RESUMO
During the Last Glacial Maximum (LGM; ~20,000 years ago), the global ocean sequestered a large amount of carbon lost from the atmosphere and terrestrial biosphere. Suppressed CO2 outgassing from the Southern Ocean is the prevailing explanation for this carbon sequestration. By contrast, the North Atlantic Ocean-a major conduit for atmospheric CO2 transport to the ocean interior via the overturning circulation-has received much less attention. Here we demonstrate that North Atlantic carbon pump efficiency during the LGM was almost doubled relative to the Holocene. This is based on a novel proxy approach to estimate air-sea CO2 exchange signals using combined carbonate ion and nutrient reconstructions for multiple sediment cores from the North Atlantic. Our data indicate that in tandem with Southern Ocean processes, enhanced North Atlantic CO2 absorption contributed to lowering ice-age atmospheric CO2.
RESUMO
Considerable ambiguity remains over the extent and nature of millennial/centennial-scale climate instability during the Last Interglacial (LIG). Here we analyse marine and terrestrial proxies from a deep-sea sediment sequence on the Portuguese Margin and combine results with an intensively dated Italian speleothem record and climate-model experiments. The strongest expression of climate variability occurred during the transitions into and out of the LIG. Our records also document a series of multi-centennial intra-interglacial arid events in southern Europe, coherent with cold water-mass expansions in the North Atlantic. The spatial and temporal fingerprints of these changes indicate a reorganization of ocean surface circulation, consistent with low-intensity disruptions of the Atlantic meridional overturning circulation (AMOC). The amplitude of this LIG variability is greater than that observed in Holocene records. Episodic Greenland ice melt and runoff as a result of excess warmth may have contributed to AMOC weakening and increased climate instability throughout the LIG.
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As the largest reservoir of carbon exchanging with the atmosphere on glacial-interglacial timescales, the deep ocean has been implicated as the likely location of carbon sequestration during Pleistocene glaciations. Despite strong theoretical underpinning for this expectation, radiocarbon data on watermass ventilation ages conflict, and proxy interpretations disagree about the depth, origin and even existence of the respired carbon pool. Because any change in the storage of respiratory carbon is accompanied by corresponding changes in dissolved oxygen concentrations, proxy data reflecting oxygenation are valuable in addressing these apparent inconsistencies. Here, we present a record of redox-sensitive uranium from the central equatorial Pacific Ocean to identify intervals associated with respiratory carbon storage over the past 350 kyr, providing evidence for repeated carbon storage over the last three glacial cycles. We also synthesise our data with previous work and propose an internally consistent picture of glacial carbon storage and equatorial Pacific Ocean watermass structure.
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The most recent ice age was characterized by rapid and hemispherically asynchronous climate oscillations, whose origin remains unresolved. Variations in oceanic meridional heat transport may contribute to these repeated climate changes, which were most pronounced during marine isotope stage 3, the glacial interval 25 thousand to 60 thousand years ago. We examined climate and ocean circulation proxies throughout this interval at high resolution in a deep North Atlantic sediment core, combining the kinematic tracer protactinium/thorium (Pa/Th) with the deep water-mass tracer, epibenthic δ(13)C. These indicators suggest reduced Atlantic overturning circulation during every cool northern stadial, with the greatest reductions during episodic Hudson Strait iceberg discharges, while sharp northern warming followed reinvigorated overturning. These results provide direct evidence for the ocean's persistent, central role in abrupt glacial climate change.
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The position of the Intertropical Convergence Zone (ITCZ) is sensitive to changes in the balance of heat between the hemispheres which has fundamental implications for tropical hydrology and atmospheric circulation. Although the ITCZ is thought to experience the largest shifts in position during deglacial stadial events, the magnitude of shifts has proven difficult to reconstruct, in part because of a paucity of high-resolution records, particularly those including spatial components. Here we track the position of the ITCZ from 150 to 110 ka at three sites in the central equatorial Pacific at sub-millennial time resolution. Our results provide evidence of large, abrupt changes in tropical climate during the penultimate deglaciation, coincident with North Atlantic Heinrich Stadial 11 (â¼136-129 ka). We identify this event both as a Northern Hemisphere increase in aeolian dust and as a shift in the mean position of the ITCZ a minimum of 4° southwards at 160° W.
