bluuebunny/crossref_metadata_2025 huggingface dataset:
Desenvolvimento de projetos de vida de jovens no ensino médio: análise de uma proposta embasada na aprendizagem baseada em problemas e por projetos (ABPP)
Authors: Pinheiro Viviane Potenza Guimarães , Arantes Valeria Amorim
Published: June 2022

O presente artigo objetiva analisar uma proposta com base na Aprendizagem Baseada em Problemas e por Projetos (ABPP) para o desenvolvimento de projetos de vida de estudantes do Ensino Médio de uma escola particular da Zona Sul da cidade de São Paulo. A análise centrou-se no trabalho realizado no ano de 2015, com jovens do 3º ano do Ensino Médio, na construção de protótipos pautados nas áreas de atuação profissional que desejam seguir futuramente, com vistas a atender problemáticas sociais. Foi analisado o percurso do total de 92 estudantes (em 40 grupos de até três alunos) e da tutora. Como resultados, observou-se: a área de atuação profissional escolhida, as características dos protótipos desenvolvidos e o engajamento dos jovens no percurso de construção do trabalho. Verificou-se que os jovens estão centrados em um número restrito de profissões, mas os protótipos efetivamente atendem à proposta de atuação social, com o olhar das áreas escolhidas. Também foi verificada grande participação dos estudantes e reconhecimento de que o processo foi benéfico para sua formação. Concluímos que o trabalho com ABPP, relacionado aos projetos de vida dos jovens, pode ser profícuo para oportunizar reflexões acerca das conexões entre carreira profissional e atuação ética na sociedade.
As formas de organização das crianças para o brincar em uma instituição de educação infantil
Authors: Oliveira Fabiana de , Ito Tammy Silveira
Published: June 2022

A pesquisa buscou compreender o modo como as crianças se organizam para o brincar considerando as interações e as trocas entre os pares. A pesquisa foi realizada em uma instituição de educação infantil localizada no sul de Minas Gerais e a metodologia utilizada contemplou observação do cotidiano, filmagens seguidas de produção do diário de campo e realização de entrevista. Os resultados encontrados apontam que o brincar fazia parte das atividades diárias da instituição pesquisada, porém, ocorria a partir de duas perspectivas distintas: a dos adultos e a das crianças. A compreensão institucional sobre o brincar está pautada na sua utilização como recurso pedagógico ou controle, porém, as crianças subvertem essas propostas baseadas numa lógica adulta.
Hydrogels for Treatment of Different Degrees of Osteoarthritis
Authors: Wang Shuze , Qiu Yueyang , Qu Liu , Wang Qiang , Zhou Qing
Published: June 2022

Osteoarthritis (OA) is a common disease that severely restricts human activities and degrades the quality of life. Every year, millions of people worldwide are diagnosed with osteoarthritis, placing a heavy burden on society. Hydrogels, a polymeric material with good biocompatibility and biodegradability, are a novel approach for the treatment of osteoarthritis. In recent years, this approach has been widely studied with the development of materials science and tissue engineering technology. We reviewed the research progress of hydrogels in the treatment of osteoarthritis in the past 3 years. We summarized the required hydrogel properties and current applications according to the development and treatment of osteoarthritis. Furthermore, we listed the challenges of hydrogels for different types of osteoarthritis and presented prospects for future development.
Oleaginous Microalga Coccomyxa subellipsoidea as a Highly Effective Cell Factory for CO2 Fixation and High-Protein Biomass Production by Optimal Supply of Inorganic Carbon and Nitrogen
Authors: Liu Yu , Wei Dong , Chen Weining
Published: June 2022

Microalgae used for CO2 biofixation can effectively relieve CO2 emissions and produce high-value biomass to achieve “waste-to-treasure” bioconversion. However, the low CO2 fixation efficiency and the restricted application of biomass are currently bottlenecks, limiting the economic viability of CO2 biofixation by microalgae. To achieve high-efficient CO2 fixation and high-protein biomass production, the oleaginous microalga Coccomyxa subellipsoidea (C. subellipsoidea) was cultivated autotrophically through optimizing inorganic carbon and nitrogen supply. 0.42 g L−1 NaHCO3 supplemented with 2% CO2 as a hybrid carbon source resulted in high biomass concentration (3.89 g L−1) and productivity (318.33) with CO2 fixation rate 544.21 mg L−1 d−1 in shake flasks. Then, used in a 5-L photo-fermenter, the maximal protein content (60.93% DW) in batch 1, and the highest CO2 fixation rate (1043.95 mg L−1 d−1) with protein content (58.48% DW) in batch 2 of repeated fed-batch cultures were achieved under 2.5 g L−1 nitrate. The relative expression of key genes involved in photosynthesis, glycolysis, and protein synthesis showed significant upregulation. This study developed a promising approach for enhancing carbon allocation to protein synthesis in oleaginous microalga, facilitating the bioconversion of the fixed carbon into algal protein instead of oil in green manufacturing.
Event-Based Supply Chain Network Modeling: Blockchain for Good Coffee
Authors: Bager Simon L. , Düdder Boris , Henglein Fritz , Hébert Juan Manuel , Wu Haiqin
Published: June 2022

