Phenotypic Changes In Response Research Articles

Molecular basis of phenotypic plasticity in a marine ciliate.

Phenotypic plasticity, which involves phenotypic transformation in the absence of genetic change, may serve as a strategy for organisms to survive in complex and highly-fluctuating environments. However, its reaction norm, molecular basis, and evolution remain unclear in most organisms, especially microbial eukaryotes. In this study, we explored these questions by investigating the reaction norm, regulation, and evolution of phenotypic plasticity in the cosmopolitan marine free-living ciliates Glauconema spp., which undergo significant phenotypic changes in response to food shortages. This study led to the de novo assembly of macronuclear genomes using long-read sequencing, identified hundreds of differentially expressed genes associated with phenotypic plasticity in different life stages, validated the function of two of these genes, and revealed that the reaction norm of body shape in response to food density follows a power-law distribution. Purifying selection may be the dominant evolutionary force acting on the genes associated with phenotypic plasticity, and the overall data support the hypothesis that phenotypic plasticity is a trait maintained by natural selection. This study provides novel insight into the developmental genetics of phenotypic plasticity in non-model unicellular eukaryotes, and sheds light on the complexity and long evolutionary history of this important survival strategy.

From genetic mosaicism to tumorigenesis through indirect genetic effects.

Genetic mosaicism has long been linked to aging, and several hypotheses have been proposed to explain the potential connections between mosaicism and susceptibility to cancer. It has been proposed that mosaicism may disrupt tissue homeostasis by affecting intercellular communications and releasing microenvironmental constraints within tissues. The underlying mechanisms driving these tissue-level influences remain unidentified, however. Here, we present an evolutionary perspective on the interplay between mosaicism and cancer, suggesting that the tissue-level impacts of genetic mosaicism can be attributed to Indirect Genetic Effects (IGEs). IGEs can increase the level of cellular stochasticity and phenotypic instability among adjacent cells, thereby elevating the risk of cancer development within the tissue. Moreover, as cells experience phenotypic changes in response to challenging microenvironmental conditions, these changes can initiate a cascade of nongenetic alterations, referred to as Indirect non-Genetic Effects (InGEs), which in turn catalyze IGEs among surrounding cells. We argue that incorporating both InGEs and IGEs into our understanding of the process of oncogenic transformation could trigger a major paradigm shift in cancer research with far-reaching implications for practical applications.

Regulatory mechanism of macrophage polarization based on Hippo pathway.

Macrophages are found to infiltrate and migrate in a large number of Tumor-associated macrophages (TMEs) and other macrophages in the microenvironment of tumors and related diseases, and undergo phenotypic changes in response to a variety of cytokines, mainly including the primary phenotype M2 and the anti-tumor phenotype M1. The Hippo signaling pathway affects the development of cancer and other diseases through various biological processes, such as inhibition of cell growth. In this review, we focus on immune cells within the microenvironment of tumors and other diseases, and the role of the Hippo pathway in tumors on macrophage polarization in the tumor microenvironment (TME) and other diseases.

Endothelial cell dysfunction in cardiac disease: driver or consequence?

The vascular endothelium is a multifunctional cellular system which directly influences blood components and cells within the vessel wall in a given tissue. Importantly, this cellular interface undergoes critical phenotypic changes in response to various biochemical and hemodynamic stimuli, driving several developmental and pathophysiological processes. Multiple studies have indicated a central role of the endothelium in the initiation, progression, and clinical outcomes of cardiac disease. In this review we synthesize the current understanding of endothelial function and dysfunction as mediators of the cardiomyocyte phenotype in the setting of distinct cardiac pathologies; outline existing in vivo and in vitro models where key features of endothelial cell dysfunction can be recapitulated; and discuss future directions for development of endothelium-targeted therapeutics for cardiac diseases with limited existing treatment options.

Microphysiological Models of Lung Epithelium-Alveolar Macrophage Co-Cultures to Study Chronic Lung Disease.