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The equatorial Pacific Ocean is one of the major high-nutrient, low-chlorophyll regions in the global ocean. In such regions, the consumption of the available macro-nutrients such as nitrate and phosphate is thought to be limited in part by the low abundance of the critical micro-nutrient iron. Greater atmospheric dust deposition could have fertilized the equatorial Pacific with iron during the last ice age--the Last Glacial Period (LGP)--but the effect of increased ice-age dust fluxes on primary productivity in the equatorial Pacific remains uncertain. Here we present meridional transects of dust (derived from the (232)Th proxy), phytoplankton productivity (using opal, (231)Pa/(230)Th and excess Ba), and the degree of nitrate consumption (using foraminifera-bound δ(15)N) from six cores in the central equatorial Pacific for the Holocene (0-10,000 years ago) and the LGP (17,000-27,000 years ago). We find that, although dust deposition in the central equatorial Pacific was two to three times greater in the LGP than in the Holocene, productivity was the same or lower, and the degree of nitrate consumption was the same. These biogeochemical findings suggest that the relatively greater ice-age dust fluxes were not large enough to provide substantial iron fertilization to the central equatorial Pacific. This may have been because the absolute rate of dust deposition in the LGP (although greater than the Holocene rate) was very low. The lower productivity coupled with unchanged nitrate consumption suggests that the subsurface major nutrient concentrations were lower in the central equatorial Pacific during the LGP. As these nutrients are today dominantly sourced from the Subantarctic Zone of the Southern Ocean, we propose that the central equatorial Pacific data are consistent with more nutrient consumption in the Subantarctic Zone, possibly owing to iron fertilization as a result of higher absolute dust fluxes in this region. Thus, ice-age iron fertilization in the Subantarctic Zone would have ultimately worked to lower, not raise, equatorial Pacific productivity.
Assuntos
Camada de Gelo , Ferro/análise , Ferro/química , Água do Mar/química , Atmosfera/química , Poeira/análise , Foraminíferos/metabolismo , História Antiga , Nitratos/metabolismo , Oceano Pacífico , Fitoplâncton/metabolismoRESUMO
Androgens mediate their effects in target cells via the androgen receptor (AR), which acts predominantly as a ligand-dependent transcription factor. In addition, androgens induce rapid activation of second messenger signal transduction cascades, and this is thought to occur via non-genomic mechanisms. We have used the Cre/loxP system to generate an AR knockout (ARKO) mouse targeting exon 3, which encodes the second zinc finger of the DNA-binding domain. To generate universal ARKO mice, floxed AR mice were mated with CMV-Cre mice, which express Cre recombinase ubiquitously. Deletion of the floxed allele in our mice does not disrupt the reading frame, and has been designed so that the mutant AR can bind ligand but not target genes. ARKO males displayed a complete androgen insensitivity phenotype, with female external genitalia and a reduction in body weight compared with wild-type males (P < 0.001). Testes of ARKO males were smaller than control males (P < 0.0001) and were located intra-abdominally. We have demonstrated that genotypically XY mice lacking the second zinc finger of the AR have a female phenotype, and we conclude that the genomic actions of the AR (mediated by DNA binding) are indispensable for normal male sexual differentiation.
