Organ Level Research Articles

Bioassays with Allium cepa for the Monitoring of Toxicity in the Groundwater of Yucatan, Mexico

This study employed the Allium cepa bioassay to evaluate the toxic effects of contaminants in the Yucatan aquifer. Seven monitoring wells were studied during September and October 2021. Nutrient concentrations showed significant variation between sites, with samples closer to the coast (P3 and P7) presenting higher ammonia and phosphate concentrations. The pesticides found at the highest concentration were δ-HCH and chlorpyrifos, with 141.44 and 175.92 ng/L, respectively. Heptachlor and aldrin were present in sites P4oct and P2sept. Interestingly, DDT values were highly correlated with caffeine concentrations. The PAHs acenaphthylene and the sum of B(k)fluoranthene and B(b)fluoranthene presented the highest prevalence. B(k)fluoranthene and B(b)fluoranthene were the PAHs found at the highest concentration. The results of the A. cepa bioassay indicated no nuclear abnormalities. The study also found no statistical differences in the mitotic index, root length, biomarkers of oxidative stress, and inhibition of B-esterases between sites and controls. In summary, the wells sampled in the present study had low concentrations of contaminants that can be used as a proxy of anthropogenic discharges; the lack of effect in the biomarkers used at organism, cellular, and biochemical levels indicated no toxic effect on A. cepa roots.

CYRI controls epidermal wound closure and cohesion of invasive border cell cluster in Drosophila.

Cell motility is crucial for many biological processes including morphogenesis, wound healing, and cancer invasion. The WAVE regulatory complex (WRC) is a central Arp2/3 regulator driving cell motility downstream of activation by Rac GTPase. CYFIP-related Rac1 interactor (CYRI) proteins are thought to compete with WRC for interaction with Rac1 in a feedback loop regulating lamellipodia dynamics. However, the physiological role of CYRI proteins in vivo in healthy tissues is unclear. Here, we used Drosophila as a model system to study CYRI function at the cellular and organismal levels. We found that CYRI is not only a potent WRC regulator in single macrophages that controls lamellipodial spreading but also identified CYRI as a molecular brake on the Rac-WRC-Arp2/3 pathway to slow down epidermal wound healing. In addition, we found that CYRI limits invasive border cell migration by controlling cluster cohesion and migration. Thus, our data highlight CYRI as an important regulator of cellular and epithelial tissue dynamics conserved across species.

Sirtuins: Emergent Players in Tissue and Organ Regeneration

Sirtuins are a family of lysine deacetylases that regulate cellular homeostasis and energy sensing. Regeneration is the process that restores structural and functional homeostasis at the cellular, tissue, organ, and appendage levels. Several cellular processes, such as epithelial–mesenchymal transition (EMT), proliferation, migration, and differentiation, contribute to restoration after an injury. This review highlights the role of sirtuins in tissue, organ, and anatomical structure regeneration, showing how sirtuins modulate signalling pathways by deacetylating targets such as transcription factors. Furthermore, understanding the role of this protein family could help elucidate the molecular and cellular mechanisms underlying tissue regeneration, which may hold significant potential for fields such as regenerative medicine. The review compiles evidence suggesting that sirtuins are emerging factors in the regeneration of various organs (e.g., skin, liver, heart) and tissues (e.g., bone, muscle, cornea, spinal cord).

An automatic 3D tomato plant stemwork phenotyping pipeline at internode level based on tree quantitative structural modelling algorithm