The interactions between immune cells and epithelial cells influence the progression of many respiratory diseases, such as chronic obstructive pulmonary disease (COPD). In vitro models allow for the examination of cells in controlled environments. However, these models lack the complex 3D architecture and vast multicellular interactions between the lung resident cells and infiltrating immune cells that can mediate cellular response to insults. In this study, three complementary microphysiological systems are presented to delineate the effects of cigarette smoke and respiratory disease on the lung epithelium. First, the Transwell system allows the co-culture of pulmonary immune and epithelial cells to evaluate cellular and monolayer phenotypic changes in response to cigarette smoke exposure. Next, the human and mouse precision-cut lung slices system provides a physiologically relevant model to study the effects of chronic insults like cigarette smoke with the dissection of specific interaction of immune cell subtypes within the structurally complex tissue environment. Finally, the lung-on-a-chip model provides an adaptable system for live imaging of polarized epithelial tissues that mimic the in vivo environment of the airways. Using a combination of these models, a complementary approach is provided to better address the intricate mechanisms of lung disease.

Dendritic Cells: The Long and Evolving Road towards Successful Targetability in Cancer.

Dendritic cells (DCs) are a unique myeloid cell lineage that play a central role in the priming of the adaptive immune response. As such, they are an attractive target for immune oncology based therapeutic approaches. However, targeting these cells has proven challenging with many studies proving inconclusive or of no benefit in a clinical trial setting. In this review, we highlight the known and unknown about this rare but powerful immune cell. As technologies have expanded our understanding of the complexity of DC development, subsets and response features, we are now left to apply this knowledge to the design of new therapeutic strategies in cancer. We propose that utilization of these technologies through a multiomics approach will allow for an improved directed targeting of DCs in a clinical trial setting. In addition, the DC research community should consider a consensus on subset nomenclature to distinguish new subsets from functional or phenotypic changes in response to their environment.

Abstract 354: Beiging Of Perivascular Adipose Tissue Regulates Its Inflammation And Vascular Remodeling

Background: Inflammation plays a primordial role in atherosclerosis. Perivascular adipose tissue (PVAT) that surrounds the vasculature has been reported to undergo phenotypic changes in response to vascular inflammation. However, regulatory roles of PVAT in vascular inflammation and subsequent pathological remodeling remain unclear. Methods and Results: Endovascular injury was generated by wire insertion into the mice femoral artery. Here, we showed that vascular injury induced the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response and thus vascular remodeling as a protective mechanism. In a mouse model of endovascular injury, macrophages accumulated in PVAT, causing beiging phenotype change. Inhibition of PVAT beiging by adipose tissue-specific genetic ablation of PRDM16, a key regulator to beiging, exacerbated inflammation and vascular remodeling following injury. Local knockdown of Prdm16 in perivascular tissues of wild-type mice using small interfering RNA similarly exacerbated inflammation and vascular remodeling. Conversely, activation of PVAT beiging attenuated inflammation and pathological vascular remodeling. Single-cell RNA sequencing revealed that beige adipocytes abundantly expressed neuregulin 4 ( Nrg4 ) which critically regulated alternative macrophage activation. Furthermore, Nrg4 knockdown abolished the PVAT-mediated anti-inflammatory effects on macrophages. Importantly, significant beiging was observed in the diseased aortic PVAT in patients with acute aortic dissection. Conclusions: Endovascular injury induced the beiging of adjacent PVAT with macrophage accumulation, where NRG4 secreted from the beige PVAT facilitated alternative activation of macrophages, leading to the resolution of vascular inflammation. Our study demonstrated the pivotal roles of PVAT in vascular inflammation and remodeling and will open a new avenue for treating atherosclerosis.

Transcriptome analysis provides new insights into cold adaptation of corsac fox (Vulpes Corsac).

Vulpesare widely distributed throughout the world and have undergone drastic physiological and phenotypic changes in response to their environment. However, little is known about the underlying genetic causes of these traits, especially Vulpes corsac. In this study, RNA‐Seq was used to obtain a comprehensive dataset for multiple pooled tissues of corsac fox, and selection analysis of orthologous genes was performed to identify the genes that may be influenced by the low‐temperature environment. More than 6.32 Gb clean reads were obtained and assembled into a total of 173,353 unigenes with an average length of 557 bp for corsac fox. Selective pressure analysis showed that 16 positively selected genes (PSGs) were identified in corsac fox, red fox, and arctic fox. Enrichment analysis of PSGs showed that the LRP11 gene was enriched in several pathways related to the low‐temperature response and might play a key role in response to environmental stimuli of foxes. In addition, several positively selected genes were related to DNA damage repair (ELP2 and CHAF1A), innate immunity (ARRDC4 and S100A12), and the respiratory chain (NDUFA5), and these positively selected genes might play a role in adaptation to harsh wild fox environments. The results of common orthologous gene analysis showed that gene flow or convergent evolution might be an important factor in promoting regional differentiation of foxes. Our study provides a valuable transcriptomic resource for the evolutionary history of the corsac fox and the adaptations to the extreme environments.

