such as increased cell proliferation, migration, and invasion. The mutant that overexpresses EhVps23 can be a good study model to explore different events related to the transformation of malignant cells.
Human Organotypic Airway and Lung Organoid Cells of Bronchiolar and Alveolar Differentiation Are Permissive to Infection by Influenza and SARS-CoV-2 Respiratory Virus
Authors: Ekanger Camilla Tvedt , Zhou Fan , Bohan Dana , Lotsberg Maria Lie , Ramnefjell Maria , Hoareau Laurence , Røsland Gro Vatne , Lu Ning , Aanerud Marianne , Gärtner Fabian , Salminen Pirjo Riitta , Bentsen Mariann , Halvorsen Thomas , Ræder Helge , Akslen Lars A. , Langeland Nina , Cox Rebecca , Maury Wendy , Stuhr Linda Elin Birkhaug , Lorens James B. , Engelsen Agnete S. T.
Published: March 2022

The ongoing coronavirus disease 2019 (COVID-19) pandemic has led to the initiation of unprecedented research efforts to understand the pathogenesis mediated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). More knowledge is needed regarding the cell type-specific cytopathology and its impact on cellular tropism. Furthermore, the impact of novel SARS-CoV-2 mutations on cellular tropism, alternative routes of entry, the impact of co-infections, and virus replication kinetics along the respiratory tract remains to be explored in improved models. Most applied virology models are not well suited to address the remaining questions, as they do not recapitulate the histoarchitecture and cellular composition of human respiratory tissues. The overall aim of this work was to establish from single biopsy specimens, a human adult stem cell-derived organoid model representing the upper respiratory airways and lungs and explore the applicability of this model to study respiratory virus infection. First, we characterized the organoid model with respect to growth pattern and histoarchitecture, cellular composition, and functional characteristics. Next, in situ expression of viral entry receptors, including influenza virus-relevant sialic acids and SARS-CoV-2 entry receptor ACE2 and TMPRSS2, were confirmed in organoids of bronchiolar and alveolar differentiation. We further showed successful infection by pseudotype influenza A H7N1 and H5N1 virus, and the ability of the model to support viral replication of influenza A H7N1 virus. Finally, successful infection and replication of a clinical isolate of SARS-CoV-2 were confirmed in the organoids by TCID50 assay and immunostaining to detect intracellular SARS-CoV-2 specific nucleocapsid and dsRNA. The prominent syncytia formation in organoid tissues following SARS-CoV-2 infection mimics the findings from infected human tissues in situ. We conclude that the human organotypic model described here may be particularly useful for virology studies to evaluate regional differences in the host response to infection. The model contains the various cell types along the respiratory tract, expresses respiratory virus entry factors, and supports successful infection and replication of influenza virus and SARS-CoV-2. Thus, the model may serve as a relevant and reliable tool in virology and aid in pandemic preparedness, and efficient evaluation of antiviral strategies.
Association Between Gut Dysbiosis and Sepsis-Induced Myocardial Dysfunction in Patients With Sepsis or Septic Shock
Authors: Chen Yu , Zhang Fu , Ye Xin , Hu Jing-Juan , Yang Xiao , Yao Lin , Zhao Bing-Cheng , Deng Fan , Liu Ke-Xuan
Published: March 2022

Objective

Sepsis-induced myocardial dysfunction (SIMD) seriously affects the evolution and prognosis of the sepsis patient. The gut microbiota has been confirmed to play an important role in sepsis or cardiovascular diseases, but the changes and roles of the gut microbiota in SIMD have not been reported yet. This study aims to assess the compositions of the gut microbiota in sepsis or septic patients with or without myocardial injury and to find the relationship between the gut microbiota and SIMD.

Methods

The prospective, observational, and 1:1 matched case–control study was conducted to observe gut microbiota profiles from patients with SIMD (n = 18) and matched non-SIMD (NSIMD) patients (n = 18) by 16S rRNA gene sequencing. Then the relationship between the relative abundance of microbial taxa and clinical indicators and clinical outcomes related to SIMD was analyzed. The receiver operating characteristic (ROC) curves were used to evaluate the predictive efficiencies of the varied gut microbiota to SIMD.

