Exploration of quality variation and stability of hybrid rice under multi-environments.

Improving quality is an essential goal of rice breeding and production. However, rice quality is not solely determined by genotype, but is also influenced by the environment. Phenotype plasticity refers to the ability of a given genotype to produce different phenotypes under different environmental conditions, which can be a representation of the stability of traits. Seven quality traits of 141 hybrid combinations, deriving from the test-crossing of 7 thermosensitive genic male sterile (TGMS) and 25 restorer lines, were evaluated at 5 trial sites with intermittent sowing of three to five in Southern China. In the Yangtze River Basin, it was observed that delaying the sowing time of hybrid rice combinations leads to an improvement in their overall quality. Twelve parents were identified to have lower plasticity general combing ability (GCA) values with increased ability to produce hybrids with a more stable quality. The parents with superior quality tend to exhibit lower GCA values for plasticity. The genome-wide association study (GWAS) identified 13 and 15 quantitative trait loci (QTLs) associated with phenotype plasticity and BLUP measurement, respectively. Notably, seven QTLs simultaneously affected both phenotype plasticity and BLUP measurement. Two cloned rice quality genes, ALK and GL7, may be involved in controlling the plasticity of quality traits in hybrid rice. The direction of the genetic effect of the QTL6 (ALK) on alkali spreading value (ASV) plasticity varies in different cropping environments. This study provides novel insights into the dynamic genetic basis of quality traits in response to different cropping regions, cultivation practices, and changing climates. These findings establish a foundation for precise breeding and production of stable and high-quality rice. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01442-3.

Unifying Different Cancer Theories in a Unique Tumour Model: Chronic Inflammation and Deaminases as Meeting Points.

The increase in cancer incidences shows that there is a need to better understand tumour heterogeneity to achieve efficient treatments. Interestingly, there are several common features among almost all types of cancers, with chronic inflammation induction and deaminase dysfunctions singled out. Deaminases are a family of enzymes with nucleotide-editing capacity, which are classified into two main groups: DNA-based and RNA-based. Remarkably, a close relationship between inflammation and the dysregulation of these molecules has been widely documented, which may explain the characteristic intratumor heterogeneity, both at DNA and transcriptional levels. Indeed, heterogeneity in cancer makes it difficult to establish a unique tumour progression model. Currently, there are three main cancer models-stochastic, hierarchic, and dynamic-although there is no consensus on which one better resembles cancer biology because they are usually overly simplified. Here, to accurately explain tumour progression, we propose interactions among chronic inflammation, deaminases dysregulation, intratumor genetic heterogeneity, cancer phenotypic plasticity, and even the previously proposed appearance of cancer stem-like cell populations in the edges of advanced solid tumour masses (instead of being the cells of origin of primary malignancies). The new tumour development model proposed in this study does not contradict previously accepted models and it may open up a window to interesting therapeutic approaches.

Estimating the contribution of plant traits to light partitioning in simultaneous maize/soybean intercropping.

Spatial configuration and plant phenotypic plasticity contribute to increased light capture in relay intercropping, but there is little information on whether these factors also increase light capture in simultaneous intercropping. We developed and validated a three-dimensional functional-structural plant model to simulate light capture in maize and soybean sole crops and intercrop scenarios, using species traits observed in sole crops and intercrops. The intercrop maize phenotype had 2% greater light capture than the sole crop phenotype in a pure stand. The soybean intercrop phenotype had 5-10% lower light capture than the sole crop phenotype in a pure stand. The intercrop configuration increased the light capture of maize by 29% and reduced the light capture of soybean by 42%, compared with the light capture expected from sole crops. However, intercrop configuration only marginally affected total light capture by the intercrop system (+1%). Testing of individual soybean plant traits revealed that plasticity in leaf dimensions was the main reason for differences in light capture by soybean in simulated sole crops and intercrops. The results of this study illustrate a major shift of light capture from shorter species (soybean) to the taller component (maize) in a simultaneous strip intercrop. Plastic plant traits modulate this overall effect, but only marginally.

High-resolution genetic linkage map of European pear (Pyrus communis) and QTL fine-mapping of vegetative budbreak time.

