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BACKGROUND: Small songbirds respond and adapt to various geographical barriers during their annual migration. Global flyways reveal the diverse migration strategies in response to different geographical barriers, among which are high-elevation plateaus. However, few studies have been focused on the largest and highest plateau in the world, the Qinghai-Tibet Plateau (QTP) which poses a significant barrier to migratory passerines. The present study explored the annual migration routes and strategies of a population of Siberian Rubythroats (Calliope calliope) that breed on the north-eastern edge of the QTP. METHODS: Over the period from 2021 to 2023, we applied light-level geolocators (13 deployed, seven recollected), archival GPS tags (45 deployed, 17 recollected), and CAnMove multi-sensor loggers (with barometer, accelerometer, thermometer, and light sensor, 20 deployed, six recollected) to adult males from the breeding population of Siberian Rubythroat on the QTP. Here we describe the migratory routes and phenology extracted or inferred from the GPS and multi-sensor logger data, and used a combination of accelerometric and barometric data to describe the elevational migration pattern, flight altitude, and flight duration. All light-level geolocators failed to collect suitable data. RESULTS: Both GPS locations and positions derived from pressure-based inference revealed that during autumn, the migration route detoured from the bee-line between breeding and wintering grounds, leading to a gradual elevational decrease. The spring route was more direct, with more flights over mountainous areas in western China. This different migration route during spring probably reflects a strategy for faster migration, which corresponds with more frequent long nocturnal migration flights and shorter stopovers during spring migration than in autumn. The average flight altitude (1856 ± 781 m above sea level) was correlated with ground elevation but did not differ between the seasons. CONCLUSIONS: Our finding indicates strong, season-dependent impact of the Qinghai-Tibet Plateau on shaping passerine migration strategies. We hereby call for more attention to the unexplored central-China flyway to extend our knowledge on the environment-migration interaction among small passerines.
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The Hippo pathway transducers yes-associated protein (YAP) and WW-domain containing transcription regulator 1 (WWTR1/TAZ) are key regulators of liver tumorigenesis, promoting tumor formation and progression. Although the first inhibitors are in clinical trials, targeting the relevant upstream regulators of YAP/TAZ activity could prove equally beneficial. To identify regulators of YAP/TAZ activity in hepatocarcinoma (HCC) cells, we carried out a proximity labelling approach (BioID) coupled with mass spectrometry. We verified CRK-like proto-oncogene adaptor protein (CRKL) as a new YAP-exclusive interaction partner. CRKL is highly expressed in HCC patients, and its expression is associated with YAP activity as well as poor survival prognosis. In vitro experiments demonstrated CRKL-dependent cell survival and the loss of YAP binding induced through actin disruption. Moreover, we delineated the activation of the JNK/JUN pathway by CRKL, which promoted YAP transcription. Our data illustrate that CRKL not only promoted YAP activity through its binding but also through the induction of YAP transcription by JNK/JUN activation. This emphasizes the potential use of targeting the JNK/JUN pathway to suppress YAP expression in HCC patients.
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Proteínas Adaptadoras de Transdução de Sinal , Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteínas Nucleares , Fatores de Transcrição , Proteínas de Sinalização YAP , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas de Sinalização YAP/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Proto-Oncogene Mas , Linhagem Celular Tumoral , Ligação Proteica , Sistema de Sinalização das MAP Quinases , Regulação Neoplásica da Expressão Gênica , Transdução de SinaisRESUMO
Whether avian migrants can adapt to their changing world depends on the relative importance of genetic and environmental variation for the timing and direction of migration. In the classic series of field experiments on avian migration, A. C. Perdeck discovered that translocated juveniles failed to reach goal areas, whereas translocated adults performed 'true-goal navigation'. His translocations of > 14 000 common starlings (Sturnus vulgaris) suggested that genetic mechanisms guide juveniles into a population-specific direction, i.e. 'vector navigation'. However, alternative explanations involving social learning after release in juveniles could not be excluded. By adding historical data from translocation sites, data that was unavailable in Perdeck's days, and by integrated analyses including the original data, we could not explain juvenile migrations from possible social information upon release. Despite their highly social behaviour, our findings are consistent with the idea that juvenile starlings follow inherited information and independently reach their winter quarters. Similar to more solitarily migrating songbirds, starlings would require genetic change to adjust the migration route in response to global change.