Results

SIMD was associated with poor outcomes in sepsis patients. The beta-diversity of the gut microbiota was significantly different between the SIMD patients and NSIMD subjects. The gut microbiota profiles in different levels significantly differed between the two groups. Additionally, the abundance of some microbes (Klebsiella variicola, Enterobacteriaceae, and Bacteroides vulgatus) was correlated with clinical indicators and clinical outcomes. Notably, ROC analysis indicated that K. variicola may be a potential biomarker of SIMD.

Conclusion

Our study indicates that SIMD patients may have a particular gut microbiota signature and that the gut microbiota might be a potential diagnostic marker for evaluating the risk of developing SIMD.
Late Fontan Circulatory Failure. What Drives Systemic Venous Congestion and Low Cardiac Output in Adult Fontan Patients?
Authors: Van De Bruaene Alexander , Claessen Guido , Salaets Thomas , Gewillig Marc
Published: March 2022

The Fontan circulation provides definite palliation for children born with a single anatomical or functional ventricle by diverting systemic venous blood directly to the pulmonary arteries, effectively rendering systemic venous return into portal vessels to the lung. Although this restores pulmonary blood flow and avoids the mixture of oxygenated and deoxygenated blood, it also results in elevated systemic venous pressures and low cardiac output. These are the two hallmarks of any Fontan circulation and the cause of Fontan circulatory failure later in life. We highlight the determinants of systemic venous return, its changed relationship with the pulmonary circulation, how it affects preload, and the changed role of the heart (myocardium, valves, and heart rate). By critically evaluating the components of the Fontan circulation, we hope to give some clues in how to optimize the Fontan circulation and avenues for future research.
Comparison of the Characteristics, Management, and Outcomes of STEMI Patients Presenting With vs. Those of Patients Presenting Without COVID-19 Infection: A Systematic Review and Meta-Analysis
Authors: Wang Yanjiao , Kang Linlin , Chien Ching-Wen , Xu Jiawen , You Peng , Xing Sizhong , Tung Tao-Hsin
Published: March 2022

Objectives

This study aimed to investigate the differences in the characteristics, management, and clinical outcomes of patients with and that of those without coronavirus disease 2019 (COVID-19) infection who had ST-segment elevation myocardial infarction (STEMI).

Methods

Databases including Web of Science, PubMed, Cochrane Library, and Embase were searched up to July 2021. Observational studies that reported on the characteristics, management, or clinical outcomes and those published as full-text articles were included. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of all included studies.

Results

A total of 27,742 patients from 13 studies were included in this meta-analysis. Significant delay in symptom onset to first medical contact (SO-to-FMC) time (mean difference = 23.42 min; 95% CI: 5.85–40.99 min; p = 0.009) and door-to-balloon (D2B) time (mean difference = 12.27 min; 95% CI: 5.77–18.78 min; p = 0.0002) was observed in COVID-19 patients. Compared to COVID-19 negative patients, those who are positive patients had significantly higher levels of C-reactive protein, D-dimer, and thrombus grade (p < 0.05) and showed more frequent use of thrombus aspiration and glycoprotein IIbIIIa (Gp2b3a) inhibitor (p < 0.05). COVID-19 positive patients also had higher rates of in-hospital mortality (OR = 5.98, 95% CI: 4.78–7.48, p < 0.0001), cardiogenic shock (OR = 2.75, 95% CI: 2.02–3.76, p < 0.0001), and stent thrombosis (OR = 5.65, 95% CI: 2.41–13.23, p < 0.0001). They were also more likely to be admitted to the intensive care unit (ICU) (OR = 4.26, 95% CI: 2.51–7.22, p < 0.0001) and had a longer length of stay (mean difference = 4.63 days; 95% CI: 2.56–6.69 days; p < 0.0001).

