2,025 research outputs found
Monovinyl sulfone beta-cyclodextrin. A flexible drug carrier system
Cyclodextrins have been conjugated to target various receptors and have also been functionalized with carbohydrates for targeting specific organs. However, this approach is based on a rigid design that implies the ad hoc synthesis of each cyclodextrin-targeting agent conjugate. We hypothesized that: 1) a modular design that decouples the carrier function from the targeting function leads to a flexible system, 2) combining the reactivity of the vinyl sulfone group toward biomolecules that act as targeting agents with the ability of cyclodextrin to form complexes with a wide range of drugs may yield a versatile system that allows the targeting of different organs with different drugs, and 3) the higher reactivity of histidine residues toward the vinyl sulfone group can be exploited to couple the cyclodextrin to the targeting system with a degree of regioselectivity. As a proof of concept, we synthesized a monovinyl sulfone beta-cyclodextrin (module responsible for the payload), which, after coupling to recombinant antibody fragments raised against Trypanosoma brucei (module responsible for targeting) and loading with nitrofurazone (module responsible for therapeutic action) resulted in an effective delivery system that targets the surface of the parasites and shows trypanocidal activity
Association of VAV2 and VAV3 polymorphisms with cardiovascular risk factors
Hypertension, diabetes and obesity are cardiovascular risk factors closely associated to the development of renal and cardiovascular target organ damage. VAV2 and VAV3, members of the VAV family proto-oncogenes, are guanosine nucleotide exchange factors for the Rho and Rac GTPase family, which is related with cardiovascular homeostasis. We have analyzed the relationship between the presence of VAV2 rs602990 and VAV3 rs7528153 polymorphisms with cardiovascular risk factors and target organ damage (heart, vessels and kidney) in 411 subjects. Our results show that being carrier of the T allele in VAV2 rs602990 polymorphism is associated with an increased risk of obesity, reduced levels of ankle-brachial index and diastolic blood pressure and reduced retinal artery caliber. In addition, being carrier of T allele is associated with increased risk of target organ damage in males. On the other hand, being carrier of the T allele in VAV3 rs7528153 polymorphism is associated with a decreased susceptibility of developing a pathologic state composed by the presence of hypertension, diabetes, obesity or cardiovascular damage, and with an increased risk of developing altered basal glycaemia. This is the first report showing an association between VAV2 and VAV3 polymorphisms with cardiovascular risk factors and target organ damage
Decoding the molecular heterogeneity of pediatric monomorphic post-solid organ transplant lymphoproliferative disorders
The skull of Epidolops ameghinoi from the early Eocene ItaboraĂ fauna, southeastern Brazil, and the affinities of the extinct marsupialiform order Polydolopimorphia
The skull of the polydolopimorphian marsupialiform Epidolops ameghinoi is described
in detail for the first time, based on a single well-preserved cranium and associated left
and right dentaries plus additional craniodental fragments, all from the early Eocene
(53-50 million year old) ItaboraĂ fauna in southeastern Brazil. Notable craniodental
features of E. ameghinoi include absence of a masseteric process, very small
maxillopalatine fenestrae, a prominent pterygoid fossa enclosed laterally by a
prominent ectopterygoid crest, an absent or tiny transverse canal foramen, a simple,
planar glenoid fossa, and a postglenoid foramen that is immediately posterior to the
postglenoid process. Most strikingly, the floor of the hypotympanic sinus was
apparently unossified, a feature found in several stem marsupials but absent in all
known crown marsupials. "Type II" marsupialiform petrosals previously described from
ItaboraĂ plausibly belong to E. ameghinoi; in published phylogenetic analyses, these
petrosals fell outside (crown-clade) Marsupialia. "IMG VII" tarsals previously referred to
E. ameghinoi do not share obvious synapomorphies with any crown marsupial clade,
nor do they resemble those of the only other putative polydolopimorphians represented
by tarsal remains, namely the argyrolagids. Most studies have placed
Polydolopimorphia within Marsupialia, related to either Paucituberculata, or to
Microbiotheria and Diprotodontia. However, diprotodonty almost certainly evolved
independently in polydolopimorphians, paucituberculatans and diprotodontians, and
Epidolops does not share obvious synapomorphies with any marsupial order.