Phenotypic traits of stemwork are important indicators of plant growing status, contributing to multiple research domains including yield estimation, breeding engineering, and disease control. Traditional plant phenotyping with human work faces serious bottlenecks on labour intensity and time consumption. In recent years, the application of Quantitative Structural Modeling (QSM) together with three-dimensional (3D) sensor-based data acquisition techniques provides a feasible solution towards the automatic stemwork phenotyping. Nevertheless, existing QSM-based pipelines are sensitive towards the point cloud quality, and mostly focus on the phenotyping at plant or organ level. Information at internode level which are closely related to photosynthesis and light absorption was generally overlooked. To this end, a 3D automatic stemwork phenotyping pipeline is developed for tomato plants at both plant and internode level. Coloured point clouds are taken as the sensor input of the pipeline. A semantic segmentation based on PointNet++ was used to detect and localise the stemwork points. To improve the quality of the segmented stemwork point clouds, a density-based refining pipeline is proposed containing three main processes: non-replacement resampling, interference branch removal, and noise removal. A Tree Quantitative Structural Modeling (TreeQSM) algorithm was then applied to the stemwork point cloud to construct a digital reconstruction. The target phenotypic traits were finally calculated from the digital model by employing an internode association process. The proposed phenotyping pipeline was evaluated with a test dataset containing three tomato plant cultivars: Merlice, Brioso, and Gardener Delight. The related rooted mean squared errors of calculated internode length, internode diameters, leaf branching angle, leaf phyllotactic angle, and stem length range from 4.8 to 64.4%. Considering the time consuming manual phenotyping process, the proposed work provides a feasible solution towards the high throughput plant phenotyping, from which facilitates the related research on plant breeding and crop management.

Multi-scale influences on Escherichia coli concentrations in shellfish: from catchment to estuary.

Sustainability of bivalve shellfish farming relies on clean coastal waters, however, high levels of faecal indicator organisms (FIOs, e.g. Escherichia coli) in shellfish results in temporary closure of shellfish harvesting beds to protect human health, but with economic consequences for the shellfish industry. Active Management Systems which can predict FIO contamination may help reduce shellfishery closures. This study evaluated predictors of E. coli concentrations in two shellfish species, the blue mussel (Mytilus edulis) and the Pacific oyster (Crassostrea gigas), at different spatial and temporal scales, within 12 estuaries in England and Wales. We aimed to: (i) identify consistent catchment-scale or within-estuary predictors of elevated E. coli levels in shellfish, (ii) evaluate whether high river flows associated with rainfall events were a significant predictor of shellfish E. coli concentrations, and the time lag between these events and E. coli accumulation, and (iii) whether operation of Combined Sewer Overflows (CSO) is associated with higher E. coli concentrations in shellfish. A cross-catchment analysis gave a good predictive model for contamination management (R2 = 0.514), with positive relationships between E. coli concentrations and river flow (p=0.001), turbidity (p=0.002) and nitrate (p=0.042). No effect was observed for catchment area, the number of point source discharges, or agricultural land use type. 64% of all shellfish beds showed a significant relationship between E. coli and river flow, with typical lag-times of 1-3 days. Detailed analysis of the Conwy estuary indicated that E. coli counts were consistently higher when the CSO had been active the previous week. In conclusion, we demonstrate that real-time river flow and water quality data may be used to predict potential risk of E. coli contamination in shellfish at the catchment level, however, further refinement (coupling to fine-scale hydrodynamic models) is needed to make accurate predictions for individual shellfish beds within estuaries.

Source vs sink limitations on tree growth: from physiological mechanisms to evolutionary constraints and terrestrial carbon cycle implications.

The potential for widespread sink-limited plant growth has received increasing attention in the literature in the past few years. Despite recent evidence for sink limitations to plant growth, there are reasons to be cautious about a sink-limited world view. First, source-limited vegetation models do a reasonable job at capturing geographic patterns in plant productivity and responses to resource limitations. Second, from an evolutionary perspective, it is nonadaptive for plants to invest in increasing carbon assimilation if growth is primarily sink-limited. In this review, we synthesize the potential evidence for and underlying physiology of sink limitation across terrestrial ecosystems and contrast mechanisms of sink limitation with those of source-limited productivity. We highlight evolutionary restrictions on the magnitude of sink limitation at the organismal level. We also detail where mechanisms regulating sink limitation at the organismal and ecosystem scale (e.g. the terrestrial carbon sink) diverge. Although we find that there is currently no direct evidence for widespread organismal sink limitation, we propose a series of follow-up growth chamber manipulations, systematized measurements, and modeling experiments targeted at diagnosing nonadaptive buildup of excess nonstructural carbohydrates that will help illuminate the prevalence and magnitude of organismal sink limitation.

