Gene expression is significantly stochastic making modeling of genetic networks challenging. We present an approximation that allows the calculation of not only the mean and variance, but also the ...distribution of protein numbers. We assume that proteins decay substantially more slowly than their mRNA and confirm that many genes satisfy this relation by using high-throughput data from budding yeast. For a two-stage model of gene expression, with transcription and translation as first-order reactions, we calculate the protein distribution for all times greater than several mRNA lifetimes and thus qualitatively predict the distribution of times for protein levels to first cross an arbitrary threshold. If in addition the fluctuates between inactive and active states, we can find the steady-state protein distribution, which can be bimodal if fluctuations of the promoter are slow. We show that our assumptions imply that protein synthesis occurs in geometrically distributed bursts and allows mRNA to be eliminated from a master equation description. In general, we find that protein distributions are asymmetric and may be poorly characterized by their mean and variance. Through maximum likelihood methods, our expressions should therefore allow more quantitative comparisons with experimental data. More generally, we introduce a technique to derive a simpler, effective dynamics for a stochastic system by eliminating a fast variable.
Results from the phase III trial CLEOPATRA in human epidermal growth factor receptor 2-positive first-line metastatic breast cancer demonstrated significant improvements in progression-free and ...overall survival with pertuzumab, trastuzumab, and docetaxel over placebo, trastuzumab, and docetaxel. We carried out exploratory analyses of the incidence and time to development of central nervous system (CNS) metastases in patients from CLEOPATRA.
Patients received pertuzumab/placebo: 840mg in cycle 1, then 420mg; trastuzumab: 8mg/kg in cycle 1, then 6mg/kg; docetaxel: initiated at 75mg/m2. Study drugs were administered i.v. every 3 weeks. The log-rank test was used for between-arm comparisons of time to CNS metastases as first site of disease progression and overall survival in patients with CNS metastases as first site of disease progression. The Kaplan–Meier approach was used to estimate median time to CNS metastases as first site of disease progression and median overall survival.
The incidence of CNS metastases as first site of disease progression was similar between arms; placebo arm: 51 of 406 (12.6%), pertuzumab arm: 55 of 402 (13.7%). Median time to development of CNS metastases as first site of disease progression was 11.9 months in the placebo arm and 15.0 months in the pertuzumab arm; hazard ratio (HR) = 0.58, 95% confidence interval (CI) 0.39–0.85, P = 0.0049. Overall survival in patients who developed CNS metastases as first site of disease progression showed a trend in favor of pertuzumab, trastuzumab, and docetaxel; HR = 0.66, 95% CI 0.39–1.11. Median overall survival was 26.3 versus 34.4 months in the placebo and pertuzumab arms, respectively. Treatment comparison of the survival curves was not statistically significant for the log-rank test (P = 0.1139), but significant for the Wilcoxon test (P = 0.0449).
While the incidence of CNS metastases was similar between arms, our results suggest that pertuzumab, trastuzumab, and docetaxel delays the onset of CNS disease compared with placebo, trastuzumab, and docetaxel.
NCT00567190.
Optical density (OD) measurements of microbial growth are one of the most common techniques used in microbiology, with applications ranging from studies of antibiotic efficacy to investigations of ...growth under different nutritional or stress environments, to characterization of different mutant strains, including those harbouring synthetic circuits. OD measurements are performed under the assumption that the OD value obtained is proportional to the cell number, i.e. the concentration of the sample. However, the assumption holds true in a limited range of conditions, and calibration techniques that determine that range are currently missing. Here we present a set of calibration procedures and considerations that are necessary to successfully estimate the cell concentration from OD measurements.
Eukaryotic genomes often encode multiple transporters for the same nutrient. For example, budding yeast has 17 hexose transporters (HXTs), all of which potentially transport glucose. Using ...mathematical modelling, we show that transporters that use either facilitated diffusion or symport can have a rate-affinity tradeoff, where an increase in the maximal rate of transport decreases the transporter's apparent affinity. These changes affect the import flux non-monotonically, and for a given concentration of extracellular nutrient there is one transporter, characterised by its affinity, that has a higher import flux than any other. Through encoding multiple transporters, cells can therefore mitigate the tradeoff by expressing those transporters with higher affinities in lower concentrations of nutrients. We verify our predictions using fluorescent tagging of seven HXT genes in budding yeast and follow their expression over time in batch culture. Using the known affinities of the corresponding transporters, we show that their regulation in glucose is broadly consistent with a rate-affinity tradeoff: as glucose falls, the levels of the different transporters peak in an order that mostly follows their affinity for glucose. More generally, evolution is constrained by tradeoffs. Our findings indicate that one such tradeoff often occurs in the cellular transport of nutrients.