Epidolops is dentally specialized, but several morphological features appear to be
more plesiomorphic than any crown marsupial. It seems likely Epidolops that falls
outside Marsupialia, as do morphologically similar forms such as Bonapartherium and
polydolopids. Argyrolagids differ markedly in their known morphology from Epidolops
but share some potential apomorphies with paucituberculatans. It is proposed that
Polydolopimorphia as currently recognised is polyphyletic, and that argyrolagids (and
possibly other taxa currently included in Argyrolagoidea, such as groeberiids and
patagoniids) are members of Paucituberculata. This hypothesis is supported by
Bayesian non-clock phylogenetic analyses of a total evidence matrix comprising DNA
sequence data from five nuclear protein-coding genes, indels, retroposon insertions
and morphological characters: Epidolops falls outside Marsupialia, whereas
argyrolagids form a clade with the paucituberculatans Caenolestes and Palaeothentes,
regardless of whether the Type II petrosals and IMG VII tarsals are used to score
characters for Epidolops or not. There is no clear evidence for the presence of crown
marsupials at ItaboraĂ, and it is possible that the origin and early evolution of
Marsupialia was restricted to the "Austral Kingdom" (southern South America,
Antarctica, and Australia)
Deletion of iRhom2 protects against diet-induced obesity by increasing thermogenesis
Objective: Obesity is the result of positive energy balance. It can be caused by excessive energy consumption but also by decreased energy dissipation, which occurs under several conditions including when the development or activation of brown adipose tissue (BAT) is impaired. Here we evaluated whether iRhom2, the essential cofactor for the Tumour Necrosis Factor (TNF) sheddase ADAM17/TACE, plays a role in the pathophysiology of metabolic syndrome.Methods: We challenged WT versus iRhom2 KO mice to positive energy balance by chronic exposure to a high fat diet and then compared their metabolic phenotypes. We also carried out ex vivo assays with primary and immortalized mouse brown adipocytes to establish the autonomy of the effect of loss of iRhom2 on thermogenesis and respiration.Results: Deletion of iRhom2 protected mice from weight gain, dyslipidemia, adipose tissue inflammation, and hepatic steatosis and improved insulin sensitivity when challenged by a high fat diet. Crucially, the loss of iRhom2 promotes thermogenesis via BAT activation and beige adipocyte recruitment, enabling iRhom2 KO mice to dissipate excess energy more efficiently than WT animals. This effect on enhanced thermogenesis is cell-autonomous in brown adipocytes as iRhom2 KOs exhibit elevated UCP1 levels and increased mitochondrial proton leak.Conclusion: Our data suggest that iRhom2 is a negative regulator of thermogenesis and plays a role in the control of adipose tissue homeostasis during metabolic disease. (C) 2019 The Authors. Published by Elsevier GmbH
Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015
SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factorsâthe summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57¡8% (95% CI 56¡6â58¡8) of global deaths and 41¡2% (39¡8â42¡8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211¡8 million [192¡7 million to 231¡1 million] global DALYs), smoking (148¡6 million [134¡2 million to 163¡1 million]), high fasting plasma glucose (143¡1 million [125¡1 million to 163¡5 million]), high BMI (120¡1 million [83¡8 million to 158¡4 million]), childhood undernutrition (113¡3 million [103¡9 million to 123¡4 million]), ambient particulate matter (103¡1 million [90¡8 million to 115¡1 million]), high total cholesterol (88¡7 million [74¡6 million to 105¡7 million]), household air pollution (85¡6 million [66¡7 million to 106¡1 million]), alcohol use (85¡0 million [77¡2 million to 93¡0 million]), and diets high in sodium (83¡0 million [49¡3 million to 127¡5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation
Search for supersymmetric particles in scenarios with a gravitino LSP and stau NLSP
Sleptons, neutralinos and charginos were searched for in the context of
scenarios where the lightest supersymmetric particle is the gravitino. It was
assumed that the stau is the next-to-lightest supersymmetric particle. Data
collected with the DELPHI detector at a centre-of-mass energy near 189 GeV were
analysed combining the methods developed in previous searches at lower
energies. No evidence for the production of these supersymmetric particles was
found. Hence, limits were derived at 95% confidence level.Comment: 31 pages, 14 figure
Azimuthal anisotropy of charged particles at high transverse momenta in PbPb collisions at sqrt(s[NN]) = 2.76 TeV
The azimuthal anisotropy of charged particles in PbPb collisions at
nucleon-nucleon center-of-mass energy of 2.76 TeV is measured with the CMS
detector at the LHC over an extended transverse momentum (pt) range up to
approximately 60 GeV. The data cover both the low-pt region associated with
hydrodynamic flow phenomena and the high-pt region where the anisotropies may
reflect the path-length dependence of parton energy loss in the created medium.
The anisotropy parameter (v2) of the particles is extracted by correlating
charged tracks with respect to the event-plane reconstructed by using the
energy deposited in forward-angle calorimeters. For the six bins of collision
centrality studied, spanning the range of 0-60% most-central events, the
observed v2 values are found to first increase with pt, reaching a maximum
around pt = 3 GeV, and then to gradually decrease to almost zero, with the
decline persisting up to at least pt = 40 GeV over the full centrality range
measured.Comment: Replaced with published version. Added journal reference and DO
Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV
The performance of muon reconstruction, identification, and triggering in CMS
has been studied using 40 inverse picobarns of data collected in pp collisions
at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection
criteria covering a wide range of physics analysis needs have been examined.
For all considered selections, the efficiency to reconstruct and identify a
muon with a transverse momentum pT larger than a few GeV is above 95% over the
whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4,
while the probability to misidentify a hadron as a muon is well below 1%. The
efficiency to trigger on single muons with pT above a few GeV is higher than
90% over the full eta range, and typically substantially better. The overall
momentum scale is measured to a precision of 0.2% with muons from Z decays. The
transverse momentum resolution varies from 1% to 6% depending on pseudorapidity
for muons with pT below 100 GeV and, using cosmic rays, it is shown to be
better than 10% in the central region up to pT = 1 TeV. Observed distributions
of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO
Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV
The performance of muon reconstruction, identification, and triggering in CMS
has been studied using 40 inverse picobarns of data collected in pp collisions
at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection
criteria covering a wide range of physics analysis needs have been examined.
For all considered selections, the efficiency to reconstruct and identify a
muon with a transverse momentum pT larger than a few GeV is above 95% over the
whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4,
while the probability to misidentify a hadron as a muon is well below 1%. The
efficiency to trigger on single muons with pT above a few GeV is higher than
90% over the full eta range, and typically substantially better. The overall
momentum scale is measured to a precision of 0.2% with muons from Z decays. The
transverse momentum resolution varies from 1% to 6% depending on pseudorapidity
for muons with pT below 100 GeV and, using cosmic rays, it is shown to be
better than 10% in the central region up to pT = 1 TeV. Observed distributions
of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO
- âŚ