Immunolocalization of RANKL is Increased and OPG Decreased During Dietary Magnesium Deficiency in the Rat

BACKGROUND: Epidemiological studies have linked low dietary magnesium (Mg) to low bone mineral density and osteoporosis. Mg deficiency in animal models has demonstrated a reduction in bone mass and increase in skeletal fragility. One major mechanism appears to be an increase in osteoclast number and bone resorption. The final pathway of osteoclastogenesis involves three constituents of a cytokine system: receptor activator of nuclear factor kB ligand (RANKL); its receptor, receptor activator of nuclear factor kB (RANK); and its soluble decoy receptor, osteoprotegerin (OPG). The relative presence of RANKL and OPG dictates osteoclastogenesis. The objective of this study was to assess the presence of RANKL and OPG in rats on a low Mg diet. METHODS: RANKL and OPG were assessed by immunocytochemistry staining in the tibia for up to 6 months in control rats on regular Mg intake (0.5 g/kg) and experimental rats on reduction of dietary Mg (.04%, 25% and 50% of this Nutrient Requirement). RESULTS: At all dietary Mg intakes, alteration in the presence of immunocytochemical staining of RANKL and OPG was observed. In general, OPG was decreased and RANKL increased, reflecting an alteration in the RANKL/OPG ratio toward increased osteoclastogenesis. CONCLUSION: We have, for the first time demonstrated that a reduction in dietary Mg in the rat alters the presence of RANKL and OPG and may explain the increase in osteoclast number and decrease in bone mass in this animal model. As some of these dietary intake reductions in terms of the RDA are present in a large segment of or population, Mg deficiency may be another risk factor for osteoporosis

Remodeling of the Metabolome during Early Frog Development

A rapid series of synchronous cell divisions initiates embryogenesis in many animal species, including the frog Xenopus laevis. After many of these cleavage cycles, the nuclear to cytoplasmic ratio increases sufficiently to somehow cause cell cycles to elongate and become asynchronous at the mid-blastula transition (MBT). We have discovered that an unanticipated remodeling of core metabolic pathways occurs during the cleavage cycles and the MBT in X.laevis, as evidenced by widespread changes in metabolite abundance. While many of the changes in metabolite abundance were consistently observed, it was also evident that different female frogs laid eggs with different levels of at least some metabolites. Metabolite tracing with heavy isotopes demonstrated that alanine is consumed to generate energy for the early embryo. dATP pools were found to decline during the MBT and we have confirmed that maternal pools of dNTPs are functionally exhausted at the onset of the MBT. Our results support an alternative hypothesis that the cell cycle lengthening at the MBT is triggered not by a limiting maternal protein, as is usually proposed, but by a decline in dNTP pools brought about by the exponentially increasing demands of DNA synthesis

Early changes in cardiovascular structure and function in adolescents with type 1 diabetes.

BACKGROUND: Children with type 1 diabetes (T1D) are at higher risk of early adult-onset cardiovascular disease. We assessed cardiovascular structure and function in adolescents with T1D compared with healthy controls and the relationships between peripheral vascular function and myocardial parameters. METHODS AND RESULTS: 199 T1D [14.4 ± 1.6 years, diabetes duration 6.2 (2.0-12.8) years] and 178 controls (14.4 ± 2.1 years) completed endothelial function by flow mediated vasodilatation (FMD), arterial stiffness using pulse wave velocity (PWV) along with M-mode, pulse wave and tissue Doppler, and myocardial deformation echocardiographic imaging. Systolic (113 ± 10 vs. 110 ± 9 mmHg; p = 0.0005) and diastolic (62 ± 7 vs. 58 ± 7 mmHg; p < 0.0001) blood pressures, carotid femoral PWV and endothelial dysfunction measurements were increased in T1D compared with controls. Systolic and diastolic left ventricular dimensions and function by M-mode and pulse wave Doppler assessment were not significantly different. Mitral valve lateral e' (17.6 ± 2.6 vs. 18.6 ± 2.6 cm/s; p < 0.001) and a' (5.4 ± 1.1 vs. 5.9 ± 1.1 cm/s; p < 0.001) myocardial velocities were decreased and E/e' (7.3 ± 1.2 vs. 6.7 ± 1.3; p = 0.0003) increased in T1D. Left ventricular mid circumferential strain (-20.4 ± 2.3 vs. -19.5 ± 1.7 %; p < 0.001) was higher, whereas global longitudinal strain was lower (-19.0 ± 1.9 vs. -19.8 ± 1.5 % p < 0.001) in T1D. CONCLUSIONS: Adolescents with T1D exhibit early changes in blood pressure, peripheral vascular function and left ventricular myocardial deformation indices with a shift from longitudinal to circumferential shortening. Longitudinal follow-up of these changes in ongoing prospective trials may allow detection of those most at risk for cardiovascular abnormalities including hypertension that could preferentially benefit from early therapeutic interventions.Funding was provided by the Juvenile Diabetes Research Foundation- Canadian Clinical Trial Network (JDRF-CCTN), the Canadian Diabetes Association, the Heart and Stroke Foundation of Canada and the Sick Kids Labatt Family Heart Center Innovation fund. Funding was also provided by the British Heart Foundation, Diabetes UK and the Juvenile Diabetes Research Foundation

