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This paper explores the spatial coverage potential of a vision sensor to implement a dual service for a museum security system. Services include object monitoring and invisible visual Multiple-Input and Multiple-Output (MIMO) communication. For object monitoring, the Kalman filter algorithm is used. To implement a secret visual MIMO communication, an Adaptive Row-Column (ARC)-based LSB substitution technique is used along with the Integer Wavelet Transform method. These proposed services are implemented using existing electronic visual displays and surveillance cameras. Experiments are carried out using a sample object and four stego images. The performance of the object tracking system is measured in terms of accuracy by comparing the actual and estimated position of an object. Similarly, the performance of the covert visual MIMO system is measured at two different stages. On the transmitter side, differences between the cover and stego-images are used to measure imperceptibility. Likewise, at the receiver, differences between the original and the reconstructed data images are used to measure the accuracy. Results illustrate that the proposed system has improved imperceptibility, accuracy, and robustness, as compared to existing techniques.

Zebrafish is a natural host of various Mycobacterium species and a surrogate model organism for tuberculosis research. Mycobacterium marinum is evolutionarily one of the closest non-tuberculous species related to M. tuberculosis and shares the majority of virulence genes. Although zebrafish is not a natural host of the human pathogen, we have previously demonstrated successful robotic infection of zebrafish embryos with M. tuberculosis and performed drug treatment of the infected larvae. In the present study, we examined for how long M. tuberculosis can be propagated in zebrafish larvae and tested a time series of infected larvae to study the transcriptional response via Illumina RNA deep sequencing (RNAseq). Bacterial aggregates carrying fluorescently labeled M. tuberculosis could be detected up to 9 days post-infection. The infected larvae showed a clear and specific transcriptional immune response with a high similarity to the inflammatory response of zebrafish larvae infected with the surrogate species M. marinum. We conclude that M. tuberculosis can be propagated in zebrafish larvae for at least one week after infection and provide further evidence that M. marinum is a good surrogate model for M. tuberculosis. The generated extensive transcriptome data sets will be of great use to add translational value to zebrafish as a model for infection of tuberculosis using the M. marinum infection system. In addition, we identify new marker genes such as dusp8 and CD180 that are induced by M. tuberculosis infection in zebrafish and in human macrophages at later stages of infection that can be further investigated.

Glutathione-S-transferases (GST) enzymes detoxify xenobiotics and are implicated in response to anticancer therapy. This study evaluated the association of GST theta 1 (GSTT1), GSTT2, and GSTT2B with Mycobacterium bovis Bacillus Calmette–Guérin (BCG) response in non-muscle-invasive bladder cancer treatment. In vitro assessments of GSTT2 knockout (KO) effects were performed using cell lines and dendritic cells (DCs) from GSTT2KO mice. Deletion of GSTT2B, GSTT1, and single-nucleotide polymorphisms in the promoter region of GSTT2 was analysed in patients (n = 205) and healthy controls (n = 150). Silencing GSTT2 expression in MGH cells (GSTT2BFL/FL) resulted in increased BCG survival (p < 0.05) and decreased cellular reactive oxygen species. In our population, there are 24.2% with GSTT2BDel/Del and 24.5% with GSTT2BFL/FL. With ≤ 8 instillations of BCG therapy (n = 51), 12.5% of GSTT2BDel/Del and 53.8% of GSTT2BFL/FL patients had a recurrence (p = 0.041). With ≥9 instillations (n = 153), the disease recurred in 45.5% of GSTT2BDel/Del and 50% of GSTT2BFL/FL. GSTT2FL/FL patients had an increased likelihood of recurrence post-BCG therapy (HR 5.5 [1.87–16.69] p < 0.002). DCs from GSTT2KO mice produced three-fold more IL6 than wild-type DCs, indicating a robust inflammatory response. To summarise, GSTT2BDel/Del patients respond better to less BCG therapy and could be candidates for a reduced surveillance regimen.