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Migração Animal , Comportamento Social , Estorninhos , Animais , Estorninhos/fisiologia , Estorninhos/genética , Estações do AnoRESUMO
ALK-positive NSCLC patients demonstrate initial responses to ALK tyrosine kinase inhibitor (TKI) treatments, but eventually develop resistance, causing rapid tumor relapse and poor survival rates. Growing evidence suggests that the combination of drug and immune therapies greatly improves patient survival; however, due to the low immunogenicity of the tumors, ALK-positive patients do not respond to currently available immunotherapies. Tumor-associated macrophages (TAMs) play a crucial role in facilitating lung cancer growth by suppressing tumoricidal immune activation and absorbing chemotherapeutics. However, they can also be programmed toward a pro-inflammatory tumor suppressive phenotype, which represents a highly active area of therapy development. Iron loading of TAMs can achieve such reprogramming correlating with an improved prognosis in lung cancer patients. We previously showed that superparamagnetic iron oxide nanoparticles containing core-cross-linked polymer micelles (SPION-CCPMs) target macrophages and stimulate pro-inflammatory activation. Here, we show that SPION-CCPMs stimulate TAMs to secrete reactive nitrogen species and cytokines that exert tumoricidal activity. We further show that SPION-CCPMs reshape the immunosuppressive Eml4-Alk lung tumor microenvironment (TME) toward a cytotoxic profile hallmarked by the recruitment of CD8+ T cells, suggesting a multifactorial benefit of SPION-CCPM application. When intratracheally instilled into lung cancer-bearing mice, SPION-CCPMs delay tumor growth and, after first line therapy with a TKI, halt the regrowth of relapsing tumors. These findings identify SPIONs-CCPMs as an adjuvant therapy, which remodels the TME, resulting in a delay in the appearance of resistant tumors.
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Crizotinibe , Neoplasias Pulmonares , Nanopartículas Magnéticas de Óxido de Ferro , Microambiente Tumoral , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Microambiente Tumoral/efeitos dos fármacos , Animais , Nanopartículas Magnéticas de Óxido de Ferro/química , Humanos , Camundongos , Crizotinibe/farmacologia , Crizotinibe/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Linhagem Celular Tumoral , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/metabolismo , Proliferação de Células/efeitos dos fármacos , FemininoRESUMO
Precision oncology has revolutionized the treatment of ALK-positive lung cancer with targeted therapies. However, an unmet clinical need still to address is the treatment of refractory tumors that contain drug-induced resistant mutations in the driver oncogene or exhibit resistance through the activation of diverse mechanisms. In this study, we established mouse tumor-derived cell models representing the two most prevalent EML4-ALK variants in human lung adenocarcinomas and characterized their proteomic profiles to gain insights into the underlying resistance mechanisms. We showed that Eml4-Alk variant 3 confers a worse response to ALK inhibitors, suggesting its role in promoting resistance to targeted therapy. In addition, proteomic analysis of brigatinib-treated cells revealed the upregulation of SRC kinase, a protein frequently activated in cancer. Co-targeting of ALK and SRC showed remarkable inhibitory effects in both ALK-driven murine and ALK-patient-derived lung tumor cells. This combination induced cell death through a multifaceted mechanism characterized by profound perturbation of the (phospho)proteomic landscape and a synergistic suppressive effect on the mTOR pathway. Our study demonstrates that the simultaneous inhibition of ALK and SRC can potentially overcome resistance mechanisms and enhance clinical outcomes in ALK-positive lung cancer patients. ONE SENTENCE SUMMARY: Co-targeting ALK and SRC enhances ALK inhibitor response in lung cancer by affecting the proteomic profile, offering hope for overcoming resistance and improving clinical outcomes.