RELAÇÃO ENTRE A TURBULÊNCIA DO DOSSEL E DISTRIBUIÇÃO VERTICAL DE GASES REATIVOS NA FLORESTA TROPICAL DA AMAZÔNIA CENTRAL

Ozone plays a crucial role in the chemistry of the tropical atmospheric boundary layer. In the rainforest, ozone sources and sinks are complex due to numerous chemical reactions and surface deposition. Turbulent transport controls the vertical distribution of ozone. A field study in the Amazonia, near Manaus, Brazil during 2014 shows different shapes of ozone profiles as a response to changes in air turbulence during night-to-day and day-to-night transitions. During the night-to-day transition following sunrise ozone levels increase within the canopy due to photochemical production and increased vertical mixing. The vertical transport of ozone to the lower layers of the canopy is enhanced after the thermal inversion in the canopy disappears. At night, the ozone deposition to the ground and the foliage in the lower canopy is strong. After midnight, the lower canopy is devoid of ozone. Relatively high gradients of ozone levels within the forest during the nighttime also result from the decoupling between the in- and above-canopy environment that limits the forest-atmosphere ozone exchange. Processes responsible for the vertical distribution ozone are necessary to estimate the oxidation of the plant-emitted gases whose reaction products are aerosol precursors.O ozônio desempenha um papel fundamental na química da camada-limite atmosférica tropical. Sobre uma floresta tropical, as fontes e sumidouros de ozônio são complexas, devido a numerosas reações químicas e à deposição seca e úmida na superfície. O transporte turbulento controla a distribuição vertical de ozônio. Um estudo de campo na Amazônia, nas proximidades de Manaus, Brasil, durante 2014, revelou diferentes formas para o perfil de ozônio dependendo da turbulência atmosférica durante as transições noite-dia e dia-noite.  Após o nascer do sol, os resultados mostram que durante a transição noite-dia os níveis de ozônio aumentam no dossel devido à produção fotoquímica. O transporte vertical de ozônio para os níveis mais baixos do dossel é intensificado depois que a inversão térmica dentro do dossel desaparece.  Durante a noite, o sumidouro de ozônio no solo é forte, em comparação com a deposição nas folhas. Após a meia-noite, a parte mais baixa do dossel não contém mais ozônio, e como resultado os perfis de ozônio deixam de se modificar durante várias horas.  Gradientes relativamente fortes de ozônio dentro da floresta durante o período noturno também aparecem como resultado do desacoplamento entre o dossel e a atmosfera acima da copa. Isso limita as trocas de ozônio entre a floresta e a atmosfera acima. Dado que o ozônio reage com compostos orgânicos emitidos pela vegetação, e que os produtos dessas reações podem se condensar, o resultado final é a produção de aerossóis: desta forma, a distribuição vertical de ozônio é um indicador importante de quais reações são possíveis, e em particular do potencial de produção de aerossóis

The Lamb shift in muonic hydrogen

The long quest for a measurement of the Lamb shift in muonic hydrogen is over. Last year we measured the 2S1/2F=1–2P3/2F=2 energy splitting (Pohl et al., Nature, 466, 213 (2010)) in μp with an experimental accuracy of 15 ppm, twice better than our proposed goal. Using current QED calculations of the fine, hyperfine, QED, and finite size contributions, we obtain a root-mean-square proton charge radius of rp = 0.841 84 (67) fm. This value is 10 times more precise, but 5 standard deviations smaller, than the 2006 CODATA value of rp. The origin of this discrepancy is not known. Our measurement, together with precise measurements of the 1S–2S transition in regular hydrogen and deuterium, gives improved values of the Rydberg constant, R∞ = 10 973 731.568 160 (16) m⁻¹ and the rms charge radius of the deuteron rd = 2.128 09 (31) fm

The size of the proton and the deuteron

We have recently measured the 2S1/2⁼¹ − 2P3/2 ⁼ ² energy splitting in the muonic hydrogen atom μp to be 49881.88 (76) GHz. Using recent QED calculations of the fine-, hyperfine, QED and finite size contributions we obtain a root-mean-square proton charge radius of rp = 0.84184 (67) fm. This value is ten times more precise, but 5 standard deviations smaller, than the 2006 CODATA value of rp = 0.8768 (69) fm. The source of this discrepancy is unknown. Using the precise measurements of the 1S-2S transition in regular hydrogen and deuterium and our value of rp we obtain improved values of the Rydberg constant, R∞ = 10973731.568160 (16) m⁻¹and the rms charge radius of the deuteron rd = 2.12809 (31) fm

