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1.
Science ; 375(6576): 101-104, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-34990239

RESUMO

Climate change is expected to result in smaller fish size, but the influence of fishing has made it difficult to substantiate the theorized link between size and ocean warming and deoxygenation. We reconstructed the fish community and oceanographic conditions of the most recent global warm period (last interglacial; 130 to 116 thousand years before present) by using sediments from the northern Humboldt Current system off the coast of Peru, a hotspot of small pelagic fish productivity. In contrast to the present-day anchovy-dominated state, the last interglacial was characterized by considerably smaller (mesopelagic and goby-like) fishes and very low anchovy abundance. These small fish species are more difficult to harvest and are less palatable than anchovies, indicating that our rapidly warming world poses a threat to the global fish supply.


Assuntos
Mudança Climática , Ecossistema , Peixes , Sedimentos Geológicos , Oxigênio/análise , Água do Mar , Animais , Tamanho Corporal , Peixes/anatomia & histologia , Oceano Pacífico , Paleontologia , Peru , Água do Mar/química , Temperatura
2.
Proc Natl Acad Sci U S A ; 118(49)2021 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-34873057

RESUMO

During the last glacial interval, marine sediments recorded reduced current ventilation within the ocean interior below water depths of approximately >1,500 m [B. A. Hoogakker et al., Nat. Geosci. 8, 40-43 (2015)]. The degree of the associated oxygen depletion in the different ocean basins, however, is still poorly constrained. Here, we present sedimentary records of redox-sensitive metals from the southwest African margin. These records show evidence of continuous bottom water anoxia in the eastern South Atlantic during the last glaciation that led to enhanced carbon burial over a prolonged period of time. Our geochemical data indicate that upwelling-related productivity and the associated oxygen minimum zone in the eastern South Atlantic shifted far seaward during the last glacial period and only slowly retreated during deglaciation times. While increased productivity during the last ice age may have contributed to oxygen depletion in bottom waters, especially on the upper slope, slow-down of the Late Quaternary deep water circulation pattern [Rutberg et al., Nature 405, 935-938 (2000)] appears to be the ultimate driver of anoxic conditions in deep waters.

3.
Commun Biol ; 4(1): 1006, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433861

RESUMO

Temperature and bioavailable energy control the distribution of life on Earth, and interact with each other due to the dependency of biological energy requirements on temperature. Here we analyze how temperature-energy interactions structure sediment microbial communities in two hydrothermally active areas of Guaymas Basin. Sites from one area experience advective input of thermogenically produced electron donors by seepage from deeper layers, whereas sites from the other area are diffusion-dominated and electron donor-depleted. In both locations, Archaea dominate at temperatures >45 °C and Bacteria at temperatures <10 °C. Yet, at the phylum level and below, there are clear differences. Hot seep sites have high proportions of typical hydrothermal vent and hot spring taxa. By contrast, high-temperature sites without seepage harbor mainly novel taxa belonging to phyla that are widespread in cold subseafloor sediment. Our results suggest that in hydrothermal sediments temperature determines domain-level dominance, whereas temperature-energy interactions structure microbial communities at the phylum-level and below.


Assuntos
Sedimentos Geológicos/microbiologia , Fontes Hidrotermais/microbiologia , Microbiota , Água do Mar/microbiologia , Fenômenos Fisiológicos Bacterianos , Metabolismo Energético , Temperatura
4.
Cell Mol Life Sci ; 78(7): 3525-3542, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33469705

RESUMO

Metastasis Associated in Colon Cancer 1 (MACC1) is a novel prognostic, predictive and causal biomarker for tumor progression and metastasis in many cancer types, including colorectal cancer. Besides its clinical value, little is known about its molecular function. Its similarity to SH3BP4, involved in regulating uptake and recycling of transmembrane receptors, suggests a role of MACC1 in endocytosis. By exploring the MACC1 interactome, we identified the clathrin-mediated endocytosis (CME)-associated proteins CLTC, DNM2 and AP-2 as MACC1 binding partners. We unveiled a MACC1-dependent routing of internalized transferrin receptor towards recycling. Elevated MACC1 expression caused also the activation and internalization of EGFR, a higher rate of receptor recycling, as well as earlier and stronger receptor activation and downstream signaling. These effects are limited by deletion of CME-related protein interaction sites in MACC1. Thus, MACC1 regulates CME and receptor recycling, causing increased growth factor-mediated downstream signaling and cell proliferation. This novel mechanism unveils potential therapeutic intervention points restricting MACC1-driven metastasis.


