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BACKGROUND: Worldwide, cancer pain management follows the World Health Organization (WHO) three-step analgesic ladder. Using weak opioids (e.g. codeine) at step 2 is debatable with low-dose strong opioids being potentially better, particularly in low- and middle-income countries where weak opioids are expensive. We wanted to assess the efficiency, safety and cost of omitting step 2 of the WHO ladder. PATIENTS AND METHODS: We carried out an international, open-label, randomised (1 : 1) parallel group trial. Eligible patients had cancer, pain ≥4/10 on a 0-10 numerical rating scale, required at least step 1 (paracetamol) of the WHO ladder and were randomised to the control arm (weak opioid, step 2 of the WHO ladder) or the experimental arm (strong opioid, step 3). Primary outcome was time to stable pain control (3 consecutive days with pain ≤3). Secondary outcomes included distress, opioid-related side-effects and costs. The primary outcome analysis was by intention to treat and the follow-up was for 20 days. RESULTS: One hundred and fifty-three patients were randomised (76 control, 77 experimental). There was no statistically significant difference in time to stable pain control between the arms, P = 0.667 (log-rank test). The adjusted hazard ratio for the control arm was 1.03 (95% confidence interval 0.72-1.49). In the control arm, 38 patients (53%) needed to change to a strong opioid due to ineffective analgesia. The median time to change was day 6 (interquartile range 4-11). Compared to the control arm, patients in the experimental arm had less nausea (P = 0.009) and costs were less. CONCLUSION: This trial provides some evidence that the two-step approach is an alternative option for cancer pain management.
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Analgésicos Opioides , Neoplasias , Humanos , Analgésicos Opioides/efeitos adversos , Acetaminofen , Dor/tratamento farmacológico , Dor/etiologia , Neoplasias/tratamento farmacológico , Organização Mundial da SaúdeRESUMO
Kolkata, the capital city of West Bengal, exploits groundwater for public water-supply. The groundwater has been reported to be widely polluted by arsenic (As). Analysis for As in 280 groundwaters from across Kolkata, failed to detect As concentrations >10 µg/L from natural processes. Arsenic concentrations between 10 and 79 µg/L found in 14 of the 280 groundwaters are remnant from a pollution-plume emanating from a single factory site where Paris Green, an arsenical pesticide, was manufactured between 1965 and 1985. In 45% of groundwaters sampled, concentrations of Mn exceed 0.4 mg/L, a putative health guideline value for drinking water. Sporadic minor hazards are posed by Pb > 10 µg/L introduced into groundwater from well-fittings, from 4% of groundwaters with F concentrations between 0.75 and 1 mg/L, and the 14% of groundwaters containing more than 500 mg/L Na, concentrations that might contribute to excessive daily intake of Na. Compounding hazards from As, F, Mn, Na, and Pb, shows that 64% of public wells and 40% of municipal wells supply groundwater of suspect quality. Groundwaters comply with WHO Guideline Values for drinking water in terms of Cr, Cu, Co, NO2, NO3, Sb, Se, and U. Aesthetic guideline values for Fe, Mn, SO4, and Cl are exceeded for many groundwaters.
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Arsênio , Água Subterrânea , Poluentes Químicos da Água , Monitoramento Ambiental , Índia , ManganêsRESUMO
OBJECTIVE: To assess the associations between depression and incident cancer risk. STUDY DESIGN: Systematic review and meta-analysis. METHODS: The Cochrane Library, Web of Science, MEDLINE, and PubMed databases were searched to identify studies. The quality of included studies was assessed using the Newcastle Ottawa Scale. Risk ratios (RRs) were used to measure effect size. A random-effects model was applied to synthesize the associations between depression and cancer risk. A forest plot was produced to visually assess RRs and 95% confidence intervals (CIs). Heterogeneity across studies was assessed using the I-squared statistic. A funnel plot was generated to assess potential publication bias, and Egger's regression was applied to test the symmetry of the funnel plot. RESULTS: In total, 1,469,179 participants and 89,716 incident cases of cancer from 25 studies were included. Depression was significantly associated with overall cancer risk (RR = 1.15, 95% CI: 1.09-1.22) and with liver cancer (RR = 1.20, 95% CI: 1.01-1.43) and lung cancer (RR = 1.33, 95% CI: 1.04-1.72). Subgroup analysis of studies in North America resulted in a significant summary relative risk (RR = 1.30, 95% CI: 1.15-1.48). No significant associations were found for breast, prostate, or colorectal/colon cancer. The average Newcastle Ottawa score was 7.56 for all included studies. CONCLUSION: Our findings showed a small and positive association between depression and the overall occurrence risk of cancer, as well as liver cancer and lung cancer risks. However, multinational and larger sample studies are required to further research and support these associations. Moreover, confounding factors such as cigarette smoking and alcohol use/abuse should be considered in future studies.
