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Abstract Genome-scale metabolic models (GEMs) can facilitate metabolism-focused multi-omics integrative analysis. Since Yeast8, the yeast-GEM of Saccharomyces cerevisiae, published in 2019, has been continuously updated by the community. This has increased the quality and scope of the model, culminating now in Yeast9. To evaluate its predictive performance, we generated 163 condition-specific GEMs constrained by single-cell transcriptomics from osmotic pressure or reference conditions. Comparative flux analysis showed that yeast adapting to high osmotic pressure benefits from upregulating fluxes through central carbon metabolism. Furthermore, combining Yeast9 with proteomics revealed metabolic rewiring underlying its preference for nitrogen sources. Lastly, we created strain-specific GEMs (ssGEMs) constrained by transcriptomics for 1229 mutant strains. Well able to predict the strains’ growth rates, fluxomics from those large-scale ssGEMs outperformed transcriptomics in predicting functional categories for all studied genes in machine learning models. Based on those findings we anticipate that Yeast9 will continue to empower systems biology studies of yeast metabolism.

The precise segmentation of different regions of the prostate is crucial in the diagnosis and treatment of prostate-related diseases. However, the scarcity of labeled prostate data poses a challenge for the accurate segmentation of its different regions. We perform the segmentation of different regions of the prostate using U-Net- and Vision Transformer (ViT)-based architectures. We use five semi-supervised learning methods, including entropy minimization, cross pseudo-supervision, mean teacher, uncertainty-aware mean teacher (UAMT), and interpolation consistency training (ICT) to compare the results with the state-of-the-art prostate semi-supervised segmentation network uncertainty-aware temporal self-learning (UATS). The UAMT method improves the prostate segmentation accuracy and provides stable prostate region segmentation results. ICT plays a more stable role in the prostate region segmentation results, which provides strong support for the medical image segmentation task, and demonstrates the robustness of U-Net for medical image segmentation. UATS is still more applicable to the U-Net backbone and has a very significant effect on a positive prediction rate. However, the performance of ViT in combination with semi-supervision still requires further optimization. This comparative analysis applies various semi-supervised learning methods to prostate zonal segmentation. It guides future prostate segmentation developments and offers insights into utilizing limited labeled data in medical imaging.

The efficacy of the available genome-walking methods is restricted by low specificity, high background, or composite operations. We herein conceived bridging PCR, an efficient genome-walking approach. Three primers with random sequences, inner walker primer (IWP), bridging primer (BP), and outer walker primer (OWP), are involved in bridging PCR. The BP is fabricated by splicing OWP to the 5′-end of IWP’s 5′-part. A bridging PCR set is constituted by three rounds of amplification reactions, sequentially performed by IWP, BP plus OWP, and OWP, respectively pairing with three nested sequence-specific primers (SSP). A non-target product arising from IWP alone undergoes end-lengthening mediated by BP. This modified non-target product is a preferentially formed hairpin between the lengthened ends, instead of binding with shorter OWP. Meanwhile, a non-target product, triggered by SSP alone or SSP plus IWP, is removed by nested SSP. As a result, only the target DNA is accumulated. The efficacy of bridging PCR was validated by walking the gadA/R genes of Levilactobacillus brevis CD0817 and the hyg gene of rice.

Genome-walking has been frequently applied to molecular biology and related areas. Herein, a simple but reliable genome-walking technique, termed semi-site-specific primer PCR (3SP-PCR), is presented. The key to 3SP-PCR is the use of a semi-site-specific primer in secondary PCR that partially overlaps its corresponding primary site-specific primer. A 3SP-PCR set comprises two rounds of nested amplification reactions. In each round of reaction, any primer is allowed to partially anneal to the DNA template once only in the single relaxed-stringency cycle, creating a pool of single-stranded DNAs. The target single-stranded DNA can be converted into a double-stranded molecule directed by the site-specific primer, and thus can be exponentially amplified by the subsequent high-stringency cycles. The non-target one cannot be converted into a double-strand due to the lack of a perfect binding site to any primer, and thus fails to be amplified. We validated the 3SP-PCR method by using it to probe the unknown DNA regions of rice hygromycin genes and Levilactobacillus brevis CD0817 glutamic acid decarboxylase genes.