Blockchain and distributed ledger technology (BC/DLT) provides distributed databases with decentralized governance, tamper-proof recording, high availability and non-copyable digital assets, which have made it a natural technological basis for supply chain management. In this paper, we introduce REALISTIC, a novel event-based modeling framework for supply chain networks (SCNs) that includes production processes. It extends McCarty’s Resources-Events-Agents (REA) accounting model with secure transformations, which, across the entire SCN, guarantee that certified output resources cannot be digitally produced ex nihilo, but require certified input resources of at least the same amount as what is produced. This generalizes the no-double-spend guarantee of current BC/DLT to (digital twins of) physical resources and their production. Authenticated human or robotic Internet of Things (IoT) actors digitally sign and cryptographically commit to the veracity of real-world events on an immutable database, without having to take responsibility for their aggregate consequences. User-specifiable interpretations, corresponding to queries and analytical functions in database systems, provide auditable aggregate information computed from recorded events across the entire SCN. This includes fine-grained and trustworthy tracing of final products through multiple stages of production processes, semi-finished products, quality certifications and transportation all the way back to their raw materials. We present a case study for an end-to-end coffee supply chain that tracks fine-grained and detailed information from a farmer’s coffee cherries to retail coffee bags, involving all its actors. Our model handles product provenance; auditable sustainability, quality and trade information; production processes from parchment via green to roasted coffee; product quality tests; farmer certifications; and transportation across the entire coffee supply chain. It is based on field work involving farmers, cooperatives, processors, traders, importers, and a major roasting company stretching from Colombia to Scandinavia. Its REALISTIC-based modeling is the foundation for the design of our prototype implementation, which includes Ethereum blockchain code, RDBMS-based server code and a web app client. Their source code is publicly available on GitHub.
Advances in Single-Cell Multi-Omics and Application in Cardiovascular Research
Authors: Zhang Xingwu , Qiu Hui , Zhang Fengzhi , Ding Shuangyuan
Published: June 2022

With the development of ever more powerful and versatile high-throughput sequencing techniques and innovative ways to capture single cells, mapping the multicellular tissues at the single-cell level is becoming routine practice. However, it is still challenging to depict the epigenetic landscape of a single cell, especially the genome-wide chromatin accessibility, histone modifications, and DNA methylation. We summarize the most recent methodologies to profile these epigenetic marks at the single-cell level. We also discuss the development and advancement of several multi-omics sequencing technologies from individual cells. Advantages and limitations of various methods to compare and integrate datasets obtained from different sources are also included with specific practical notes. Understanding the heart tissue at single-cell resolution and multi-modal levels will help to elucidate the cell types and states involved in physiological and pathological events during heart development and disease. The rich information produced from single-cell multi-omics studies will also promote the research of heart regeneration and precision medicine on heart diseases.
A Novel Approach for Visualizing Mixing Phenomena of Reactive Liquid-Liquid Flows in Milli- and Micro-Channels
Authors: Frey Torben , Kexel Felix , Dittmer Kayla Reata , Bohne Sven , Hoffmann Marko , Trieu Hoc Khiem , Schlüter Michael
Published: June 2022

Modular milli- and micro-structured systems represent a promising approach to exploit the potential of micro-process technology, including precise reaction control and scale-up. A major drawback of micro-structured devices is fouling and mixing mechanisms need to be investigated phenomenologically to better understand the processes that lead to fouling. Previous work was conducted to resolve 3D concentration fields by means of Laser-Induced Fluorescence (LIF) using a Confocal Laser Scanning Microscope (CLSM) (Frey et al., J Flow Chem, 2021, 11, 599–609). While the CLSM-LIF method yields detailed insight into concentration fields down to a few micrometers, it is limited to stationary flow structures only. Aubin et al. (Chemical Engineering Science, 2010, 65, 2065–2093) give a comprehensive review of methods to analyze mixing behavior. Most recent optical measurement methods rely on the detection of a single compound in mixtures. In case of reactive mixing, Tthe state of the art procedures to locally visualize micro mixing relies on tracking a reaction product which forms on molecular scale. In literature, only small micro-structures are manufactured from transparent materials, however larger milli-structures often lack optical accesses with sufficient quality. Selective laser-induced etching (SLE) is a new technique which enables the fabrication of larger milli-structures in transparent materials that are relevant for industry-scale applications. This work develops a method based on a concept of Kexel et al. (Chemie Ingenieur Technik, 2021, 93, 830–837) visualizing the selectivity of a competitive-consecutive gas-liquid reaction in a Taylor bubble flow. The main goal of this work is the analysis of the absorbance spectra of bromothymol blue (BTB) at different pH values in a miscible liquid-liquid system in a fused silica split-and-recombine mixer. The milli-structure of the mixer is manufactured by means of SLE. Backlight at different wavelengths is pulsed matching the recording frequency. In contrast to conventional UV/Vis setups, the absorbance is recorded locally within the mixer. The proposed method yields the 2D concentration distribution of multiple species with high spatial resolution. The spatially resolved reactant and product distribution unveils micro mixing and can yield important information about local root causes of fouling.
Inhibitors Targeting Multiple Janus Kinases From Zanthoxylum simulans Mediate Inhibition and Apoptosis Against Gastric Cancer Cells via the Estrogen Pathway
Authors: Tian Yong-Qiang , Hu Dai , Zhang Yong-Li , Zou Jian , Chen Gui-Lin , Guo Ming-Quan
Published: June 2022