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Depressão/epidemiologia , Neoplasias/epidemiologia , Neoplasias/psicologia , Humanos , Incidência , RiscoRESUMO
Large Igneous Provinces (LIPs) are associated with global warming and carbon cycle perturbations during Oceanic Anoxic Event 2 (OAE2, ~94 Ma) and the Mid-Cenomanian Event (MCE, ~96.5 Ma). However, there is still no consensus on the role volcanism played as a trigger, or its source - previously ascribed to the Caribbean LIP or High Arctic LIP. Here, we use Mentelle Basin sedimentary mercury (Hg) concentrations to determine the timing of volcanism, and neodymium (Nd) and strontium (Sr) isotopes for sedimentary provenance. High Hg concentrations compared to Northern Hemisphere records, and a shift to radiogenic Nd isotopes, indicates Kerguelen LIP volcanic activity and plateau uplift occurred in the lead up to and within OAE2. Whilst we find limited evidence that a volcanic event caused the MCE, pulsed Hg spikes before and during OAE2 imply volcanic emissions were key in driving climate and carbon cycle changes and triggering OAE2.
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The southeast Asian fluke Opisthorchis viverrini remains endemic, particularly in Thailand, Lao PDR, Cambodia, Vietnam, and Myanmar. However, there is a lack of data on the prevalence of liver fluke infection in Kratie Province in northeastern Cambodia. The present study aimed to detect O. viverrini DNA in fecal specimens by using the internal transcribed spacer 2 (ITS2) region of ribosomal DNA (rDNA) based on polymerase chain reaction (PCR). The prevalence and percentage of O. viverrini infection were described by data analysis. Bivariate binary logistic regression analysis was used to look at the related prevalence of O. viverrini infection. A total of 6.89% from 377 fecal samples were found positive of O. viverrini DNA. The prevalence of O. viverrini infection was found to be higher in men (8.92%) than in women (5.45%), and to be associated more frequently with younger age groups (13.40%), illiteracy (8.74%), participation in other careers (non-specific occupations) (11.63%), and residence in the Trapaing Srae village (9.94%) of the Snuol district, Kratie Province. Age groups under 20 years old were significantly linked with O. viverrini infection, with ORadj=0.601, 95% CI=0.410-0.882, p=0.009 and significant value established at (P<0.05). This study demonstrates that O. viverrini infection is distributed in rural areas located near freshwater reservoirs. Therefore, active surveillance, clinical examination of association with hepatobiliary, cholangiocarcinoma, and health education are needed.
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Neoplasias dos Ductos Biliares , Opistorquíase , Opisthorchis , Masculino , Animais , Humanos , Feminino , Adulto Jovem , Adulto , Opisthorchis/genética , Opistorquíase/epidemiologia , Camboja/epidemiologia , Reação em Cadeia da Polimerase , Tailândia/epidemiologia , Ductos Biliares Intra-Hepáticos , Neoplasias dos Ductos Biliares/complicações , Neoplasias dos Ductos Biliares/epidemiologia , DNARESUMO
Biomechanical microenvironment refers to a variety of mechanical signals in the extracellular mechanical microenvironment, which will change correspondingly with time and space. It plays an important role in histological changes such as cell migration, proliferation, and differentiation, and can further affect wound healing. Wound healing is a complex pathophysiological process, and one of the important factors that affects wound healing is whether the cells can efficiently and quickly migrate to the wound center or not. Previous studies have shown that biomechanical microenvironment can not only induce the directional migration of cells, but also improve the migration rate of cells. In the complex natural environment, cells adopt various migration patterns and are dominated by special patterns such as local myosin contractility and extracellular microenvironment. In addition to overcoming the extracellular barrier, cells also need to interact with neighboring cells and tissue through local physical and mechanical forces and signals to complete migration and thus accelerate wound healing. Therefore, in recent years, scholars at home and abroad have been actively developing biological materials based on improving biomechanical microenvironment in order to further promote cell migration and thus accelerate wound healing. This paper reviews the recent research advances on the role of biomechanical environment in wound healing promotion via the regulating of cell migration and the development of related biomaterials.
