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91.
Manish Jaiswal Nele A. Haelterman Hector Sandoval Bo Xiong Taraka Donti Auinash Kalsotra Shinya Yamamoto Thomas A. Cooper Brett H. Graham Hugo J. Bellen 《PLoS biology》2015,13(7)
Two insults often underlie a variety of eye diseases including glaucoma, optic atrophy, and retinal degeneration—defects in mitochondrial function and aberrant Rhodopsin trafficking. Although mitochondrial defects are often associated with oxidative stress, they have not been linked to Rhodopsin trafficking. In an unbiased forward genetic screen designed to isolate mutations that cause photoreceptor degeneration, we identified mutations in a nuclear-encoded mitochondrial gene, ppr, a homolog of human LRPPRC. We found that ppr is required for protection against light-induced degeneration. Its function is essential to maintain membrane depolarization of the photoreceptors upon repetitive light exposure, and an impaired phototransduction cascade in ppr mutants results in excessive Rhodopsin1 endocytosis. Moreover, loss of ppr results in a reduction in mitochondrial RNAs, reduced electron transport chain activity, and reduced ATP levels. Oxidative stress, however, is not induced. We propose that the reduced ATP level in ppr mutants underlies the phototransduction defect, leading to increased Rhodopsin1 endocytosis during light exposure, causing photoreceptor degeneration independent of oxidative stress. This hypothesis is bolstered by characterization of two other genes isolated in the screen, pyruvate dehydrogenase and citrate synthase. Their loss also causes a light-induced degeneration, excessive Rhodopsin1 endocytosis and reduced ATP without concurrent oxidative stress, unlike many other mutations in mitochondrial genes that are associated with elevated oxidative stress and light-independent photoreceptor demise. 相似文献
92.
Matt J. Keeling Edward M. Hill Erin E. Gorsich Bridget Penman Glen Guyver-Fletcher Alex Holmes Trystan Leng Hector McKimm Massimiliano Tamborrino Louise Dyson Michael J. Tildesley 《PLoS computational biology》2021,17(1)
Efforts to suppress transmission of SARS-CoV-2 in the UK have seen non-pharmaceutical interventions being invoked. The most severe measures to date include all restaurants, pubs and cafes being ordered to close on 20th March, followed by a “stay at home” order on the 23rd March and the closure of all non-essential retail outlets for an indefinite period. Government agencies are presently analysing how best to develop an exit strategy from these measures and to determine how the epidemic may progress once measures are lifted. Mathematical models are currently providing short and long term forecasts regarding the future course of the COVID-19 outbreak in the UK to support evidence-based policymaking. We present a deterministic, age-structured transmission model that uses real-time data on confirmed cases requiring hospital care and mortality to provide up-to-date predictions on epidemic spread in ten regions of the UK. The model captures a range of age-dependent heterogeneities, reduced transmission from asymptomatic infections and produces a good fit to the key epidemic features over time. We simulated a suite of scenarios to assess the impact of differing approaches to relaxing social distancing measures from 7th May 2020 on the estimated number of patients requiring inpatient and critical care treatment, and deaths. With regard to future epidemic outcomes, we investigated the impact of reducing compliance, ongoing shielding of elder age groups, reapplying stringent social distancing measures using region based triggers and the role of asymptomatic transmission. We find that significant relaxation of social distancing measures from 7th May onwards can lead to a rapid resurgence of COVID-19 disease and the health system being quickly overwhelmed by a sizeable, second epidemic wave. In all considered age-shielding based strategies, we projected serious demand on critical care resources during the course of the pandemic. The reintroduction and release of strict measures on a regional basis, based on ICU bed occupancy, results in a long epidemic tail, until the second half of 2021, but ensures that the health service is protected by reintroducing social distancing measures for all individuals in a region when required. Our work confirms the effectiveness of stringent non-pharmaceutical measures in March 2020 to suppress the epidemic. It also provides strong evidence to support the need for a cautious, measured approach to relaxation of lockdown measures, to protect the most vulnerable members of society and support the health service through subduing demand on hospital beds, in particular bed occupancy in intensive care units. 相似文献
93.
Hector Neff 《American anthropologist》1999,101(4):849-850
Traces of the Past: Unraveling the Secrets of Archaeology through Chemistry. Joseph B. Lambert. Reading, MA: Perseus Books, 1997. 318 pp. 相似文献
94.
Burgos JM Altcheh J Bisio M Duffy T Valadares HM Seidenstein ME Piccinali R Freitas JM Levin MJ Macchi L Macedo AM Freilij H Schijman AG 《International journal for parasitology》2007,37(12):1319-1327
Congenital transmission of Trypanosoma cruzi may occur in some or all the gestations from a T. cruzi-infected mother. Variable rates of congenital transmission have been reported in different geographical areas where different parasitic strains predominate, suggesting that parasitic genotypes might play a role in the risk of congenital transmission. Moreover, in cases of transmission it is unknown if the whole maternal T. cruzi population or certain clones are preferentially transmitted by the transplacental route. In this study, bloodstream T. cruzi lineages were identified in blood samples from congenitally infected children, transmitting and non-transmitting mothers and unrelated Chagas disease patients, using improved PCR strategies targeted to nuclear genomic markers. T. cruzi IId was the prevalent genotype among 36/38 PCR-positive congenitally infected infants, 5/5 mothers who transmitted congenital Chagas disease, 12/13 mothers who delivered non-infected children and 28/34 unrelated Chagas disease patients, all coming from endemic localities of Argentina and Bolivia. These figures indicate no association between a particular genotype and vertical transmission. Furthermore, minicircle signatures from the maternal and infants' bloodstream trypanosomes were profiled by restriction fragment length polymorphism of the 330-bp PCR-amplified variable regions in seven cases of mothers and congenitally infected infants. Minicircle signatures were nearly identical between each mother and her infant/s and unique to each mother-infant/s case, a feature that was also observed in twin deliveries. Moreover, allelic size polymorphism analysis of microsatellite loci from populations transmitted to twins showed that all clones from the maternal polyclonal population were equally infective to both siblings. 相似文献
95.