Janus kinases (JAKs) play a key role in subtly regulating proliferation, apoptosis, and differentiation of cancer cells, and their inhibitors are actively sought as new drug leads. By developing JAKs based affinity ultrafiltration method coupled with LC/Q-TOF-MS in order to discover selective JAKs inhibitors from total quaternary alkaloids (QAs) from Zanthoxylum simulans, peak 19 (Berberine) and peak 21 (Chelerythrine) were revealed to exhibit notable selectivity on JAK1, JAK2, and JAK3 over Tyk2. In addition, Chelerythrine showed stronger inhibitory activity than the positive control (Cerdulatinib) on gastric cancer cells (AGS), while Berberine, with weaker inhibition. Chelerythrine and Berberine also showed obvious inhibition on human hepatocyte cells (LO2). Furthermore, molecular docking analysis revealed their discrepancies due to different interaction bonds and characteristic residues. Quaternary N was proposed as the functional group to enhance the selectivity of JAK1, and some specific moieties towards Asp1021, Leu855, and Leu828 were suggested to increase the selectivity for JAK1, JAK2, and JAK3, respectively. As the most potential inhibitor of JAKs from QAs, Chelerythrine exhibited distinct suppression of adhesion, migration, invasion, and stimulating apoptosis of AGS cells, which was consistent with the significant down-regulation of estrogen receptors (ER-α36, ER-α66, and ER-β1) and Src expression. In conclusion, an efficient screening approach was developed to identify Berberine and Chelerythrine as potential selective candidates from Zanthoxylum simulans with significant anti-proliferative activity against gastric carcinoma. As we know, it was the first report to propose an estrogen signal pathway for Chelerythrine in anti-gastric cancer cells (AGS) study. The results supported Chelerythrine inhibitory effects on AGS by not only direct inhibiting JAKs but also down-regulating the estrogen pathway.
La Plata Basin Hydroclimate Response to Solar Radiation Modification With Stratospheric Aerosol Injection
Authors: Camilloni Inés , Montroull Natalia , Gulizia Carla , Saurral Ramiro I.
Published: June 2022

This study analyses the La Plata Basin (LPB) hydroclimate response to Solar Radiation Modification (SRM) with Stratospheric Aerosol Injection (SAI) in terms of changes in mean and extreme temperature, rainfall, and river flows simulations from the Geoengineering Large Ensemble (GLENS). The GLENS data used consists of three members simulations of a single model under the high anthropogenic emission scenario RCP8.5 with and without sulfur injection in the tropical stratosphere. The response of such an intervention is compared to a historical period (1980–2010) and to projections under the RCP8.5 scenario for two time slices: 2021–2050 and 2051–2080. The analysis of changes in extreme temperature and precipitation focuses on a subset of climate indices from the Expert Team of Climate Change Detection and Indices (ETCCDI). To determine the possible effects of SRM in the LPB water cycle, we use the distributed Variable Infiltration Capacity (VIC) hydrologic model in combination with daily extreme temperature and precipitation outputs from GLENS. Systematic errors in both fields were corrected by the application of a statistical bias correction method. Results show robust impacts on the water cycle of the LPB due to SRM implementation, particularly associated with increased precipitation over the northern part of the region and a general reduced warming compared to the RCP8.5 scenario. These variations would lead to regional-dependent responses in the river flows, mostly related to reductions in the severity of the extremely low flow conditions. Additionally, under the SRM scenario a reduction in extreme precipitation and a cooling effect on extreme temperatures could be expected over the LPB.
Tracing the Anharmonicity and Superionic Phase Transition of Hydrous FeO2H
Authors: Hu Qingyang , Tang Mingxue
Published: June 2022

The weak x-ray scattering of hydrogen (H) has brought major challenges to the characterization of superionic transitions in high-pressure ice, hydrides, and hydroxides. Combining first-principles molecular dynamics and simulated nuclear magnetic resonance (NMR) spectroscopy, we investigated the behavior of the hydroxyl bonding and structural transitions in the hydrous FeO2H between 300 and 2750 K and up to 130 GPa. Evidence show that an intermediate plastic state with regional H diffusion and anharmonic O-H vibration exists in between the ordinary solid and the superionic phase. The intermediate state features asymmetric hydrogen bonds and anharmonic vibrations, which are readily distinguished from the high-temperature superionic phase. Our work shows NMR is a more sensitive probe to detect H diffusion in superionic solids even in the extreme conditions of Earth’s deep interiors.
SecMOD: An Open-Source Modular Framework Combining Multi-Sector System Optimization and Life-Cycle Assessment
Authors: Reinert Christiane , Schellhas Lars , Mannhardt Jacob , Shu David Yang , Kämper Andreas , Baumgärtner Nils , Deutz Sarah , Bardow André
Published: June 2022

Optimization models can support decision-makers in the synthesis and operation of multi-sector energy systems. To identify the optimal design and operation of a low-carbon system, we need to consider high temporal and spatial variability in the electricity supply, sector coupling, and environmental impacts over the whole life cycle. Incorporating such aspects in optimization models is demanding. To avoid redundant research efforts and enhance transparency, the developed models and used data sets should be shared openly. In this work, we present the SecMOD framework for multi-sector energy system optimization incorporating life-cycle assessment (LCA). The framework allows optimizing multiple sectors jointly, ranging from industrial production and their linked energy supply systems to sector-coupled national energy systems. The framework incorporates LCA to account for environmental impacts. We hence provide the first open-source framework to consistently include a holistic life-cycle perspective in multi-sector optimization by a full integration of LCA. We apply the framework to a case-study of the German sector-coupled energy system. Starting with few base technologies, we demonstrate the modular capabilities of SecMOD by the stepwise addition of technologies, sectors and existing infrastructure. Our modular open-source framework SecMOD aims to accelerate research for sustainable energy systems by combining multi-sector energy system optimization and life-cycle assessment.
Impact of the Belt and Road Initiative on Economic-Social-Natural Ecological Niches and Their Coupling Coordination: Evidence From 11 Countries Along the Route
Authors: Cao Ying , Jiang Anyin , Cao Zijian , Fayyaz Ahmad , Li Jing , Chen Weiqiang , Guo Wenjun
Published: June 2022