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Materiais Biocompatíveis , Cicatrização , Diferenciação Celular , Movimento CelularRESUMO
Many species of helminths and protozoa caused intestinal parasitic infections (IPIs). It belongs to neglected tropical diseases (NTDs) and remains a major public health problem in several Southeast Asian countries. The present study aimed to investigate the prevalence of IPIs and associated risk factors among the population in Kratie Province in northeastern Cambodia and Phnom Penh is the capital that locates in southern Cambodia. Fecal specimens (n=366) were collected in 10 villages in Kratie Province and Phnom Penh from 2019 to 2021. They were processed using the formalin ethyl-acetate concentration technique (FECT) to investigate parasites at egg and cyst stages and then examined under a light microscope. The results revealed that the prevalence of IPIs among the population in Kratie Province (n=317) and Phnom Penh (n=49) was 16.12% (n=59); of Kratie Province (n=50, 13.66%) and Phnom Penh (n=9, 2.46%), 12.02% (n=44) were helminths and 4.10% (n=15) were protozoa. The parasitic infection rate was higher in males (9.02%) than in females (7.10%) and more likely to be due to helminths (7.38%) than protozoa (1.64%). Prevalence of Opisthorchis viverrini was the highest (5.74%), followed by those of Entamoeba coli (4.10%), hookworm (3.83%), Ascaris lumbricoides (1.10%), Hymenolepis nana (1.09%), Taenia spp. (0.54%), Trichuris trichiura (0.55%), and Enterobius vermicularis (0.27%), respectively. Moreover, O. viverrini infection was the most common infection in the <20-year age group in Kratie Province. In addition, the bivariate and multivariate analyses showed that the association between gender. Gender was a significant risk factor positively associated with O. viverrini and hookworm infections (ORadj=0.318, 95% CI=0.122-0.8270, P=0.019 and ORadj=0.085, 95% CI=0.017-0.436, P=0.003, respectively). In conclusion, the IPIs were highly prevalent, especially O. viverrini and hookworm infections, among the population in Cambodia. These IPIs impact the public health burden but can be prevented by education regarding good sanitary practices in this community.
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Helmintos , Enteropatias Parasitárias , Humanos , Masculino , Animais , Feminino , Camboja/epidemiologia , Fezes/parasitologia , Enteropatias Parasitárias/epidemiologia , Fatores de Risco , PrevalênciaRESUMO
PURPOSE: To investigate how weight loss correlates with changes in generic and weight-specific quality of life (QoL). METHODS: Youth generic (YQOL-S) and weight-specific instruments (YQOL-W) from 133 youth age 11-19 were analyzed at the beginning and end of 4-week immersion camp sessions known to produce weight loss. Paired samples t tests were used to test mean difference between baseline and final Body Mass Index (BMI) and YQOL-S and YQOL-W scores. YQOL-S and YQOL-W scores were transformed to values between 0 and 100, with higher values indicating better QOL. Cohen's d effect sizes were calculated to assess magnitude of effects. Percent weight loss (as % of baseline weight), change in BMI (baseline kg/m²-follow-up kg/m²), and change in % overweight ((BMI-50th% BMI for age and sex)/50th% BMI for age and sex × 100) were calculated. Multiple regressions were used to model final YQOL scores in the 11-14 and 15-19 age groups as functions of each measure of weight change, sex, age, and baseline YQOL score. RESULTS: Youth experienced significant reductions in BMI (Mean change = 3.7, SD = 1.4, t = 34.1, P < 0.001) and in the other measures of weight change. YQOL-S and YQOL-W scores improved significantly (P < 0.001), and effect sizes were 0.61 and 0.66, respectively. CONCLUSION: Changes in generic and weight-specific quality of life scores are associated with weight loss. The weight-specific measure is slightly more sensitive to weight changes; however, when controlling for modifiers, the YQOL-W remained significantly associated with weight loss, while the generic QoL measure did not.