BACKGROUND: Genomic analysis technologies can promote efficient fruit tree breeding. Genotyping by sequencing (GBS) enables generating efficient data for high-quality genetic map construction and QTL analysis in a relatively accessible way. Furthermore, High-resolution genetic map construction and accurate QTL detection can significantly narrow down the putative candidate genes associated with important plant traits. RESULTS: We genotyped 162 offspring in the F1 'Spadona' x 'Harrow Sweet' pear population using GBS. An additional 21 pear accessions, including the F1 population's parents, from our germplasm collection were subjected to GBS to examine diverse genetic backgrounds that are associated to agriculturally relevant traits and to enhance the power of SNP calling. A standard SNP calling pipeline identified 206,971 SNPs with Asian pear ('Suli') as the reference genome and 148,622 SNPs with the European genome ('Bartlett'). These results enabled constructing a genetic map, after further stringent SNP filtering, consisting of 2036 markers on 17 linkage groups with a length of 1433 cM and an average marker interval of 0.7 cM. We aligned 1030 scaffolds covering a total size of 165.5 Mbp (29%) of the European pear genome to the 17 linkage groups. For high-resolution QTL analysis covering the whole genome, we used phenotyping for vegetative budbreak time in the F1 population. New QTLs associated to vegetative budbreak time were detected on linkage groups 5, 13 and 15. A major QTL on linkage group 8 and an additional QTL on linkage group 9 were confirmed. Due to the significant genotype-by-environment (GxE) effect, we were able to identify novel interaction QTLs on linkage groups 5, 8, 9 and 17. Phenotype-genotype association analysis in the pear accessions for main genotype effect was conducted to support the QTLs detected in the F1 population. Significant markers were detected on every linkage group to which main genotype effect QTLs were mapped. CONCLUSIONS: This is the first vegetative budbreak study of European pear that makes use of high-resolution genetic mapping. These results provide tools for marker-assisted selection and accurate QTL analysis in pear, and specifically at vegetative budbreak, considering the significant GxE and phenotype-plasticity effects.

Combined analysis identifies six genes correlated with augmented malignancy from non-small cell to small cell lung cancer.

With increased malignancy, lung cancer can be classified into adenocarcinoma (ADC), squamous cell carcinoma (SQC), large cell carcinoma (LCC), and the small cell subtype (SCLC); yet, elucidations to this augmented malignancy has not been addressed. In this study, we elucidated the molecular diversity among these subtypes by investigating large-scale sequencing datasets. Among genes upregulated from normal, ADC, SQC, LCC to SCLC, six hub genes were found closely correlated with adverse clinical outcome and were testified on cellular or tissue level with quantitative RT-PCR. Cox regression model was then built to generate a risk signature. The possible linkages among these genes were also explored. Transcript levels of BUB1, E2F1, ESPL1, GTSE1, RAB3B, and U2AF2 were found significantly elevated from normal, ADC, SQC, LCC to SCLC. Overexpression of one or multiple of these genes was correlated with adverse overall survival (OS) and relapse-free survival (RFS) in the whole patient cohort or groups stratified according to clinical variables, while most of all six genes were independent prognostic factors. When used as a six-gene risk signature, patients with high signature score displayed more unfavorable clinical variables and poorer outcome. Tight regulative relationships were found within these genes, while BUB1 and E2F1 were likely to be the drivers. We considered the augmented malignancy from non-small cell lung cancer (NSCLC) to SCLC might be due to the elevation of these six genes. We believe these genes were powerful cancer prognostic markers and potential therapeutic targets in lung cancer; moreover, changes of their level might be correlated with lung cancer phenotype plasticity.

The role of cardiac fibroblasts in post-myocardial heart tissue repair.

The relative resistance of fibroblasts to hypoxia and their remarkable adaptive plasticity in response to rapid changes in local tissue microenvironment made interstitial cardiac fibroblasts to be a key player in post-myocardial infarction myocardial repair. Cardiac fibroblasts are abundantly presented in the interstitial and perivascular extracellular matrix. These cells can be rapidly mobilized in response to cardiac injury. Inflammatory activation of fibroblasts leads to the loss of their quiescent phenotype and inhibition of matrix-producing capacity. Acute inflammation that follows the infarct induces production of inflammatory mediators, matrix-degrading activity, proliferation, and migration of fibroblasts. Fibroblasts migrate to the injured myocardial site where undergo transdifferentiation to myofibroblasts in response to anti-inflammatory and mitogenic stimuli. They acquire capacity to synthesize matrix and contractile proteins. In the infarcted zone, fibroblasts/myofibroblasts actively proliferate, expand, and extensively produce and deposit collagen and other matrix proteins. The proliferative stage of heart healing transits to the scar maturation stage, in which collagen-based scar exhibits formation of intramolecular and extramolecular cross-links, deactivation and apoptosis of fibroblasts/myofibroblasts. Generally, cardiac reparation is strongly controlled. Inability to pass from one repair stage to another in a timely manner can induce detrimental events such as expansion of the infarct area due to advanced inflammation, cardiac fibrosis and adverse remodeling due to the excessive proliferative and profibrotic response, left ventricular hypertrophy, arrhythmogenicity, and heart failure.