Hypertrophic cardiomyopathy (HCM) is a genetic disease characterized by unexplained left ventricular hypertrophy (LVH), diastolic dysfunction, and increased sudden-death risk. Early detection of the phenotypic expression of the disease in genetic carriers without LVH (Gen+/Phen−) is crucial for emerging therapies. This clinical study aims to identify echocardiographic predictors of phenotypic development in Gen+/Phen−. Sixteen Gen+/Phen− (one subject with troponin T, six with myosin heavy chain-7, and nine with myosin-binding protein C3 mutations), represented the study population. At first and last visit we performed comprehensive 2D speckle-tracking strain echocardiography. During a follow-up of 8 ± 5 years, five carriers developed LVH (LVH+). At baseline, these patients were older than those who did not develop LVH (LVH−) (30 ± 8 vs. 15 ± 8 years, p = 0.005). LVH+ had reduced peak global strain rate during the isovolumic relaxation period (SRIVR) (0.28 ± 0.05 vs. 0.40 ± 0.11 1/s, p = 0.048) and lower global longitudinal strain (GLS) (−19.8 ± 0.4 vs. −22.3 ± 1.1%; p < 0.0001) than LVH- at baseline. SRIVR and GLS were not correlated with age (overall, p > 0.08). This is the first HCM study investigating subjects before they manifest clinically significant or relevant disease burden or symptomatology, comparing at baseline HCM Gen+/Phen− subjects who will develop LVH with those who will not. Furthermore, we identified highly sensitive, easily obtainable, age- and load-independent echocardiographic predictors of phenotype development in HCM gene carriers who may undergo early preventive treatment.

Metastasis is the leading cause of cancer-related deaths. During this process, cancer cells are likely to navigate discrete tissue-tissue interfaces, enabling them to infiltrate and spread throughout the body. Three-dimensional (3D) spheroid modeling is receiving more attention due to its strengths in studying the invasive behavior of metastatic cancer cells. While microscopy is a conventional approach for investigating 3D invasion, post-invasion image analysis, which is a time-consuming process, remains a significant challenge for researchers. In this study, we presented an image processing pipeline that utilized a deep learning (DL) solution, with an encoder-decoder architecture, to assess and characterize the invasion dynamics of tumor spheroids. The developed models, equipped with feature extraction and measurement capabilities, could be successfully utilized for the automated segmentation of the invasive protrusions as well as the core region of spheroids situated within interfacial microenvironments with distinct mechanochemical factors. Our findings suggest that a combination of the spheroid culture and DL-based image analysis enable identification of time-lapse migratory patterns for tumor spheroids above matrix-substrate interfaces, thus paving the foundation for delineating the mechanism of local invasion during cancer metastasis.

Abstract Background High-dimensional prediction considers data with more variables than samples. Generic research goals are to find the best predictor or to select variables. Results may be improved by exploiting prior information in the form of co-data, providing complementary data not on the samples, but on the variables. We consider adaptive ridge penalised generalised linear and Cox models, in which the variable-specific ridge penalties are adapted to the co-data to give a priori more weight to more important variables. The R-package ecpc originally accommodated various and possibly multiple co-data sources, including categorical co-data, i.e. groups of variables, and continuous co-data. Continuous co-data, however, were handled by adaptive discretisation, potentially inefficiently modelling and losing information. As continuous co-data such as external p values or correlations often arise in practice, more generic co-data models are needed. Results Here, we present an extension to the method and software for generic co-data models, particularly for continuous co-data. At the basis lies a classical linear regression model, regressing prior variance weights on the co-data. Co-data variables are then estimated with empirical Bayes moment estimation. After placing the estimation procedure in the classical regression framework, extension to generalised additive and shape constrained co-data models is straightforward. Besides, we show how ridge penalties may be transformed to elastic net penalties. In simulation studies we first compare various co-data models for continuous co-data from the extension to the original method. Secondly, we compare variable selection performance to other variable selection methods. The extension is faster than the original method and shows improved prediction and variable selection performance for non-linear co-data relations. Moreover, we demonstrate use of the package in several genomics examples throughout the paper. Conclusions The R-package ecpc accommodates linear, generalised additive and shape constrained additive co-data models for the purpose of improved high-dimensional prediction and variable selection. The extended version of the package as presented here (version number 3.1.1 and higher) is available on ( https://cran.r-project.org/web/packages/ecpc/ ).