DNA barcoding of Iranian leeches (Annelida: Clitellata: Hirudinida)

The diversity of freshwater leeches (Clitellata; Hirudinida) of Iran was estimated by employing both DNA barcoding and species delimitation methods. Phylogenetic relationships of arhynchobdellid (including Hirudinidae, Praobdellidae, Haemopidae, and Erpobdellidae) and rhynchobdellid (Glossiphoniidae) leeches were reconstructed, based on the cytochrome c oxidase subunit I (COI) locus, using both new sequence data and those available from GenBank. Our results suggest that each of Helobdella stagnalis (Linnaeus, 1758), Glossiphonia concolor (Aphathy, 1888), Erpobdella borisi Cichocka & Bielecki, 2015, Dina lineata (O.F. Müller, 1774), Hirudo orientalis Utevsky and Trontelj, 2005, Haemopis sanguisuga (Linnaeus, 1758), Limnatis paluda (Tennent, 1859), and two unidentified species of Dina and Trocheta (these did not find species-level matches in GenBank) are present in Iran. A potential case of phenotypic change in response to ecological adaptation was observed in E. borisi insofar as two genetically identical sub- and super-terranean morphotypes were distinguished. The glossiphoniids of Iran and Europe are admixed in the phylogenetic tree, revealing low COI variation and no divergence within species between the continents for these taxa.

Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells.

Resistance in clear cell renal cell carcinoma (ccRCC) against sunitinib is a multifaceted process encompassing numerous molecular aberrations. This induces clinical complications, reducing the treatment success. Understanding these aberrations helps us to select an adapted treatment strategy that surpasses resistance mechanisms, reverting the treatment insensitivity. In this regard, we investigated the dominant mechanisms of resistance to sunitinib and validated an optimized multidrug combination to overcome this resistance. Human ccRCC cells were exposed to single or chronic treatment with sunitinib to obtain three resistant clones. Upon manifestation of sunitinib resistance, morphometric changes in the cells were observed. At the molecular level, the production of cell membrane and extracellular matrix components, chemotaxis, and cell cycle progression were dysregulated. Molecules enforcing the cell cycle progression, i.e., cyclin A, B1, and E, were upregulated. Mass spectrometry analysis revealed the intra- and extracellular presence of N-desethyl sunitinib, the active metabolite. Lysosomal sequestration of sunitinib was confirmed. After treatment with a synergistic optimized drug combination, the cell metabolic activity in Caki-1-sunitinib-resistant cells and 3D heterotypic co-cultures was reduced by >80%, remaining inactive in non-cancerous cells. These results demonstrate geno- and phenotypic changes in response to sunitinib treatment upon resistance induction. Mimicking resistance in the laboratory served as a platform to study drug responses.

Genomic stability through time despite decades of exploitation in cod on both sides of the Atlantic

The mode and extent of rapid evolution and genomic change in response to human harvesting are key conservation issues. Although experiments and models have shown a high potential for both genetic and phenotypic change in response to fishing, empirical examples of genetic responses in wild populations are rare. Here, we compare whole-genome sequence data of Atlantic cod (Gadus morhua) that were collected before (early 20th century) and after (early 21st century) periods of intensive exploitation and rapid decline in the age of maturation from two geographically distinct populations in Newfoundland, Canada, and the northeast Arctic, Norway. Our temporal, genome-wide analyses of 346,290 loci show no substantial loss of genetic diversity and high effective population sizes. Moreover, we do not find distinct signals of strong selective sweeps anywhere in the genome, although we cannot rule out the possibility of highly polygenic evolution. Our observations suggest that phenotypic change in these populations is not constrained by irreversible loss of genomic variation and thus imply that former traits could be reestablished with demographic recovery.

Cross-Generational Effects and Non-random Developmental Response to Temperature Variation in Paramecium.