Kobayashi E Shimazaki M Miyamoto Y Masuno H Yamamoto K DeLuca HF Yamada S Shimizu M 《Bioorganic & medicinal chemistry》2007,15(3):1475-1482
We have synthesized four new geometric isomers of 1alpha,25-dihydroxy-2-(2'-fluoroethylidene)-19-norvitamin D analogs 1 and 2 having a 20R- and 20S-configuration, whose structures are correlated with 2MD possessing high potencies in stimulating bone formation in vitro and in vivo. The E-isomers of (20R)- and (20S)-2-fluoroethylidene analogs 1a and 1b were comparable with the natural hormone 1alpha,25-(OH)(2)D(3) in binding to the vitamin D receptor (VDR), while two Z-isomers 2a and 2b were about 15-20 times less active than the hormone. In inducing expression of the vitamin D responsive element-based luciferase reporter gene, the E-isomers 1a and 1b were 1.2- and 8.6-fold more potent than the hormone, respectively, while the Z-isomers 2a and 2b had 27-55% of the potency. On the basis of the biological activities and a docking simulation based on X-ray crystallographic analysis of the VDR ligand-binding pocket, the structure-activity relationships of the fluorinated 19-norvitamin D analogs are discussed. 相似文献
96.
Glebocka A Sicinski RR Plum LA DeLuca HF 《The Journal of steroid biochemistry and molecular biology》2007,103(3-5):310-315
Our recent studies with 2-(3'-hydroxypropylidene) analogs of 1alpha,25-dihydroxy-19-norvitamin D(3) showed that this 2-substituent creates compounds with very potent biological activity. In the continuing search for vitamin D compounds with selective activity profiles, we prepared a series of 1alpha-hydroxy-19-norvitamin D analogs characterized by the presence of a 3'-hydroxypropylidene substituent at C-2 and a truncated side chain. These vitamin D compounds were efficiently prepared using convergent syntheses. The C,D-fragments, namely the Grundmann ketones 19, 20, 27, 36 and 37 were synthesized from the known 8beta-benzoyloxy-22-aldehydes 12 and 29. These hydrindanones were subjected to Lythgoe type Wittig-Horner coupling with phosphine oxide 21, prepared by us previously, and after hydroxyl deprotection the set of 19-norvitamins 7-11 was successfully obtained. According to our expectations, all analogs (with an exception of the 20R-compound 7) have pronounced in vitro activity. When compared to the natural hormone 1alpha,25-(OH)(2)D(3) (1), they show the same or only slightly reduced affinity for the vitamin D receptor while being similarly effective as 1 in differentiation of HL-60 cells into monocytes. 相似文献
97.
98.
99.
Jorge Mansur Medina Juliany Cola Fernandes Rodrigues Otacilio C Moreira Geórgia Atella Wanderley de Souza Hector Barrabin 《Memórias do Instituto Oswaldo Cruz》2015,110(1):48-55
Phytomonas serpens are flagellates in the family Trypanosomatidae that parasitise the
tomato plant (Solanum lycopersicum L.), which results in fruits with low commercial
value. The tomato glycoalkaloid tomatine and its aglycone tomatidine inhibit the
growth of P. serpens in axenic cultures. Tomatine, like many other saponins, induces
permeabilisation of the cell membrane and a loss of cell content, including the
cytosolic enzyme pyruvate kinase. In contrast, tomatidine does not cause
permeabilisation of membranes, but instead provokes morphological changes, including
vacuolisation. Phytomonas treated with tomatidine show an increased accumulation of
labelled neutral lipids (BODYPY-palmitic), a notable decrease in the amount of
C24-alkylated sterols and an increase in zymosterol content. These
results are consistent with the inhibition of 24-sterol methyltransferase (SMT),
which is an important enzyme that is responsible for the methylation of sterols at
the 24 position. We propose that the main target of tomatidine is the sterols
biosynthetic pathway, specifically, inhibition of the 24-SMT. Altogether, the results
obtained in the present paper suggest a more general effect of alkaloids in
trypanosomatids, which opens potential therapeutic possibilities for the treatment of
the diseases caused by these pathogens. 相似文献
100.
Franziska Volland-Voigt Achim Br?uning Oswaldo Ganzhi Thorsten Peters Hector Maza 《Trees - Structure and Function》2011,25(1):39-48
Stem diameter increments of the broadleaved deciduous tree species Tabebuia chrysantha were measured with high-resolution dendrometers in a tropical lower montane forest and in a dry forest in southern Ecuador,
the latter showing a distinct dry season. Those analyses were complemented by wood anatomical studies on regularly collected
microcores to determine the season of active cambial growth and the time of formation of annual growth boundaries. The length
of the cambial active period varied between 3 and 7 months at the tropical lower montane forest and 2 and 4 months in the
dry forest, respectively. During dry days, amplitudes of daily stem diameter variations correlated with vapour pressure deficit.
During October and November, inter-annual climate variations may lead to dry and sunny conditions in the tropical lower montane
forest, causing water deficit and stem diameter shrinkage in T. chrysantha. The results of the climate–growth analysis show a positive relationship between tree growth and rainfall as well as vapour
pressure deficit in certain periods of the year, indicating that rainfall plays a major role for tree growth. 相似文献