Assuntos
Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Diferenciação Sexual/genética , Síndrome de Resistência a Andrógenos/genética , Síndrome de Resistência a Andrógenos/metabolismo , Síndrome de Resistência a Andrógenos/patologia , Animais , Sequência de Bases , Sítios de Ligação/genética , DNA Complementar/genética , Feminino , Marcação de Genes , Genoma , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fenótipo , Gravidez , Receptores Androgênicos/química , Receptores Androgênicos/deficiência , Dedos de Zinco/genéticaRESUMO
To study the physiological control of osteoclasts, the bone resorbing cells, we generated transgenic mice carrying the Cre recombinase gene driven by either the tartrate-resistant acid phosphatase (TRAP) or cathepsin K (Ctsk) promoters. TRAP-Cre and Ctsk-Cre transgenic mouse lines were characterized by breeding with LacZ ROSA 26 (R26R) reporter mice and immunohistochemistry for Cre recombinase. The Cre transgene was functional in all lines, with Cre-mediated recombination occurring primarily in the long bones, vertebrae, ribs, and calvaria. Histological analyses of the bones demonstrated that functional Cre protein was present in 1) osteoclasts (Ctsk-Cre); 2) osteoclasts, columnar proliferating, and hypertrophic chondrocytes (TRAP-Cre line 4); and 3) round proliferating chondrocytes (TRAP-Cre line 3). In conclusion, we generated transgenic mouse lines that will enable the deletion of floxed target genes in osteoclasts, which will be valuable tools for studying the regulation of osteoclast function.
Assuntos
Marcação de Genes/métodos , Integrases/metabolismo , Osteoclastos/metabolismo , Fosfatase Ácida/genética , Animais , Northern Blotting , Southern Blotting , Catepsina K , Catepsinas/genética , Condrócitos/metabolismo , Cruzamentos Genéticos , Primers do DNA , DNA Complementar , Perfilação da Expressão Gênica , Imuno-Histoquímica , Isoenzimas/genética , Camundongos , Camundongos Transgênicos , Regiões Promotoras Genéticas/genética , Fosfatase Ácida Resistente a Tartarato , Distribuição TecidualRESUMO
The Atlantic meridional overturning circulation is widely believed to affect climate. Changes in ocean circulation have been inferred from records of the deep water chemical composition derived from sedimentary nutrient proxies, but their impact on climate is difficult to assess because such reconstructions provide insufficient constraints on the rate of overturning. Here we report measurements of 231Pa/230Th, a kinematic proxy for the meridional overturning circulation, in a sediment core from the subtropical North Atlantic Ocean. We find that the meridional overturning was nearly, or completely, eliminated during the coldest deglacial interval in the North Atlantic region, beginning with the catastrophic iceberg discharge Heinrich event H1, 17,500 yr ago, and declined sharply but briefly into the Younger Dryas cold event, about 12,700 yr ago. Following these cold events, the 231Pa/230Th record indicates that rapid accelerations of the meridional overturning circulation were concurrent with the two strongest regional warming events during deglaciation. These results confirm the significance of variations in the rate of the Atlantic meridional overturning circulation for abrupt climate changes.
Assuntos
Clima , Gelo , Água do Mar , Movimentos da Água , Oceano Atlântico , Sedimentos Geológicos/química , Efeito Estufa , Plâncton/isolamento & purificação , Água do Mar/química , Fatores de TempoRESUMO
We have characterised three new mutations in the uroporphyrinogen decarboxylase gene in familial porphyria cutanea tarda. The first of these was a G to A substitution in the 5' splice junction of exon 4 which generated an mRNA that lacked exon 4. The second was a nonsense mutation in exon 5 which changed the arginine residue at position 142 to a stop codon, and the third mutation, also in exon 5, was a triple base substitution from nucleotide position 417 to 419. This mutation encompassed two codons but only changed the amino acid predicted from the second codon, resulting in the replacement of valine with glutamine at position 134. This missense mutation has been described previously by Meguro et al. 1994, on one allele in a compound heterozygote with hepatoerythropoietic porphyria. This is the third case of an hepatoerythropoietic porphyria mutation in an individual diagnosed with familial porphyria cutanea tarda.