Suppurative arthritis has an acute onset and mostly affects old people and children. Recently, the incidence of adult suppurative hip arthritis, as well as its serious consequences, has increased. The deep hip joint and surrounding hypertrophic muscle tissue limit physical examination. Furthermore, they may cause variable and atypical symptoms of suppurative hip arthritis, possibly inducing delayed diagnosis and treatment. This atypical presentation is uncommon, causing delayed diagnosis and treatment, thus worsening the outcomes. We herein report the case of a 58-year-old man with Staphylococcus aureus (S. aureus) septicemia and multiple organ failure due to left pyogenic arthritis of the hip. The patient’s early symptoms were extremely atypical given that he only presented hip pain. Moreover, there was no obvious history of trauma or inflammatory manifestations, such as fever or local swelling, and laboratory examination results and imaging findings were atypical. However, the disease progressed rapidly, developing into systemic sepsis within a short period of time followed by multiple organ failure and death. Early diagnosis and effective treatment of S. aureus hip arthritis are essential to avoid poor outcomes.

Stem cell-based and stem cell-derived exosome-based therapies have shown promising potential for endometrial regeneration and the clinical treatment of intrauterine adhesions (IUAs). Evidence shows that apoptosis occurs in a majority of grafted stem cells, and apoptotic bodies (ABs) play a critical role in compensatory tissue regeneration. However, the therapeutic potential of AB-based therapy and its mechanism have not been explored in detail. Here, a cell-free therapeutic strategy was developed by incorporating mesenchymal stem cell-derived ABs into a hyaluronic acid (HA) hydrogel to achieve endometrial regeneration and fertility restoration. Specifically, we found that the ABs could induce macrophage immunomodulation, cell proliferation, and angiogenesis in vitro. The HA hydrogel promoted the retention of ABs and facilitated their continuous release. In a murine model of acute endometrial damage and a rat model of IUAs, in situ injection of the AB-laden HA hydrogel could efficiently reduce fibrosis and promote endometrial regeneration, resulting in the fertility restoration. Consequently, ABs show good potential as therapeutic vesicles, and the AB-laden HA hydrogel appears to be a clinically feasible and cell-free alternative for endometrial regeneration and IUA treatment.

With the increasing amount of space debris, it is necessary to develop space debris active cleaning technology. The space netted pocket system is a flexible mechanism system which can be used to capture a non-cooperative target flexibly due to the advantages of having a stable structure, strong adaptability and a large capture range. In this paper, the dynamics of the space netted pocket system capturing a non-cooperative target are investigated. The dynamics model of the space netted pocket system is established based on the absolute nodal coordinate formulation (ANCF). The mathematic model of the closing rope is modeled using an ANCF flexible cable dynamics model. Then, the contact collision force model is presented to describe the collision characteristics during the space netted pocket system capturing the target. Finally, the dynamic characteristics of the space netted pocket system capturing the non-cooperative target are analyzed and discussed for different capturing strategies. The simulation results indicate that the target is captured successfully and the target contacts and collides with the rope net in the capturing process, which is subjected to contact and collision forces.