Conclusions

This study revealed that COVID-19 infection had an impact on the time of initial medical intervention for patients with STEMI after symptom onset and showed that COVID-19 patients with STEMI were more likely to have thrombosis and had poorer outcomes.
Sustained Downregulation of Vascular Smooth Muscle Acta2 After Transient Angiotensin II Infusion: A New Model of “Vascular Memory”
Authors: Pothen Lucie , Verdoy Roxane , De Mulder Delphine , Esfahani Hrag , Farah Charlotte , Michel Lauriane Y. M. , Dei Zotti Flavia , Bearzatto Bertrand , Ambroise Jerome , Bouzin Caroline , Dessy Chantal , Balligand Jean-Luc
Published: March 2022

Background

Activation of the renin-angiotensin-aldosterone system (RAAS) plays a critical role in the development of hypertension. Published evidence on a putative “memory effect” of AngII on the vascular components is however scarce.

Aim

To evaluate the long-term effects of transient exposure to AngII on the mouse heart and the arterial tissue.

Methods

Blood pressure, cardiovascular tissue damage and remodeling, and systemic oxidative stress were evaluated in C57/B6/J mice at the end of a 2-week AngII infusion (AngII); 2 and 3 weeks after the interruption of a 2-week AngII treatment (AngII+2W and AngII +3W; so-called “memory” conditions) and control littermate (CTRL). RNAseq profiling of aortic tissues was used to identify potential key regulated genes accounting for legacy effects on the vascular phenotype. RNAseq results were validated by RT-qPCR and immunohistochemistry in a reproduction cohort of mice. Key findings were reproduced in a homotypic cell culture model.

Results

The 2 weeks AngII infusion induced cardiac hypertrophy and aortic damage that persisted beyond AngII interruption and despite blood pressure normalization, with a sustained vascular expression of ICAM1, infiltration by CD45+ cells, and cell proliferation associated with systemic oxidative stress. RNAseq profiling in aortic tissue identified robust Acta2 downregulation at transcript and protein levels (α-smooth muscle actin) that was maintained beyond interruption of AngII treatment. Among regulators of Acta2 expression, the transcription factor Myocardin (Myocd), exhibited a similar expression pattern. The sustained downregulation of Acta2 and Myocd was associated with an increase in H3K27me3 in nuclei of aortic sections from mice in the “memory” conditions. A sustained downregulation of ACTA2 and MYOCD was reproduced in the cultured human aortic vascular smooth muscle cells upon transient exposure to Ang II.

Conclusion

A transient exposure to Ang II produces prolonged vascular remodeling with robust ACTA2 downregulation, associated with epigenetic imprinting supporting a “memory” effect despite stimulus withdrawal.
The Diagnosis of Dengue in Patients Presenting With Acute Febrile Illness Using Supervised Machine Learning and Impact of Seasonality
Authors: Ming Damien K. , Tuan Nguyen M. , Hernandez Bernard , Sangkaew Sorawat , Vuong Nguyen L. , Chanh Ho Q. , Chau Nguyen V. V. , Simmons Cameron P. , Wills Bridget , Georgiou Pantelis , Holmes Alison H. , Yacoub Sophie
Published: March 2022

Background

Symptomatic dengue infection can result in a life-threatening shock syndrome and timely diagnosis is essential. Point-of-care tests for non-structural protein 1 and IgM are used widely but performance can be limited. We developed a supervised machine learning model to predict whether patients with acute febrile illnesses had a diagnosis of dengue or other febrile illnesses (OFI). The impact of seasonality on model performance over time was examined.

Methods

We analysed data from a prospective observational clinical study in Vietnam. Enrolled patients presented with an acute febrile illness of <72 h duration. A gradient boosting model (XGBoost) was used to predict final diagnosis using age, sex, haematocrit, platelet, white cell, and lymphocyte count collected on enrolment. Data was randomly split 80/20% into a training and hold-out set, respectively, with the latter not used in model development. Cross-validation and hold out set testing was used, with performance over time evaluated through a rolling window approach.

