900 resultados para model potential


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Community health workers (CHWs) can serve as a bridge between healthcare providers and communities to positively impact social determinants of health and, thus, the overall health of the population. The potential to effect lasting change is particularly significant within resource-poor settings with limited access to formally trained health care providers such as the small, rural village of Santa Ana Intibucá, Honduras and surrounding areas—located on the geographically and politically isolated border of Honduras and El Salvador. The Baylor Shoulder to Shoulder Foundation (BSTS) works in conjunction with Santa Ana's volunteer health committee to bring a health brigade that has provided health care and public health projects to the area at least twice a year since 2001. They have also hired a full-time Honduran physician, a Honduran in-country administrative director, and built a clinic; yet, no community health worker program exists. This CHW program model is the response to a clear need for a CHW program within the area served by BSTS and presents a CHW program model specific to Santa Ana Intibucá and surrounding areas to be implemented by BSTS. Methods used to develop this model include reviewing the literature for recommendations from leading authorities as well as successfully implemented CHW programs in comparable regions. This information was incorporated into existing knowledge and materials currently being used in the area. Using the CHW model proposed here, each brigade, in conjunction with the communities served, can help develop new modules to respond to the specific health priorities of the region at that time, incorporating consistent modes of contact with the local physician and the CHWs to provide refresher courses, training in new topics of interest, and to be reminded of the importance of community health workers' role as the critical link to healthy societies. With cooperation, effort, and support, the brigade can continue to help integrate a sustainable CHW system in which communities may be able to maximize the care they receive while also learning to care for their own health and the future of their communities.^

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Tuberous sclerosis complex (TSC) is a dominant tumor suppressor disorder caused by mutations in either TSC1 or TSC2. The proteins of these genes form a complex to inhibit the mammalian target of rapamycin complex 1 (mTORC1), which controls protein translation and cell growth. TSC causes substantial neuropathology, often leading to autism spectrum disorders (ASDs) in up to 60% of patients. The anatomic and neurophysiologic links between these two disorders are not well understood. However, both disorders share cerebellar abnormalities. Therefore, we have characterized a novel mouse model in which the Tsc2 gene was selectively deleted from cerebellar Purkinje cells (Tsc2f/-;Cre). These mice exhibit progressive Purkinje cell degeneration. Since loss of Purkinje cells is a well-reported postmortem finding in patients with ASD, we conducted a series of behavior tests to assess if Tsc2f/-;Cre mice displayed autistic-like deficits. Using the three chambered social choice assay, we found that Tsc2f/-;Cre mice showed behavioral deficits, exhibiting no preference between a stranger mouse and an inanimate object, or between a novel and a familiar mouse. Tsc2f/-;Cre mice also demonstrated increased repetitive behavior as assessed with marble burying activity. Altogether, these results demonstrate that loss of Tsc2 in Purkinje cells in a haploinsufficient background lead to behavioral deficits that are characteristic of human autism. Therefore, Purkinje cells loss and/or dysfunction may be an important link between TSC and ASD. Additionally, we have examined some of the cellular mechanisms resulting from mutations in Tsc2 leading to Purkinje cell death. Loss of Tsc2 led to upregulation of mTORC1 and increased cell size. As a consequence of increased protein synthesis, several cellular stress pathways were upregulated. Principally, these included altered calcium signaling, oxidative stress, and ER stress. Likely as a consequence of ER stress, there was also upregulation of ubiquitin and autophagy. Excitingly, treatment with an mTORC1 inhibitor, rapamycin attenuated mTORC1 activity and prevented Purkinje cell death by reducing of calcium signaling, the ER stress response, and ubiquitin. Remarkably, rapamycin treatment also reversed the social behavior deficits, thus providing a promising potential therapy for TSC-associated ASD.