The Belt and Road Initiative (BRI) significantly contributes to the world economy. However, the central part of the Belt and Road (B&R) is located in fragile ecological zones that are arid, semi-arid, or sub-humid. Using the entropy method, the economic-social-natural ecological niches and their coupling coordination during 2007–2019 along B&R’s 11 countries were explored along with regional differences and spatiotemporal characteristics. The economic-social-natural ecological niches were low, with a fluctuating upward trend. Additionally, the average annual growth rate of the synthesis ecological niche dramatically improved after the BRI. Further, the BRI facilitated inter-country trade and promoted the economic ecological niche. However, the BRI marginally affected the social ecological position, possibly because the social ecological niche was high pre-BRI. The natural ecological niche showed a negative growth after the BRI. Further, the coupling coordination of economic-social ecological niche and natural ecological niche showed an upward trend, transforming from severe discoordination to advanced coordination. Although BRI promoted advanced coordination, it did not affect internal categories. Policy recommendations for sustainable development in China-ASEAN Free Trade Area were provided. This study can assist policymakers to balance economic-social development and environmental protection.
Comprehensive Analysis of Expression and Prognostic Value of MS4As in Glioma
Authors: Zeng Yingying , Tan Peixin , Ren Chen , Gao Lianxuan , Chen Yulei , Hu Shushu , Tang Nan , Chen Chen , Du Shasha
Published: June 2022

Glioma is the most common malignancy of the nervous system with high mortality rates. The MS4A family members have been reported as potential prognostic biomarkers in several cancers; however, the relationship between the MS4A family and glioma has not been clearly confirmed. In our study, we explored the prognostic value of MS4As as well as their potential pro-cancer mechanisms of glioma. Using bioinformatics analysis methods based on the data from public databases, we found that the expression of MS4A4A, MS4A4E, MS4A6A, MS4A7, TMEM176A, and TMEM176B was significantly overexpressed in glioma tissues compared with that of normal tissues. The Kaplan–Meier method and Cox proportional hazards models revealed that high levels of MS4As can be associated with a poorer prognosis; TMEM176A, TMEM176B, age, WHO grade, and IDH status were identified as independent prognostic factors. Enrichment analysis predicted that MS4As were related to tumor-related pathways and immune response, which might regulate the process of MS4As promoting tumorigenesis. Additionally, we analyzed the correlations of MS4A expression with immune cells and immune inhibitory molecules. Finally, data from the cell culture suggested that knockdown of the TMEM176B gene contributes to the decreased proliferation and migration of glioma cells. In conclusion, MS4A4A, MS4A4E, MS4A6A, MS4A7, TMEM176A, and TMEM176B may act as potential diagnostic or prognostic biomarkers in glioma and play a role in forming the immune microenvironment in gliomas.
Mutant B3GALT6 in a Multiplex Family: A Dominant Variant Co-Segregated With Moderate Malformations
Authors: Shen Fang , Yang Yongjia , Zheng Yu , Tu Ming , Zhao Liu , Luo Zhenqing , Fu Yuyan , Zhu Yimin
Published: June 2022

B3GALT6 is a well-documented disease-related gene. Several B3GALT6-recessive variants have been reported to cause Ehlers–Danlos syndrome (EDS). To the best of our knowledge, no dominant B3GALT6 variant that causes human disease has been reported. In 2012, we reported on a three-generation, autosomal-dominant family with multiple members who suffered from radioulnar joint rotation limitation, scoliosis, thick vermilion of both lips, and others, but the genetic cause was unknown. Here, exome sequencing of the family identified mutant B3GALT6 as the cause of the multiplex affected family. We observed that, in the compound heterozygous pattern (i.e., c.883C>T:p.R295C and c.510_517del:p.L170fs*268), mutant B3GALT6 led to severe consequences, and in the dominant pattern, an elongated B3GALT6 variant co-segregated with moderate phenotypes. The functional experiments were performed in vitro. The R295C variant led to subcellular mislocalization, whereas the L170fs*268 showed normal subcellular localization, but it led to an elongated protein. Given that most of the catalytic galactosyltransferase domain was disrupted for the L170fs*268 (it is unlikely that such a protein has activity), we propose that the L170fs*268 occupies the normal B3GALT6 protein position in the Golgi and exerts a dominant-negative effect.
A Sparse Mixture-of-Experts Model With Screening of Genetic Associations to Guide Disease Subtyping
Authors: Courbariaux Marie , De Santiago Kylliann , Dalmasso Cyril , Danjou Fabrice , Bekadar Samir , Corvol Jean-Christophe , Martinez Maria , Szafranski Marie , Ambroise Christophe
Published: June 2022

Motivation: Identifying new genetic associations in non-Mendelian complex diseases is an increasingly difficult challenge. These diseases sometimes appear to have a significant component of heritability requiring explanation, and this missing heritability may be due to the existence of subtypes involving different genetic factors. Taking genetic information into account in clinical trials might potentially have a role in guiding the process of subtyping a complex disease. Most methods dealing with multiple sources of information rely on data transformation, and in disease subtyping, the two main strategies used are 1) the clustering of clinical data followed by posterior genetic analysis and 2) the concomitant clustering of clinical and genetic variables. Both of these strategies have limitations that we propose to address.