Actin-binding filamin C (FLNC) is expressed in cardiomyocytes, where it localizes to Z-discs, sarcolemma, and intercalated discs. Although FLNC truncation variants (FLNCtv) are an established cause of arrhythmias and heart failure, changes in biomechanical properties of cardiomyocytes are mostly unknown. Thus, we investigated the mechanical properties of human-induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) carrying FLNCtv. CRISPR/Cas9 genome-edited homozygous FLNCKO−/− hiPSC-CMs and heterozygous knock-out FLNCKO+/− hiPSC-CMs were analyzed and compared to wild-type FLNC (FLNCWT) hiPSC-CMs. Atomic force microscopy (AFM) was used to perform micro-indentation to evaluate passive and dynamic mechanical properties. A qualitative analysis of the beating traces showed gene dosage-dependent-manner “irregular” peak profiles in FLNCKO+/− and FLNCKO−/− hiPSC-CMs. Two Young’s moduli were calculated: E1, reflecting the compression of the plasma membrane and actin cortex, and E2, including the whole cell with a cytoskeleton and nucleus. Both E1 and E2 showed decreased stiffness in mutant FLNCKO+/− and FLNCKO−/− iPSC-CMs compared to that in FLNCWT. The cell adhesion force and work of adhesion were assessed using the retraction curve of the SCFS. Mutant FLNC iPSC-CMs showed gene dosage-dependent decreases in the work of adhesion and adhesion forces from the heterozygous FLNCKO+/− to the FLNCKO−/− model compared to FLNCWT, suggesting damaged cytoskeleton and membrane structures. Finally, we investigated the effect of crenolanib on the mechanical properties of hiPSC-CMs. Crenolanib is an inhibitor of the Platelet-Derived Growth Factor Receptor α (PDGFRA) pathway which is upregulated in FLNCtv hiPSC-CMs. Crenolanib was able to partially rescue the stiffness of FLNCKO−/− hiPSC-CMs compared to control, supporting its potential therapeutic role.

Fibroblasts are known for their ability to make and modify the extracellular matrix. However, there is more to them than meets the eye. It is now clear that they help define tissue microenvironments and support immune responses in organs. As technology advances, we have started to uncover the secrets of fibroblasts. In this Essay, we present fibroblasts as not only the builders and renovators of tissue environments but also the rheostat cells for immune circuits. Although they perform location-specific functions, they do not have badges of fixed identity. Instead, they display a spectrum of functional states and can swing between these states depending on the needs of the organ. As fibroblasts participate in a range of activities both in health and disease, finding the key factors that alter their development and functional states will be an important goal to restore homeostasis in maladapted tissues.

Human exposure to microplastics through inhalation has been widely reported in recent years. There is a paucity of work focusing on the direct effect of accumulation of microplastics in airways and how it may impact the respiratory function. This study aimed to investigate whether the exposure of microplastic would change the contractility of isolated airway smooth muscle tissue. Microplastics were obtained through milling of high-density polyethylene (HDPE) pellets by using a centrifugal mill. To confirm that the milled microplastic particle size range fell within the definition of microplastic, field-emission scanning electron microscope (FESEM) was employed. The milled microplastics particle size ranged from 44.2 µm to 552.4 µm. The organ bath technique was employed to study the direct change of tissue contractility of rat isolated tracheal rings. Tracheal rings were incubated with polyethylene microplastics of different concentrations (0.3 mg/ml to 10 mg/ml) for a minimum of 18 hours in physiological Krebs buffer, followed by the construction of concentration-response curves to a contractile agent, carbachol (muscarinic agonist). Exposure to all concentrations of polyethylene microplastics enhanced the contractile responses of the tissues to carbachol. However, the effect was only statistically significant in tissues incubated at 3 mg/ml and above (p < 0.05). Findings from this study provide preliminary evidence that exposure to polyethylene microplastics adversely affects airway function. Heightened contractile responses of airways mimic the pathophysiological responses in respiratory diseases such as asthma, chronic cough and chronic obstructive pulmonary disease. Further experiments focusing on the possible mechanism of actions of these microplastics affecting the airway tissue function are now needed.

Fibrotic tissues share many common features with neoplasms where there is an increased stiffness of the extracellular matrix (ECM). In this review, we present recent discoveries related to the role of the mechanosensitive ion channel Piezo1 in several diseases, especially in regulating tumor progression, and how this can be compared with cardiac mechanobiology. Based on recent findings, Piezo1 could be upregulated in cardiac fibroblasts as a consequence of the mechanical stress and pro-inflammatory stimuli that occurs after myocardial injury, and its increased activity could be responsible for a positive feedback loop that leads to fibrosis progression. The increased Piezo1-mediated calcium flow may play an important role in cytoskeleton reorganization since it induces actin stress fibers formation, a well-known characteristic of fibroblast transdifferentiation into the activated myofibroblast. Moreover, Piezo1 activity stimulates ECM and cytokines production, which in turn promotes the phenoconversion of adjacent fibroblasts into new myofibroblasts, enhancing the invasive character. Thus, by assuming the Piezo1 involvement in the activation of intrinsic fibroblasts, recruitment of new myofibroblasts, and uncontrolled excessive ECM production, a new approach to blocking the fibrotic progression can be predicted. Therefore, targeted therapies against Piezo1 could also be beneficial for cardiac fibrosis.