Significance Cells have finite resources. Committing resources to one task therefore reduces the amount of resources available to others. These trade-offs are often overlooked but potentially modify ...all cellular processes. Building a mathematical cell model that respects such trade-offs and describes the mechanisms of protein synthesis and how cells extract resources from their environment, we quantitatively recover the typical behavior of an individual growing cell and of a population of cells. As trade-offs are experienced by all cells and because growth largely determines cellular fitness, a predictive understanding of how biochemical processes affect others and affect growth is important for diverse applications, such as the use of microbes for biotechnology, the inhibition of antibiotic resistance, and the growth of cancers.
Intracellular processes rarely work in isolation but continually interact with the rest of the cell. In microbes, for example, we now know that gene expression across the whole genome typically changes with growth rate. The mechanisms driving such global regulation, however, are not well understood. Here we consider three trade-offs that, because of limitations in levels of cellular energy, free ribosomes, and proteins, are faced by all living cells and we construct a mechanistic model that comprises these trade-offs. Our model couples gene expression with growth rate and growth rate with a growing population of cells. We show that the model recovers Monod’s law for the growth of microbes and two other empirical relationships connecting growth rate to the mass fraction of ribosomes. Further, we can explain growth-related effects in dosage compensation by paralogs and predict host–circuit interactions in synthetic biology. Simulating competitions between strains, we find that the regulation of metabolic pathways may have evolved not to match expression of enzymes to levels of extracellular substrates in changing environments but rather to balance a trade-off between exploiting one type of nutrient over another. Although coarse-grained, the trade-offs that the model embodies are fundamental, and, as such, our modeling framework has potentially wide application, including in both biotechnology and medicine.
The strategies involved in the development of therapeutics for neurodegenerative disorders are very complex and challenging due to the existence of the blood-brain barrier (BBB), a closely spaced ...network of blood vessels and endothelial cells that functions to prevent the entry of unwanted substances in the brain. The emergence and advancement of nanotechnology shows favourable prospects to overcome this phenomenon. Engineered nanoparticles conjugated with drug moieties and imaging agents that have dimensions between 1 and 100 nm could potentially be used to ensure enhanced efficacy, cellular uptake, specific transport, and delivery of specific molecules to the brain, owing to their modified physico-chemical features. The conjugates of nanoparticles and medicinal plants, or their components known as nano phytomedicine, have been gaining significance lately in the development of novel neuro-therapeutics owing to their natural abundance, promising targeted delivery to the brain, and lesser potential to show adverse effects. In the present review, the promising application, and recent trends of combined nanotechnology and phytomedicine for the treatment of neurological disorders (ND) as compared to conventional therapies, have been addressed. Nanotechnology-based efforts performed in bioinformatics for early diagnosis as well as futuristic precision medicine in ND have also been discussed in the context of computational approach.
To understand how cells control and exploit biochemical fluctuations, we must identify the sources of stochasticity, quantify their effects, and distinguish informative variation from confounding ..."noise." We present an analysis that allows fluctuations of biochemical networks to be decomposed into multiple components, gives conditions for the design of experimental reporters to measure all components, and provides a technique to predict the magnitude of these components from models. Further, we identify a particular component of variation that can be used to quantify the efficacy of information flow through a biochemical network. By applying our approach to osmosensing in yeast, we can predict the probability of the different osmotic conditions experienced by wild-type yeast and show that the majority of variation can be informational if we include variation generated in response to the cellular environment. Our results are fundamental to quantifying sources of variation and thus are a means to understand biological "design."