Osteoplastic biomaterials from organic and mineral components of the bone matrix: a literature review

Introduction. The bones of the human and animal have a unique ability to remodel. The ability to constantly renew bone tissue determines the healing of fractures and the adaptation of bones to mechanical loads. However, the process of bone self-healing is effective only for defects of non-critical size. In segmental and critical defects, endogenous stimulation of bone tissue regeneration is required. In this regard, there remains a need to design osteoplastic biomaterials with improved pro-regenerative action. Every year, new data appear that expand our understanding of the methods and mechanisms for stimulating bone tissue restoration using artificial osteoplastic materials. Aim. Characteristics of modern methods of constructing biomimetic materials from organic and mineral components of bone matrix. Materials and methods. The literature review was conducted using the PubMed and ScienceDirect databases. Query dates — may–july 2024, query depth — 1965–2024. Main content of the review. Effective use of bone polymers for the creation of biomimetic osteoplastic materials is possible only with an understanding of the principles of molecular-cellular interaction of biopolymers with bone cells and tissues. By now, it has been established that the ability of collagen to influence the functional activity of cells involved in the reparative regeneration of bone tissue is due to the presence of special patterns in its structure - binding sites with cellular receptors, which are formed by a specific sequence of amino acids in the collagen polypeptide chain. In the case of inorganic bone material, the functionally significant elements are the chemical composition and crystal structure of calcium phosphate salts. A current trend in the design of osteoplastic materials is to impart biomimetic properties to them. At the molecular level, this approach is implemented using as intrafibrillar and extrafibrillar mineralization of collagen fibrils. At the tissue and organ level, biomimicry is achieved through the use of three-dimensional bioprinting technologies. Conclusion. Thus, thanks to advances in biology, physics, chemistry and engineering sciences, it was possible to develop new technologies for designing osteoplastic materials that imitate the structure and function of native bone tissue. The use of biomaterials created using biomimetics principles increases the efficiency of bone tissue damage restoration.

Anatomical complexity allows for heat-stressed giant clams to undergo symbiont shuffling at both organism and organ levels

Anatomical complexity allows for heat-stressed giant clams to undergo symbiont shuffling at both organism and organ levels

Potential Probiotic Bacillus Strains with Antioxidant and Antimutagenic Activity Increased Weight Gain and Altered hsp70, cxc, tnfα, il1β, and lysC Gene Expression in Clarias gariepinus

The potential probiotic properties of three Bacillus strains were studied. A probiotic supplement for the African catfish Clarias gariepinus was produced via the solid-state fermentation protocol and incorporated into the fish feed for a period of seven weeks. Since the 36th day of the experiment, all experimental groups had a statistically significant increase in their weight gain than the control group. The maximum weight gain observed in fish fed the probiotic-supplemented feed was 29.16% higher than that of the control group, and the maximum feed conversion rate improvement was 24%. Cell-free extracts from these strains showed antioxidant (11.55–27.40%) and DNA-protective (45.33–61.83%) activity in a series of in vitro biosensor tests. Further investigation into the antimutagenic activity of the strains revealed that two of them reduced the level of induced mutagenesis in an Escherichia coli model (by 33.58% and 54.35%, respectively). We also assessed the impact of probiotic strains on the expression of several key genes in the host (C. gariepinus), including hsp70, cxc, tnfα, il1β, and lysC. More than a 10-fold increase in expression rates was observed for hsp70 in gonads and liver; for cxc in muscles and gonads; for tnfα in brain, gills, and liver; for il1β in the brain, gills, gonads, and liver; and for lysC in gills, gonads, liver, and muscles. This study provides evidence that probiotics exhibiting antioxidant and antimutagenic properties can provide significant benefits in vivo within aquaculture systems. The molecular effects of these probiotics appear to be complex and tissue-specific, with both upregulation and downregulation of immune system genes observed. Nevertheless, at the organismal level, the impact was unequivocally positive in terms of aquaculture objectives, manifested as enhanced body weight gain in the fish. Consequently, these Bacillus strains warrant serious consideration as potential probiotics for this species.