Coordinating among the demands of the external environment and internal plans requires cognitive control supported by a fronto-parietal control network (FPCN). Evidence suggests that multiple control systems span the FPCN whose operations are poorly understood. Previously (Nee and D’Esposito, 2016; 2017), we detailed frontal dynamics that support control processing, but left open their role in broader cortical function. Here, I show that the FPCN consists of an external/present-oriented to internal/future-oriented cortical gradient extending outwardly from sensory-motor cortices. Areas at the ends of this gradient act in a segregative manner, exciting areas at the same level, but suppressing areas at different levels. By contrast, areas in the middle of the gradient excite areas at all levels, promoting integration of control processing. Individual differences in integrative dynamics predict higher level cognitive ability and amenability to neuromodulation. These data suggest that an intermediary zone within the FPCN underlies integrative processing that supports cognitive control.

Over the past few decades, microplastics have become increasingly ubiquitous in the environment and now contaminate the bodies of many living organisms, including humans. Microplastics, as defined here, are plastics within the size range 0.1 μm and 5 mm and are a worrying form of pollution due to public health concerns. This mini-review aims to summarise the route of entry of microplastics into humans and explore the potential detrimental health effects of microplastics. Trophic transfer is an important pathway for microplastic to be transferred across different groups of organisms, with ingestion is regarded as one of the major routes of exposure for humans. Other pathways include inhalation and dermal contact. The health consequences of microplastics manifest because these materials can translocate into the circulatory system and accumulate in the lungs, liver, kidney, and even brain, regardless of the route of entry. Health effects include gastrointestinal disturbances such as inflammation and gut microbiota disruption, respiratory conditions, neurotoxicity and potential cancers. Overall, while it is apparent that microplastics are causing adverse effects on different biological groups and ecosystems, current research is largely focused on marine organisms and aquaculture. Therefore, more studies are needed to investigate specific effects in mammalian cells and tissues, with more long-term epidemiological studies needed on human population considered to be at high-risk due to socioeconomic or other circumstance. Knowledge of the toxicity and long-term health impacts of microplastics is currently limited and requires urgent attention.

Endophytic fungi are a promising source of bioactive metabolites with a wide range of pharmacological activities. In the present study, MS-based metabolomics was conducted to study the metabolomes variations of endophytic Diaporthe fraxini ED2 grown in different culture media. Total phenolic content (TPC), total flavonoid content (TFC), 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, 2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), and ferric reducing antioxidant power (FRAP) assays were conducted to assess the antioxidant potential of the fungal extracts. Multivariate data analysis (MVDA) was employed in data analysis and interpretation to elucidate the complex metabolite profile. The supplemented culture medium of D. fraxini fungal extract stimulated the production of metabolites not occurring in the normal culture medium. Antioxidant activity studies revealed the potential of supplemented cultured fungal extract of D. fraxini as a source of antioxidants. The present findings highlight that fungal culture medium supplementation is an effective approach to unravelling the hidden metabolome in plant-associated fungal diversity.

Ophiocordyceps sinensis is one of the most sought-after medicinal fungi used to treat various medical conditions such as respiratory diseases, liver and kidney dysfunctions. In China, it is widely used for alleviation of frequent urination where patients treated with O. sinensis have shown improvement in nocturia, which is the most common symptom of overactive bladder (OAB). Many studies have reported its anticancer, anti-inflammatory, anti-oxidative, hypoglycaemic and vasorelaxation properties. These properties are attributable to the presence of bioactive components such as polysaccharides, proteins and nucleosides. This mini-review highlights the medicinal potential of O. sinensis in alleviating OAB, which is a debilitating condition with a profound impact on the quality of life in a high proportion of older people. Four possible mechanisms of action of O. sinensis are suggested. Firstly, the relaxation of bladder smooth muscle through calcium dynamic, production of nitric acid (NO) and adenosine triphosphate (ATP). A second mechanism proposed is through the suppression of micturition reflex. The unequivocal properties of O. sinensis as anti-inflammatory and anti-oxidant, are two other plausible explanations, as both chronic inflammation and accumulation of oxidative stress molecules are associated with OAB exacerbation. With the recent success in cultivation of O. sinensis and the positive results from toxicity studies, a better understanding of its pharmacological actions can be further substantiated, including its use for relieving OAB.