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Qualidade de Vida , Redução de Peso , Programas de Redução de Peso , Adolescente , Índice de Massa Corporal , Acampamento , Criança , Feminino , Humanos , Masculino , Obesidade , Adulto JovemRESUMO
Burn children would experience pain and anxiety during treatment and rehabilitation, thus analgesic and sedative treatment should be applied throughout the whole process of burn treatment. Due to the unique physiological and psychological status of burn children, analgesic and sedative treatment for burn children is a relatively complex process compared with that for adult burn patients. Therefore, how to provide the effective and safe analgesic and sedative treatment for burn children is a clinical challenge. This paper reviewed the related progress of assisted analgesic and sedative treatment of burn children, in order to provide a reference for clinical treatment.
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Analgesia , Queimaduras/complicações , Dor/tratamento farmacológico , Analgésicos/uso terapêutico , Criança , Humanos , Hipnóticos e Sedativos/uso terapêutico , Dor/etiologiaRESUMO
Angiogenesis is the core step of wound repair, and vascular endothelial progenitor cells (EPC) play an extremely important role during wound repair. Recent studies have shown that vascular EPC-derived exosomes (EPC-Exo) can protect vessels, promote the proliferation and migration of vascular endothelial cells, and have anti-inflammatory, anti-oxidant and anti-apoptotic effects on vascular endothelial cells. This article reviews the mechanism of vascular EPC-Exo in angiogenesis and its potential applications in wound repair in recent years.
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Células Progenitoras Endoteliais , Exossomos , Movimento Celular , Proliferação de Células , Humanos , Neovascularização Fisiológica , CicatrizaçãoRESUMO
Helminth infections (HIs) are an important public health problem in tropical countries, and the associated problems have been neglected in rural areas of Thailand. Therefore, this study reports the prevalence and intensity of HIs among inhabitants of the Khon Sawan district, Chaiyaphum province, and Kaeng Samnam Nang district, Nakhon Ratchasima province, which are located near the Chi River and Lahanna water reservoir, northeastern Thailand. A cross-sectional descriptive study was conducted between July 31, 2018, and June 30, 2019, among rural villagers from 40 rural villages in 4 subdistricts. The participants were selected from the village enrolment list after proportional allocation of the total sample size. Faecal samples from 691 inhabitants were prepared using solvent-free faecal parasite concentrator, and helminths were then detected using a light microscope. Statistical analysis included the Chi-square test with Yates correction, and multivariable logistic regression was performed. A P-value of <0.05 was considered statistically significant. The prevalence of HIs was 2.03%. The most prevalent helminths were Opisthorchis viverrini (1.31%), followed by Strongyloides stercoralis (0.44%), Ascaris lumbricoides (0.29%), hookworm (0.15%), Teania spp. (0.15%) and one minute intestinal fluke (0.15%). Coinfections were identified in 2 cases for S. stercoralis and hookworm and 1 case for O. viverrini and S. stercoralis infection. All infected participants had a light intensity of HI. There was no significant difference between general characteristics for all HIs. The prevalence of HIs was not significantly associated with general characteristics. This study indicates that the infections result mainly from foodborne helminths and skin-penetrating nematodes. Therefore, interventions should concentrate on the personal hygiene of the population and improving sanitation to reduce HIs in this area.
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Helmintíase/epidemiologia , Helmintos/isolamento & purificação , Adulto , Ancylostomatoidea , Animais , Ascaris lumbricoides , Estudos Transversais , Fezes/parasitologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Opisthorchis , Contagem de Ovos de Parasitas , Rios , População Rural , Strongyloides stercoralis , Tailândia/epidemiologia , Adulto JovemRESUMO
Oxygen isotopes are sensitive tracers of climate change in tropical regions. Abrupt shifts of up to 18 per mil in the oxygen isotope ratio of diatom silica have been found in a 14,000-year record from two alpine lakes on Mt. Kenya. Interpretation of tropical-montane isotope records is controversial, especially concerning the relative roles of precipitation and temperature. Here, we argue that Holocene variations in delta(18)O are better explained by lake moisture balance than by temperature-induced fractionation. Episodes of heavy convective precipitation dated approximately 11,100 to 8600, 6700 to 5600, 2900 to 1900, and <1300 years before the present were linked to enhanced soil erosion, neoglacial ice advances, and forest expansion on Mt. Kenya.