Unicellular organisms such as ciliates are largely neglected in research on adaptive developmental plasticity, although their nuclear dualism offers ideal circumstances to study development outside an embryonic context. Here, we gain first insights into the ability of the ciliate Paramecium to develop potentially adaptive phenotypic changes in response to early-life adversity. We show that, upon exposure to unconventional culture temperatures, germ line-to-soma differentiation gives rise to coordinated molecular changes that may help attune the number of functional gene copies to the new external conditions. The non-random somatic heterogeneity that developmental plasticity generates is largely epigenetically controlled, shaped by the parental experience, and may prompt a stress response. These findings establish Paramecium as a new model system to study the molecular basis and evolutionary significance of developmental plasticity. In echoing previous indications in mammals, they call for an incorporation of intergenerational effects in adaptation studies.

Rapid genomic and phenotypic change in response to climate warming in a widespread plant invader.

Predicting plant distributions under climate change is constrained by our limited understanding of potential rapid adaptive evolution. In an experimental evolution study with the invasive common ragweed (Ambrosia artemisiifolia L.) we subjected replicated populations of the same initial genetic composition to simulated climate warming. Pooled DNA sequencing of parental and offspring populations showed that warming populations experienced greater genetic divergence from their parents, than control populations. In a common environment, offspring from warming populations showed more convergent phenotypes in seven out of nine plant traits, with later flowering and larger biomass, than plants from control populations. For both traits, we also found a significantly higher ratio of phenotypic to genetic differentiation across generations for warming than for control populations, indicating stronger response to selection under warming conditions. As a measure for evolutionary rate, the phenotypic and sequence divergence between generations were assessed using the Haldane metric. Our approach combining comparisons between generations (allochronic) and between treatments (synchronic) in an experimental evolutionary field study, and linking population genomic data with phenotyping analyses provided a powerful test to detect rapid responses to selection. Our findings demonstrate that ragweed populations can rapidly evolve in response to climate change within a single generation. Short-term evolutionary responses to climate change may aggravate the impact of some plant invaders in the future and should be considered when making predictions about future distributions and impacts of plant invaders.

A new mode of NPR1 action via an NB-ARC-NPR1 fusion protein negatively regulates the defence response in wheat to stem rust pathogen.

Summary NPR1 has been found to be a key transcriptional regulator in some plant defence responses. There are nine NPR1 homologues (TaNPR1) in wheat, but little research has been done to understand the function of those NPR1‐like genes in the wheat defence response against stem rust (Puccinia graminis f. sp. tritici) pathogens.We used bioinformatics and reverse genetics approaches to study the expression and function of each TaNPR1.We found six members of TaNPR1 located on homoeologous group 3 chromosomes (designated as TaG3NPR1) and three on homoeologous group 7 chromosomes (designated as TaG7NPR1). The group 3 NPR1 proteins regulate transcription of SA‐responsive PR genes. Downregulation of all the TaNPR1 homologues via virus‐induced gene co‐silencing resulted in enhanced resistance to stem rust. More specifically downregulating TaG7NPR1 homeologues or Ta7ANPR1 expression resulted in stem rust resistance phenotype. By contrast, knocking down TaG3NPR1 alone did not show visible phenotypic changes in response to the rust pathogen. Knocking out Ta7ANPR1 enhanced resistance to stem rust. The Ta7ANPR1 locus is alternatively spliced under pathogen inoculated conditions.We discovered a new mode of NPR1 action in wheat at the Ta7ANPR1 locus through an NB‐ARC–NPR1 fusion protein negatively regulating the defence to stem rust infection.

Rapid genomic and phenotypic change in response to climate warming in a widespread plant invader

Rapid genomic and phenotypic change in response to climate warming in a widespread plant invader

Rapid genomic and phenotypic change in response to climate warming in a widespread plant invader

Rapid genomic and phenotypic change in response to climate warming in a widespread plant invader

Rapid genomic and phenotypic change in response to climate warming in a widespread plant invader

Rapid genomic and phenotypic change in response to climate warming in a widespread plant invader

Rapid genomic and phenotypic change in response to climate warming in a widespread plant invader

Rapid genomic and phenotypic change in response to climate warming in a widespread plant invader

Rapid genomic and phenotypic change in response to climate warming in a widespread plant invader

Rapid genomic and phenotypic change in response to climate warming in a widespread plant invader

Rapid genomic and phenotypic change in response to climate warming in a widespread plant invader

Rapid genomic and phenotypic change in response to climate warming in a widespread plant invader