Assuntos
Mutação de Sentido Incorreto , Mutação Puntual , Porfiria Cutânea Tardia/genética , Uroporfirinogênio Descarboxilase/genética , HumanosRESUMO
Idiopathic Parkinson's disease involves the loss of midbrain dopaminergic neurons, resulting in the presynaptic breakdown of dopaminergic transmission in the striatum. Huntington's disease and some neurodegenerative diseases with Parkinsonian features have postsynaptic defects caused by striatal cell death. Mice were generated in which an attenuated form of the diphtheria toxin gene (tox-176) was expressed exclusively in D1 dopamine receptor (D1R)-positive cells with the aim of determining the effect of this mutation on development of the basal ganglia and on the locomotor phenotype. Transgenic mice expressing Cre, a site-specific DNA recombinase, were crossed with a second line in which a transcriptionally silenced tox-176 gene was inserted into the D1R gene locus by homologous recombination. Young doubly transgenic mutant mice expressing the tox-176 gene displayed bradykinesia, dystonia, and had falls caused by myoclonic jerks. The mutant brain had evidence of apoptosis and reactive gliosis and, consistent with the D1R expression pattern, the striatum was reduced in volume, and the Islands of Calleja were absent. In contrast, the cortex was of normal thickness. D1Rs were not detectable in mutants by in situ hybridization or ligand autoradiography, whereas D2 dopamine receptor (D2R) mRNA and protein was present in the striatum. In addition, substance P and dynorphin, neuropeptides known to be expressed in D1R-positive striatonigral projection neurons were not detectable. Enkephalin, a marker found in D2-positive striatopallidal projection neurons was expressed in the mutant brain. The mutant represents a novel neurodegenerative disease model with a dramatic extrapyramidal phenotype.
Assuntos
Gânglios da Base/química , Gânglios da Base/enzimologia , Integrases/genética , Mioclonia/metabolismo , Receptores de Dopamina D1/fisiologia , Proteínas Virais , Animais , Apoptose/fisiologia , Gânglios da Base/citologia , Toxina Diftérica/genética , Encefalinas/análise , Regulação Enzimológica da Expressão Gênica , Proteína Glial Fibrilar Ácida/análise , Gliose/fisiopatologia , Hibridização In Situ , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica , Transtornos dos Movimentos/metabolismo , Mioclonia/genética , Neurônios/química , Neurônios/fisiologia , Neurônios/ultraestrutura , Doença de Parkinson Secundária/metabolismo , Fenótipo , RNA Mensageiro/análise , Ensaio Radioligante , Substância P/análiseRESUMO
We describe five new mutations in the uroporphyrinogen decarboxylase (UROD) gene. All mutations were observed in conjunction with decreased erythrocyte UROD and clinical familial porphyria cutanea tarda (fPCT), (four families) or hepatoerythropoietic porphyria (HEP), (one family). The fPCT mutations included three point mutations that resulted in amino acid substitutions: a lysine to glutamine at amino acid position 253 (exon 7); a glycine to arginine at position 318 (exon 10); an isoleucine to threonine at position 334 (exon 10). The lysine to glutamine at amino acid position 253 was found in conjunction with a single C nucleotide deletion in exon 8 on the same allele of the UROD gene in the same family. This deletion resulted in a shift in the reading frame and the introduction of a premature stop codon 8 amino acids downstream. In the fourth family, a 31-bp deletion (nucleotides 828-858: exon 8) of the coding region, resulted in a frameshift and the introduction of a stop codon 19 amino acids downstream. A point mutation was observed in an individual diagnosed with HEP, resulting in an alanine to glycine change at amino acid position 80 and was present on both alleles. All mutations were confirmed in at least one other family member. The impact of these mutations on the function of the UROD protein was examined using in vitro protein expression and with activity assessed using pentacarboxylic acid porphyrinogen I as a substrate for UROD. Although three mutations reduced UROD activity to < 15% of normal, one resulted in a UROD protein with 50% functional activity and the other had near normal activity. These results indicate that many different genetic lesions of the UROD gene are associated with fPCT.