Assuntos
Clatrina/metabolismo , Neoplasias Colorretais/patologia , Endocitose , Regulação Neoplásica da Expressão Gênica , Receptores da Transferrina/metabolismo , Transativadores/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Camundongos , Proteoma/análise , Proteoma/metabolismo , Receptores da Transferrina/genética , Transativadores/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Proc Natl Acad Sci U S A ; 117(42): 26328-26339, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33020261

RESUMO

Dendritic cell (DC) maturation is a prerequisite for the induction of adaptive immune responses against pathogens and cancer. Transcription factor (TF) networks control differential aspects of early DC progenitor versus late-stage DC cell fate decisions. Here, we identified the TF C/EBPß as a key regulator for DC maturation and immunogenic functionality under homeostatic and lymphoma-transformed conditions. Upon cell-specific deletion of C/EBPß in CD11c+MHCIIhi DCs, gene expression profiles of splenic C/EBPß-/- DCs showed a down-regulation of E2F cell cycle target genes and associated proliferation signaling pathways, whereas maturation signatures were enriched. Total splenic DC cell numbers were modestly increased but differentiation into cDC1 and cDC2 subsets were unaltered. The splenic CD11c+MHCIIhiCD64+ DC compartment was also increased, suggesting that C/EBPß deficiency favors the expansion of monocytic-derived DCs. Expression of C/EBPß could be mimicked in LAP/LAP* isoform knockin DCs, whereas the short isoform LIP supported a differentiation program similar to deletion of the full-length TF. In accordance with E2F1 being a negative regulator of DC maturation, C/EBPß-/- bone marrow-derived DCs matured much faster enabling them to activate and polarize T cells stronger. In contrast to a homeostatic condition, lymphoma-exposed DCs exhibited an up-regulation of the E2F transcriptional pathways and an impaired maturation. Pharmacological blockade of C/EBPß/mTOR signaling in human DCs abrogated their protumorigenic function in primary B cell lymphoma cocultures. Thus, C/EBPß plays a unique role in DC maturation and immunostimulatory functionality and emerges as a key factor of the tumor microenvironment that promotes lymphomagenesis.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Células Dendríticas/metabolismo , Animais , Proteína beta Intensificadora de Ligação a CCAAT/fisiologia , Diferenciação Celular , Linhagem Celular , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos/metabolismo , Isoformas de Proteínas/genética , Transdução de Sinais , Linfócitos T/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo , Microambiente Tumoral/fisiologia
6.
Future Oncol ; 16(8): 317-328, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32050787

RESUMO

Aim: There is a growing body of data on real-world use of talimogene laherparepvec (T-VEC). We aimed to characterize real-world T-VEC use using a nationally representative German prescription database covering 60% of prescriptions reimbursed. Patients & methods: A retrospective analysis was conducted using the German IMS® LRx prescription database, analyzing patients aged ≥18 years with an initial T-VEC prescription at 106 plaque-forming units (PFU)/ml and ≥1 subsequent prescription at 108 PFU/ml. Median time on T-VEC treatment, patient characteristics and patterns of T-VEC use were described. Results: Of 127 patients prescribed T-VEC, 72 patients (57%) met study criteria. About two-thirds of these patients initiated T-VEC in 2017. Median age at T-VEC initiation was 74 years (range: 44 to 91). Most prescriptions (88%) were dispensed from hospitals. At study end, 26 (36%) patients remained on T-VEC; 46 (64%) had ended treatment. Median duration of T-VEC treatment for all patients was 18.7 weeks (95% CI: 15.3-26.9) and was longer among those who initiated treatment in 2017 versus 2016 (26.7 vs 15.6 weeks, respectively). Median volume administered for the first 106 PFU/ml and second 108 PFU/ml was 4 ml; the volume decreased for subsequent administrations (2 ml by the eighth administration and 1 ml by the 16th administration). Conclusion: This real-world prescription database study showed that patients who initiated treatment in 2017 had a treatment duration in clinical practice that corresponded with the European Summary of Product Characteristics guideline of continuing T-VEC for ≥6 months. Additional long-term data linking drug use with clinical outcomes are needed.


Assuntos
Produtos Biológicos , Herpesvirus Humano 1 , Terapia Viral Oncolítica/métodos , Terapia Viral Oncolítica/estatística & dados numéricos , Vírus Oncolíticos , Adulto , Idoso , Idoso de 80 Anos ou mais , Produtos Biológicos/uso terapêutico , Terapia Combinada , Bases de Dados Factuais , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/epidemiologia , Melanoma/terapia , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
7.
Nat Commun ; 5: 5057, 2014 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-25266931