Results

We included 8,100 patients recruited between 16th October 2010 and 10th December 2014. In total 2,240 (27.7%) patients were diagnosed with dengue infection. The optimised model from training data had an overall median area under the receiver operator curve (AUROC) of 0.86 (interquartile range 0.84–0.86), specificity of 0.92, sensitivity of 0.56, positive predictive value of 0.73, negative predictive value (NPV) of 0.84, and Brier score of 0.13 in predicting the final diagnosis, with similar performances in hold-out set testing (AUROC of 0.86). Model performances varied significantly over time as a function of seasonality and other factors. Incorporation of a dynamic threshold which continuously learns from recent cases resulted in a more consistent performance throughout the year (NPV >90%).

Conclusion

Supervised machine learning models are able to discriminate between dengue and OFI diagnoses in patients presenting with an early undifferentiated febrile illness. These models could be of clinical utility in supporting healthcare decision-making and provide passive surveillance across dengue endemic regions. Effects of seasonality and changing disease prevalence must however be taken into account—this is of significant importance given unpredictable effects of human-induced climate change and the impact on health.
Correction of Atmospheric Delay Error of Airborne and Spaceborne GNSS-R Sea Surface Altimetry
Authors: Yan Zhengjie , Zheng Wei , Wu Fan , Wang Cheng , Zhu Huizhong , Xu Aigong
Published: March 2022

Improving the measurement accuracy is a necessary condition for sea surface altimetry using the Global Navigation Satellite System Reflectometry (GNSS-R). The ionosphere and troposphere delay the transmission of satellite signals, which directly affect the measuring accuracy. The influence of the atmospheric environment on GNSS-R altimetry differs from different platforms. By analyzing and sorting out the altimetry data of airborne and spaceborne platforms, this paper studies the variation law of signal delay in the altimetry process from the point of view of mathematical geometry, which provides an example for improving the precision of GNSS-R altimetry measurements. Firstly, in order to facilitate data analysis, this paper constructed an altimetry model with the GNSS satellite position, specular reflection point position, receiver position as nodes, classified direct signals, and reflected signals. Secondly, calculate ionospheric puncture point coordinates , and interpolate GIM products provided by IGS using time and puncture point coordinates to obtain the VTEC value in the vertical direction of the puncture point, which was converted into the path direction STEC by projection function, the ionospheric delay of each part was obtained in this way. The tropospheric delay of each part is considered for the along-path component and the geometric component, the delay of along-path component was calculated by the UNB3m model, and the delay of geometric component was calculated by the equation provided by Nikolaidou (Nikolaidou et al., 2021). Thirdly, by comparing the sea surface height inversion results with or without atmospheric delay correction with the mean sea surface height provided by DTU15, the measurement accuracy with atmospheric delay correction is obviously improved. The study results of the influence of atmospheric delay on the altimetry experiments precision error of airborne and spaceborne platforms show that the error magnitude is consistent with the existing literature. In the airborne experiment, the influence of the ionosphere is negligible and the troposphere has sub-meter influence on altimetry results, among which the tropospheric along-path delay component occupies a high proportion. The geometric delay component has a high correlation with the satellite elevation angle and its influence on the measurement accuracy decreases with the elevation angle increase. The effect of this factor can be effectively weakened by setting a high satellite cutoff angle. In the spaceborne experiment, the effect of atmospheric delay on altimetry results fluctuates in the range of 3∼5 m when the satellite elevation angle is greater than 60°. In this paper, the method of calculating signal atmospheric delay through geometric relation to improving the measurement accuracy can provide an example for the atmospheric delay correction of GNSS-R ocean altimetry with high precision and spatial resolution in future research.
Identification of Key Blocks Considering Finiteness of Discontinuities in Tunnel Engineering
Authors: Yang Yong , Wang Shuhong , Zhang Minsi , Wu Bo
Published: March 2022