Dragon fruit (Hylocereus spp.), an important tropical fruit belonging to the family Cactaceae, is rich in essential nutrients such as vitamins, minerals, complex carbohydrates, dietary fibres and ...antioxidants. This study aims to distinguish three dragon fruit species well adapted to Andaman and Nicobar Island through morphological (34 quantitative and 26 qualitative traits), biochemical (5 traits) and molecular (14 ISSR primers) characterization. Morphological characterization revealed that presence of considerable amount of genetic variations among them especially for fruit characters viz., colour of peel and pulp. Cladode characters such as number of spines (3-5), length of areoles (mm) as 1-4, margin ribs of cladode (convex or concave) and its waxiness (weak or strong white waxy or light waxy) could be used for identification of three Hylocereus spp. under present study. Highest co-efficient of variation (%) obtained for pulp weight (88.7), whereas, lowest in distance of anthers belowstigma (3.3). Fruit and pulp weight (g) ranged from 26.5-419.3 and 10.3-258.8 with mean value of 204.8 and 125.3, respectively. Comparatively, high phenol (71.3-161.3) and flavonoid (26.6-508.2) content observed in peels than pulp (32.5-130.0 and 45.0-258.2) of fruit indicating higher antioxidant potential. Highest total carotenoids (µg 100 g
), β-carotene (µg 100 g
) and xanthophyll (µg g
) content obtained in pulp on DGF3 (33.8), DGF4 (55.9) and DGF3 (32.7), whereas, in peel on DGF2 (24.3), DGF4 (18.5) and DGF2 (24.1), respectively. DPPH-based scavenging activity (%) revealed higher scavenging activity of peels (55.6-81.2) than pulp (36.0-75.3) extracts. Comparatively, ABTS-based scavenging activity (%) was found more than DPPH-based one. Sixteen ISSR primers screened, 14 were produced 178 reproducible amplified bands. Number of amplified bands varied from 5 in UBC887 to 19 in UBC811 with an average of 12.71 bands per primer. Range of polymorphic bands and % polymorphism observed were 1-13 and 20.0-92.8, respectively. The polymorphic information content value of ISSR marker ranged from 0.42 (UBC895) to 0.91 (UBC 856). Cluster analysis distinguished three different Hylocereus species on the basis of geographic origin and pulp colour by forming separate groups and two genotypes each showed 52% (DGF1 and DGF3) and 76% (DGF2 and DGF4) genetic similarity. Key traits identified for distinguishing three different Hylocereus species were: Pulp/ peel colour of fruits, number of spines and length of areoles in cladode. Genotypes with high carotenoid and xanthophylls content (DGF4 and DGF2) identified under present study may be of industrial importance for development of nutraceutical products to meet out the vitamin-A deficiency among humans in tropical regions needed future focus.
This study aimed to explore the incidence and prevalence of OA in the UK in 2017 and their trends from 1997 to 2017 using a large nationally representative primary care database.
The UK Clinical ...Practice Research Datalink (CPRD) comprising data on nearly 17.5 million patients was used for the study. The incidence and prevalence of general practitioner diagnosed OA over a 20 years period (1997–2017) were estimated and age-sex and length of data contribution standardized using the 2017 CPRD population structure. Cohort effects were examined through Age-period-cohort analysis.
During 1997–2017, there were 494,716 incident OA cases aged ≥20 years. The standardised incidence of any OA in 2017 was 6.8 per 1000 person-years (95% CI 6.7 to 6.9) and prevalence was 10.7% (95% CI 10.7–10.8%). Both incidence and prevalence were higher in women than men. The incidence of any-OA decreased gradually in the past 20 years at an annual rate of −1.6% (95%CI -2.0 to −1.1%), and the reduction speeded up for people born after 1960. The prevalence of any-OA increased gradually at an annual rate of 1.4% (95% CI 1.3–1.6%). Although the prevalence was highest in Scotland and Northern Ireland, incidence was highest in the East Midlands. Both incidence and prevalence reported highest in the knee followed by hip, wrist/hand and ankle/foot.
In the UK approximately one in 10 adults have symptomatic clinically diagnosed OA, the knee being the commonest. While prevalence has increased and become static after 2008, incidence is slowly declining. Further research is required to understand these changes.
Fluorescence fluctuation spectroscopy (FFS) refers to techniques that analyze fluctuations in the fluorescence emitted by fluorophores diffusing in a small volume and can be used to distinguish ...between populations of molecules that exhibit differences in brightness or diffusion. For example, fluorescence correlation spectroscopy (FCS) resolves species through their diffusion by analyzing correlations in the fluorescence over time; photon counting histograms (PCH) and related methods based on moment analysis resolve species through their brightness by analyzing fluctuations in the photon counts. Here we introduce correlated photon counting histograms (cPCH), which uses both types of information to simultaneously resolve fluorescent species by their brightness and diffusion. We define the cPCH distribution by the probability to detect both a particular number of photons at the current time and another number at a later time. FCS and moment analysis are special cases of the moments of the cPCH distribution, and PCH is obtained by summing over the photon counts in either channel. cPCH is inherently a dual channel technique, and the expressions we develop apply to the dual colour case. Using simulations, we demonstrate that two species differing in both their diffusion and brightness can be better resolved with cPCH than with either FCS or PCH. Further, we show that cPCH can be extended both to longer dwell times to improve the signal-to-noise and to the analysis of images. By better exploiting the information available in fluorescence fluctuation spectroscopy, cPCH will be an enabling methodology for quantitative biology.
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