Laminin drives survival signals to promote a contractile smooth muscle phenotype and airway hyperreactivity.

Increased airway smooth muscle (ASM) mass is believed to underlie the relatively fixed airway hyperresponsiveness (AHR) in asthma. Developments of therapeutic approaches to reverse airway remodeling are impeded by our lack of insight on the mechanisms behind the increase in mass of contractile ASM cells. Increased expression of laminin, an extracellular matrix protein, is associated with asthma. Our studies investigate the role of laminin-induced ASM survival signals in the development of increased ASM and AHR. Antagonizing laminin integrin binding using the laminin-selective competing peptide, YIGSR, and mimicking laminin with exogenous α2-chain laminin, we show that laminin is both necessary and sufficient to induce ASM cell survival, concomitant with the induction of ASM contractile phenotype. Using siRNA, we show that the laminin-binding integrin α7ß1 mediates this process. Moreover, in laminin-211-deficient mice, allergen-induced AHR was not observed. Notably, ASM cells from asthmatic airways express a higher abundance of intracellular cell survival proteins, consistent with a role for reduced rates of cell apoptosis in development of ASM hyperplasia. Targeting the laminin-integrin α7ß1 signaling pathway may offer new avenues for the development of therapies to reduce the increase in mass of contractile phenotype ASM cells that underlie AHR in asthma.

The apparent seasonal biphenism in Drosophila suzukii stems in reality from continuous reaction norms.

The spotted wing drosophila (SWD) is supposed to show only two distinct seasonal phenotypes: the dark, diapausing winter morph (WM) and the light, reproductively active summer morph (SM). It is unclear if these phenotypes result from a true developmental switch or from the expression of extreme phenotypes of continuous thermal reaction norms. This study aims to investigate this question by examining traits across a range of temperatures. Using 12 developmental temperatures (8 to 30 °C), we assessed traits including viability, growth, morphology, cold tolerance, metabolic rate, and ovarian maturation. Gradual increases in temperature induced gradual changes in all these traits, indicating classical nonlinear thermal reaction norms. Low temperatures (14 °C and below) produced flies with extended development, dark color, larger size, increased cold tolerance, reduced metabolism, and delayed oogenesis, characteristic of the WM. Given the months required for emergence and egg maturation at cold, distinct generations of SWD may develop in discrete environments resulting in an apparent biphenism. What appears to be distinct phenotypes (WM and SM) may actually result from continuous thermal reaction norms. This implies the need for precise terminology in SWD. We recommend using terms like 'winter-acclimated' or 'winter phenotype' rather than 'winter morph'. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

The cellular-centered view of hypoxia tumor microenvironment: Molecular mechanisms and therapeutic interventions.

Cancer is a profoundly dynamic, heterogeneous and aggressive systemic ailment, with a coordinated evolution of various types of tumor niches. Hypoxia plays an indispensable role in the tumor micro-ecosystem, drastically enhancing the plasticity of cancer cells, fibroblasts and immune cells and orchestrating intercellular communication. Hypoxia-induced signals, particularly hypoxia-inducible factor-1α (HIF-1α), drive the reprogramming of genetic, transcriptional, and proteomic profiles. This leads to a spectrum of interconnected processes, including augmented survival of cancer cells, evasion of immune surveillance, metabolic reprogramming, remodeling of the extracellular matrix, and the development of resistance to conventional therapeutic modalities like radiotherapy and chemotherapy. Here, we summarize the latest research on the multifaceted effects of hypoxia, where a multitude of cellular and non-cellular elements crosstalk with each other and co-evolve in a synergistic manner. Additionally, we investigate therapeutic approaches targeting hypoxic niche, encompassing hypoxia-activated prodrugs, HIF inhibitors, nanomedicines, and combination therapies. Finally, we discuss some of the issues to be addressed and highlight the potential of emerging technologies in the treatment of cancer.