The traditional cutting algorithm has a clear concept and is easy to implement, but it cannot consider the finiteness of the discontinuities. Based on the traditional cutting algorithm, an accurate identification method of blocks is proposed, which can identify blocks formed by finite discontinuities and excavation surface. A visual program for identifying blocks and stability analysis is developed by using Microsoft Foundation Class and OpenGL, and then it is applied to tunnel engineering. The shape and the number of the key blocks identified by this method are not limited and consistent with actual engineering. In the case that the size of the discontinuities cannot be accurately obtained, the influence of the size change of the dominant discontinuities on the key block is discussed, which will make up the lack of parameters. The number and volume of the key blocks are large when discontinuities are assumed to be infinite, and the calculation results are conservative. However, the volume and location of the blocks have great reference value and guiding significance for practical engineering.
Simulation Study on Interactive Propagation of Hydraulic Fractures and Natural Fractures in Shale Oil Reservoir
Authors: Tian Fuchun , Jin Yan , Shi Lin , Cong Ziyuan , Li Yuwei
Published: March 2022

Natural fractures are developed in the shale oil reservoir, and the hydraulic fracture (HF) morphology is complex. The fracture shape can be inverted by using fracture propagation numerical simulation technology, which provides guidance for fracturing parameter design and fracturing process optimization. However, the existing models still have many deficiencies in the interactive propagation mechanism of HF and natural fracture (NF). Based on the three interactive modes of HF and NF (HF propagation without NF, HF propagation with full NF, and HF propagation with half NF), this work establishes the fracture propagation model and puts forward the simulation calculation method. The Brinkman equation is used to modify the leakage model based on Darcy’s law, and G1701H well is taken as an example to simulate the fracture propagation law under different interaction modes. The research shows that there is a transition region between the HF wall and rock matrix. The greater the porosity and permeability of the rock matrix, the more significant the influence of the transition region on leakage. The NF zone will change the propagation direction of the main fracture. When there are multiple clusters of fractures in the same fracturing section, only some HFs meet with natural fractures, and it is easy to form a “T”-shaped fracture network. The results improve the existing hydraulic fracturing model and provide help for fracturing parameter design and fracture parameter inversion of the shale oil reservoir.
One-step Synthesis of Biomass-Based Carbon Dots for Detection of Metal Ions and Cell Imaging
Authors: Huang Xiaolin , Liu Jiaheng , Zhao Bin , Bai Yibing , Peng Zhibin , Zhou Jundan , Wang Chenxi , Zhao Xuan , Han Shiyan , Zhang Chunlei
Published: March 2022

Biomass-based carbon dots (Bio-CDs) were prepared from dehydroabietic acid using a one-step hydrothermal process. Characterization by TEM, XPS and FTIR spectroscopy showed that the Bio-CDs are spherical nanoparticles containing mainly C, N and O elements, with functional groups such as amino and carbonyl groups on their surface. The optical properties of the Bio-CDs were studied in detail. A solution of Bio-CDs exhibited excitation-dependent blue fluorescence emission. The solution showed excellent photostability under ultraviolet light and the fluorescence intensity could be enhanced by decreasing the temperature. The intensity of fluorescence emission of the solution was essentially unchanged over the pH range 3.91–8.69, and in the presence of different anions and cations, other than Fe3+ and Pb2+. Fe3+ and Pb2+ ions, respectively, quenched and enhanced the intensity of the fluorescence emission of the solution, allowing sensitive and selective detection of Fe3+ (LOD = 2.33 μM, Em = 437 nm) and of Pb2+ (LOD = 0.27 μM, Em = 437 nm and LOD = 0.33 μM, Em = 500 nm). As a further demonstration of potential applications, the Bio-CDs were shown to have low cytotoxicity and to stain cell nuclei as effectively as the commonly used nuclear stain 4′,6-diamino-2-phenylindole (DAPI), demonstrating their promise in the field of cell imaging.
Characteristic Changes of Bioaerosols in Beijing and Tsogt-Ovoo During Dust Events
Authors: Dong Xiaofei , Chen Bin , Maki Teruya , Shi Guangyu , Duan Minzheng , Khalid Bushra
Published: March 2022