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Quinase do Linfoma Anaplásico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares , Compostos Organofosforados , Inibidores de Proteínas Quinases , Proteoma , Quinases da Família src , Animais , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Humanos , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/metabolismo , Camundongos , Proteoma/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linhagem Celular Tumoral , Pirimidinas/farmacologia , Proteômica/métodos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Artificial light at night (ALAN) widely affects wildlife by blurring light-dark differences, including transitions such as sunrise and sunset, thereby affecting regulation of diel rhythms. As a result, activity onsets in many wild diurnal songbirds advance under ALAN. From chronobiological studies, it is known that the direction and strength of the response to light depends on when during the night exposure takes place. However, these experiments are mostly done under continuous light conditions, when animals have free-running rhythms. It remains unclear whether phase-dependence also holds in entrained, wild songbirds; i.e., does the effect of ALAN on activity patterns differ between exposure in the morning compared to the evening? This information is essential to assess the effects of mitigation measures by limiting ALAN to selected times of the night. We exposed incubating great tits (Parus major) inside the nest-box to 4 h of dim light, of which 1 h overlapped with dawn before sunrise or dusk after sunset. We found a small advancing effect of morning-light on activity onset and of evening-light on offset compared to dark controls but not vice versa. Breeding success and chick condition were unaffected by the light treatments. However, light-treated females had lower weights 9-18 days after the end of the treatment compared to the controls, independent of whether ALAN occurred in the morning or the evening, indicating possible costs of ALAN. Despite the weak behavioral response, ALAN might have affected the females' circadian clock or physiology resulting in lower body condition.
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Passeriformes , Aves Canoras , Feminino , Animais , Luz , Passeriformes/fisiologia , Aves Canoras/fisiologia , Animais Selvagens , Comportamento Animal/fisiologiaRESUMO
Avian long-distance migration requires refined programming to orchestrate the birds' movements on annual temporal and continental spatial scales. Programming is particularly important as long-distance movements typically anticipate future environmental conditions. Hence, migration has long been of particular interest in chronobiology. Captivity studies using a proxy, the shift to nocturnality during migration seasons (i.e., migratory restlessness), have revealed circannual and circadian regulation, as well as an innate sense of direction. Thanks to rapid development of tracking technology, detailed information from free-flying birds, including annual-cycle data and actograms, now allows relating this mechanistic background to behaviour in the wild. Likewise, genomic approaches begin to unravel the many physiological pathways that contribute to migration. Despite these advances, it is still unclear how migration programmes are integrated with specific environmental conditions experienced during the journey. Such knowledge is imminently important as temporal environments undergo rapid anthropogenic modification. Migratory birds as a group are not dealing well with the changes, yet some species show remarkable adjustments at behavioural and genetic levels. Integrated research programmes and interdisciplinary collaborations are needed to understand the range of responses of migratory birds to environmental change, and more broadly, the functioning of timing programmes under natural conditions.
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Migração Animal , Aves , Ritmo Circadiano , Animais , Migração Animal/fisiologia , Aves/fisiologia , Ritmo Circadiano/fisiologia , Estações do Ano , Relógios Biológicos/fisiologiaRESUMO
Biological clocks are evolved time-keeping systems by which organisms rhythmically coordinate physiology within the body, and align it with rhythms in their environment. Clocks are highly sensitive to light and are at the interface of several major endocrine pathways. Worryingly, exposure to artificial-light-at-night (ALAN) is rapidly increasing in ever more extensive parts of the world, with likely impact on wild organisms mediated by endocrine-circadian pathways. In this overview, we first give a broad-brush introduction to biological rhythms. Then, we outline interactions between the avian clock, endocrine pathways, and environmental and internal modifiers. The main focus of this review is on the circadian hormone, melatonin. We summarize information from avian field and laboratory studies on melatonin and its relationships with behaviour and physiology, including often neglected developmental aspects. When exposed to ALAN, birds are highly vulnerable to disruption of behavioural rhythms and of physiological systems under rhythmic control. Several studies suggest that melatonin is likely a key mediator for a broad range of effects. We encourage further observational and experimental studies of ALAN impact on melatonin, across the full functional range of this versatile signalling molecule, as well as on other candidate compounds at the endocrine-circadian interface. This article is part of the theme issue 'Endocrine responses to environmental variation: conceptual approaches and recent developments'.
