313 research outputs found
Network Medicine Framework for Identifying Drug Repurposing Opportunities for COVID-19
The current pandemic has highlighted the need for methodologies that can
quickly and reliably prioritize clinically approved compounds for their
potential effectiveness for SARS-CoV-2 infections. In the past decade, network
medicine has developed and validated multiple predictive algorithms for drug
repurposing, exploiting the sub-cellular network-based relationship between a
drug's targets and disease genes. Here, we deployed algorithms relying on
artificial intelligence, network diffusion, and network proximity, tasking each
of them to rank 6,340 drugs for their expected efficacy against SARS-CoV-2. To
test the predictions, we used as ground truth 918 drugs that had been
experimentally screened in VeroE6 cells, and the list of drugs under clinical
trial, that capture the medical community's assessment of drugs with potential
COVID-19 efficacy. We find that while most algorithms offer predictive power
for these ground truth data, no single method offers consistently reliable
outcomes across all datasets and metrics. This prompted us to develop a
multimodal approach that fuses the predictions of all algorithms, showing that
a consensus among the different predictive methods consistently exceeds the
performance of the best individual pipelines. We find that 76 of the 77 drugs
that successfully reduced viral infection do not bind the proteins targeted by
SARS-CoV-2, indicating that these drugs rely on network-based actions that
cannot be identified using docking-based strategies. These advances offer a
methodological pathway to identify repurposable drugs for future pathogens and
neglected diseases underserved by the costs and extended timeline of de novo
drug development
Epidemiological associations between brachycephaly and upper respiratory tract disorders in dogs attending veterinary practices in England
Background: Brachycephalic dog breeds are increasingly common. Canine brachycephaly has been associated with upper respiratory tract (URT) disorders but reliable prevalence data remain lacking. Using primary-care veterinary clinical data, this study aimed to report the prevalence and breed-type risk factors for URT disorders in dogs. Results: The sampling frame included 170,812 dogs attending 96 primary-care veterinary clinics participating within the VetCompass Programme. Two hundred dogs were randomly selected from each of three extreme brachycephalic breed types (Bulldog, French Bulldog and Pug) and three common small-to medium sized breed types (moderate brachycephalic: Yorkshire Terrier and non-brachycephalic: Border Terrier and West Highland White Terrier). Information on all URT disorders recorded was extracted from individual patient records. Disorder prevalence was compared between groups using the chi-squared test or Fisherâs test, as appropriate. Risk factor analysis used multivariable logistic regression modelling. During the study, 83 (6.9 %) study dogs died. Extreme brachycephalic dogs (median longevity: 8.6 years, IQR: 2.4-10.8) were significantly younger at death than the moderate and non-brachycephalic group of dogs (median 12.7 years, IQR 11.1-15.0) (Pâ\u3câ0.001). A higher proportion of deaths in extreme brachycephalic breed types were associated with URT disorders (4/24 deaths, 16.7 %) compared with the moderate and non-brachycephalic group (0/59 deaths, 0.0 %) (Pâ=â0.001). The prevalence of having at least one URT disorder in the extreme brachycephalic group was higher (22.0 %, 95 % confidence interval (CI): 18.0-26.0) than in the moderate and non-brachycephalic group (9.7 %, 95 % CI: 7.1-12.3, Pâ\u3câ0.001). The prevalence of URT disorders varied significantly by breed type: Bulldogs 19.5 %, French Bulldogs 20.0 %, Pugs 26.5 %, Border Terriers 9.0 %, West Highland White Terriers 7.0 % and Yorkshire Terriers 13.0 % (Pâ\u3câ0.001). After accounting for the effects of age, bodyweight, sex, neutering and insurance, extreme brachycephalic dogs had 3.5 times (95 % CI: 2.4-5.0, Pâ\u3câ0.001) the odds of at least one URT disorder compared with the moderate and non-brachycephalic group. Conclusions: In summary, this study reports that URT disorders are commonly diagnosed in Bulldog, French Bulldog, Pug, Border Terrier, WHWT and Yorkshire Terrier dogs attending primary-care veterinary practices in England. The three extreme brachycephalic breed types (Bulldog, French Bulldog and Pug) were relatively short-lived and predisposed to URT disorders compared with three other small-to-medium size breed types that are commonly owned (moderate brachycephalic Yorkshire Terrier and non-brachycephalic: Border Terrier and WHWT). Conclusions: In summary, this study reports that URT disorders are commonly diagnosed in Bulldog, French Bulldog, Pug, Border Terrier, WHWT and Yorkshire Terrier dogs attending primary-care veterinary practices in England. The three extreme brachycephalic breed types (Bulldog, French Bulldog and Pug) were relatively short-lived and predisposed to URT disorders compared with three other small-to-medium size breed types that are commonly owned (moderate brachycephalic Yorkshire Terrier and non-brachycephalic: Border Terrier and WHWT)
Thermal conductivity measurement of liquids in a microfluidic device