Dust events moving at high altitudes by westerly wind can transport aerosols from Asian deserts to eastern Asia deposition areas such as China. Aerosols do not include only mineral particles but also microbial particles, which are called bioaerosols, and impact the ecosystem and air environment of the deposition area. For identifying the airborne microbial communities transported from the source area to the deposition area, bioaerosol samples were collected in the typical source region (Tsogt-Ovoo in Gobi deserts) and the deposition region (Beijing in Chinese industrial area) during dust events and non-dust days and the sampling sites were compared. The microscopic observation using DAPI fluorescent techniques revealed that the concentration of bioaerosols increased during the dust events in both the source and deposition regions. For the community structures of airborne bacteria at both sites, the dust-event occurrences changed the structure of the bacterial community and increased the diversity of bacterial communities during dust events. Some specific bacterial populations, such as members of Bacteroidetes, dominated during dust events. There is the possibility that specific bacteria can be maintained for a longer time in the atmosphere and might be transported from the source area to the deposition area.
Spatial Memory Drives Foraging Strategies of Wolves, but in Highly Individual Ways
Authors: Gurarie Eliezer , Bracis Chloe , Brilliantova Angelina , Kojola Ilpo , Suutarinen Johanna , Ovaskainen Otso , Potluri Sriya , Fagan William F.
Published: March 2022

The ability of wild animals to navigate and survive in complex and dynamic environments depends on their ability to store relevant information and place it in a spatial context. Despite the centrality of spatial memory, and given our increasing ability to observe animal movements in the wild, it is perhaps surprising how difficult it is to demonstrate spatial memory empirically. We present a cognitive analysis of movements of several wolves (Canis lupus) in Finland during a summer period of intensive hunting and den-centered pup-rearing. We tracked several wolves in the field by visiting nearly all GPS locations outside the den, allowing us to identify the species, location and timing of nearly all prey killed. We then developed a model that assigns a spatially explicit value based on memory of predation success and territorial marking. The framework allows for estimation of multiple cognitive parameters, including temporal and spatial scales of memory. For most wolves, fitted memory-based models outperformed null models by 20 to 50% at predicting locations where wolves chose to forage. However, there was a high amount of individual variability among wolves in strength and even direction of responses to experiences. Some wolves tended to return to locations with recent predation success—following a strategy of foraging site fidelity—while others appeared to prefer a site switching strategy. These differences are possibly explained by variability in pack sizes, numbers of pups, and features of the territories. Our analysis points toward concrete strategies for incorporating spatial memory in the study of animal movements while providing nuanced insights into the behavioral strategies of individual predators.
Dietary Choices of a Foregut-Fermenting Primate, Colobus guereza: A Comprehensive Approach Including Leaf Chemical and Mechanical Properties, Digestibility and Abundance
Authors: Matsuda Ikki , Hashimoto Chie , Ihobe Hiroshi , Yumoto Takakazu , Baranga Deborah , Clauss Marcus , Hummel Jürgen
Published: March 2022

Free-ranging animals make dietary choices that affect their nutritional status and, ultimately, their health and fitness. We investigated food selection by a leaf-eating foregut-fermenting primate, the guereza (Colobus guereza), using multiple criteria, including chemical and mechanical properties, in vitro digestibility and leaf abundance, on the basis of 30 consecutive months of behavioral observations (4308 h in total) of a family group in the Kalinzu Forest, Uganda, as well as vegetation surveys. We noted that leaf toughness may be a proximate cue for the chemical properties of plant foods, especially for protein, which is an important selection factor used by primates. We also found that the in vitro digestibility of plant foods was greatly influenced by the concentrations of fiber and secondary compounds. At a broad level, none of the studied factors, including leaf chemical and mechanical properties, digestibility and abundance, affected whether guerezas consumed specific leaf items. At a more detailed level, however, protein content, digestibility and toughness were related to the percentage of foraging effort that guerezas devoted to specific items in our study site.
What Are the “Costs and Benefits” of Meat-Eating in Human Evolution? The Challenging Contribution of Behavioral Ecology to Archeology
Authors: Daujeard Camille , Prat Sandrine
Published: March 2022