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Diatomáceas/química , Sedimentos Geológicos/química , Isótopos de Oxigênio/análise , Clima Tropical , Ecossistema , Água Doce , Quênia , Pólen , Chuva , Dióxido de Silício/química , Temperatura , TempoRESUMO
The La Niña and El Niño phases of the El Niño-Southern Oscillation (ENSO) have major impacts on regional rainfall patterns around the globe, with substantial environmental, societal and economic implications. Long-term perspectives on ENSO behaviour, under changing background conditions, are essential to anticipating how ENSO phases may respond under future climate scenarios. Here, we derive a 7700-year, quantitative precipitation record using carbon isotope ratios from a single species of leaf preserved in lake sediments from subtropical eastern Australia. We find a generally wet (more La Niña-like) mid-Holocene that shifted towards drier and more variable climates after 3200 cal. yr BP, primarily driven by increasing frequency and strength of the El Niño phase. Climate model simulations implicate a progressive orbitally-driven weakening of the Pacific Walker Circulation as contributing to this change. At centennial scales, high rainfall characterised the Little Ice Age (~1450-1850 CE) in subtropical eastern Australia, contrasting with oceanic proxies that suggest El Niño-like conditions prevail during this period. Our data provide a new western Pacific perspective on Holocene ENSO variability and highlight the need to address ENSO reconstruction with a geographically diverse network of sites to characterise how both ENSO, and its impacts, vary in a changing climate.
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This study aimed to determine the prevalence and intensity of intestinal helminth infections (IHIs) among rural villagers in Waeng Noi district, Khon Kaen Province, northeastern Thailand. A cross-sectional study was conducted between March 1 and July 30, 2018, among rural villagers from 30 rural villages in 2 subdistricts. The participants were selected from the village enrollment list after proportional allocation of the total sample size. The background characteristic data were collected using a structured questionnaire. Specimens from patients with IHIs were prepared by concentration with a Faecal Parasite Concentrator-Solvent-Free (Mini Parasep® SF), and helminths were then detected using a light microscope. Of the 400 faecal specimens examined, 23 were positive for at least one intestinal helminth, resulting in a prevalence of 5.75%. The most prevalent helminths were Taenia spp., 10 (2.50%); followed by hookworm, 5 (1.25%); Trichuris trichiura, 4 (1.0%); Ascaris lumbricoides, 3(0.50%); and Opisthorchis viverrini, 1 (0.25%). All infected participants had a light intensity of IHI. Location (adjusted OR=2.52; 95% CI=1.30-3.52; P =0.042) showed a significant association with the prevalence of intestinal helminths. This study reveals that IHIs, particularly those with foodborne and soil-transmitted species of helminths, are prevalent in adults in rural subdistricts. A greater focus on interventions to improve personal hygiene and sanitation to prevent the spread of IHIs is required. Further studies should be performed to implement interdisciplinary research approaches in the study area.
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The Antarctic Peninsula Ice Sheet is currently experiencing sustained and accelerating loss of ice. Determining when these changes were initiated and identifying the main drivers is hampered by the short instrumental record (1992 to present). Here we present a 6,250 year record of glacial discharge based on the oxygen isotope composition of diatoms (δ18Odiatom) from a marine core located at the north-eastern tip of the Antarctic Peninsula. We find that glacial discharge - sourced primarily from ice shelf and iceberg melting along the eastern Antarctic Peninsula - remained largely stable between ~6,250 to 1,620 cal. yr BP, with a slight increase in variability until ~720 cal. yr. BP. An increasing trend in glacial discharge occurs after 550 cal. yr BP (A.D. 1400), reaching levels unprecedented during the past 6,250 years after 244 cal. yr BP (A.D. 1706). A marked acceleration in the rate of glacial discharge is also observed in the early part of twentieth century (after A.D. 1912). Enhanced glacial discharge, particularly after the 1700s is linked to a positive Southern Annular Mode (SAM). We argue that a positive SAM drove stronger westerly winds, atmospheric warming and surface ablation on the eastern Antarctic Peninsula whilst simultaneously entraining more warm water into the Weddell Gyre, potentially increasing melting on the undersides of ice shelves. A possible implication of our data is that ice shelves in this region have been thinning for at least ~300 years, potentially predisposing them to collapse under intensified anthropogenic warming.