Mevalonate pyrophosphate decarboxylase (MPD) is a key enzyme in terpenoid biosynthesis. MPD plays an important role in the upstream regulation of secondary plant metabolism. However, studies on the MPD gene are relatively very few despite its importance in plant metabolism. Currently, no systematic analysis has been conducted on the MPD gene in plants under the order Apiales, which comprises important medicinal plants such as Panax ginseng and Panax notoginseng. This study sought to explore the structural characteristics of the MPD gene and the effect of adaptive evolution on the gene by comparing and analyzing MPD gene sequences of different campanulids species. For that, phylogenetic and adaptive evolution analyses were carried out using sequences for 11 Campanulids species. MPD sequence characteristics of each species were then analyzed, and the collinearity analysis of the genes was performed. As a result, a total of 21 MPD proteins were identified in 11 Campanulids species through BLAST analysis. Phylogenetic analysis, physical and chemical properties prediction, gene family analysis, and gene structure prediction showed that the MPD gene has undergone purifying selection and exhibited highly conserved structure. Analysis of physicochemical properties further showed that the MPD protein was a hydrophilic protein without a transmembrane region. Moreover, collinearity analysis in Apiales showed that MPD gene on chromosome 2 of D. carota and chromosome 1 of C. sativum were collinear. The findings showed that MPD gene is highly conserved. This may be a common characteristic of all essential enzymes in the biosynthesis pathways of medicinal plants. Notably, MPD gene is significantly affected by environmental factors which subsequently modulate its expression. The current study’s findings provide a basis for follow-up studies on MPD gene and key enzymes in other medicinal plants.

Atherosclerosis (AS) is universally defined as chronic vascular inflammation induced by dyslipidaemia, obesity, hypertension, diabetes and other risk factors. Extracellular vesicles as information transmitters regulate intracellular interactions and their important cargo circular RNAs are involved in the pathological process of AS. In this review, we summarize the current data to elucidate the emerging roles of extracellular vesicle-derived circular RNAs (EV-circRNAs) in AS and the mechanism by which EV-circRNAs affect the development of AS. Additionally, we discuss their vital role in the progression from risk factors to AS and highlight their great potential for use as diagnostic biomarkers of and novel therapeutic strategies for AS.

Over the last few years, a number of studies have quantified the role of radiomics, dynamic contrast enhancement and standard MRI (T2WI + DWI) in detecting prostate cancer; however, the aim of this paper was to assess the advantage of combining radiomics with other multiparametric magnetic resonance imaging (mpMRI) (T2-DWI-DCE) in improving the detection of prostate cancer. This study used 10 prostate-cancer-tissue-mimicking phantoms to obtain preclinical data. We then focused on 46 patients who underwent mpMRI and Transrectal Ultrasound (TRUS) guided biopsy between September 2016 and December 2017. The texture analysis parameters combined with the mpMRI and compared with the histopathology of TRUS biopsy have been assessed statistically by principal component analysis (PCA) and discriminant component analysis (DCA). The prediction model and goodness-of-fit were examined with the Akaike information criterion (AIC) and McFadden pseudo-R-squared. In the PCA, there was a higher separation between cancerous and noncancerous tissue in the preclinical compared with the clinical data. Both AIC and R2 showed an improvement in the model in cancer prediction by adding the radiomics to mpMRI. The discriminant analysis showed an accuracy of cancer prediction of 81% compared with 100% in the pre-clinical phantom data. Combining radiomics with mpMRI showed an improvement in prostate cancer prediction. The ex vivo experiments validated the findings of this study.

Theabrownins are macromolecular compounds with many hydroxyl, carboxyl, and phenolic functional groups. They are usually extracted from dark tea, in which they are present at low concentrations. In this paper, a low-cost microbial liquid fermentation method was established by inoculating Aspergillus niger with minced tea extract as the raw material. After applying the Box–Behnken and response surface approach design, the optimum fermentation conditions in the fermentor were determined to be an 8% (80 g/L) sucrose concentration, 1:31 (0.03226 g/mL) solid–liquid ratio, 4.141 × 106 CFU/mL bacterial liquid concentration, 5 d fermentation time, 28 °C fermentation temperature, 187 r/min (rpm) rotation speed, and an oxygenation of 0.5 V/V·min (V). After fermenting about 168 h, the theabrownins content reached the maximum of 28.34%. The total phenolic content of the liquid-fermented theabrownins was 25.74% higher than that of solid fermentation. Acidic functional groups were determined, indicating that the phenolic hydroxyl groups were the main acidic groups of the theabrownins. The antioxidant activity of theabrownins was verified by measuring the potassium ferricyanide reducing power, hydroxyl radical scavenging rate, superoxide anion radical scavenging rate, and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging rate of solid- and liquid-fermented chabein. The results of this study show that the production of theabrownins by the liquid fermentation of Aspergillus niger is fast, high in yield, and has antioxidant activity, which provides a basis for industrial production of theabrownins.