Dynamic phenotypic shifts and M2 receptor downregulation in bladder smooth muscle cells induced by mirabegron.

Introduction: Mirabegron is available for treatment of overactive bladder (OAB). However, mechanisms underlying symptom improvements and long-term effects on bladder smooth muscle cells are uncertain. Contractility and growth of bladder smooth muscle contribute to OAB, and depend on smooth muscle phenotypes, and on muscarinic receptor expression. Here, we examined prolonged exposure to mirabegron (20-48 h) on phenotype markers, muscarinic receptor expression, and phenotype-dependent functions in human bladder smooth muscle cells (hBSMC). Methods: Expression of markers for contractile (calponin, MYH11) and proliferative (MYH10, vimentin) phenotypes, proliferation (Ki-67), and of muscarinic receptors were assessed by RT-PCR. Proliferation, viability, actin organization and contractions in cultured hBSMC were examined by EdU, CCK-8, phalloidin staining and matrix contraction assays. Results: Calponin-1 mRNA decreased with 100 nM and 150 nM mirabegron applied for 20 h (0.56-0.6 fold of controls). Decreases were resistant to the ß3-AR antagonist L-748,337 (0.34-0.55 fold, 100-150 nM, 20 h). After 40 h, decreases occured in the presence of L-748,337, but not without L-748,337. MYH11 mRNA increased with 150 nM mirabegron (40 h, 1.9 fold). This was partly preserved with L-748,337, but not observed after 20 h mirabegron exposure. Vimentin mRNA reduced with 150 nM mirabegron after 20 h, but not after 40 h, with and without L-748,337 (0.71-0.63 fold). MYH10 mRNA expression remained unaffected by mirabegron. Exposure to 150 nM mirabegron increased Ki-67 mRNA after 20 h in the presence of, but not without L-748,337, and after 40 h without, but not with L-748,337. Proliferation rates and actin organization were stable with 50-150 nM mirabegron (24 h, 48 h). Viability increased significantly after mirabegron exposure for 20 h, and by trend after 40 h, which was fully sensitive to L-748,337. M2 mRNA was reduced by 20 h mirabegron, which was resistant to L-748,337. Carbachol (3 µM) enhanced time-dependent contractions of hBSMC, which was inhibited by mirabegron (150 nM) in late phases (24 h), but not in early phases of contractions. Conclusion: Mirabegron induces dynamic phenotype alterations and M2 downregulation in hBSMC, which is paralleled by time-shifted anticontractile effects. Phenotype transitions may be involved in improvements of storage symptoms in OAB by mirabegron.

Unraveling molecular mechanisms underlying low-temperature adaptation in Laguncularia racemosa.

Laguncularia racemosa (L.) C.F. Gaertn is a controversial species in China, in terms of being a pioneer species for mangrove restoration and a putative invasive species occupying natural habitats. The tolerance to chilling stress allows L. racemosa to adapt to extreme climate change. However, little is known about the molecular-level chilling resistance mechanisms in L. racemosa, which restricts our understanding of its biological features and invasion potential. In this study, L. racemosa seedlings were treated with freezing temperature (0 °C) at four durations (0 h, 3 h, 12 h and 24 h of recovery after treatment), and both physiological and transcriptional regulations underlying chilling stress resistance were investigated. Chilling stress caused damage to the cell membrane system and reduced photosynthesis efficiency of L. racemosa seedlings. To combat the adverse impacts, plasma membrane biosynthesis and antioxidant processes were substantially enhanced. After 24 h of recovery, the seedlings nearly recovered to normal growth condition, except for the processes related to photosynthesis, indicating their vigorous adaptation to short-term chilling stress. Importantly, the individuals from higher latitude displayed better adaptation to chilling injury than those from lower latitude, highlighting the role of long-term heredity × environment interactions in promoting the chilling resistance capacity of L. racemosa. These features allow L. racemosa to survive in extremely cold weather, but may also increase its risk of invasion into intertidal ecosystems. Together, our findings present a comprehensive view of the chilling-adaptative mechanisms of L. racemosa, which provide clues for better evaluating the invasive potential of L. racemosa.

Chronic Heat Stress Part 2: Increased Stress and Fear Responses in F1 Pekin Ducks Raised from Parents That Experienced Heat Stress.