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Inflammatory breast cancer (IBC) is a rare but very aggressive form of locally advanced breast cancer (1-6% of total breast cancer patients in United States), with a 5-year overall survival rate of only 40.5%, compared with 85% of the non-IBC patients. So far, a unique molecular signature for IBC able to explain the dramatic differences in the tumor biology between IBC and non-IBC has not been identified. As immune cells in the tumor microenvironment plays an important role in regulating tumor progression, we hypothesized that tumor-associated dendritic cells (TADC) may be responsible for regulating the development of the aggressive characteristics of IBC. MiRNAs can be released into the extracellular space and mediate the intercellular communication by regulating target gene expression beyond their cells of origin. We hypothesized that miRNAs released by IBC cells can induce an increased activation status, secretion of pro-inflammatory cytokines and migration ability of TADC. In an in vitro model of IBC tumor microenvironment, we found that the co-cultured of the IBC cell line SUM-149 with immature dendritic cells (iDCSUM-149) induced a higher degree of activation and maturation of iDCSUM-149 upon stimulation with lipopolysaccharide (LPS) compared with iDCs co-cultured with the non-IBC cell line SUM-159 (iDCSUM-159), resulting in: increased expression of the costimulatory and activation markers; higher production of pro-inflammatory cytokines (TNF-a, IL-6); and 3) higher migratory ability. These differences were due to the exosome-mediated transfer of miR-19a and miR-146a from SUM-149 and SUM-159, respectively, to iDCs, causing the downregulation of the miR-19a target genes PTEN, SOCS-1 and the miR-146a target genes IRAK1, TRAF6. PTEN, SOCS-1 and IRAK1, TRAF6 are important negative and positive regulator of cytokine- and TLR-mediated activation/maturation signaling pathway in DCs. Increased levels of IL-6 induced the upregulation of miR-19a synthesis in SUM-149 cells that was associated with the induction of CD44+CD24-ALDH1+ cancer stem cells (CSCs) with epithelial-to-mesenchymal transition (EMT) characteristics. In conclusion, in IBC tumor microenvironment IL-6/miR-19a axis can represent a self-sustaining loop able to maintain a pro-inflammatory status of DCs, leading to the development of tumor cells with high metastatic potential (EMT CSCs) responsible of the poor prognosis in IBC patients.

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A common pathological hallmark of most neurodegenerative disorders is the presence of protein aggregates in the brain. Understanding the regulation of aggregate formation is thus important for elucidating disease pathogenic mechanisms and finding effective preventive avenues and cures. Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a selective neurodegenerative disorder predominantly affecting motor neurons. The majority of ALS cases are sporadic, however, mutations in superoxide dismutase 1 (SOD1) are responsible for about 20% of familial ALS (fALS). Mutated SOD1 proteins are prone to misfold and form protein aggregates, thus representing a good candidate for studying aggregate formation. The long-term goal of this project is to identify regulators of aggregate formation by mutant SOD1 and other ALS-associated disease proteins. The specific aim of this thesis project is to assess the possibility of using the well-established Drosophila model system to study aggregation by human SOD1 (hSOD1) mutants. To this end, using wild type and the three mutant hSOD1 (A4V, G85R and G93A) most commonly found among fALS, I have generated 16 different SOD1 constructs containing either eGFP or mCherry in-frame fluorescent reporters, established and tested both cell- and animal-based Drosophila hSOD1 models. The experimental strategy allows for clear visualization of ectopic hSOD1 expression as well as versatile co-expression schemes to fully investigate protein aggregation specifically by mutant hSOD1. I have performed pilot cell-transfection experiments and verified induced expression of hSOD1 proteins. Using several tissue- or cell type-specific Gal4 lines, I have confirmed the proper expression of hSOD1 from established transgenic fly lines. Interestingly, in both Drosophila S2 cells and different fly tissues including the eye and motor neurons, robust aggregate formation by either wild type or mutant hSOD1 proteins was not observed. These preliminary observations suggest that Drosophila might not be a good experimental organism to study aggregation and toxicity of mutant hSOD1 protein. Nevertheless this preliminary conclusion implies the potential existence of a potent protective mechanism against mutant hSOD1 aggregation and toxicity in Drosophila. Thus, results from my SOD1-ALS project in Drosophila will help future studies on how to best employ this classic model organism to study ALS and other human brain degenerative diseases.