Plant-derived terpenes are the prolific source of modern drugs such as taxol, chloroquine and artemisinin, which are widely used to treat cancer and malaria infections. There are research interests in recent years on terpene-derived metabolites (diterpenes, triterpenes and sesquiterpenes), which are believed to serve as excellent cholinesterase inhibitors. As cholinesterase inhibitors are the current treatment for Alzheimer’s disease, terpene-derived metabolites will have the potential to be involved in the future drug development for Alzheimer’s disease. Hence, a bibliographic search was conducted by using the keywords “terpene”, “cholinesterase” and “Alzheimer’s disease”, along with cross-referencing from 2011 to 2020, to provide an overview of natural terpenes with potential anticholinesterase properties. This review focuses on the extraction, chemical structures and anti-cholinesterase mechanisms of terpenes, which support and encourage future research on drug discovery and development in treating Alzheimer’s disease.

Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and progression to chronic kidney disease (CKD). However, no effective therapeutic intervention has been established for ischemic AKI. Endothelial progenitor cells (EPCs) have major roles in the maintenance of vascular integrity and the repair of endothelial damage; they also serve as therapeutic agents in various kidney diseases. Thus, we examined whether EPCs have a renoprotective effect in an IRI mouse model. Mice were assigned to sham, EPC, IRI-only, and EPC-treated IRI groups. EPCs originating from human peripheral blood were cultured. The EPCs were administered 5 min before reperfusion, and all mice were killed 72 h after IRI. Blood urea nitrogen, serum creatinine, and tissue injury were significantly increased in IRI mice; EPCs significantly improved the manifestations of IRI. Apoptotic cell death and oxidative stress were significantly reduced in EPC-treated IRI mice. Administration of EPCs decreased the expression levels of NLRP3, cleaved caspase-1, p-NF-κB, and p-p38. Furthermore, the expression levels of F4/80, ICAM-1, RORγt, and IL-17RA were significantly reduced in EPC-treated IRI mice. Finally, the levels of EMT-associated factors (TGF-β, α-SMA, Snail, and Twist) were significantly reduced in EPC-treated IRI mice. This study shows that inflammasome-mediated inflammation accompanied by immune modulation and fibrosis is a potential target of EPCs as a treatment for IRI-induced AKI and the prevention of progression to CKD.

Abstract Background While CRISPR-Cas systems hold tremendous potential for engineering the human genome, it is unclear how well each system performs against one another in both non-homologous end joining (NHEJ)-mediated and homology-directed repair (HDR)-mediated genome editing. Results We systematically compare five different CRISPR-Cas systems in human cells by targeting 90 sites in genes with varying expression levels. For a fair comparison, we select sites that are either perfectly matched or have overlapping seed regions for Cas9 and Cpf1. Besides observing a trade-off between cleavage efficiency and target specificity for these natural endonucleases, we find that the editing activities of the smaller Cas9 enzymes from Staphylococcus aureus (SaCas9) and Neisseria meningitidis (NmCas9) are less affected by gene expression than the other larger Cas proteins. Notably, the Cpf1 nucleases from Acidaminococcus sp. BV3L6 and Lachnospiraceae bacterium ND2006 (AsCpf1 and LbCpf1, respectively) are able to perform precise gene targeting efficiently across multiple genomic loci using single-stranded oligodeoxynucleotide (ssODN) donor templates with homology arms as short as 17 nucleotides. Strikingly, the two Cpf1 nucleases exhibit a preference for ssODNs of the non-target strand sequence, while the popular Cas9 enzyme from Streptococcus pyogenes (SpCas9) exhibits a preference for ssODNs of the target strand sequence instead. Additionally, we find that the HDR efficiencies of Cpf1 and SpCas9 can be further improved by using asymmetric donors with longer arms 5′ of the desired DNA changes. Conclusions Our work delineates design parameters for each CRISPR-Cas system and will serve as a useful reference for future genome engineering studies.

Endophytic fungi are microorganisms that colonize living plants’ tissues without causing any harm. They are known as a natural source of bioactive metabolites with diverse pharmacological functions. Many structurally different chemical metabolites were isolated from endophytic fungi. Recently, the increasing trends in human health problems and diseases have escalated the search for bioactive metabolites from endophytic fungi. The conventional bioassay-guided study is known as laborious due to chemical complexity. Thus, metabolomics studies have attracted extensive research interest owing to their potential in dealing with a vast number of metabolites. Metabolomics coupled with advanced analytical tools provides a comprehensive insight into systems biology. Despite its wide scientific attention, endophytic fungi metabolomics are relatively unexploited. This review highlights the recent developments in metabolomics studies of endophytic fungi in obtaining the global metabolites picture.