The effects of HS on the welfare of poultry have been reported to have a transgenerational effect on phenotype plasticity. The goal of our experiment was to determine whether parental exposure to HS would impair the performance, HPA axis response, or behavior of their offspring. We treated adult drakes and hens (n = 80 ducks/treatment) at peak lay with HS or the control temperature for 3 weeks and incubated eggs collected from the last 3 days of the experiment. We utilized 76 ducklings/parental treatment group: control (CON-F1) and HS (HS-F1). Weekly data for body weights, body condition scores (BCSs), and novel object test (NOT) were collected. At 3 weeks of age, the ducks (n = 6/treatment) were subjected to adrenocorticotropic hormone (ACTH/cosyntropin, 0.0625 mg/kg) challenge or vehicle as the control. Blood samples were collected at 0, 1, 2, 3, and 4 h relative to treatment for serum glucocorticoid and heterophil-to-lymphocyte ratio (HLR) analyses. All injected birds were euthanized with pentobarbital on the second day relative to ACTH administration, and the spleen and bursa were removed and weighed immediately. Duck level analyses were completed using one- or two-way ANOVA as appropriate. BCSs were analyzed using a chi-squared test. The HS-F1 ducks had a lower hatch weight (p < 0.05) compared with the CON-F1 ducks but no significant difference in growth rates during the 5-week period. NOT (n = 4) analyses showed that the HS-F1 ducks had a greater fear response (p < 0.001) compared with the CON-F1 ducks. Similarly, an ACTH stimulation test showed that the HS-F1 ducks had significantly (p < 0.05) heightened corticosterone and HLR responses compared with the CON-F1 ducks. The HS-F1 ducks showed altered baseline and ACTH-stimulated levels of cortisol compared with the controls. Our data suggest that parental exposure to HS impacts the HPA response and fearfulness of the F1 generation in Pekin ducks.

Chronic Inflammation, Oxidative Stress and Metabolic Plasticity: Three Players Driving the Pro-Tumorigenic Microenvironment in Malignant Mesothelioma.

Malignant pleural mesothelioma (MPM) is a lethal and rare cancer, even if its incidence has continuously increased all over the world. Asbestos exposure leads to the development of mesothelioma through multiple mechanisms, including chronic inflammation, oxidative stress with reactive oxygen species (ROS) generation, and persistent aberrant signaling. Together, these processes, over the years, force normal mesothelial cells' transformation. Chronic inflammation supported by "frustrated" macrophages exposed to asbestos fibers is also boosted by the release of pro-inflammatory cytokines, chemokines, growth factors, damage-associated molecular proteins (DAMPs), and the generation of ROS. In addition, the hypoxic microenvironment influences MPM and immune cells' features, leading to a significant rewiring of metabolism and phenotypic plasticity, thereby supporting tumor aggressiveness and modulating infiltrating immune cell responses. This review provides an overview of the complex tumor-host interactions within the MPM tumor microenvironment at different levels, i.e., soluble factors, metabolic crosstalk, and oxidative stress, and explains how these players supporting tumor transformation and progression may become potential and novel therapeutic targets in MPM.

Targeting drug-tolerant cells: A promising strategy for overcoming acquired drug resistance in cancer cells.

Drug resistance remains the greatest challenge in improving outcomes for cancer patients who receive chemotherapy and targeted therapy. Surmounting evidence suggests that a subpopulation of cancer cells could escape intense selective drug treatment by entering a drug-tolerant state without genetic variations. These drug-tolerant cells (DTCs) are characterized with a slow proliferation rate and a reversible phenotype. They reside in the tumor region and may serve as a reservoir for resistant phenotypes. The survival of DTCs is regulated by epigenetic modifications, transcriptional regulation, mRNA translation remodeling, metabolic changes, antiapoptosis, interactions with the tumor microenvironment, and activation of signaling pathways. Thus, targeting the regulators of DTCs opens a new avenue for the treatment of therapy-resistant tumors. In this review, we first provide an overview of common characteristics of DTCs and the regulating networks in DTCs development. We also discuss the potential therapeutic opportunities to target DTCs. Last, we discuss the current challenges and prospects of the DTC-targeting approach to overcome acquired drug resistance. Reviewing the latest developments in DTC research could be essential in discovering of methods to eliminate DTCs, which may represent a novel therapeutic strategy for preventing drug resistance in the future.

Role of vascular smooth muscle cell clonality in atherosclerosis.