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Dental caries is the most common chronic disease worldwide. It is characterized by the demineralization of tooth enamel caused by acid produced by cariogenic dental bacteria growing on tooth surfaces, termed bacterial biofilms. Cariogenesis is a complex biological process that is influence by multiple factors and is not attributed to a sole causative agent. Instead, caries is associated with multispecies microbial biofilm communities composed of some bacterial species that directly influence the development of a caries lesion and other species that are seemingly benign but must contribute to the community in an uncharacterized way. Clinical analysis of dental caries and its microbial populations is challenging due to many factors including low sensitivity of clinical measurement tools, variability in saliva chemistry, and variation in the microbiota. Our laboratory has developed an in vitro anaerobic biofilm model for dental carries to facilitate both clinical and basic research-based analyses of the multispecies dynamics and individual factors that contribute to cariogenicity. The rational for development of this system was to improve upon the current models that lack key elements. This model places an emphasis on physiological relevance and ease of maintenance and reproducibility. The uniqueness of the model is based on integrating four critical elements: 1) a biofilm community composed of four distinct and representative species typically associated with dental caries, 2) a semi-defined synthetic growth medium designed to mimic saliva, 3) physiologically relevant biofilm growth substrates, and 4) a novel biofilm reactor device designed to facilitate the maintenance and analysis. Specifically, human tooth sections or hydroxyapatite discs embedded into poly(methyl methacrylate) (PMMA) discs are incubated for an initial 24 hr in a static inverted removable substrate (SIRS) biofilm reactor at 37°C under anaerobic conditions in artificial saliva (CAMM) without sucrose in the presence of 1 X 106 cells/ml of each Actinomyces odontolyticus, Fusobacterium nucleatum, Streptococcus mutans, and Veillonella dispar. During days 2 and 3 the samples are maintained continually in CAMM with various exposures to 0.2% sucrose; all of the discs are transferred into fresh medium every 24 hr. To validate that this model is an appropriate in vitro representation of a caries-associated multispecies biofilm, research aims were designed to test the following overarching hypothesis: an in vitro anaerobic biofilm composed of four species (S. mutans, V. dispar, A. odontolyticus, and F. nucleatum) will form a stable biofilm with a community profile that changes in response to environmental conditions and exhibits a cariogenic potential. For these experiments the biofilms as described above were exposed on days 2 and 3 to either CAMM lacking sucrose (no sucrose), CAMM with 0.2% sucrose (constant sucrose), or were transferred twice a day for 1 hr each time into 0.2% sucrose (intermittent sucrose). Four types of analysis were performed: 1) fluorescence microscopy of biofilms stained with Syto 9 and hexidium idodine to determine the biofilm architecture, 2) quantitative PCR (qPCR) to determine the cell number of each species per cm2, 3) vertical scanning interferometry (VSI) to determine the cariogenic potential of the biofilms, and 4) tomographic pH imaging using radiometric fluorescence microscopy after exposure to pH sensitive nanoparticles to measure the micro-environmental pH. The qualitative and quantitative results reveal the expected dynamics of the community profile when exposed to different sucrose conditions and the cariogenic potential of this in vitro four-species anaerobic biofilm model, thus confirming its usefulness for future analysis of primary and secondary dental caries.

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The most common molecular alterations observed in prostate cancer are increased bcl-2 protein expression and mutations in p53. Understanding the molecular alterations associated with prostate cancer are critical for successful treatment and designing new therapeutic interventions. Hormone-ablation therapy remains the most effective nonsurgical treatment; however, most patients will relapse with hormone-independent, refractory disease. This study addresses how hormone-ablation therapy may increase bcl-2, develops a transgenic model to elucidate the role of bcl-2 multistep prostate carcinogenesis, and assesses how bcl-2 may confer resistance to cell death induction using adenoviral wild-type p53 gene therapy. ^ Two potential androgen response elements were identified in the bcl-2 promoter. Bcl-2 promoter luciferase constructs were transfected into the hormone- sensitive LNCaP prostate cell line. In the presence of dihydrotestosterone, the activity of one bcl-2 promoter luciferase construct was repressed 40% compared to control cells grown in charcoal-stripped serum. Additionally, it was demonstrated that both bcl-2 mRNA and protein were downregulated in the LNCaP cells grown in the presence DHT. This suggests that DHT represses bcl-2 expression through possible direct and indirect mechanisms and that hormone-ablation therapy may actually increases bcl-2 protein. ^ To determine the role of bcl-2 in prostate cancer progression in vivo, probasin-bcl-2 mice were generated where human bcl-2 was targeted to the prostate. Increased bcl-2 expression rendered the ventral prostate more resistant to apoptosis induction following castration. When the probasin-bcl-2 mice were crossed with TRAMP mice, the latency to tumor formation was decreased. The expression of bcl-2 in the double transgenic mice did not affect the incidence of metastases. The double transgenic model will facilitate the study of in vivo effects of specific genetic lesions during the pathogenesis of prostate cancer. ^ The effects of increased bcl-2 protein on wild-type adenoviral p53-mediated cell death were determined in prostatic cell lines. Increased bcl-2 protected PC3 and DU145 cell lines, which possess mutant p53, from p53-mediated cell death and reductions in cell viability. Bcl-2 did not provide the same protective effect in LNCaP cell line, which expresses wild-type p53. This suggests that the ability of bcl-2 to protect against p53-mediated cell death is dependent upon the endogenous status of p53. ^