Contribution: This work proposes an original method for disease subtyping on the basis of both longitudinal clinical variables and high-dimensional genetic markers via a sparse mixture-of-regressions model. The added value of our approach lies in its interpretability in relation to two aspects. First, our model links both clinical and genetic data with regard to their initial nature (i.e., without transformation) and does not require post-processing where the original information is accessed a second time to interpret the subtypes. Second, it can address large-scale problems because of a variable selection step that is used to discard genetic variables that may not be relevant for subtyping.

Results: The proposed method was validated on simulations. A dataset from a cohort of Parkinson’s disease patients was also analyzed. Several subtypes of the disease and genetic variants that potentially have a role in this typology were identified.

Software availability: The R code for the proposed method, named DiSuGen, and a tutorial are available for download (see the references).
Gene Expression Microarray Data Identify Hub Genes Involved in Osteoarthritis
Authors: Zhou Jian , Zou Dazhi , Wan Rongjun , Liu Jie , Zhou Qiong , Zhou Zhen , Wang Wanchun , Tao Cheng , Liu Tang
Published: June 2022

The present study was performed to explore the underlying molecular mechanisms and screen hub genes of osteoarthritis (OA) via bioinformatics analysis. In total, twenty-five OA synovial tissue samples and 25 normal synovial tissue samples were derived from three datasets, namely, GSE55457, GSE55235, and GSE1919, and were used to identify the differentially expressed genes (DEGs) of OA by R language. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of DEGs were conducted using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). A Venn diagram was built to show the potential hub genes identified in all three datasets. The STRING database was used for constructing the protein–protein interaction (PPI) networks and submodules of DEGs. We identified 507 upregulated and 620 downregulated genes. Upregulated DEGs were significantly involved in immune response, MHC class II receptor activity, and presented in the extracellular region, while downregulated DEGs were mainly enriched in response to organic substances, extracellular region parts, and cadmium ion binding. Results of KEGG analysis indicated that the upregulated DEGs mainly existed in cell adhesion molecules (CAMs), while downregulated DEGs were significantly involved in the MAPK signaling pathway. A total of eighteen intersection genes were identified across the three datasets. These include Nell-1, ATF3, RhoB, STC1, and VEGFA. In addition, 10 hub genes including CXCL12, CXCL8, CCL20, and CCL4 were found in the PPI network and module construction. Identification of DEGs and hub genes associated with OA may be helpful for revealing the molecular mechanisms of OA and further promotes the development of relevant biomarkers and drug targets.
Rare Variants in Novel Candidate Genes Associated With Nonsyndromic Patent Ductus Arteriosus Identified With Whole-Exome Sequencing
Authors: Gao Ying , Wu Dan , Chen Bo , Chen Yinghui , Zhang Qi , Zhao Pengjun
Published: June 2022

Background: Patent ductus arteriosus (PDA) is one of the most common congenital heart defects causing pulmonary hypertension, infective endocarditis, and even death. The important role of genetics in determining spontaneous ductal closure has been well-established. However, as many of the identified variants are rare, thorough identification of the associated genetic factors is necessary to further explore the genetic etiology of PDA.

Methods: We performed whole-exome sequencing (WES) on 39 isolated nonsyndromic PDA patients and 100 healthy controls. Rare variants and novel genes were identified through bioinformatic filtering strategies. The expression patterns of candidate genes were explored in human embryo heart samples.

Results: Eighteen rare damaging variants of six novel PDA-associated genes (SOX8, NES, CDH2, ANK3, EIF4G1, and HIPK1) were newly identified, which were highly expressed in human embryo hearts.

Conclusions: WES is an efficient diagnostic tool for exploring the genetic pathogenesis of PDA. These findings contribute new insights into the molecular basis of PDA and may inform further studies on genetic risk factors for congenital heart defects.
Bioinformatics-Led Discovery of Osteoarthritis Biomarkers and Inflammatory Infiltrates
Authors: Hu Xinyue , Ni Songjia , Zhao Kai , Qian Jing , Duan Yang
Published: June 2022