The associations between airway eosinophilia, measured in sputum or peripheral blood, and acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are inconsistent. We therefore aimed to determine the association between eosinophilia in bronchoalveolar lavage (BAL) fluid and AECOPD in a clinical cohort. We analyzed differential cell counts from baseline BAL fluid in participants in the DISARM clinical trial (Clinicaltrials.gov #NCT02833480) and classified participants by the presence or absence of BAL eosinophilia (>1% of total leukocytes). We determined the association between BAL eosinophilia and AECOPD over 1 year of follow-up using negative binomial regression and Cox proportional hazards test. N = 63 participants were randomized, and N = 57 had BAL differential cell counts available. Participants with BAL eosinophilia (N = 21) had a significantly increased rate of acute exacerbations (unadjusted incidence rate ratio (IRR) 2.0, p = 0.048; adjusted IRR 2.24, p = 0.04) and a trend toward greater probability of acute exacerbation (unadjusted hazard ratio (HR) 1.74, p = 0.13; adjusted HR 2.3, p = 0.1) in the year of follow-up compared to participants without BAL eosinophilia (N = 36). These associations were not observed for BAL neutrophilia (N = 41 participants), BAL lymphocytosis (N = 27 participants) or peripheral blood eosinophilia at various threshold definitions (2%, N = 37; 3%, N = 27; 4%, N = 16). BAL may therefore be a sensitive marker of eosinophilic inflammation in the distal lung and may be of benefit for risk stratification or biomarker-guided therapy in COPD.

This paper aims to investigate the optimal sorting of orders reflecting on the material changing lead time over the machines in the roofing manufacturing industry. Specifically, a number of jobs were sorted together based on the material used and then consolidated for subsequent processes, i.e., assigned to the corresponding machines. To achieve the optimal sorting for the received orders, a combinatorial dispatch rule was proposed, which were Earliest Due Date (EDD), First In First Out (FIFO), and Shortest Processing Time (SPT). The sequence of orders organized by the scheduling algorithm was able to minimize the changing material lead time and also maximize the number of orders to be scheduled in the production. Consequently, on-time delivery could be achieved. Tests based on real data have been set up to evaluate the performance of the proposed algorithm in sorting the received orders. As a result, the proposed algorithm has successfully reduced the material changing lead time by 47.3% and 40% in the first and second tests, respectively.

Background: Patients with chronic obstructive pulmonary disease (COPD) are commonly treated with inhaled corticosteroid/long-acting ß2-agonist combination therapy. While previous studies have investigated the host–microbiome interactions in COPD, the effects of specific steroid formulations on this complex cross-talk remain obscure. Methods: We collected and evaluated data from the Study to Investigate the Differential Effects of Inhaled Symbicort and Advair on Lung Microbiota (DISARM), a randomized controlled trial. Bronchoscopy was performed on COPD patients before and after treatment with salmeterol/fluticasone, formoterol/budesonide or formoterol-only. Bronchial brush samples were processed for microbial 16S rRNA gene sequencing and host mRNA sequencing. Longitudinal changes in the microbiome at a community, phylum and genus level were correlated with changes in host gene expression using a Spearman’s rank correlation test. Findings: In COPD patients treated with salmeterol/fluticasone, the expression levels of 676 host genes were significantly correlated to changes in the alpha diversity of the small airways. At a genus level, the expression levels of 122 host genes were significantly related to changes in the relative abundance of Haemophilus. Gene enrichment analyses revealed the enrichment of pathways and biological processes related to innate and adaptive immunity and inflammation. None of these changes were evident in patients treated with formoterol/budesonide or formoterol alone. Interpretation: Changes in the microbiome following salmeterol/fluticasone treatment are related to alterations in the host transcriptome in the small airways of patients with COPD. These data may provide insights into why some COPD patients treated with inhaled corticosteroids may be at an increased risk for airway infection, including pneumonia. Funding: The Canadian Institute of Health Research, the British Columbia Lung Association, and an investigator-initiated grant from AstraZeneca.