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Melatonina , Animais , Melatonina/metabolismo , Ritmo Circadiano/fisiologia , Relógios Biológicos/fisiologia , Aves , Transdução de Sinais , LuzRESUMO
Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, metabolic dysfunction-associated steatotic liver disease (MASLD) is gaining importance as the disease can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in MASLD development, but molecular mechanisms responsible for disease progression remained unresolved. Here, we uncover in primary hepatocytes from a preclinical model fed with a Western diet (WD) an increased basal MET phosphorylation and a strong downregulation of the PI3K-AKT pathway. Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveal patient-specific variability in basal MET phosphorylation, which correlates with patient outcome after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.
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Carcinoma Hepatocelular , Fígado Gorduroso , Neoplasias Hepáticas , Humanos , Fosforilação , Fosfatidilinositol 3-Quinases/metabolismo , Hepatócitos/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Fígado Gorduroso/metabolismo , Neoplasias Hepáticas/patologiaRESUMO
Type I interferons (IFNs) play a central role not only in innate immunity against viral infection, but also in the antitumour response, e.g. through a direct impact on cell proliferation. Particularly for cancer arising in the context of chronic inflammation, constant exposure to IFNs may constitute a strong selective pressure during tumour evolution. Expansion of neoplastic subclones resistant to the antiproliferative effects of IFNs may contribute to immunoediting of tumours, leading to more aggressive disease. Experimental evidence for this development of IFN-insensitivity has been scarce and its molecular mechanism is unclear. In this study we demonstrate that six weeks exposure of cells to IFN-ß in vitro reduces their sensitivity to its antiproliferative effects, and that this phenotype was stable for up to four weeks. Furthermore, we observed substantial differences in cellular sensitivity to growth inhibition by IFN-ß in a panel of ten different liver cancer cell lines, most prominently in a pair of highly dedifferentiated cell lines, and least in cells from well-differentiated tumours. In both, long-term IFN selection and in dedifferentiated tumour cell lines, we found IFNAR2 expression to be substantially reduced, suggesting the receptor complex to be a sensitive target amenable to immunoediting. Beyond new insights into possible molecular processes in tumour evolution, these findings might prove valuable for the development of biomarkers allowing to stratify tumours for their sensitivity to IFN treatment in the context of patient tailored therapies.
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Artificial light at night (ALAN) is rapidly increasing and so is scientific interest in its ecological and evolutionary consequences. In wild species, ALAN can modify and disrupt biological rhythms. However, experimental proof of such effects of ALAN in the wild is still scarce. Here, we compared diel rhythms of incubation behaviour, inferred from temperature sensors, of female great tits (Parus major) breeding in urban and forest sites. In parallel, we simulated ALAN by mounting LED lights (1.8 lx) inside forest nest-boxes, to determine the potentially causal role of ALAN affecting diel patterns of incubation. Urban females had an earlier onset of activity compared to forest females. Experimentally ALAN-exposed forest females were similar to urban females in their advanced onset of activity, compared to unexposed forest birds. However, forest females exposed to experimental ALAN, but not urban females, were more restless at night than forest control females. Our findings demonstrate that ALAN can explain the early activity timing in incubating urban great tits, but its effects on sleep disturbance in the forest are not reflected in urban females. Consequently, future research needs to address potential effects of ALAN-induced timing on individual health, fitness and population dynamics, in particular in populations that were not previously affected by light pollution.