The molecular mechanisms of osteoarthritis, the most common chronic disease, remain unexplained. This study aimed to use bioinformatic methods to identify the key biomarkers and immune infiltration in osteoarthritis. Gene expression profiles (GSE55235, GSE55457, GSE77298, and GSE82107) were selected from the Gene Expression Omnibus database. A protein-protein interaction network was created, and functional enrichment analysis and genomic enrichment analysis were performed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) databases. Immune cell infiltration between osteoarthritic tissues and control tissues was analyzed using the CIBERSORT method. Identify immune patterns using the ConsensusClusterPlus package in R software using a consistent clustering approach. Molecular biological investigations were performed to discover the important genes in cartilage cells. A total of 105 differentially expressed genes were identified. Differentially expressed genes were enriched in immunological response, chemokine-mediated signaling pathway, and inflammatory response revealed by the analysis of GO and KEGG databases. Two distinct immune patterns (ClusterA and ClusterB) were identified using the ConsensusClusterPlus. Cluster A patients had significantly lower resting dendritic cells, M2 macrophages, resting mast cells, activated natural killer cells and regulatory T cells than Cluster B patients. The expression levels of TCA1, TLR7, MMP9, CXCL10, CXCL13, HLA-DRA, and ADIPOQSPP1 were significantly higher in the IL-1β-induced group than in the osteoarthritis group in an in vitro qPCR experiment. Explaining the differences in immune infiltration between osteoarthritic tissues and normal tissues will contribute to the understanding of the development of osteoarthritis.
Comparisons of Long-Term Survival and Safety of Haploidentical Hematopoietic Stem Cell Transplantation After CAR-T Cell Therapy or Chemotherapy in Pediatric Patients With First Relapse of B-Cell Acute Lymphoblastic Leukemia Based on MRD-Guided Treatment
Authors: Hu Guanhua , Cheng Yifei , Zuo Yingxi , Chang Yingjun , Suo Pan , Jia Yueping , Lu Aidong , Wang Yu , Jiao Shunchang , Zhang Longji , Sun Yuqian , Yan Chenhua , Xu Lanping , Zhang Xiaohui , Liu Kaiyan , Wang Yu , Zhang Leping , Huang Xiaojun
Published: June 2022

Measurable residual disease (MRD) positivity before haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an independent prognostic factor in determining outcomes in patients with B-cell acute lymphoblastic leukemia (ALL). In this study, we conducted a parallel comparison of the efficacy and safety in patients with suboptimal MRD response after reinduction who underwent haplo-HSCT after chimeric antigen receptor T-cell (CAR-T) therapy or chemotherapy. Forty B-cell ALL patients who relapsed after first-line chemotherapy and with an MRD ≥0.1% after reinduction were analyzed. The median pre-HSCT MRD in the CAR-T group (n = 26) was significantly lower than that in the chemotherapy group (n = 14) (0.009% vs. 0.3%, p = 0.006). The CAR-T group exhibited a trend toward improved 3-year leukemia-free survival and a significantly improved 3-year overall survival compared to the chemotherapy group [71.8% (95% confidence interval (CI): 53.9–89.6) vs. 44.4% (95% CI: 15.4–73.4), p = 0.19 and 84.6% (95% CI: 70.6–98.5) vs. 40.0% (95% CI: 12.7–67.2), p = 0.008; respectively]. Furthermore, no increased risk of graft-versus-host disease, treatment-related mortality, or infection was observed in the CAR-T group. Our study suggests that CAR-T therapy effectively eliminates pre-HSCT MRD, resulting in better survival in the context of haplo-HSCT.
Availability of the Yellow Fever Vaccine in Primary Health Care Services in Brazil
Authors: Hermsdorf Marina Oliveira , da Silva Tércia Moreira Ribeiro , Lachtim Sheila Aparecida Ferreira , Matozinhos Fernanda Penido , Beinner Mark Anthony , Vieira Ed Wilson Rodrigues
Published: June 2022

Objectives

To analyze the availability of the Yellow Fever (YF) vaccine at Primary Health Care (PHC) services located in areas with vaccine recommendation in Brazil between two different periods.

Methods

Secondary data from the Program for Improving Access and Quality in PHC, with 13,666 services in 2013-14, and 19,125 in 2017-18, were used. A structured questionnaire was used for the data collection. Pearson’s chi-square and thematic cartographic maps were used to analyze the frequency of the YF vaccine, and Poisson regression with robust variances was used to analyze the associated factors.

Results

The overall frequency of PHC facilities with YF vaccine always available increased from 87.0% (CI 95%; 86.4-87.5) in 2013-14 to 89.7% (CI 95%; 89.2-90.1) in 2017-18. Facilities located in the South, Southeast, Midwest and Northern regions and in non-state capitals, as well as centers that had adequate facilities for vaccination actions, as well as an adey -50quate cold chain network, showed a greater prevalence of YF vaccine always available.

Conclusion

The frequency of a steady supply of YF vaccine available at PHC facilities, located in Areas with Routine Vaccination Recommendations, increased between 2013-14 and 2017-18. Geographical and structural characteristics related to vaccine actions at PHC facilities influenced access. The effective supply chain networks for the YF vaccine, together with adequate services at PHC facilities are essential to ensuring that the YF vaccine is always available.
Managing Marine Growth on Historic Maritime Structures: An Assessment of Perceptions and Current Management Practices
Authors: Baxter Timothy , Coombes Martin , Viles Heather
Published: June 2022

Maritime built heritage (e.g., historic harbors, breakwaters, etc.) is found widely along the coastlines of Europe. Due to its age and traditional construction, built heritage may represent important and largely unidentified hotspots of biodiversity in marine and coastal environments. At the same time, marine growth (e.g., seaweed, mussels, barnacles, etc.) found on these structures may provide both deteriorative and protective functions. To ensure future research focusing on the two-way interactions between marine growth and built heritage addresses the concerns of those responsible for their management, attitudes towards the colonization and growth of marine wildlife must first be evaluated. Such attitudes will shape how marine growth is managed at these sites, which in turn may influence biodiversity and built heritage conservation and any associated values. This study assesses how the growth of sessile species and other surface-colonizing organisms is currently perceived and managed by those responsible for maintaining maritime built heritage, with a particular focus on historic structures constructed of natural stone. Responses from a semi-quantitative online questionnaire of harbormasters, coastal engineers, environmental officers, and heritage managers from around the UK (n = 132) were analyzed alongside a series of semi-structured interviews (n = 29). Our results demonstrate that attitudes towards marine growth are generally in agreement among practitioners irrespective of their occupation or the historic maritime structures they are responsible for managing. Perceptions of marine growth are mostly positive, but concerns exist regarding its impacts on maintenance regimes, the condition of mortar, and health and safety. As well as highlighting opportunities for a more integrated approach to biodiversity and built heritage conservation, the concerns identified require further research attention to help address potential barriers and conflicts that may arise in practice.
Diagnostic Accuracy of Liquid Biomarkers in Airway Diseases: Toward Point-of-Care Applications
Authors: Landry Vivianne , Coburn Patrick , Kost Karen , Liu Xinyu , Li-Jessen Nicole Y. K.
Published: June 2022