We report the case of a thirty-eight-year-old woman admitted to our hospital due to palpitation and chest distress. ST-T segment change was found in her ECG. She was then diagnosed with hypertrophic cardiomyopathy by two-dimensional echocardiography. Physical examination showed no obvious abnormal signs and all laboratory examinations were within the normal range. Myocardial fibrosis was detected by cardiac magnetic resonance imaging (MRI). A novel heterozygous mutation (c.235C>T/p.Arg79Cys) in TNNI3 for cardiac troponin I was identified in her. Subsequently, her families were investigated. No one died suddenly in her family. Her father, one of her siblings and one of her daughters had the same genetic mutation but with different clinical manifestations while the others were healthy. Her father and brother were also diagnosed with hypertrophic cardiomyopathy with different clinical manifestation. However, the echocardiography of her daughter was absolutely normal. We hypothesized that the Arg79Cys mutation in TNNI3 leads to a slow development of cardiac hypertrophy and the phenotype of this gene mutation is diverse.

Mechanical stimulation via acupuncture and tuina massage triggers various cell responses. This study aims to understand these cellular bio-physical mechanisms by investigating the effect of different stimulation intensities on cell viability and protein expression.

Lung macrophages are the key immune effector cells in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Several studies have shown an increase in their numbers in bronchoalveolar lavage fluid (BAL) of subjects with COPD compared to controls, suggesting a pathogenic role in disease initiation and progression. Although reduced lung macrophage phagocytic ability has been previously shown in COPD, the relationship between lung macrophages’ phenotypic characteristics and functional properties in COPD is still unclear. (1) Methods: Macrophages harvested from bronchoalveolar lavage (BAL) fluid of subjects with and without COPD (GOLD grades, I–III) were immuno-phenotyped, and their function and gene expression profiles were assessed using targeted assays. (2) Results: BAL macrophages from 18 COPD and 10 (non-COPD) control subjects were evaluated. The majority of macrophages from COPD subjects were non-polarized (negative for both M1 and M2 markers; 77.9%) in contrast to controls (23.9%; p < 0.001). The percentages of these non-polarized macrophages strongly correlated with the severity of COPD (p = 0.006) and current smoking status (p = 0.008). Non-polarized macrophages demonstrated poor phagocytic function in both the control (p = 0.02) and COPD (p < 0.001) subjects. Non-polarized macrophages demonstrated impaired ability to phagocytose Staphylococcus aureus (p < 0.001). They also demonstrated reduced gene expression for CD163, CD40, CCL13 and C1QA&B, which are involved in pathogen recognition and processing and showed an increased gene expression for CXCR4, RAF1, amphiregulin and MAP3K5, which are all involved in promoting the inflammatory response. (3) Conclusions: COPD is associated with an abundance of non-polarized airway macrophages that is related to the severity of COPD. These non-polarized macrophages are predominantly responsible for the poor phagocytic capacity of lung macrophages in COPD, having reduced capacity for pathogen recognition and processing. This could be a key risk factor for COPD exacerbation and could contribute to disease progression.

Fucoxanthin, a natural carotenoid, is abundant in seaweed with antioxidant properties. This study investigated the role of fucoxanthin in the induction of antioxidant enzymes involved in the synthesis of reduced glutathione (GSH), synthesized by glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione synthetase (GSS), via Akt/nuclear factor-erythroid 2-related (Nrf2) pathway in human keratinocytes (HaCaT) and elucidated the underlying mechanism. Fucoxanthin treatment increased the mRNA and protein levels of GCLC and GSS in HaCaT cells. In addition, fucoxanthin treatment promoted the nuclear translocation and phosphorylation of Nrf2, a transcription factor for the genes encoding GCLC and GSS. Chromatin immune-precipitation and luciferase reporter gene assays revealed that fucoxanthin treatment increased the binding of Nrf2 to the antioxidant response element (ARE) sequence and transcriptional activity of Nrf2. Fucoxanthin treatment increased phosphorylation of Akt (active form), an up-regulator of Nrf2 and exposure to LY294002, a phosphoinositide 3-kinase (PI3K)/Akt inhibitor, suppressed the fucoxanthin-induced activation of Akt, Nrf2, resulting in decreased GCLC and GSS expression. In accordance with the effects on GCLC and GSS expression, fucoxanthin induced the level of GSH. In addition, fucoxanthin treatment recovered the level of GSH reduced by ultraviolet B irradiation. Taken together, these findings suggest that fucoxanthin treatment augments cellular antioxidant defense by inducing Nrf2-driven expression of enzymes involved in GSH synthesis via PI3K/Akt signaling.