Despite the omnivorous diet of most human populations, meat foraging gradually increased during the Paleolithic, in parallel with the development of hunting capacities. There is evidence of regular meat consumption by extinct hominins from 2 Ma onward, with the first occurrence prior to 3 Ma in Eastern Africa. The number of sites with cut-marked animal remains and stone tools increased after 2 Ma. In addition, toolkits became increasingly complex, and various, facilitating carcass defleshing and marrow recovery, the removal of quarters of meat to avoid carnivore competition, and allowing the emergence of cooperative (i.e., social) hunting of large herbivores. How can we assess the energy costs and benefits of meat and fat acquisition and consumption for hunter-gatherers in the past, and is it possible to accurately evaluate them? Answering this question would provide a better understanding of extinct hominin land use, food resource management, foraging strategies, and cognitive abilities related to meat and fat acquisition, processing, and consumption. According to the Optimal Foraging Theory (OFT), resources may be chosen primarily on the basis of their efficiency rank in term of calories. But, could other factors, and not only calorific return, prevail in the choice of prey, such as the acquisition of non-food products, like pelts, bone tools or ornaments, or symbolic or traditional uses? Our main goal here is to question the direct application of behavioral ecology data to archeology. For this purpose, we focus on the issue of animal meat and fat consumption in human evolution. We propose a short review of available data from energetics and ethnographic records, and provide examples of several various-sized extant animals, such as elephants, reindeer, or lagomorphs, which were some of the most common preys of Paleolithic hominins.
Differentiation of the Chestnut Tiger Butterfly Parantica sita (Lepidoptera: Nymphalidae: Danainae) in China
Authors: Hu Ping , Lu Liangzhi , Hu Shaoji , Da Wa , Huang Chia-Lung , Zhang Huihong , Wang Di , Zhang Yifan , Xu Yongqiang , Wang Rongjiang
Published: March 2022

The chestnut tiger butterfly, Parantica sita (Kollar) (Lepidoptera: Nymphalidae: Danainae), occurs in Asia, along the Himalayas, and into the Malayan region. Previous studies found three types of mitogenomes with substantial genetic divergence in samples from China. To clarify the level of differentiation within P. sita, we investigated both molecular data and morphological features in 429 individuals from China. Upon examination, mitochondrial cytochrome oxidase subunit I (COI) sequences showed three substantially diverged haplotype groups. Based on microsatellite genotypes, the samples divided into three clusters that were consistent with the COI haplotype groups. With that genetic data, we named three distinguishable P. sita lineages: PS-A, PS-B, and PS-C. We also found obvious morphological differences in wing color, male sex brand, and genitalia structures among the three lineages. According to the published structure of male genitalia, that of PS-A is identical to that of P. s. sita, and that of PS-B is identical to that of P. pedonga. Based on all the results, we tentatively propose dividing P. sita into three species: PS-A (the former P. s. sita) is the typical Parantica sita [Kollar, (1844)], mainly distributed in southwestern China; PS-C (the former P. s. niphonica) is elevated to full species as Parantica niphonica (Moore, 1883), distributed in Taiwan Island and Japan; and PS-B will be Parantica pedongaFujioka, 1970, mainly distributed in Tibet and western Sichuan. Divergence time estimates showed that PS-A separated from the PS-B + PS-C clade about 8.79 million years ago (Ma), when the Hengduan Mountains underwent an appreciable elevation increase, isolating the Tibet population from the others. PS-B and PS-C diverged about 4.87 Ma, in accord with the formation of Taiwan Island mountains. The founder effect may explain why PS-C’s genetic diversity is lower than that of the other clades.