Bioimaging and the future of whole-organismal developmental physiology

While omics has transformed the study of biology, concomitant advances made at the level of the whole organism, i.e. the phenome, have arguably not kept pace with lower levels of biological organisation. In this personal commentary we evaluate the importance of imaging as a means of measuring whole organismal developmental physiology. Image acquisition, while an important process itself, has become secondary to image analysis as a bottleneck to the use of imaging in research. Here, we explore the significant potential for increasingly sophisticated approaches to image analysis, including deep learning, to advance our understanding of how developing animals grow and function. Furthermore, unlike many species-specific methodologies, tools and technologies, we explore how computer vision has the potential to be transferable between species, life stages, experiments and even taxa in which embryonic development can be imaged. We identify what we consider are six of the key challenges and opportunities in the application of computer vision to developmental physiology carried out in our lab, and more generally. We reflect on the tangibility of transferrable computer vision models capable of measuring the integrative physiology of a broad range of developing organisms, and thereby driving the adoption of phenomics for developmental physiology. We are at an exciting time of witnessing the move from computer vision as a replacement for manual observation, or manual image analysis, to it enabling a fundamentally more powerful approach to exploring and understanding the complex biology of developing organisms, the quantification of which has long posed a challenge to researchers.

Associations between Immune-related Adverse Events and Prognosis in Cancer Patients Receiving Immune Checkpoint Inhibitor Therapy.

The number of patients with cancer qualifying for treatment with immune checkpoint inhibitors (ICIs) continues to increase, and a clearer understanding of the mechanisms underlying their activity-driven side effects or immune-related adverse events (irAEs) has become crucial. Patients receiving ICIs can develop irAEs in any organ, and numerous studies have suggested that irAE development may be associated with improved ICI efficacy. However, the robustness and magnitude of such associations are unclear, and little is known about the relationship between irAE development and ICI efficacy at the individual organ level. A precise understanding of these links could improve patient care and provide further insight into the immunological mechanisms underlying both irAE development and ICI efficacy. We herein review the prognostic implications of irAEs occurring in patients with cancer treated with ICIs and discuss outstanding issues that should be addressed in future studies.

Dosimetric and biological impact of activity extravasation of radiopharmaceuticals in PET imaging.

The increasing use of nuclear medicine and PET imaging has intensified scrutiny of radiotracer extravasation. To our knowledge, this topic is understudied but holds great potential for enhancing our understanding of extravasation in clinical PET imaging. This work aims to (1) quantify the absorbed doses from radiotracer extravasation in PET imaging, both locally at the site of extravasation and with the extravasation location as a source of exposure to bodily organs and (2) assess the biological ramifications within the injection site at the cellular level. A radiation dosimetry simulation was performed using a whole-body 4D Extended Cardiac-Torso (XCAT) phantom embedded in the GATE Monte Carlo platform. A 10-mCi dose of 18F-FDG was chosen to simulate a typical clinical PET scan scenario, with 10% of the activity extravasated in the antecubital fossa of the right arm of the phantom. The extravasation volume was modeled as a 5.5mL rectangle in the hypodermal layer of skin. Absorbed dose contributions were calculated for the first two half-lives, assuming biological clearance thereafter. Dose calculations were performed as absorbed doses at the organ and skin levels. Energy deposition was simulated both at the local extravasation site and in multiple organs of interest and converted to absorbed doses based on their respective masses. Each simulation was repeated ten times to estimate Monte Carlo uncertainties. Biological impacts on cells within the extravasated volume were evaluated by randomizing cells and exposing them to a uniform radiation source of 18F and 68Ga. Particle types, their energies, and direction cosines were recorded in phase space files using a separate Geant4 simulation to characterize their entry into the nucleus of the cellular volume. Subsequently, the phase space files were imported into the TOPAS-nBio simulation to assess the extent of DNA damage, including double-strand breaks (DSBs) and single-strand breaks (SSBs). Organ-level dosimetric estimations are presented for 18F and 68Ga radionuclides in various organs of interest. With 10% extravasation, the hypodermal layer of the skin received the highest absorbed dose of 1.32±0.01Gy for 18F and 0.99±0.01Gy for 68Ga. The epidermal and dermal layers received absorbed doses of 0.07±0.01Gy and 0.13±0.01Gy for 18F, and 0.14±0.01Gy and 0.29±0.01Gy for 68Ga, respectively. In the extravasated volume, 18F caused an average absorbed dose per nucleus of 0.17±0.01Gy, estimated to result in 10.58±0.50 DSBs and 268.11±12.43 SSBs per nucleus. For 68Ga, the absorbed dose per nucleus was 0.11±0.01Gy, leading to an estimated 6.49±0.34 DSBs and 161.24±8.12 SSBs per nucleus. Absorbed doses in other organs were on the order of micro-gray (µGy). The likelihood of epidermal erythema resulting from extravasation during PET imaging is low, as the simulated absorbed doses to the epidermis remain below the thresholds that trigger such effects. Moreover, the organ-level absorbed doses were found to be clinically insignificant across various simulated organs. The minimal DNA damage at the extravasation site suggests that long-term harm, such as radiation-induced carcinogenesis, is highly unlikely.