Background

Liquid biomarkers have shown increasing utility in the clinical management of airway diseases. Salivary and blood samples are particularly amenable to point-of-care (POC) testing due to simple specimen collection and processing. However, very few POC tests have successfully progressed to clinical application due to the uncertainty and unpredictability surrounding their diagnostic accuracy.

Objective

To review liquid biomarkers of airway diseases with well-established diagnostic accuracies and discuss their prospects for future POC applications.

Methodology

A literature review of publications indexed in Medline or Embase was performed to evaluate the diagnostic accuracy of liquid biomarkers for chronic obstructive pulmonary disease (COPD), asthma, laryngopharyngeal reflux (LPR), and COVID-19.

Results

Of 3,628 studies, 71 fulfilled the inclusion criteria. Sputum and blood eosinophils were the most frequently investigated biomarkers for the management of asthma and COPD. Salivary pepsin was the only biomarker with a well-documented accuracy for the diagnosis of LPR. Inflammatory blood biomarkers (e.g., CRP, D-dimers, ferritin) were found to be useful to predict the severity, complications, and mortality related to COVID-19 infection.

Conclusion

Multiple liquid biomarkers have well-established diagnostic accuracies and are thus amenable to POC testing in clinical settings.
Application of Internet of Medical/Health Things to Decentralized Clinical Trials: Development Status and Regulatory Considerations
Authors: Sato Takahiro , Ishimaru Hikaru , Takata Takuya , Sasaki Hajime , Shikano Mayumi
Published: June 2022

Background

The need for a new style of clinical trials, called decentralized clinical trials (DCTs), has been increasing as they do not depend on physical visits to clinical sites. DCTs are expected to provide a new opportunity to patients who cannot participate in a clinical trial due to geographical and time limitations. For the adoption of DCTs, it is essential that medical devices with Internet of Medical Things (IoMT) and Internet of Health Things (IoHT) based technologies are developed and commercially adopted. In this study, we aimed to identify the regulatory considerations when IoMT/IoHT-based technologies are used in DCTs or products developed using DCTs.

Method

To understand the study and development field of IoMT/IoHT comprehensively and panoramically, relevant papers published in Web of Science were searched online. Subsequently, a citation network was obtained and characterized as a cluster using a text mining method to identify IoMT/IoHT-based technologies expected to be utilized in DCTs or products developed using DCTs.

Result and Discussion

Upon analysis of the top 15 clusters and subsequent 51 sub-clusters, we identified the therapeutic areas (psychology, neurology) and IoMT/IoHT-based technologies (telemedicine, remote monitoring, and virtual reality) that are expected to be used in DCTs. We also identified several considerations based on the current regulatory guidance.

Conclusion

IoMT/IoHT-based technologies that are expected to be used or products developed using DCTs and key considerations made when they are used in DCTs were identified. The considerations could encourage conducting DCTs using IoMT/IoHT-based technologies.
Efficiently Predicting Vancomycin Resistance of Enterococcus Faecium From MALDI-TOF MS Spectra Using a Deep Learning-Based Approach
Authors: Wang Hsin-Yao , Hsieh Tsung-Ting , Chung Chia-Ru , Chang Hung-Ching , Horng Jorng-Tzong , Lu Jang-Jih , Huang Jia-Hsin
Published: June 2022

Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) has recently become a useful analytical approach for microbial identification. The presence and absence of specific peaks on MS spectra are commonly used to identify the bacterial species and predict antibiotic-resistant strains. However, the conventional approach using few single peaks would result in insufficient prediction power without using complete information of whole MS spectra. In the past few years, machine learning algorithms have been successfully applied to analyze the MALDI-TOF MS peaks pattern for rapid strain typing. In this study, we developed a convolutional neural network (CNN) method to deal with the complete information of MALDI-TOF MS spectra for detecting Enterococcus faecium, which is one of the leading pathogens in the world. We developed a CNN model to rapidly and accurately predict vancomycin-resistant Enterococcus faecium (VREfm) samples from the whole mass spectra profiles of clinical samples. The CNN models demonstrated good classification performances with the average area under the receiver operating characteristic curve (AUROC) of 0.887 when using external validation data independently. Additionally, we employed the score-class activation mapping (CAM) method to identify the important features of our CNN models and found some discriminative signals that can substantially contribute to detecting the ion of resistance. This study not only utilized the complete information of MALTI-TOF MS data directly but also provided a practical means for rapid detection of VREfm using a deep learning algorithm.
Transcriptomic Responses of Mycoplasma bovis Upon Treatments of trans-Cinnamaldehyde, Carvacrol, and Eugenol
Authors: Ranjitkar Saurav , Duan Jingyue Ellie , Srirattana Kanokwan , Alqahtani Fahad , Tulman Edan R. , Mandoiu Ion , Venkitanarayanan Kumar , Tian Xiuchun
Published: June 2022