Clinical effects induced by arrhythmogenic cardiomyopathy (ACM) originate from a large spectrum of genetic variations, including the missense mutation of the lamin A/C gene (LMNA), LMNA D192G. The aim of our study was to investigate the biophysical and biomechanical impact of the LMNA D192G mutation on neonatal rat ventricular fibroblasts (NRVF). The main findings in mutated NRVFs were: (i) cytoskeleton disorganization (actin and intermediate filaments); (ii) decreased elasticity of NRVFs; (iii) altered cell–cell adhesion properties, that highlighted a strong effect on cellular communication, in particular on tunneling nanotubes (TNTs). In mutant-expressing fibroblasts, these nanotubes were weakened with altered mechanical properties as shown by atomic force microscopy (AFM) and optical tweezers. These outcomes complement prior investigations on LMNA mutant cardiomyocytes and suggest that the LMNA D192G mutation impacts the biomechanical properties of both cardiomyocytes and cardiac fibroblasts. These observations could explain how this mutation influences cardiac biomechanical pathology and the severity of ACM in LMNA-cardiomyopathy.

Digital twin (DT) is an emerging and fast-growing technology which provides a promising way to connect and integrate physical and virtual spaces seamlessly [...]

This editorial aims to summarize the eight scientific papers published in the Special Issue “Genetics and Molecular Pathogenesis of Non-ischemic Cardiomyopathies” [...]

The pattern of elements accumulation in biodeposits formed by living organisms and extracellular products of their metabolism (biofouling, primary soils) on different bedrocks (of the monuments of Historical necropoleis in Saint Petersburg) were studied by a complex of biological and mineralogical methods (optical microscopy, SEM, EDX, XRD, ICP MS, XRFS). The content of 46 elements in biodeposits with various communities of microorganisms is determined. The model recreating the picture of the input and selective accumulation of elements in biodeposits on the stone surface in outdoor conditions is assumed. It is shown that the main contribution to the elemental composition of biodeposits is made by the environment and the composition of the microbial community. The contribution of leaching under the action of microbial metabolites of mineral grains, entering biodeposits from the environment, is significantly greater than that of the underlying rock.

Arrhythmogenic cardiomyopathy (ACM) is a heritable myocardial disease that manifests with cardiac arrhythmias, syncope, sudden cardiac death, and heart failure in the advanced stages. The pathological hallmark of ACM is a gradual replacement of the myocardium by fibroadiposis, which typically starts from the epicardium. Molecular genetic studies have identified causal mutations predominantly in genes encoding for desmosomal proteins; however, non-desmosomal causal mutations have also been described, including genes coding for nuclear proteins, cytoskeleton componentsand proteins involved in excitation-contraction coupling. Despite the poor prognosis, currently available treatments can only partially control symptoms and to date there is no effective therapy for ACM. Inhibition of the canonical Wnt/β-catenin pathway and activation of the Hippo and the TGF-β pathways have been implicated in the pathogenesis of ACM. Yet, our understanding of the molecular mechanisms involved in the development of the disease and the cell source of fibroadiposis remains incomplete. Elucidation of the pathogenesis of the disease could facilitate targeted approaches for treatment. In this manuscript we will provide a comprehensive review of the proposed molecular and cellular mechanisms of the pathogenesis of ACM, including the emerging evidence on abnormal calcium homeostasis and inflammatory/autoimmune response. Moreover, we will propose novel hypothesis about the role of epicardial cells and paracrine factors in the development of the phenotype. Finally, we will discuss potential innovative therapeutic approaches based on the growing knowledge in the field.

Acute kidney injury (AKI) is the most common condition in hospitalized patients. As ischemia/reperfusion-induced AKI (IR-AKI) is as a major contributor to end-stage disease, an effective therapeutic intervention for IR-AKI is imperative. Erythropoietin (EPO) is a potent stimulator of erythroid progenitor cells and is significantly upregulated during hypoxia. Here, we investigated the renoprotective effects of EPO in an IR-AKI mouse model. Mice were assigned to sham, EPO only, and IR only groups, and the IR group was treated with EPO prior to injury. EPO was administered twice at 30 min prior to bilateral renal artery occlusion, and 5 min before reperfusion, with all mice sacrificed 24 h after IR-AKI. The serum was harvested for renal functional measurements. The kidneys were subjected to histological evaluation, and the biochemical changes associated with renal injury were assessed. EPO significantly attenuated the renal dysfunction associated with IR-AKI, as well as tissue injury. Apoptotic cell death and oxidative stress were significantly reduced in EPO-treated mice. Macrophage infiltration and expression of ICAM-1 and MCP-1 were also significantly reduced in EPO-treated mice. Furthermore, the expression of inflammasome-related factors (NLRP1, NLRP3, and caspase-1 cleavage), via the activation of the COX-2 and NF-κB signaling pathways were significantly reduced following EPO treatment. To our knowledge, this is the first study to demonstrate that inflammasome-mediated inflammation might be a potential target of EPO as a treatment for ischemic AKI.