A porohyperelastic scheme targeted at High-Performance Computing frameworks for the simulation of the intervertebral disc

Background and Objective:The finite element method is widely used for studying the intervertebral disc at the organ level due to its ability to model complex geometries. An indispensable requirement for proper modelling of the intervertebral disc is a reliable porohyperelastic framework that captures the elaborate underlying mechanics. The increased complexity of such models requires significant computational power that is available within high-performance computing systems. The objective of this study is to present such a framework, validated both against literature and experiments, aiming to enable intervertebral disc research to benefit from state-of-the-art computational resources. Methods:In the context of this work, we implement a biphasic model that captures the mechanical response of the intricate, tissue-dependent models of the solid phase along with the hydrostatic pressure effects of the fluid phase. The tissue-dependent models involve the hyperelastic ground substance, fibrillar reinforcement, and osmotic swelling. The derived porohyperelastic, staggered scheme is implemented in Alya, a finite element code targeted at high-performance computing applications. The formulation is subsequently verified and validated by comparing the results of consolidation simulations with literature data for simulations and experiments using either generic or patient-specific geometries. Additionally, in-house experiments are replicated, evaluating the model’s ability to simulate alternating loading. Finally, the implementation’s circadian response is compared to previous implementation of similar material models in commercial software. Results:Results align well with experimental and literature findings in terms of disc height reduction (4% error), intradiscal pressure (14% error) and disc bulging. Validating the patient-specific geometry results in 4% and 7% deviation in measuring height loss. Simulations show excellent agreement with in-house experimental results, with less than 1% error regarding height reduction. Finally, the comparison to similar, published, earlier implementation in commercial software unveils excellent agreement of less than 1% error for the water content during circadian simulations. Simulation times are reported at 4 min per circadian cycle in the supercomputer Marenostrum V. Conclusions:This work presents a clear and validated formulation for simulating porohyperelastic materials based on assumptions that comply with the non-linear elasticity theory. The implementation in Alya enables intervertebral disc research to benefit from high-performance computing systems.

Abstract PR013: A vagal sensory-to-sympathetic axis restrains anti-tumor immunity

Abstract Solid tumors are innervated by distinct branches of the peripheral nervous system, and increased tumor innervation has been associated with poor cancer outcomes. However, it remains unexplored whether different types of nerves function together to sense and respond to a tumor, and how neural networks shape cancer immunity. As a major interoceptive system, vagal nerves sense a large variety of body signals and are critical for maintaining physiological homeostasis of visceral organs including the lung. While distinct vagal sensory neuron (VSN) subtypes have been identified to differently regulate pulmonary functions, it is unknown whether these VSNs interact with lung tumors and how they influence cancer progression. Here, we uncover that sensory nerves act through the sympathetic circuit to restrain anti-cancer immunity. Mechanistically, our data suggest that lung tumors hijack the vagal interoceptive system to activate sympathetic efferent nerves in the tumor microenvironment (TME), which in turn drive immune suppression via β2-adrenergic signaling in alveolar macrophages. Our key findings include: By applying anterograde labeling, tissue-clearing and 3D imaging to genetically engineered mouse models, we found that lung adenocarcinoma is richly innervated by vagal sensory nerves. We also showed that neurotrophic factors produced by cancer cells directly promote vagal sensory innervation. Furthermore, scRNA-seq analysis revealed tumor-induced transcriptional reprogramming of lung-innervating VSNs. Using multiple genetic tools to selectively label and deplete different VSN subtypes, we found that Npy2r + /Trpv1 + VSNs but not P2ry1 + VSNs innervate lung tumors and control lung cancer progression by inhibiting anti- cancer immunity. At the organism level, we demonstrated that vagal NPY2R/TRPV1 neurons inhibit anti-cancer immunity via the sympathetic axis. Depletion of vagal NPY2R/TRPV1 neurons resulted in reduced sympathetic nerve activity and a decreased norepinephrine level in the lung TME, whereas pharmacological activation of the sympathetic pathway suppressed the anti-tumor immune responses and restored tumor growth in mice lacking Npy2r + /Trpv1 + VSNs. At the molecular and cellular level, we identified that the vagal-to-sympathetic axis predominantly functions through β2-adrenergic signaling in alveolar macrophages (AMs) to drive immune suppression. AM depletion or selective deletion of β2-adrenergic receptor (ADRB2) in AMs derepressed the anti-tumor immunity and abolished the tumor-inhibiting effect of Npy2r + /Trpv1 + VSN ablation. Taken together, our study establishes an essential role of the sensory-to-sympathetic circuit in controlling cancer immunosurveillance, supporting the notion that the functional integration of sensory and sympathetic nerves systemically regulates anti- cancer immunity. Translationally, our findings from the preclinical model suggest that targeted disruption of the vagal sensory-to-sympathetic axis may provide new treatments for visceral organ cancers by enhancing anti-tumor immunity. Citation Format: Haohan Wei, Chuyue Yu, Bo Hu, Xing Zeng, Hiroshi Ichise, Ronald N. Germain, Rui Chang, Chengcheng Jin. A vagal sensory-to-sympathetic axis restrains anti-tumor immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR013.