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Missense mutations in the p53 tumor-suppressor gene are the most common alterations of p53 in somatic tumors and in patients with Li-Fraumeni syndrome. p53 missense mutations occur in the DNA binding region and disrupt the ability of p53 to activate transcription. In vitro studies have shown that some p53 missense mutants have a gain-of-function or dominant-negative activity. ^ The p53 175 Arg-to-His (p53 R175H) mutation in humans has been shown to have dominant-negative and gain-of-function properties in vitro. This mutation is observed in the germline of individuals with Li-Fraumeni syndrome. To accurately model Li-Fraumeni syndrome and to examine the mechanistic nature of a gain-of-function missense mutation on in vivo tumorigenesis, we generated and characterized a mouse with the corresponding mutation, p53 R172H. p53R172H homozygous and heterozygous mice developed similar tumor spectra and survival curves as p53 −/− and p53+/− mice, respectively. However, tumors in p53+/R172H mice metastasized to various organs with high frequency, suggesting a gain-of-function phenotype by p53R172H in vivo. Mouse embryonic fibroblasts (MEFs) from p53R172H mice also showed gain-of-function phenotypes in cell proliferation, DNA synthesis, and transformation potential, while cells from p53+/− and p53−/− mice did not. ^ To mechanistically characterize the gain-of-function phenotype of the p53R172H mutant, the role of p53 family members, p63 and p73, was analyzed. Disruption of p63 and p73 by siRNAs in p53 −/− MEFs increased transformation potential and reinitiated DNA synthesis to levels observed in p53R172H/R172H cells. Additionally, p63 and p73 were bound and functionally inactivated by p53R172H in metastatic p53 R172H tumor-derived cell lines, indicating a role for the p53 family members in the gain-of-function phenotype. This study provides in vivo evidence for the gain-of-function effect of p53 missense mutations and more accurately models the Li-Fraumeni syndrome. ^

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In a feasibility study, the potential of proxy data for the temperature and salinity during the Last Glacial Maximum (LGM, about 19 000 to 23 000 years before present) in constraining the strength of the Atlantic meridional overturning circulation (AMOC) with a general ocean circulation model was explored. The proxy data were simulated by drawing data from four different model simulations at the ocean sediment core locations of the Multiproxy Approach for the Reconstruction of the Glacial Ocean surface (MARGO) project, and perturbing these data with realistic noise estimates. The results suggest that our method has the potential to provide estimates of the past strength of the AMOC even from sparse data, but in general, paleo-sea-surface temperature data without additional prior knowledge about the ocean state during the LGM is not adequate to constrain the model. On the one hand, additional data in the deep-ocean and salinity data are shown to be highly important in estimating the LGM circulation. On the other hand, increasing the amount of surface data alone does not appear to be enough for better estimates. Finally, better initial guesses to start the state estimation procedure would greatly improve the performance of the method. Indeed, with a sufficiently good first guess, just the sea-surface temperature data from the MARGO project promise to be sufficient for reliable estimates of the strength of the AMOC.