Single-cell transcriptomic technologies have emerged as powerful tools to explore cellular heterogeneity at the resolution of individual cells. Previous scientific knowledge in cell biology is largely limited to data generated by bulk profiling methods, which only provide averaged read-outs that generally mask cellular heterogeneity. This averaged approach is particularly problematic when the biological effect of interest is limited to only a subpopulation of cells such as stem/progenitor cells within a given tissue, or immune cell subsets infiltrating a tumor. Great advances in single-cell RNA sequencing (scRNAseq) enabled scientists to overcome this limitation and allow for in depth interrogation of previously unexplored rare cell types. Due to the high sensitivity of scRNAseq, adequate attention must be put into experimental setup and execution. Careful handling and processing of cells for scRNAseq is critical to preserve the native expression profile that will ensure meaningful analysis and conclusions. Here, we delineate the individual steps of a typical single-cell analysis workflow from tissue procurement, cell preparation, to platform selection and data analysis, and we discuss critical challenges in each of these steps, which will serve as a helpful guide to navigate the complex field of single-cell sequencing.

The general notion of activation of Gq-protein coupled receptors involves the mobilisation of stored and extracellular calcium and leads to smooth muscle tissue contraction. The aim of this study was to investigate the involvement of calcium mediated contractions in vascular and airway smooth muscles. Using the standard organ bath procedures, aortic and tracheal rings were obtained from 6 to 8 week-old male Sprague Dawley rats. To activate the Gq protein receptors, phenylephrine (PE), an α1-adrenoceptor agonist, and carbachol, a M3 cholinoceptor agonist, was added to baths containing the aortic and tracheal rings, respectively. The maximum response (Emax) to PE was reduced from 158.8 ± 11.8% (n=6) to 62.5 ± 12.4 % (n=8) upon removal of extracellular calcium in Krebs-Ringer solution. Maximal response to PE was also suppressed in the presence of nifedipine, a L-type Ca2+ channel inhibitor, (70.3 ± 11 %, n=8) and SKF96365, a canonical transient receptor potential channel inhibitor, (26.7 ± 13.2 %, n=5) when the influx of extracellular calcium was blocked. Removal of stored calcium also attenuated the PE contraction (p0.05). From these observations, we conclude that the role of stored and extracellular calcium in Gq protein activation is not the same across different type of smooth muscle tissues.

Primordial germ cells (PGCs) are fate restricted to differentiate into gametes in vivo. However, when removed from their embryonic niche, PGCs undergo reversion to pluripotent embryonic germ cells (EGCs) in vitro. One of the major differences between EGCs and embryonic stem cells (ESCs) is variable methylation at imprinting control centers (ICCs), a phenomenon that is poorly understood. Here we show that reverting PGCs to EGCs involved stable ICC methylation erasure at Snrpn, Igf2r, and Kcnqot1. In contrast, the H19/Igf2 ICC undergoes erasure followed by de novo re-methylation. PGCs differentiated in vitro from ESCs completed Snrpn ICC erasure. However, the hypomethylated state is highly unstable. We also discovered that when the H19/Igf2 ICC was abnormally hypermethylated in ESCs, this is not erased in PGCs differentiated from ESCs. Therefore, launching PGC differentiation from ESC lines with appropriately methylated ICCs is critical to the generation of germline cells that recapitulate endogenous ICC erasure.

The lateral prefrontal cortex (LPFC) is essential for higher-level cognition, but the nature of its interactions in supporting cognitive control remains elusive. Previously (Nee and D'Esposito, 2016), dynamic causal modeling (DCM) indicated that mid LPFC integrates abstract, rostral and concrete, caudal influences to inform context-appropriate action. Here, we use continuous theta-burst transcranial magnetic stimulation (cTBS) to test this model causally. cTBS was applied to three LPFC sites and a control site in counterbalanced sessions. Behavioral modulations resulting from cTBS were largely predicted by information flow within the previously estimated DCM. However, cTBS to caudal LPFC unexpectedly impaired processes that are presumed to involve rostral LPFC. Adding a pathway from caudal to mid-rostral LPFC significantly improved the model fit and accounted for the observed behavioral findings. These data provide causal evidence for LPFC dynamics supporting cognitive control and demonstrate the utility of combining DCM with causal manipulations to test and refine models of cognition.