Abstract I001: Long noncoding RNAs at the intersection of cancer pathways

Abstract There are thousands of long noncoding RNAs (lncRNAs) in mammalian genomes. Yet, their functional significance in health and disease states remains poorly understood. We investigate the intersection of lncRNAs and cancer biology. On the one hand, we dissect the molecular and cellular mechanisms by which lncRNAs modulate cancer pathways. On the other hand, we develop mouse models to interrogate the roles of lncRNAs in tumorigenesis at the organismal level. Our work has uncovered insights into the transcriptional regulatory roles of lncRNAs during the cellular response to genotoxic and oncogenic stress. In parallel, we have elucidated roles of lncRNAs as drivers of tumor progression and metastatic dissemination. The combined functional and mechanistic studies have revealed the importance of lncRNAs in cancer and suggest therapeutic approaches to target lncRNAs or their downstream effectors in cancer. Citation Format: Nadya Dimitrova. Long noncoding RNAs at the intersection of cancer pathways [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr I001.

Non-targeted N-glycome profiling reveals multiple layers of organ-specific diversity in mice

N-glycosylation is one of the most common protein modifications in eukaryotes, with immense importance at the molecular, cellular, and organismal level. Accurate and reliable N-glycan analysis is essential to obtain a systems-wide understanding of fundamental biological processes. Due to the structural complexity of glycans, their analysis is still highly challenging. Here we make publicly available a consistent N-glycome dataset of 20 different mouse tissues and demonstrate a multimodal data analysis workflow that allows for unprecedented depth and coverage of N-glycome features. This highly scalable, LC-MS/MS data-driven method integrates the automated identification of N-glycan spectra, the application of non-targeted N-glycome profiling strategies and the isomer-sensitive analysis of glycan structures. Our delineation of critical sub-structural determinants and glycan isomers across the mouse N-glycome uncovered tissue-specific glycosylation patterns, the expression of non-canonical N-glycan structures and highlights multiple layers of N-glycome complexity that derive from organ-specific regulations of glycobiological pathways.

Antioxidant Activity of Anthocyanins and Anthocyanidins: A Critical Review.

Anthocyanins are the main plant pigments responsible for the color of flowers, fruits, and vegetative organs of many plants, and are applied also as safe food colorants. They are efficient antioxidants. In this review, the reactivity of anthocyanins and their aglycones, anthocyanidins, in the main antioxidant assays, and their reactions with reactive oxygen and nitrogen species, effects of interactions with other compounds and metal ions on the antioxidant activity of anthocyanins and the electrochemical properties of anthocyanins are presented. Numerous cases of attenuation of oxidative stress at the cellular and organismal levels by anthocyanins are cited. The direct and indirect antioxidant action of anthocyanins, the question of the specificity of anthocyanin action in complex extracts, as well as limitations of cellular in vitro assays and biomarkers used for the detection of antioxidant effects of anthocyanins, are critically discussed.