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Evolução Biológica , Florestas , Feminino , Humanos , Dinâmica PopulacionalRESUMO
The human liver has a remarkable capacity to regenerate and thus compensate over decades for fibrosis caused by toxic chemicals, drugs, alcohol, or malnutrition. To date, no protective mechanisms have been identified that help the liver tolerate these repeated injuries. In this study, we revealed dysregulation of lipid metabolism and mild inflammation as protective mechanisms by studying longitudinal multi-omic measurements of liver fibrosis induced by repeated CCl4 injections in mice (n = 45). Based on comprehensive proteomics, transcriptomics, blood- and tissue-level profiling, we uncovered three phases of early disease development-initiation, progression, and tolerance. Using novel multi-omic network analysis, we identified multi-level mechanisms that are significantly dysregulated in the injury-tolerant response. Public data analysis shows that these profiles are altered in human liver diseases, including fibrosis and early cirrhosis stages. Our findings mark the beginning of the tolerance phase as the critical switching point in liver response to repetitive toxic doses. After fostering extracellular matrix accumulation as an acute response, we observe a deposition of tiny lipid droplets in hepatocytes only in the Tolerant phase. Our comprehensive study shows that lipid metabolism and mild inflammation may serve as biomarkers and are putative functional requirements to resist further disease progression.
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Fígado Gorduroso , Relesões , Humanos , Animais , Camundongos , Inflamação , Cirrose Hepática/induzido quimicamenteRESUMO
BACKGROUND: Macrophages play an important role in maintaining liver homeostasis and regeneration. However, it is not clear to what extent the different macrophage populations of the liver differ in terms of their activation state and which other liver cell populations may play a role in regulating the same. METHODS: Reverse transcription PCR, flow cytometry, transcriptome, proteome, secretome, single cell analysis, and immunohistochemical methods were used to study changes in gene expression as well as the activation state of macrophages in vitro and in vivo under homeostatic conditions and after partial hepatectomy. RESULTS: We show that F4/80+/CD11bhi/CD14hi macrophages of the liver are recruited in a C-C motif chemokine receptor (CCR2)-dependent manner and exhibit an activation state that differs substantially from that of the other liver macrophage populations, which can be distinguished on the basis of CD11b and CD14 expressions. Thereby, primary hepatocytes are capable of creating an environment in vitro that elicits the same specific activation state in bone marrow-derived macrophages as observed in F4/80+/CD11bhi/CD14hi liver macrophages in vivo. Subsequent analyses, including studies in mice with a myeloid cell-specific deletion of the TGF-ß type II receptor, suggest that the availability of activated TGF-ß and its downregulation by a hepatocyte-conditioned milieu are critical. Reduction of TGF-ßRII-mediated signal transduction in myeloid cells leads to upregulation of IL-6, IL-10, and SIGLEC1 expression, a hallmark of the activation state of F4/80+/CD11bhi/CD14hi macrophages, and enhances liver regeneration. CONCLUSIONS: The availability of activated TGF-ß determines the activation state of specific macrophage populations in the liver, and the observed rapid transient activation of TGF-ß may represent an important regulatory mechanism in the early phase of liver regeneration in this context.
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Regeneração Hepática , Fator de Crescimento Transformador beta , Animais , Camundongos , Expressão Gênica , Hepatócitos/metabolismo , Macrófagos/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Organisms living in high-elevation habitats are usually habitat specialists who occupy a narrow ecological niche. To envision the response of alpine species to a changing environment, it is fundamental to understand their habitat preferences on multiple spatial and temporal scales. However, information on small-scale habitat use is still widely lacking. We investigated the foraging habitat preferences of the migratory northern wheatear Oenanthe oenanthe during the entire presence at a breeding site in the central Alps. We repeatedly observed 121 adult and juvenile individuals. We applied Bayesian logistic regression models to investigate which habitat characteristics influenced foraging habitat selection on a fine spatial scale, and how habitat use varied temporally. Throughout their presence on the breeding grounds, northern wheatears showed a consistent preference for a mosaic of stones and bare ground patches with slow-growing, short vegetation. The proximity of marmot burrows was preferred, whereas dense and low woody vegetation was avoided. After arrival at the breeding site, short vegetation, preferably close to the snow, was favored. The preference for open habitat patches that provide access to prey underlines the critical role of small-scale habitat heterogeneity for northern wheatears. The strong and consistent preference for a habitat that is under pressure from land-use and climate change suggests that this alpine bird species may be sensitive to habitat loss, leading to a potential range contraction. We highlight the need to conserve habitat diversity on a small spatial scale to ensure the long-term availability of suitable habitat for northern wheatears in the Alps.