Atherosclerotic cardiovascular disease remains the leading cause of death worldwide. While many cell types contribute to the growing atherosclerotic plaque, the vascular smooth muscle cell (SMC) is a major contributor due in part to its remarkable plasticity and ability to undergo phenotype switching in response to injury. SMCs can migrate into the fibrous cap, presumably stabilizing the plaque, or accumulate within the lesional core, possibly accelerating vascular inflammation. How SMCs expand and react to disease stimuli has been a controversial topic for many decades. While early studies relying on X-chromosome inactivation were inconclusive due to low resolution and sensitivity, recent advances in multi-color lineage tracing models have revitalized the concept that SMCs likely expand in an oligoclonal fashion during atherogenesis. Current efforts are focused on determining whether all SMCs have equal capacity for clonal expansion or if a "stem-like" progenitor cell may exist, and to understand how constituents of the clone decide which phenotype they will ultimately adopt as the disease progresses. Mechanistic studies are also beginning to dissect the processes which confer cells with their overall survival advantage, test whether these properties are attributable to intrinsic features of the expanding clone, and define the role of cross-talk between proliferating SMCs and other plaque constituents such as neighboring macrophages. In this review, we aim to summarize the historical perspectives on SMC clonality, highlight unanswered questions, and identify translational issues which may need to be considered as therapeutics directed against SMC clonality are developed as a novel approach to targeting atherosclerosis.

Genetic interrogation of phenotypic plasticity informs genome-enabled breeding in cotton.

Phenotypic plasticity, or the ability to adapt to and thrive in changing climates and variable environments, is essential for developmental programs in plants. Despite its importance, the genetic underpinnings of phenotypic plasticity for key agronomic traits remain poorly understood in many crops. In this study, we aim to fill this gap by using genome-wide association studies to identify genetic variations associated with phenotypic plasticity in upland cotton (Gossypium hirsutum L.). We identified 73 additive quantitative trait loci (QTLs), 32 dominant QTLs, and 6799 epistatic QTLs associated with 20 traits. We also identified 117 additive QTLs, 28 dominant QTLs, and 4691 epistatic QTLs associated with phenotypic plasticity in 19 traits. Our findings reveal new genetic factors, including additive, dominant, and epistatic QTLs, that are linked to phenotypic plasticity and agronomic traits. Meanwhile, we find that the genetic factors controlling the mean phenotype and phenotypic plasticity are largely independent in upland cotton, indicating the potential for simultaneous improvement. Additionally, we envision a genomic design strategy by utilizing the identified QTLs to facilitate cotton breeding. Taken together, our study provides new insights into the genetic basis of phenotypic plasticity in cotton, which should be valuable for future breeding.

Phenotypic Plasticity in Juvenile Frogs That Experienced Predation Pressure as Tadpoles Does Not Alter Their Locomotory Performance.

Anuran species can respond to environmental changes via phenotypic plasticity, which can also result in ecological impacts across the life history of such species. We investigated the effects of predation pressure (i.e., the non-consumption effect) from the dragonfly larva (Anax parthenope) on the phenotypical change of tadpoles into juvenile frogs (specifically the black-spotted pond frog, Pelophylax nigromaculatus), and also analyzed the impact of morphological changes on locomotory performance after metamorphosis. The experiments on predator impact were conducted in the laboratory. Body length, weight, development timing, and metamorphosis timing in the presence of dragonfly nymphs were measured in both tadpoles and juvenile frogs. The body and tail shapes of the tadpoles, as well as the skeletal shape of the juvenile frogs, were analyzed using landmark-based geometric morphometrics. Furthermore, the locomotory performance of the juvenile frogs was tested by measuring their jumping and swimming speeds. Tadpoles that had grown with predators possessed smaller bodies, deeper tail fins, and slower development rates, and they waited longer periods of time before commencing metamorphosis. Having said this, however, the effect of predator cues on the body length and weight of juvenile frogs was not found to be significant. These juvenile frogs possessed longer limbs and narrower skulls, with subtle morphological changes in the pelvis and ilium, but there was no subsequent difference in their swimming and jumping speeds. Our results showed that the changes in anatomical traits that can affect locomotor performance are so subtle that they do not affect the jumping or swimming speeds. Therefore, we support the view that these morphological changes are thus by-products of an altered tadpole period, rather than an adaptive response to predator-escape ability or to post-metamorphosis life history. On the other hand, delayed metamorphosis, without an increase in body size, may still be disadvantageous to the reproduction, growth, and survival of frogs in their life history following metamorphosis.

Unlocking phenotypic plasticity provides novel insights for immunity and personalized therapy in lung adenocarcinoma.