RESUMO

The capacity of dendritic cells (DCs) to regulate tumour-specific adaptive immune responses depends on their proper differentiation and homing status. Whereas DC-associated tumour-promoting functions are linked to T-cell tolerance and formation of an inflammatory milieu, DC-mediated direct effects on tumour growth have remained unexplored. Here we show that deletion of DCs substantially delays progression of Myc-driven lymphomas. Lymphoma-exposed DCs upregulate immunomodulatory cytokines, growth factors and the CCAAT/enhancer-binding protein ß (C/EBPß). Moreover, Eµ-Myc lymphomas induce the preferential translation of the LAP/LAP* isoforms of C/EBPß. C/EBPß(-/-) DCs are unresponsive to lymphoma-associated cytokine changes and in contrast to wild-type DCs, they are unable to mediate enhanced Eµ-Myc lymphoma cell survival. Antigen-specific T-cell proliferation in lymphoma-bearing mice is impaired; however, this immune suppression is reverted by the DC-restricted deletion of C/EBPß. Thus, we show that C/EBPß-controlled DC functions are critical steps for the creation of a lymphoma growth-promoting and -immunosuppressive niche.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/imunologia , Células Dendríticas/imunologia , Linfoma de Células B/imunologia , Proteína Oncogênica p55(v-myc)/imunologia , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Diferenciação Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Células Dendríticas/citologia , Humanos , Linfoma de Células B/genética , Linfoma de Células B/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína Oncogênica p55(v-myc)/genética
8.
Mol Ecol ; 15(11): 3231-43, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16968267

RESUMO

Gametophytic self-incompatibility (SI) systems in plants exhibit high polymorphism at the SI controlling S-locus because individuals with rare alleles have a higher probability to successfully pollinate other plants than individuals with more frequent alleles. This process, referred to as frequency-dependent selection, is expected to shape number, frequency distribution, and spatial distribution of self-incompatibility alleles in natural populations. We investigated the genetic diversity and the spatial genetic structure within a Prunus avium population at two contrasting gene loci: nuclear microsatellites and the S-locus. The S-locus revealed a higher diversity (15 alleles) than the eight microsatellites (4-12 alleles). Although the frequency distribution of S-alleles differed significantly from the expected equal distribution, the S-locus showed a higher evenness than the microsatellites (Shannon's evenness index for the S-locus: E = 0.91; for the microsatellites: E = 0.48-0.83). Also, highly significant deviations from neutrality were found for the S-locus whereas only minor deviations were found for two of eight microsatellites. A comparison of the frequency distribution of S-alleles in three age-cohorts revealed no significant differences, suggesting that different levels of selection acting on the S-locus or on S-linked sites might also affect the distribution and dynamics of S-alleles. Autocorrelation analysis revealed a weak but significant spatial genetic structure for the multilocus average of the microsatellites and for the S-locus, but could not ascertain differences in the extent of spatial genetic structure between these locus types. An indirect estimate of gene dispersal, which was obtained to explain this spatial genetic pattern, indicated high levels of gene dispersal within our population (sigma(g) = 106 m). This high gene dispersal, which may be partly due to the self-incompatibility system itself, aids the effective gene flow of the microsatellites, thereby decreasing the contrast between the neutral microsatellites and the S-locus.


Assuntos
Repetições de Microssatélites/genética , Prunus/genética , Alelos , Estudos de Coortes , DNA de Plantas/química , DNA de Plantas/genética , Fluxo Gênico , Variação Genética , Genética Populacional , Genótipo , Alemanha , Proteínas de Plantas/química , Proteínas de Plantas/genética , Reação em Cadeia da Polimerase , Seleção Genética
9.
Oecologia ; 121(2): 149-156, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28308554

RESUMO

Clones of Norway spruce (Picea abies L.) were grown for several years on an altitudinal gradient (1750 m, 1150 m and 800 m above sea level) to study the effects of environmental × genetic interactions on growth and foliar metabolites (protein, pigments, antioxidants). Clones at the tree line showed 4.3-fold lower growth rates and contained 60% less chlorophyll (per gram of dry matter) than those at valley level. The extent of growth reduction was clone-dependent. The mortality of the clones was low and not altitude-dependent. At valley level, but not at high altitude, needles of mature spruce trees showed lower pigment and protein concentrations than clones. In general, antioxidative systems in needles of the mature trees and young clones did not increase with increasing altitude. Needles of all trees at high altitude showed higher concentrations of dehydroascorbate than at lower altitudes, indicating higher oxidative stress. In one clone, previously identified as sensitive to acute ozone doses, this increase was significantly higher and the growth reduction was stronger than in the other genotypes. This clone also displayed a significant reduction in glutathione reductase activity at high altitude. These results suggest that induction of antioxidative systems is apparently not a general prerequisite to cope with altitude in clones whose mother plants originated from higher altitudes (about 650-1100 m above sea level, Hercycnic-Carpathian distribution area), but that the genetic constitution for maintenance of high antioxidative protection is important for stress compensation at the tree line.

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