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BACKGROUND: To understand the ecology of long-distance migrant bird species, it is necessary to study their full annual cycle, including migratory routes and stopovers. This is especially important for species in high-elevation habitats that are particularly vulnerable to environmental change. Here, we investigated both local and global movements during all parts of the annual cycle in a small trans-Saharan migratory bird breeding at high elevation. METHODS: Recently, multi-sensor geolocators have opened new research opportunities in small-sized migratory organisms. We tagged Northern Wheatears Oenanthe oenanthe from the central-European Alpine population with loggers recording atmospheric pressure and light intensity. We modelled migration routes and identified stopover and non-breeding sites by correlating the atmospheric pressure measured on the birds with global atmospheric pressure data. Furthermore, we compared barrier-crossing flights with other migratory flights and studied the movement behaviour throughout the annual cycle. RESULTS: All eight tracked individuals crossed the Mediterranean Sea, using islands for short stops, and made longer stopovers in the Atlas highlands. Single non-breeding sites were used during the entire boreal winter and were all located in the same region of the Sahel. Spring migration was recorded for four individuals with similar or slightly different routes compared to autumn. Migratory flights were typically nocturnal and characterized by fluctuating altitudes, frequently reaching 2000 to 4000 m a.s.l, with a maximum of up to 5150 m. Barrier-crossing flights, i.e., over the sea and the Sahara, were longer, higher, and faster compared to flights above favourable stopover habitat. In addition, we detected two types of altitudinal movements at the breeding site. Unexpected regular diel uphill movements were undertaken from the breeding territories towards nearby roosting sites at cliffs, while regional scale movements took place in response to local meteorological conditions during the pre-breeding period. CONCLUSION: Our data inform on both local and global scale movements, providing new insights into migratory behaviour and local movements in small songbirds. This calls for a wider use of multi-sensor loggers in songbird migration research, especially for investigating both local and global movements in the same individuals.
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Erythropoietin (Epo) ensures survival and proliferation of colony-forming unit erythroid (CFU-E) progenitor cells and their differentiation to hemoglobin-containing mature erythrocytes. A lack of Epo-induced responses causes embryonic lethality, but mechanisms regulating the dynamic communication of cellular alterations to the organismal level remain unresolved. By time-resolved transcriptomics and proteomics, we show that Epo induces in CFU-E cells a gradual transition from proliferation signature proteins to proteins indicative for differentiation, including heme-synthesis enzymes. In the absence of the Epo receptor (EpoR) in embryos, we observe a lack of hemoglobin in CFU-E cells and massive iron overload of the fetal liver pointing to a miscommunication between liver and placenta. A reduction of iron-sulfur cluster-containing proteins involved in oxidative phosphorylation in these embryos leads to a metabolic shift toward glycolysis. This link connecting erythropoiesis with the regulation of iron homeostasis and metabolic reprogramming suggests that balancing these interactions is crucial for protection from iron intoxication and for survival.
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Eritropoetina , Sobrecarga de Ferro , Eritropoese/fisiologia , Eritropoetina/farmacologia , Feminino , Heme , Hemoglobinas , Humanos , Ferro/metabolismo , Gravidez , Proteoma , EnxofreRESUMO
Seasonal migration is a dynamic natural phenomenon that allows organisms to exploit favourable habitats across the annual cycle. While the morphological, physiological and behavioural changes associated with migratory behaviour are well characterized, the genetic basis of migration and its link to endogenous biological time-keeping pathways are poorly understood. Historically, genome-wide research has focused on genes of large effect, whereas many genes of small effect may work together to regulate complex traits like migratory behaviour. Here, we explicitly relax stringent outlier detection thresholds and, as a result, discover how multiple biological time-keeping genes are important to migratory timing in an iconic raptor species, the American kestrel (Falco sparverius). To validate the role of candidate loci in migratory timing, we genotyped kestrels captured across autumn migration and found significant associations between migratory timing and genetic variation in metabolic and light-input pathway genes that modulate biological clocks (top1, phlpp1, cpne4 and peak1). Further, we demonstrate that migrating individuals originated from a single panmictic source population, suggesting the existence of distinct early and late migratory genotypes (i.e. chronotypes). Overall, our results provide empirical support for the existence of a within-population-level polymorphism in genes underlying migratory timing in a diurnally migrating raptor.