A new microfluidic-based approach to measuring liquid thermal conductivity is developed to address the requirement in many practical applications for measurements using small (microlitre) sample size and integration into a compact device. The approach also gives the possibility of high-throughput testing. A resistance heater and temperature sensor are incorporated into a glass microfluidic chip to allow transmission and detection of a planar thermal wave crossing a thin layer of the sample. The device is designed so that heat transfer is locally one-dimensional during a short initial time period. This allows the detected temperature transient to be separated into two distinct components: a short-time, purely one-dimensional part from which sample thermal conductivity can be determined and a remaining long-time part containing the effects of three-dimensionality and of the finite size of surrounding thermal reservoirs. Identification of the one-dimensional component yields a steady temperature difference from which sample thermal conductivity can be determined. Calibration is required to give correct representation of changing heater resistance, system layer thicknesses and solid material thermal conductivities with temperature. In this preliminary study, methanol/water mixtures are measured at atmospheric pressure over the temperature range 30â50°C. The results show that the device has produced a measurement accuracy of within 2.5% over the range of thermal conductivity and temperature of the tests. A relation between measurement uncertainty and the geometric and thermal properties of the system is derived and this is used to identify ways that error could be further reduced
Coalescent-based genome analyses resolve the early branches of the euarchontoglires
Despite numerous large-scale phylogenomic studies, certain parts of the mammalian tree are extraordinarily difficult to resolve. We used the coding regions from 19 completely sequenced genomes to study the relationships within the super-clade Euarchontoglires (Primates, Rodentia, Lagomorpha, Dermoptera and Scandentia) because the placement of Scandentia within this clade is controversial. The difficulty in resolving this issue is due to the short time spans between the early divergences of Euarchontoglires, which may cause incongruent gene trees. The conflict in the data can be depicted by network analyses and the contentious relationships are best reconstructed by coalescent-based analyses. This method is expected to be superior to analyses of concatenated data in reconstructing a species tree from numerous gene trees. The total concatenated dataset used to study the relationships in this group comprises 5,875 protein-coding genes (9,799,170 nucleotides) from all orders except Dermoptera (flying lemurs). Reconstruction of the species tree from 1,006 gene trees using coalescent models placed Scandentia as sister group to the primates, which is in agreement with maximum likelihood analyses of concatenated nucleotide sequence data. Additionally, both analytical approaches favoured the Tarsier to be sister taxon to Anthropoidea, thus belonging to the Haplorrhine clade. When divergence times are short such as in radiations over periods of a few million years, even genome scale analyses struggle to resolve phylogenetic relationships. On these short branches processes such as incomplete lineage sorting and possibly hybridization occur and make it preferable to base phylogenomic analyses on coalescent methods
An Estimation of Erinaceidae Phylogeny: A Combined Analysis Approach
BACKGROUND: Erinaceidae is a family of small mammals that include the spiny hedgehogs (Erinaceinae) and the silky-furred moonrats and gymnures (Galericinae). These animals are widely distributed across Eurasia and Africa, from the tundra to the tropics and the deserts to damp forests. The importance of these animals lies in the fact that they are the oldest known living placental mammals, which are well represented in the fossil record, a rarity fact given their size and vulnerability to destruction during fossilization. Although the Family has been well studied, their phylogenetic relationships remain controversial. To test previous phylogenetic hypotheses, we combined molecular and morphological data sets, including representatives of all the genera. METHODOLOGY AND PRINCIPAL FINDINGS: We included in the analyses 3,218 bp mitochondrial genes, one hundred and thirty-five morphological characters, twenty-two extant erinaceid taxa, and five outgroup taxa. Phylogenetic relationships were reconstructed using both partitioned and combined data sets. As in previous analyses, our results strongly support the monophyly of both subfamilies (Galericinae and Erinaceinae), the Hylomys group (to include Neotetracus and Neohylomys), and a sister-relationship of Atelerix and Erinaceus. As well, we verified that the extremely long branch lengths within the Galericinae are consistent with their fossil records. Not surprisingly, we found significant incongruence between the phylogenetic signals of the genes and the morphological characters, specifically in the case of Hylomys parvus, Mesechinus, and relationships between Hemiechinus and Paraechinus. CONCLUSIONS: Although we discovered new clues to understanding the evolutionary relationships within the Erinaceidae, our results nonetheless, strongly suggest that more robust analyses employing more complete taxon sampling (to include fossils) and multiple unlinked genes would greatly enhance our understanding of the Erinaceidae. Until then, we have left the nomenclature of the taxa unchanged; hence it does not yet precisely reflect their phylogenetic relationships or the depth of their genetic diversity
Astrobiological Complexity with Probabilistic Cellular Automata
Search for extraterrestrial life and intelligence constitutes one of the
major endeavors in science, but has yet been quantitatively modeled only rarely
and in a cursory and superficial fashion. We argue that probabilistic cellular
automata (PCA) represent the best quantitative framework for modeling
astrobiological history of the Milky Way and its Galactic Habitable Zone. The