Assuntos
Porfiria Cutânea Tardia/genética , Porfiria Hepatoeritropoética/genética , Uroporfirinogênio Descarboxilase/genética , Família , Feminino , Humanos , Masculino , Mutação , Porfiria Cutânea Tardia/enzimologia , Porfiria Hepatoeritropoética/enzimologia , Análise de Sequência de DNARESUMO
We describe multiple alternative transcripts of uroporphyrinogen decarboxylase mRNA in normal individuals and patients with familial porphyria cutanea tarda. mRNA was reverse-transcribed, subjected to the polymerase chain reaction, and analyzed for nucleotide sequence. Seven different transcripts were characterized, and a cryptic splice acceptor site was identified in intron 1. In all mRNAs the exons abutted at previously defined exon boundaries. Characterization of the splice junctions in the genomic DNA showed that splice donor and acceptor sequences complied with the consensus sequences for these sites except for the splice acceptor sequences of exons 3 and 10. THese deviations were present in two normal individuals and one patient with familial porphyria cutanea tarda and were thus unable to explain the multiple aberrant uroporphyrinogen decarboxylase transcripts. We conclude that apparent deletions observed in transcripts derived from the uroporphyrinogen decarboxylase gene in patients with familial porphyria cutanea tarda should be interpreted with caution.
Assuntos
Processamento Alternativo , Porfiria Cutânea Tardia/genética , Uroporfirinogênio Descarboxilase/genética , Sequência de Bases , Eritrócitos/enzimologia , Éxons , Humanos , Íntrons , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Porfiria Cutânea Tardia/diagnóstico , RNA Mensageiro/análise , RNA Mensageiro/química , Valores de Referência , Uroporfirinogênio Descarboxilase/sangueRESUMO
Study of 115 kidneys from 60 patients with chronic renal failure maintained by dialysis for two months to five years revealed an unexpected number and variety of epithelial proliferative processes, several types of which are hitherto unreported. Proliferative activity was defined either by the presence of epithelial structures in ectopic situations, continuity with existing structures being demonstrable by serial sections, or by mitotic figures, or by both. The tendency for renal carcinoma development may relate to these dialysis-related epithelial proliferations originating in both glomerular and tubular epithelia. Enhanced renal epithelial proliferative capacity in dialysis may be employable in the experimental study of renal regeneration and in the therapy of patients with preterminal renal disease.
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Falência Renal Crônica/terapia , Rim/patologia , Diálise Renal , Epitélio/patologia , Humanos , Hiperplasia , Falência Renal Crônica/fisiopatologia , Glomérulos Renais/patologia , Neoplasias Renais/etiologia , Túbulos Renais/patologia , Músculo Liso/patologia , RegeneraçãoRESUMO
Hyperplasia and tumors of epithelium are found in "end stage" dialysis kidneys. Epithelial hyperplasia is most conspicuous within "atypical cysts" in which the lining cells are multilayered and occasionally papillary. These features were studied in the kidneys of 66 renal failure patients by means of multiple tissue blocks and serial histologic sections. Atypical cysts were observed in 20 of the 66 cases. Solid or cystic renal cell adenomas were found in nine cases. Six of the cases having adenomas were among the 20 cases having atypical cysts. Tumors occurred in kidneys having atypical cysts, as dintinguished from kidneys without such cysts, with a frequency greater than would be expected to be due to chance alone (P = 0.0106). Renal cell adenomas are found at a younger age in dialysis patients (mean = 41.2 years) than in a control group of autopsies and surgical cases that had not received chronic dialysis (mean = 61.8 years). These observations provide histologic evidence that renal cell neoplasms are prone to develop in relatively young renal failure patients when their uremia is treated by long term dialysis. The studies further indicate that the stimulus for neoplastic growth accompanies a cystic transformation of the kidneys. Kidneys in five cases in the series, although much smaller than normal, were grossly multicystic, corresponding to the recently recognized acquired renal cystic disease. Hyperplastic cells, like those observed in atypical cysts, were present focally along the cyst walls. This form of epithelial hyperplasia, common to both atypical cysts and the multicystic dialysis kidney, may give rise to the renal cell tumors that are reported to occur with increased frequency in acquired cystic disease.