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Fossil fuel combustion leads to increased levels of air pollution, which negatively affects human health as well as the environment. Documented data for Southeast Asia (SEA) show a strong increase in fossil fuel consumption since 1980, but information on coal and oil combustion before 1980 is not widely available. Spheroidal carbonaceous particles (SCPs) and heavy metals, such as mercury (Hg), are emitted as by-products of fossil fuel combustion and may accumulate in sediments following atmospheric fallout. Here we use sediment SCP and Hg records from several freshwater lentic ecosystems in SEA (Malaysia, Philippines, Singapore) to reconstruct long-term, region-wide variations in levels of these two key atmospheric pollution indicators. The age-depth models of Philippine sediment cores do not reach back far enough to date first SCP presence, but single SCP occurrences are first observed between 1925 and 1950 for a Malaysian site. Increasing SCP flux is observed at our sites from 1960 onward, although individual sites show minor differences in trends. SCP fluxes show a general decline after 2000â¯at each of our study sites. While the records show broadly similar temporal trends across SEA, absolute SCP fluxes differ between sites, with a record from Malaysia showing SCP fluxes that are two orders of magnitude lower than records from the Philippines. Similar trends in records from China and Japan represent the emergence of atmospheric pollution as a broadly-based inter-region environmental problem during the 20th century. Hg fluxes were relatively stable from the second half of the 20th century onward. As catchment soils are also contaminated with atmospheric Hg, future soil erosion can be expected to lead to enhanced Hg flux into surface waters.
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Poluição do Ar , Monitoramento Ambiental/métodos , Sedimentos Geológicos/química , Lagos , Sudeste Asiático , Ecossistema , Combustíveis Fósseis , Humanos , Mercúrio/análise , Metais Pesados , SoloRESUMO
Various studies report substantial increases in intrinsic water-use efficiency (W i ), estimated using carbon isotopes in tree rings, suggesting trees are gaining increasingly more carbon per unit water lost due to increases in atmospheric CO2. Usually, reconstructions do not, however, correct for the effect of intrinsic developmental changes in W i as trees grow larger. Here we show, by comparing W i across varying tree sizes at one CO2 level, that ignoring such developmental effects can severely affect inferences of trees' W i . W i doubled or even tripled over a trees' lifespan in three broadleaf species due to changes in tree height and light availability alone, and there are also weak trends for Pine trees. Developmental trends in broadleaf species are as large as the trends previously assigned to CO2 and climate. Credible future tree ring isotope studies require explicit accounting for species-specific developmental effects before CO2 and climate effects are inferred.Intrinsic water-use efficiency (W i ) reconstructions using tree rings often disregard developmental changes in W i as trees age. Here, the authors compare W i across varying tree sizes at a fixed CO2 level and show that ignoring developmental changes impacts conclusions on trees' W i responses to CO2 or climate.
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Dióxido de Carbono/metabolismo , Clima , Árvores/metabolismo , Água/metabolismo , Algoritmos , Isótopos de Carbono/metabolismo , Cedrela/crescimento & desenvolvimento , Cedrela/metabolismo , Fagus/crescimento & desenvolvimento , Fagus/metabolismo , Modelos Teóricos , Pinus/crescimento & desenvolvimento , Pinus/metabolismo , Quercus/crescimento & desenvolvimento , Quercus/metabolismo , Especificidade da Espécie , Temperatura , Fatores de Tempo , Árvores/crescimento & desenvolvimentoRESUMO
The DNA duplex d(CTCTCG*AGTCTC).d(GAGAC-TC*GAGAG) containing a single trans- diammine-dichloroplatinum(II) interstrand cross-link (where G* and C* represent the platinated bases) has been studied by two-dimensional NMR. All the exchangeable and non-exchangeable proton resonance lines were assigned (except H5'/H5") and the NOE intensities were transformed into distances via the RELAZ program. By combining the NOESY and COSY data (330 constraints) and NMR-constrained molecular mechanics using JUMNA, a solution structure of the cross-linked duplex has been determined. The duplex is distorted over two base pairs on each side of the interstrand cross-link and exhibits a slight bending of its axis ( approximately 20 degrees ) towards the minor groove. The platinated guanine G* adopts a syn conformation. The rotation results in a Hoogsteen-type pairing between the complementary G(6)* and C(19)* residues which is mediated by the platinum moiety and is stabilized by a hydrogen bond between O6(G(6)*) and N4H(C(19)*). The rise between the cross-linked residues and the adjacent residues is increased owing to the interaction between these adjacent residues and the ammine groups of the platinum moiety. These results are discussed in relation to the slow rate of closure of the monofunctional adducts into interstrand cross-links.