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Falconiformes , Aves Predatórias , Migração Animal/fisiologia , Animais , Falconiformes/genética , Humanos , Polimorfismo Genético , Aves Predatórias/genética , Estações do AnoRESUMO
Timing is essential for survival and reproduction of organisms across the tree of life. The core circadian clock gene Clk is involved in the regulation of annual timing events and shows highly conserved sequence homology across vertebrates except for one variable region of poly-glutamine repeats. Clk genotype varies in some species with latitude, seasonal timing and migration. However, findings are inconsistent, difficult to disentangle from environmental responses, and biased towards high latitudes. Here we combine field data with a common-garden experiment to study associations of Clk polymorphism with latitude, migration and annual-cycle timing within the stonechat species complex across its trans-equatorial distribution range. Our dataset includes 950 records from 717 individuals from nine populations with diverse migratory strategies. Gene diversity was lowest in resident African and Canary Island populations and increased with latitude, independently of migration distance. Repeat length and annual-cycle timing was linked in a population-specific way. Specifically, equatorial African stonechats showed delayed timing with longer repeat length for all annual-cycle stages. Our data suggest that at low latitudes with nearly constant photoperiod, Clk genotype might orchestrate a range of consistent, individual chronotypes. In contrast, the influence of Clk on annual-cycle timing at higher latitudes might be mediated by its interactions with genes involved in (circadian) photoperiodic pathways.
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Relógios Circadianos , Fotoperíodo , Animais , Ritmo Circadiano , Polimorfismo Genético , ReproduçãoRESUMO
Globally increasing levels of artificial light at night (ALAN) are associated with shifting rhythms of behaviour in many wild species. However, it is unclear whether changes in behavioural timing are paralleled by consistent shifts in the molecular clock and its associated physiological pathways. Inconsistent shifts between behavioural and molecular rhythms, and between different tissues and physiological systems, disrupt the circadian system, which coordinates all major body functions. We therefore compared behavioural, transcriptional and metabolomic responses of captive great tits (Parus major) to three ALAN intensities or to dark nights, recording activity and sampling brain, liver, spleen and blood at mid-day and midnight. ALAN advanced wake-up time, and this shift was paralleled by advanced expression of the clock gene BMAL1 in all tissues, suggesting close links between behaviour and clock gene expression across tissues. However, further analysis of gene expression and metabolites revealed that clock shifts were inconsistent across physiological systems. Untargeted metabolomic profiling showed that only 9.7% of the 755 analysed metabolites followed the behavioural shift. This high level of desynchronization indicates that ALAN disrupted the circadian system on a deep, easily overlooked level. Thus, circadian disruption could be a key mediator of health impacts of ALAN on wild animals.
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Poluição LuminosaRESUMO
Summary: Mass spectrometry-based proteomics is increasingly employed in biology and medicine. To generate reliable information from large datasets and ensure comparability of results, it is crucial to implement and standardize the quality control of the raw data, the data processing steps and the statistical analyses. MSPypeline provides a platform for importing MaxQuant output tables, generating quality control reports, data preprocessing including normalization and performing exploratory analyses by statistical inference plots. These standardized steps assess data quality, provide customizable figures and enable the identification of differentially expressed proteins to reach biologically relevant conclusions. Availability and implementation: The source code is available under the MIT license at https://github.com/siheming/mspypeline with documentation at https://mspypeline.readthedocs.io. Benchmark mass spectrometry data are available on ProteomeXchange (PXD025792). Supplementary information: Supplementary data are available at Bioinformatics Advances online.