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This paper assesses the impact of climate change on China's agricultural production at a cross-provincial level using the Ricardian approach, incorporating a multilevel model with farm-level group data. The farm-level group data includes 13379 farm households, across 316 villages, distributed in 31 provinces. The empirical results show that, firstly, the marginal effects and elasticities of net crop revenue per hectare with respect to climate factors indicated that the annual impact of temperature on net crop revenue per hectare was positive, and the effect of increased precipitation was negative when looking at the national totals; secondly, the total impact of simulated climate change scenarios on net crop revenues per hectare at a Chinese national total level, was an increase of between 79 USD per hectare and 207 USD per hectare for the 2050s, and an increase from 140 USD per hectare to 355 USD per hectare for the 2080s. As a result, climate change may create a potential advantage for the development of Chinese agriculture, rather than a risk, especially for agriculture in the provinces of the Northeast, Northwest and North regions. However, the increased precipitation can lead to a loss of net crop revenue per hectare, especially for the provinces of the Southwest, Northwest, North and Northeast regions.

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This study provides a theoretical assessment of the potential bias due to differential lateral transport on multi-proxy studies based on a range of marine microfossils. Microfossils preserved in marine sediments are at the centre of numerous proxies for paleoenvironmental reconstructions. The precision of proxies is based on the assumption that they accurately represent the overlying watercolumn properties and faunas. Here we assess the possibility of a syn-depositional bias in sediment assemblages caused by horizontal drift in the water column, due to differential settling velocities of sedimenting particles based on their shape, size and density, and due to differences in current velocities. Specifically we calculate the post-mortem lateral transport undergone by planktic foraminifera and a range of other biological proxy carriers (diatoms, radiolaria and fecal pellets transporting coccolithophores) in several regions with high current velocities. We find that lateral transport of different planktic foraminiferal species is minimal due to high settling velocities. No significant shape- or size-dependent sorting occurs before reaching the sediment, making planktic foraminiferal ideal proxy carriers. In contrast, diatoms, radiolaria and fecal pellets can be transported up to 500km in some areas. For example in the Agulhas current, transport can lead to differences of up to 2°C in temperature reconstructions between different proxies in response to settling velocities. Therefore, sediment samples are likely to contain different proportions of local and imported particles, decreasing the precision of proxies based on these groups and the accuracy of the temperature reconstruction.

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The purpose of this study was the estimation of current and potential water erosion rates in Castellon Province (Spain) using RUSLE3D (Revised Universal Soil Loss Equation-3D) model with Geographical Information System (GIS) support. RUSLE3D uses a new methodology for topographic factor estimation (LS factor) based on the impact of flow convergence allowing better assessment of sediment distribution detached by water erosion. In RUSLE3D equation, the effect that vegetation cover has on soil erosion rate is reflected by the C factor. Potential erosion indicates soil erosion rate without considering C factor in RUSLE3D equation. The results showed that 57% of estimated current erosion does not exceed 10 t/ha.year (low erosion). In the case of potential erosion rates, 5% of the area of Castellon Province does not exceed 10 t/ha.year but 55% exceed 200 t/ha.year. Based on these results, the current vegetation cover of Castellon Province is adequate but needs to be conserved to avoid an increase in the current soil erosion rates as shown by potential erosion rates.

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Time variable gravity fields, reflecting variations of mass distribution in the system Earth is one of the key parameters to understand the changing Earth. Mass variations are caused either by redistribution of mass in, on or above the Earth's surface or by geophysical processes in the Earth's interior. The first set of observations of monthly variations of the Earth gravity field was provided by the US/German GRACE satellite mission beginning in 2002. This mission is still providing valuable information to the science community. However, as GRACE has outlived its expected lifetime, the geoscience community is currently seeking successor missions in order to maintain the long time series of climate change that was begun by GRACE. Several studies on science requirements and technical feasibility have been conducted in the recent years. These studies required a realistic model of the time variable gravity field in order to perform simulation studies on sensitivity of satellites and their instrumentation. This was the primary reason for the European Space Agency (ESA) to initiate a study on ''Monitoring and Modelling individual Sources of Mass Distribution and Transport in the Earth System by Means of Satellites''. The goal of this interdisciplinary study was to create as realistic as possible simulated time variable gravity fields based on coupled geophysical models, which could be used in the simulation processes in a controlled environment. For this purpose global atmosphere, ocean, continental hydrology and ice models were used. The coupling was performed by using consistent forcing throughout the models and by including water flow between the different domains of the Earth system. In addition gravity field changes due to solid Earth processes like continuous glacial isostatic adjustment (GIA) and a sudden earthquake with co-seismic and post-seismic signals were modelled. All individual model results were combined and converted to gravity field spherical harmonic series, which is the quantity commonly used to describe the Earth's global gravity field. The result of this study is a twelve-year time-series of 6-hourly time variable gravity field spherical harmonics up to degree and order 180 corresponding to a global spatial resolution of 1 degree in latitude and longitude. In this paper, we outline the input data sets and the process of combining these data sets into a coherent model of temporal gravity field changes. The resulting time series was used in some follow-on studies and is available to anybody interested.