The UniProt-GO Annotation database in 2011

The GO annotation dataset provided by the UniProt Consortium (GOA: http://www.ebi.ac.uk/GOA) is a comprehensive set of evidenced-based associations between terms from the Gene Ontology resource and UniProtKB proteins. Currently supplying over 100 million annotations to 11 million proteins in more than 360 000 taxa, this resource has increased 2-fold over the last 2 years and has benefited from a wealth of checks to improve annotation correctness and consistency as well as now supplying a greater information content enabled by GO Consortium annotation format developments. Detailed, manual GO annotations obtained from the curation of peer-reviewed papers are directly contributed by all UniProt curators and supplemented with manual and electronic annotations from 36 model organism and domain-focused scientific resources. The inclusion of high-quality, automatic annotation predictions ensures the UniProt GO annotation dataset supplies functional information to a wide range of proteins, including those from poorly characterized, non-model organism species. UniProt GO annotations are freely available in a range of formats accessible by both file downloads and web-based views. In addition, the introduction of a new, normalized file format in 2010 has made for easier handling of the complete UniProt-GOA data se

High-Throughput Sequencing of RNA Silencing-Associated Small RNAs in Olive (Olea europaea L.)

Small RNAs (sRNAs) of 20 to 25 nucleotides (nt) in length maintain genome integrity and control gene expression in a multitude of developmental and physiological processes. Despite RNA silencing has been primarily studied in model plants, the advent of high-throughput sequencing technologies has enabled profiling of the sRNA component of more than 40 plant species. Here, we used deep sequencing and molecular methods to report the first inventory of sRNAs in olive (Olea europaea L.). sRNA libraries prepared from juvenile and adult shoots revealed that the 24-nt class dominates the sRNA transcriptome and atypically accumulates to levels never seen in other plant species, suggesting an active role of heterochromatin silencing in the maintenance and integrity of its large genome. A total of 18 known miRNA families were identified in the libraries. Also, 5 other sRNAs derived from potential hairpin-like precursors remain as plausible miRNA candidates. RNA blots confirmed miRNA expression and suggested tissue- and/or developmental-specific expression patterns. Target mRNAs of conserved miRNAs were computationally predicted among the olive cDNA collection and experimentally validated through endonucleolytic cleavage assays. Finally, we use expression data to uncover genetic components of the miR156, miR172 and miR390/TAS3-derived trans-acting small interfering RNA (tasiRNA) regulatory nodes, suggesting that these interactive networks controlling developmental transitions are fully operational in olive

Cell-Cell Transmission Enables HIV-1 to Evade Inhibition by Potent CD4bs Directed Antibodies

HIV is known to spread efficiently both in a cell-free state and from cell to cell, however the relative importance of the cell-cell transmission mode in natural infection has not yet been resolved. Likewise to what extent cell-cell transmission is vulnerable to inhibition by neutralizing antibodies and entry inhibitors remains to be determined. Here we report on neutralizing antibody activity during cell-cell transmission using specifically tailored experimental strategies which enable unambiguous discrimination between the two transmission routes. We demonstrate that the activity of neutralizing monoclonal antibodies (mAbs) and entry inhibitors during cell-cell transmission varies depending on their mode of action. While gp41 directed agents remain active, CD4 binding site (CD4bs) directed inhibitors, including the potent neutralizing mAb VRC01, dramatically lose potency during cell-cell transmission. This implies that CD4bs mAbs act preferentially through blocking free virus transmission, while still allowing HIV to spread through cell-cell contacts. Thus providing a plausible explanation for how HIV maintains infectivity and rapidly escapes potent and broadly active CD4bs directed antibody responses in vivo

Scaling up data curation using deep learning: An application to literature triage in genomic variation resources.

Manually curating biomedical knowledge from publications is necessary to build a knowledge based service that provides highly precise and organized information to users. The process of retrieving relevant publications for curation, which is also known as document triage, is usually carried out by querying and reading articles in PubMed. However, this query-based method often obtains unsatisfactory precision and recall on the retrieved results, and it is difficult to manually generate optimal queries. To address this, we propose a machine-learning assisted triage method. We collect previously curated publications from two databases UniProtKB/Swiss-Prot and the NHGRI-EBI GWAS Catalog, and used them as a gold-standard dataset for training deep learning models based on convolutional neural networks. We then use the trained models to classify and rank new publications for curation. For evaluation, we apply our method to the real-world manual curation process of UniProtKB/Swiss-Prot and the GWAS Catalog. We demonstrate that our machine-assisted triage method outperforms the current query-based triage methods, improves efficiency, and enriches curated content. Our method achieves a precision 1.81 and 2.99 times higher than that obtained by the current query-based triage methods of UniProtKB/Swiss-Prot and the GWAS Catalog, respectively, without compromising recall. In fact, our method retrieves many additional relevant publications that the query-based method of UniProtKB/Swiss-Prot could not find. As these results show, our machine learning-based method can make the triage process more efficient and is being implemented in production so that human curators can focus on more challenging tasks to improve the quality of knowledge bases