Mycoplasma bovis (M. bovis) is an insidious, wall-less primary bacterial pathogen that causes bovine pneumonia, mid-ear infection, mastitis, and arthritis. The economic losses caused by M. bovis due to culling, diminished milk production, and feed conversion are underestimated because of poor diagnosis/recognition. Treatment with common antibiotics targeting the cell wall is ineffective. Plant-derived antimicrobials (PDAs) such as food-grade trans-cinnamaldehyde (TC), eugenol (EU), and carvacrol (CAR) are inexpensive and generally regarded as safe for humans and animals yet possess strong anti-bacterial properties. In preliminary studies, we found that all three PDAs inhibited the growth of M. bovis in vitro. Through RNA sequencing, we report here that CAR affected the expression of 153 genes which included the downregulation of energy generation-related proteins, pentose phosphate pathway, and upregulation of ribosomes and translation-related proteins. Few differentially expressed genes were found when M. bovis was treated with TC, EU, or when the three PDAs were double or triple combined. Our results suggest that, as opposed to the effect of CAR, the growth-inhibitory effects of TC and EU at levels tested may be exerted through mechanisms other than gene expression regulations.
Enhancing the Discovery of Bioactive Secondary Metabolites From Fungal Endophytes Using Chemical Elicitation and Variation of Fermentation Media
Authors: Gakuubi Martin Muthee , Ching Kuan Chieh , Munusamy Madhaiyan , Wibowo Mario , Liang Zhao-Xun , Kanagasundaram Yoganathan , Ng Siew Bee
Published: June 2022

Endophytic microorganisms are an important source of bioactive secondary metabolites. In this study, fungal endophytes obtained from A*STAR’s Natural Product Library (NPL) and previously isolated from different habitats of Singapore were investigated for their diversity, antimicrobial, and cytotoxic activities. A total of 222 fungal strains were identified on the basis of sequence analysis of ITS region of the rDNA gene. The identified fungal strains belong to 59 genera distributed in 20 orders. Majority of the identified strains (99%; 219 strains) belong to the phylum Ascomycota, while two strains belonged to the phylum Basidiomycota, and only one strain was from Mucoromycota phylum. The most dominant genus was Colletotrichum accounting for 27% of all the identified strains. Chemical elicitation using 5-azacytidine and suberoylanilide hydroxamic acid (SAHA) and variation of fermentation media resulted in the discovery of more bioactive strains. Bioassay-guided isolation and structure elucidation of active constituents from three prioritized fungal strains: Lophiotrema sp. F6932, Muyocopron laterale F5912, and Colletotrichum tropicicola F10154, led to the isolation of a known compound; palmarumycin C8 and five novel compounds; palmarumycin CP30, muyocopronol A-C and tropicicolide. Tropicicolide displayed the strongest antifungal activity against Aspergillus fumigatus with an IC50 value of 1.8 μg/ml but with a weaker activity against the Candida albicans presenting an IC50 of 7.1 μg/ml. Palmarumycin C8 revealed the best antiproliferative activity with IC50 values of 1.1 and 2.1 μg/ml against MIA PaCa-2 and PANC-1 cells, respectively.
Metformin Induces PRODH/POX-Dependent Apoptosis in Breast Cancer Cells
Authors: Huynh Thi Yen Ly , Oscilowska Ilona , Szoka Lukasz , Piktel Ewelina , Baszanowska Weronika , Bielawska Katarzyna , Bucki Robert , Miltyk Wojciech , Palka Jerzy
Published: June 2022

Although the antineoplastic activity of metformin (MET) is well established, the underlying mechanism of the activity is not understood. Since MET activates AMP kinase (AMPK) and proline dehydrogenase/proline oxidase (PRODH/POX) is stimulated by AMPK ligands (implicated in the regulation of cancer cell survival/apoptosis), the effect of MET on PRODH/POX-dependent apoptosis in wild-type MCF-7 cells (MCF-7WT) and POX knockdown MCF-7 cells (MCF-7crPOX cells) was studied. PRODH/POX catalyzes proline degradation generating ROS-induced apoptosis or autophagy. Availability of proline for PRODH/POX functions is regulated by the activity of prolidase (enzyme releasing proline from imidodipeptides), collagen biosynthesis (process consuming proline), and metabolism of proline, ornithine, and glutamic acid. We have found that MET is cytotoxic for MCF-7 cells (IC50∼17 mM), and to the lower extent for MCF-7crPOX cells (IC50∼28 mM). In MCF-7WT cells, the effect was accompanied by the inhibition of DNA biosynthesis, collagen biosynthesis, stimulation of ROS formation, AMPKα phosphorylation, and expression of prolidase, p53, caspase 8, caspase 9, and cleaved PARP. In MET-treated MCF-7crPOX cells, the processes were less affected than in MCF-7WT cells and the expression of caspase 9 was decreased, while cleaved caspase 8 and cleaved PARP were not detected. The effects were accompanied by an increase in the prolidase activity and proline concentration. The mechanism for MET-induced apoptosis involves the up-regulation of prolidase activity and a decrease in collagen biosynthesis contributing to an increase in the concentration of substrate (proline) for PRODH/POX-dependent ROS formation and activation of caspases −9 and −8. The data suggest that PRODH/POX participates in the MET-induced intrinsic and extrinsic apoptosis in MCF-7 cells.