The evolutionary landscape of prokaryotic chromosome/plasmid balance

The balance between chromosomal and plasmid DNAs determines the genomic plasticity of prokaryotes. Natural selections, acting on the level of organisms or plasmids, shape the abundances of plasmid DNAs in prokaryotic genomes. Despite the importance of plasmids in health and engineering, there have been rare systematic attempts to quantitatively model and predict the determinants underlying the strength of different selection forces. Here, we develop a metabolic flux model that describes the intracellular resource competition between chromosomal and plasmid-encoded reactions. By coarse graining, this model predicts a landscape of natural selections on chromosome/plasmid balance, which is featured by the tradeoff between phenotypic and non-phenotypic selection pressures. This landscape is further validated by the observed pattern of plasmid distributions in the vast collection of prokaryotic genomes retrieved from the NCBI database. Our results establish a universal paradigm to understand the prokaryotic chromosome/plasmid interplay and provide insights into the evolutionary origin of plasmid diversity.

RRAGD variants cause cardiac dysfunction in a zebrafish model.

The Ras-related GTP-binding protein D (RRAGD) gene plays a crucial role in cellular processes. Recently, RRAGD variants found in patients have been implicated in a novel disorder with kidney tubulopathy and dilated cardiomyopathy. Currently, the consequences of RRAGD variants at the organismal level are unknown. Therefore, this study investigated the impact of RRAGD variants on cardiac function using a zebrafish embryo model. Furthermore, the potential usage of rapamycin, an mTOR inhibitor, as a therapy was assessed in this model. Zebrafish embryos were injected with RRAGD p.S76L and p.P119R cRNA and the resulting heart phenotypes were studied. Our findings reveal that overexpression of RRAGD mutants resulted in decreased ventricular fractional shortening, ejection fraction, and pericardial swelling. In RRAGD S76L-injected embryos, lower survival and heartbeat were observed, whereas survival was unaffected in RRAGD P119R embryos. These observations were reversible following therapy with the mTOR inhibitor rapamycin. Moreover, no effects on electrolyte homeostasis were observed. Together, these findings indicate a crucial role of RRAGD in cardiac function. In the future, the molecular mechanisms by which RRAGD variants result in cardiac dysfunction and if the effects of rapamycin are specific for RRAGD-dependent cardiomyopathy should be studied in clinical studies.NEW & NOTEWORTHY The resultant heart-associated phenotypes in the zebrafish embryos of this study serve as a valuable experimental model for this rare cardiomyopathy. Moreover, the potential therapeutic property of rapamycin in cardiac dysfunctions was highlighted, making this study a pivotal step toward prospective clinical applications.

Electrophysiological tolerance: a new concept for understanding the electrical stability of the heart.

The co-ordinated electrical activity of ∼2 billion cardiac cells ensures stability of the heartbeat. Indeed, the remarkably low incidence (<1%) of ventricular arrhythmias in the healthy heart is only possible when the electrical event across this syncytium is closely controlled. In contrast, the diseased myocardium is associated with increased electrophysiological heterogeneity, unstable rhythm, and increased incidence of lethal arrhythmias. But what is the link between cellular and tissue level heterogeneity? Recent research has shown the existence of considerable cellular heterogeneity even in the healthy heart, suggesting that cell-to-cell variability in electrical (e.g. action potential duration) and mechanical performance (e.g. twitch amplitude) is a normal property. This observation has been previously unappreciated because the aggregated function in the form of QT-interval and cardiac output varies <1% on a beat-to-beat basis. This article describes the underlying cellular variability that is tolerated-and perhaps needed-by different regions of the heart for normal function and indicates why this variability is not apparent in function at the chamber and organ level. Thus, in contrast to the current dominant view, this article postulates that heterogeneity is normal and potentially endows various functional benefits. This new view of how the component parts of the heart come together to function also suggests novel mechanisms for cardiac pathologies, namely that dysfunction may emerge from changes in the extent and/or nature of heterogeneity. Once understood, restoring normal forms of heterogeneity could be a novel approach to treatment.