Assuntos
Adenocarcinoma/complicações , Falência Renal Crônica/complicações , Neoplasias Renais/complicações , Adenocarcinoma/patologia , Adulto , Fatores Etários , Feminino , Células Espumosas/patologia , Humanos , Hiperplasia , Rim/patologia , Córtex Renal/patologia , Doenças Renais Císticas/complicações , Doenças Renais Císticas/patologia , Falência Renal Crônica/patologia , Túbulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Diálise Renal , Fatores de TempoRESUMO
Examination of kidneys of ten patients with uremia and severe hypertension treated by chronic intermittent hemodialysis revealed a deposition of glycogen within interstitial cells of the renal medulla. This is unlike any described renal distribution of glycogen. Electron microscopic studies performed in one case demonstrated monoparticulate glycogen both diffuse in the interstitial cell cytoplasm and locally aggregated beside lipid droplets. The findings provide evidence for a metabolic abnormality of renal medullary interstitial cells in patients who have protracted uremia.
Assuntos
Glicogênio/metabolismo , Hipertensão Renal/patologia , Falência Renal Crônica/patologia , Medula Renal/patologia , Adulto , Feminino , Humanos , Glomérulos Renais/patologia , Medula Renal/metabolismo , Medula Renal/ultraestrutura , Masculino , Pessoa de Meia-Idade , Uremia/patologiaRESUMO
Tubule-like cells were found lining an artery and several arterioles and within the capillaries of infarcted glomeruli in one block of kidney from one of 54 cases of end-stage/dialysis kidneys. Three other blocks showed tubule-like structures within infarcted glomeruli and adjacent arterioles. Squamous metaplasia of remaining tubule epithelium was found in sections from four blocks of the same kidney. In two of these blocks, infarcted glomeruli had capillaries which were occupied by squamous cells. These findings are discussed as examples of metaplasia of the endothelium or alternatively as epithelial growth and invasion. The use of special stains and multiple blocks for this study seem to have been justified. These changes offer further evidence that the end-stage kidney after dialysis has unique alterations.
Assuntos
Nefropatias/patologia , Rim/patologia , Adulto , Endotélio/patologia , Epitélio/patologia , Humanos , Glomérulos Renais/patologia , Masculino , Metaplasia/patologia , Diálise RenalRESUMO
Histologic and immunofluorescence studies were performed in nine rabbits after daily administration of human serum albumin at a fixed dosage for periods up to 26 weeks. All but one of the rabbits studied by immunofluorescence showed IgG, C3, and fibrinogen deposits in the renal glomeruli and in the tubules or peritubular tissues. In most cases, human serum albumin could also be identified in the deposits. In two rabbits killed at week 10, kidney pathology was minimal; in one of the rabbits killed in the early phases of the disease and in all rabbits killed after week 20, there were obvious pathologic changes affecting glomeruli, tubules, and/or interstitium. Tubulointerstitial changes were absent in only one of the rabbits killed at late stages of human serum albumin administration, in spite of evidence of tubular deposition of immune complexes. These observations suggest that tubulointerstitial damage is at least as frequent as glomerular damage during the induction of chronic serum sickness.
Assuntos
Rim/patologia , Doença do Soro/patologia , Animais , Complexo Antígeno-Anticorpo , Doença Crônica , Complemento C3/análise , Fibrinogênio/análise , Imunofluorescência , Imunoglobulina G/análise , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Túbulos Renais/patologia , Coelhos , Albumina Sérica/análise , Doença do Soro/imunologia , Fatores de TempoRESUMO
End-stage kidneys in patients who are receiving long-term intermittent treatment with hemodialysis are metabolic structures that participate in many body processes and that themselves develop and change despite severe excretory deficiencies. Nephron loss is severe. Other lesions in such kidneys include the following: smooth muscle nodules that arise in necrotic arteries and arterioles; embryonal hyperplasia of Bowman's capsular epithelium; remodeling of the arteries and veins; tubular atrophy; dilation and cyst formation (acquired cystic disease); arteriolar granular cell hyperplasia and hypertension; deposits of oxalate, calcium, and immune complexes; interstitial fibrosis with collagen and smooth muscle; mucoid change; and cellular infiltration. This list does not include all pathologic conditions found in the end-stage--dialysis kidney. The necessity of and the criteria for an experimental model of human long-term intermittent hemodialysis for end-stage renal disease, presently lacking, are indicated.