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Cisplatino/metabolismo , Reagentes de Ligações Cruzadas/metabolismo , DNA/química , DNA/metabolismo , Ressonância Magnética Nuclear Biomolecular , Conformação de Ácido Nucleico , Pareamento de Bases , Sequência de Bases , Nucleotídeos de Citosina/química , Nucleotídeos de Citosina/genética , Nucleotídeos de Citosina/metabolismo , DNA/genética , Adutos de DNA/química , Adutos de DNA/genética , Adutos de DNA/metabolismo , Nucleotídeos de Guanina/química , Nucleotídeos de Guanina/genética , Nucleotídeos de Guanina/metabolismo , Ligação de Hidrogênio , Cinética , Modelos Moleculares , Oligodesoxirribonucleotídeos/química , Oligodesoxirribonucleotídeos/genética , Oligodesoxirribonucleotídeos/metabolismo , Platina/metabolismo , Prótons , Software , SoluçõesRESUMO
A 2'-O-methylribooligonucleotide containing a G1.U.G3 triad modified by trans-diamminedichloro-platinum(II) was targeted to the RNA region responsible for the gag-pol frameshifting during translation of the HIV-1 mRNA. The binding of the platinated oligonucleotide to its target RNA induced a rearrangement of the (G1, G3)-intrastrand crosslink, leading to the formation of an intermolecular oligonucleotide-RNA G-A crosslink. This resulted in the selective arrest of translation of a luciferase gene placed downstream of the HIV-1 frameshift signal both in a cell-free extract (rabbit reticulocyte lysate) and in RNA-transfected cells. A specific inhibition of luciferase activity was still observed when the oligonucleotide-RNA complex was not pre-formed prior to either translation or transfection. Moreover, a selective inhibition was also observed when the oligonucleotide and the plasmid DNA encoding the luciferase and bearing the RNA gag- pol frameshifting signal were co-transfected in NIH 3T3 cultured cells. Therefore the intra-strand-->interstrand conversion of the platinum crosslink kinetically competes with the translation machinery and blocks the polypeptide elongation. These transplatin-modified oligonucleotides which operate within a live cell on a 'real-time' basis and do not need an external triggering signal constitute a promising new class of selective reactive probes.
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Cisplatino/química , Mudança da Fase de Leitura do Gene Ribossômico , Proteínas de Fusão gag-pol/genética , HIV-1/genética , Oligorribonucleotídeos/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Células 3T3 , Animais , Sequência de Bases , Camundongos , Dados de Sequência Molecular , Oligorribonucleotídeos/química , RNA Viral/genética , Transcrição Gênica/efeitos dos fármacosRESUMO
Formation of the dorsoventral axis in Drosophila melanogaster is mediated through control of the expression of several genes by the morphogen Dorsal. In the ventral part of the embryo Dorsal activates twist and represses zen amongst others. Recently, several proteins have been shown to assist Dorsal in the repression of zen, one of which is DSP1, a HMG box protein that was isolated as a putative co-repressor of Dorsal. In this report we used a DSP1 null mutant to ascertain in vivo the involvement of DSP1 in Dorsal-mediated repression of zen but not in the activation of twist. We show that Dorsal has the ability to interact with DSP1 in vitro as well as with rat HMG1. Using truncated versions of the proteins we located the domains of interaction as being the HMG boxes for DSP1 and HMG1 and the Rel domain for Dorsal. Finally, studies of the zen DNA binding properties of Dorsal and another related Rel protein (Gambif1 from Anopheles gambiae) revealed that their DNA binding affinities were increased in the presence of DSP1 and HMG1.