Background: Unlocking phenotype plasticity (UPP) has been shown to have an essential role in the mechanism of tumor development and therapeutic response. However, the clinical significance of unlocking phenotypic plasticity in patients with lung adenocarcinoma is unclear. This study aimed to explore the roles of unlocking phenotypic plasticity in immune status, prognosis, and treatment in patients with lung adenocarcinoma (LUAD). Methods: Differentially expressed genes (DEGs) and clinical information of UPP were selected from the cancer genome atlas (TCGA) database, and the GO, KEGG enrichment analyses were performed. The independent prognostic genes were determined by univariate and multivariate Cox regression, and the UPP signature score was constructed. Patients with LUAD were divided into high- and low-risk groups according to the median of score, and the immunocytes and immune function, the gene mutation, and drug sensitivities between the two groups were analyzed. Finally, the results were validated in the GEO database. Results: Thirty-nine significantly DEGs were determined. Enrichment analysis showed that UPP-related genes were related to protein polysaccharides and drug resistance. The prognostic results showed that the survival of patients in the high-risk group was poorer than that in the low-risk group (p < 0.001). In the high- and low-risk groups, single nucleotide polymorphism (SNP) and C > T are the most common dissent mutations. The contents of immune cells were significantly different between high- and low-risk groups. And the immune functions were also significantly different, indicating that UPP affects the immunity in LUAD. The results from TCGA were validated in the GEO. Conclusion: Our research has proposed a new and reliable prognosis indicator to predict the overall survival. Evaluation of the UPP could help the clinician to predict therapeutic responses and make individualized treatment plans in patients with LUAD.

Detection of phenotype-specific therapeutic vulnerabilities in breast cells using a CRISPR loss-of-function screen.

Cellular phenotype plasticity between the epithelial and mesenchymal states has been linked to metastasis and heterogeneous responses to cancer therapy, and remains a challenge for the treatment of triple-negative breast cancer (TNBC). Here, we used isogenic human breast epithelial cell lines, D492 and D492M, representing the epithelial and mesenchymal phenotypes, respectively. We employed a CRISPR-Cas9 loss-of-function screen targeting a 2240-gene 'druggable genome' to identify phenotype-specific vulnerabilities. Cells with the epithelial phenotype were more vulnerable to the loss of genes related to EGFR-RAS-MAPK signaling, while the mesenchymal-like cells had increased sensitivity to knockout of G2 -M cell cycle regulators. Furthermore, we discovered knockouts that sensitize to the mTOR inhibitor everolimus and the chemotherapeutic drug fluorouracil in a phenotype-specific manner. Specifically, loss of EGFR and fatty acid synthase (FASN) increased the effectiveness of the drugs in the epithelial and mesenchymal phenotypes, respectively. These phenotype-associated genetic vulnerabilities were confirmed using targeted inhibitors of EGFR (gefitinib), G2 -M transition (STLC), and FASN (Fasnall). In conclusion, a CRISPR-Cas9 loss-of-function screen enables the identification of phenotype-specific genetic vulnerabilities that can pinpoint actionable targets and promising therapeutic combinations.

Cooperative behaviour and phenotype plasticity evolve during melanoma progression.

A major challenge for managing melanoma is its tumour heterogeneity based on individual co-existing melanoma cell phenotypes. These phenotypes display variable responses to standard therapies, and they drive individual steps of melanoma progression; hence, understanding their behaviour is imperative. Melanoma phenotypes are defined by distinct transcriptional states, which relate to different melanocyte lineage development phases, ranging from a mesenchymal, neural crest-like to a proliferative, melanocytic phenotype. It is thought that adaptive phenotype plasticity based on transcriptional reprogramming drives melanoma progression, but at which stage individual phenotypes dominate and moreover, how they interact is poorly understood. We monitored melanocytic and mesenchymal phenotypes throughout melanoma progression and detected transcriptional reprogramming at different stages, with a gain in mesenchymal traits in circulating melanoma cells (CTCs) and proliferative features in metastatic tumours. Intriguingly, we found that distinct phenotype populations interact in a cooperative manner, which generates tumours of greater "fitness," supports CTCs and expands organotropic cues in metastases. Fibronectin, expressed in mesenchymal cells, acts as key player in cooperativity and promotes survival of melanocytic cells. Our data reveal an important role for inter-phenotype communications at various stages of disease progression, suggesting these communications could act as therapeutic target.