Abstract Background Over the past decade, gene expression microarray studies have greatly expanded our knowledge of genetic mechanisms of human diseases. Meta-analysis of substantial amounts of accumulated data, by integrating valuable information from multiple studies, is becoming more important in microarray research. However, collecting data of special interest from public microarray repositories often present major practical problems. Moreover, including low-quality data may significantly reduce meta-analysis efficiency. Results M2DB is a human curated microarray database designed for easy querying, based on clinical information and for interactive retrieval of either raw or uniformly pre-processed data, along with a set of quality-control metrics. The database contains more than 10,000 previously published Affymetrix GeneChip arrays, performed using human clinical specimens. M2DB allows online querying according to a flexible combination of five clinical annotations describing disease state and sampling location. These annotations were manually curated by controlled vocabularies, based on information obtained from GEO, ArrayExpress, and published papers. For array-based assessment control, the online query provides sets of QC metrics, generated using three available QC algorithms. Arrays with poor data quality can easily be excluded from the query interface. The query provides values from two algorithms for gene-based filtering, and raw data and three kinds of pre-processed data for downloading. Conclusion M2DB utilizes a user-friendly interface for QC parameters, sample clinical annotations, and data formats to help users obtain clinical metadata. This database provides a lower entry threshold and an integrated process of meta-analysis. We hope that this research will promote further evolution of microarray meta-analysis.

Abstract Background Anatomical studies of neural circuitry describing the basic wiring diagram of the brain produce intrinsically spatial, highly complex data of great value to the neuroscience community. Published neuroanatomical atlases provide a spatial framework for these studies. We have built an informatics framework based on these atlases for the representation of neuroanatomical knowledge. This framework not only captures current methods of anatomical data acquisition and analysis, it allows these studies to be collated, compared and synthesized within a single system. Results We have developed an atlas-viewing application ('NeuARt II') in the Java language with unique functional properties. These include the ability to use copyrighted atlases as templates within which users may view, save and retrieve data-maps and annotate them with volumetric delineations. NeuARt II also permits users to view multiple levels on multiple atlases at once. Each data-map in this system is simply a stack of vector images with one image per atlas level, so any set of accurate drawings made onto a supported atlas (in vector graphics format) could be uploaded into NeuARt II. Presently the database is populated with a corpus of high-quality neuroanatomical data from the laboratory of Dr Larry Swanson (consisting 64 highly-detailed maps of PHAL tract-tracing experiments, made up of 1039 separate drawings that were published in 27 primary research publications over 17 years). Herein we take selective examples from these data to demonstrate the features of NeuArt II. Our informatics tool permits users to browse, query and compare these maps. The NeuARt II tool operates within a bioinformatics knowledge management platform (called 'NeuroScholar') either as a standalone or a plug-in application. Conclusion Anatomical localization is fundamental to neuroscientific work and atlases provide an easily-understood framework that is widely used by neuroanatomists and non-neuroanatomists alike. NeuARt II, the neuroinformatics tool presented here, provides an accurate and powerful way of representing neuroanatomical data in the context of commonly-used brain atlases for visualization, comparison and analysis. Furthermore, it provides a framework that supports the delivery and manipulation of mapped data either as a standalone system or as a component in a larger knowledge management system.