relevant astrobiological parameters are to be modeled as the elements of the
input probability matrix for the PCA kernel. With the underlying simplicity of
the cellular automata constructs, this approach enables a quick analysis of
large and ambiguous input parameters' space. We perform a simple clustering
analysis of typical astrobiological histories and discuss the relevant boundary
conditions of practical importance for planning and guiding actual empirical
astrobiological and SETI projects. In addition to showing how the present
framework is adaptable to more complex situations and updated observational
databases from current and near-future space missions, we demonstrate how
numerical results could offer a cautious rationale for continuation of
practical SETI searches.Comment: 37 pages, 11 figures, 2 tables; added journal reference belo
A rocky composition for an Earth-sized exoplanet
Planets with sizes between that of Earth (with radius R[subscript circle in cross]) and Neptune (about 4 R[subscript circle in cross]) are now known to be common around Sun-like stars. Most such planets have been discovered through the transit technique, by which the planetâs size can be determined from the fraction of starlight blocked by the planet as it passes in front of its star. Measuring the planetâs massâand hence its density, which is a clue to its compositionâis more difficult. Planets of size 2â4 R[subscript circle in cross] have proved to have a wide range of densities, implying a diversity of compositions, but these measurements did not extend to planets as small as Earth. Here we report Doppler spectroscopic measurements of the mass of the Earth-sized planet Kepler-78b, which orbits its host star every 8.5âhours (ref. 6). Given a radius of 1.20â±â0.09 R[subscript circle in cross] and a mass of 1.69â±â0.41 M[subscript circle in cross], the planetâs mean density of 5.3â±â1.8âgâcm[superscript â3] is similar to Earthâs, suggesting a composition of rock and iron.Kepler Participating Scientist Progra
Vibrational microscopy and imaging of skin: from single cells to intact tissue
Vibrational microscopy and imaging offer several advantages for a variety of dermatological applications, ranging from studies of isolated single cells (corneocytes) to characterization of endogenous components in intact tissue. Two applications are described to illustrate the power of these techniques for skin research. First, the feasibility of tracking structural alterations in the components of individual corneocytes is demonstrated. Two solvents, DMSO and chloroform/methanol, commonly used in dermatological research, are shown to induce large reversible alterations (α-helix to ÎČ-sheet) in the secondary structure of keratin in isolated corneocytes. Second, factor analysis of image planes acquired with confocal Raman microscopy to a depth of 70 Όm in intact pigskin, demonstrates the delineation of specific skin regions. Two particular components that are difficult to identify by other means were observed in the epidermis. One small region was formed from a conformationally ordered lipid phase containing cholesterol. In addition, the presence of nucleated cells in the tissue (most likely keratinocytes) was revealed by the spectral signatures of the phosphodiester and cytosine moieties of cellular DNA
Surgical treatment of scoliosis: a review of techniques currently applied
In this review, basic knowledge and recent innovation of surgical treatment for scoliosis will be described. Surgical treatment for scoliosis is indicated, in general, for the curve exceeding 45 or 50 degrees by the Cobb's method on the ground that
Atopic dermatitis and indoor use of energy sources in cooking and heating appliances
Background: Atopic dermatitis (AD) prevalence has considerably increased worldwide in recent years. Studying indoor environments is particularly relevant, especially in industrialised countries where many people spend 80% of their time at home, particularly children. This study is aimed to identify the potential association between AD and the energy source (biomass, gas and electricity) used for cooking and domestic heating in a Spanish schoolchildren population.
Methods: As part of the ISAAC (International Study of Asthma and Allergies in Childhood) phase III study, a cross-sectional population-based survey was conducted with 21,355 6-to-7-year-old children from 8 Spanish ISAAC centres. AD prevalence, environmental risk factors and the use of domestic heating/cooking devices were assessed using the validated ISAAC questionnaire. Crude and adjusted odds ratios (cOR, aOR) and 95% confidence intervals (CIs) were obtained. A logistic regression analysis was performed (Chi-square test, p-valueâ<â0.05).
Results: It was found that the use of biomass systems gave the highest cORs, but only electric cookers showed a significant cOR of 1.14 (95% CI: 1.01-1.27). When the geographical area and the motherâs educational level were included in the logistic model, the obtained aOR values differed moderately from the initial cORs. Electric heating was the only type which obtained a significant aOR (1.13; 95% CI: 1.00-1.27). Finally, the model with all selected confounding variables (sex, BMI, number of siblings, motherâs educational level, smoking habits of parents, truck traffic and geographical area), showed aOR values which were very similar to those obtained in the previous adjusted logistic analysis. None of the results was statistically significant, but the use of electric heating showed an aOR close to significance (1.14; 95% CI: 0.99-1.31).
Conclusion: In our study population, no statistically significant associations were found between the type of indoor energy sources used and the presence of AD
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