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The ~90-year Gleissberg and ~200-year de Vries cycles have been identified as two distinctive quasi-periodic components of Holocene solar activity. Evidence exists for the impact of such multi-decadal to centennial-scale variability in total solar irradiance (TSI) on climate, but concerning the ocean, this evidence is mainly restricted to the surface response. Here we use a comprehensive global climate model to study the impact of idealized solar forcing, representing the Gleissberg and de Vries cycles, on global ocean potential temperature at different depth levels, after a recent proxy record indicates a signal of TSI anomalies in the northeastern Atlantic at mid-depth. Potential impacts of TSI anomalies on deeper oceanic levels are climatically relevant due to their possible effect on ocean circulation by altering water mass characteristics. Simulated solar anomalies are shown to penetrate the ocean down to at least deep-water levels. Despite the fact that the two forcing periods differ only by a factor of ~2, the spatial pattern of response is significantly distinctive between the experiments, suggesting different mechanisms for solar signal propagation. These are related to advection by North Atlantic Deep Water flow (200-year forcing), and barotropic adjustment in the South Atlantic in response to a latitudinal shift of the westerly wind belt (90-year forcing).

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Euphausiids constitute major biomass component in shelf ecosystems and play a fundamental role in the rapid vertical transport of carbon from the ocean surface to the deeper layers during their daily vertical migration (DVM). DVM depth and migration patterns depend on oceanographic conditions with respect to temperature, light and oxygen availability at depth, factors that are highly dependent on season in most marine regions. Changes in the abiotic conditions also shape Euphausiid metabolism including aerobic and anaerobic energy production. Here we introduce a global krill respiration model which includes the effect of latitude (LAT), the day of the year of interest (DoY), and the number of daylight hours on the day of interest (DLh), in addition to the basal variables that determine ectothermal oxygen consumption (temperature, body mass and depth) in the ANN model (Artificial Neural Networks). The newly implemented parameters link space and time in terms of season and photoperiod to krill respiration. The ANN model showed a better fit (r**2=0.780) when DLh and LAT were included, indicating a decrease in respiration with increasing LAT and decreasing DLh. We therefore propose DLh as a potential variable to consider when building physiological models for both hemispheres. We also tested for seasonality the standard respiration rate of the most common species that were investigated until now in a large range of DLh and DoY with Multiple Linear Regression (MLR) or General Additive model (GAM). GAM successfully integrated DLh (r**2= 0.563) and DoY (r**2= 0.572) effects on respiration rates of the Antarctic krill, Euphausia superba, yielding the minimum metabolic activity in mid-June and the maximum at the end of December. Neither the MLR nor the GAM approach worked for the North Pacific krill Euphausia pacifica, and MLR for the North Atlantic krill Meganyctiphanes norvegica remained inconclusive because of insufficient seasonal data coverage. We strongly encourage comparative respiration measurements of worldwide Euphausiid key species at different seasons to improve accuracy in ecosystem modelling.

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The aim of this study was to evaluate the potential of constructing an oxygen and carbon isotope stratigraphy for the late Pleistocene succession from Hole 1127B drilled on the Great Australian Bight. Stable isotope analyses were performed on bulk- and fine-fraction (<38 µm) sediment samples. The oxygen isotope variations are generally smaller in magnitude than expected from global pelagic records. This is most likely due to the neriticly dominated sediment composition. Correlation of the oxygen isotope data with carbonate mineralogy and downhole logging data shows simultaneous variations and trends, which are particularly evident in the mid-Pleistocene sediments. Correlation of the oxygen isotope data with the classic SPECMAP curve is used to evaluate the stratigraphic potential of the Site 1127 sediments. This study indicates that an isotope stratigraphy based on planktonic and benthic foraminifers is needed to fully evaluate the response of cool-water carbonates deposited in a margin setting to global ice-volume fluctuations and, hence, the associated sea level variations.