Higher-level cognition depends on the lateral prefrontal cortex (LPFC), but its functional organization has remained elusive. An influential proposal is that the LPFC is organized hierarchically whereby progressively rostral areas of the LPFC process/represent increasingly abstract information facilitating efficient and flexible cognition. However, support for this theory has been limited. Here, human fMRI data revealed rostral/caudal gradients of abstraction in the LPFC. Dynamic causal modeling revealed asymmetrical LPFC interactions indicative of hierarchical processing. Contrary to dominant assumptions, the relative strength of efferent versus afferent connections positioned mid LPFC as the apex of the hierarchy. Furthermore, cognitive demands induced connectivity modulations towards mid LPFC consistent with a role in integrating information for control operations. Moreover, the strengths of these dynamics were related to trait-measured higher-level cognitive ability. Collectively, these results suggest that the LPFC is hierarchically organized with the mid LPFC positioned to synthesize abstract and concrete information to control behavior.

Nanocellulose has high specific surface area, hydration properties, and ease of derivatization to prepare protease sensors. A Human Neutrophil Elastase sensor designed with a nanocellulose aerogel transducer surface derived from cotton is compared with cotton filter paper, and nanocrystalline cellulose versions of the sensor. X-ray crystallography was employed along with Michaelis–Menten enzyme kinetics, and circular dichroism to contrast the structure/function relations of the peptide-cellulose conjugate conformation to enzyme/substrate binding and turnover rates. The nanocellulosic aerogel was found to have a cellulose II structure. The spatiotemporal relation of crystallite surface to peptide-cellulose conformation is discussed in light of observed enzyme kinetics. A higher substrate binding affinity (Km) of elastase was observed with the nanocellulose aerogel and nanocrystalline peptide-cellulose conjugates than with the solution-based elastase substrate. An increased Km observed for the nanocellulosic aerogel sensor yields a higher enzyme efficiency (kcat/Km), attributable to binding of the serine protease to the negatively charged cellulose surface. The effect of crystallite size and β-turn peptide conformation are related to the peptide-cellulose kinetics. Models demonstrating the orientation of cellulose to peptide O6-hydroxymethyl rotamers of the conjugates at the surface of the cellulose crystal suggest the relative accessibility of the peptide-cellulose conjugates for enzyme active site binding.

Methylation of cytosines (5meC) is a widespread heritable DNA modification. During mammalian development, two global demethylation events are followed by waves of de novo DNA methylation. In vivo mechanisms of DNA methylation establishment are largely uncharacterized. Here, we use Saccharomyces cerevisiae as a system lacking DNA methylation to define the chromatin features influencing the activity of the murine DNMT3B. Our data demonstrate that DNMT3B and H3K4 methylation are mutually exclusive and that DNMT3B is co-localized with H3K36 methylated regions. In support of this observation, DNA methylation analysis in yeast strains without Set1 and Set2 shows an increase of relative 5meC levels at the transcription start site and a decrease in the gene-body, respectively. We extend our observation to the murine male germline, where H3K4me3 is strongly anti-correlated while H3K36me3 correlates with accelerated DNA methylation. These results show the importance of H3K36 methylation for gene-body DNA methylation in vivo.

Solanum is one of the largest flowering-angiosperm genera with 1500 species approximately. Five clados are recognized in Solanum, Leptostemonum is the largest group with 350-450 species distributed in the Old and Neotropic world. In the Neotropic 200 species are recognized. This study is an initial base for posterior studies of taxonomic and evolution diversity of Leptostemonum. The checklist of the names presented here is the result of the study of herbaria COL, COAH, FMB, HUA, JAUM, UPTC, INPA and MG collections and the revision of data bases as International Plant Name Index, Solanaceae Source, The New York virtual Herbarium and Tropicos. There were found 54 valid and effective-published names, 12 of these names associated to 14 synonyms in Colombia.

Abstract Genome-wide association studies (GWAS) look for correlations between traits of interest and genetic markers spread throughout the genome. A recent study in BMC Genetics has found that populations of the malaria parasite Plasmodium vivax should be amenable to GWAS searching for a genetic basis of parasite pathogenicity. Geographical substructure in populations may, however, prove a problem in interpreting the results. See research article http://www.biomedcentral.com/1471-2156/11/65