Systems biology of energetic and atomic costs in the yeast transcriptome, proteome, and metabolome

Proteins vary in their cost to the cell and natural selection may favour the use of proteins that are cheaper to produce. We develop a novel approach to estimate the amino acid biosynthetic cost based on genome-scale metabolic models, and directly investigate the effects of biosynthetic cost on transcriptomic, proteomic and metabolomic data in _Saccharomyces cerevisiae_. We find that our systems approach to formulating biosynthetic cost produces a novel measure that explains similar levels of variation in gene expression compared with previously reported cost measures. Regardless of the measure used, the cost of amino acid synthesis is weakly associated with transcript and protein levels, independent of codon usage bias. In contrast, energetic costs explain a large proportion of variation in levels of free amino acids. In the economy of the yeast cell, there appears to be no single currency to compute the cost of amino acid synthesis, and thus a systems approach is necessary to uncover the full effects of amino acid biosynthetic cost in complex biological systems that vary with cellular and environmental conditions

Proteome-wide landscape of solubility limits in a bacterial cell

Proteins are prone to aggregate when expressed above their solubility limits. Aggregation may occur rapidly, potentially as early as proteins emerge from the ribosome, or slowly, following synthesis. However, in vivo data on aggregation rates are scarce. Here, we classified the Escherichia coli proteome into rapidly and slowly aggregating proteins using an in vivo image-based screen coupled with machine learning. We find that the majority (70%) of cytosolic proteins that become insoluble upon overexpression have relatively low rates of aggregation and are unlikely to aggregate co-translationally. Remarkably, such proteins exhibit higher folding rates compared to rapidly aggregating proteins, potentially implying that they aggregate after reaching their folded states. Furthermore, we find that a substantial fraction (similar to 35%) of the proteome remain soluble at concentrations much higher than those found naturally, indicating a large margin of safety to tolerate gene expression changes. We show that high disorder content and low surface stickiness are major determinants of high solubility and are favored in abundant bacterial proteins. Overall, our study provides a global view of aggregation rates and hence solubility limits of proteins in a bacterial cell.Peer reviewe

Treatment of benign prostatic hyperplasia by natural drugs

Benign prostatic hyperplasia (BPH) is one of the most common urinary diseases affecting men, generally after the age of 50. The prevalence of this multifactorial disease increases with age. With aging, the plasma level of testosterone decreases, as well as the testosterone/estrogen ratio, resulting in increased estrogen activity, which may facilitate the hyperplasia of the prostate cells. Another theory focuses on dihydrotestosterone (DHT) and the activity of the enzyme 5α-reductase, which converts testosterone to DHT. In older men, the activity of this enzyme increases, leading to a decreased testosterone/DHT ratio. DHT may promote prostate cell growth, resulting in hyperplasia. Some medicinal plants and their compounds act by modulating this enzyme, and have the above-mentioned targets. This review focuses on herbal drugs that are most widely used in the treatment of BPH, including pumpkin seed, willow herb, tomato, maritime pine bark, Pygeum africanum bark, rye pollen, saw palmetto fruit, and nettle root, highlighting the latest results of preclinical and clinical studies, as well as safety issues. In addition, the pharmaceutical care and other therapeutic options of BPH, including pharmacotherapy and surgical options, are discussed, summarizing and comparing the advantages and disadvantages of each therapy

Validation of an automated morphological MRI-based 123I-FP-CIT SPECT evaluation method

INTRODUCTION Dopamine transporter imaging with (123)I-FP-CIT single photon emission computed tomography (SPECT) is helpful for the differential diagnosis between Parkinsonian syndrome (PS) and essential tremor (ET). Although visual assessment and time-consuming manual evaluation techniques are readily available, a fully objective and automated dopamine transporter quantification technique is always preferable, at least in research and follow-up investigations. Our aim was to develop a novel automated magnetic resonance imaging (MRI)-based evaluation technique of dopamine transporter SPECT images and to compare its diagnostic accuracy with those of the gold-standard visual grading and manual dopamine transporter binding quantification methods. METHODS (123)I-FP-CIT SPECT and MRI sessions were conducted in 33 patients with PS (15 men; mean age: 60.3 ± 9.7 years) and 15 patients with ET (8 men; mean age: 54.7 ± 16.3 years). Striatal dopamine transporter binding was visually classified by 2 independent experts as normal or abnormal grade I, II and III. Caudal and putaminal specific uptake ratios were calculated by both automated MRI-based and manual evaluation techniques. RESULTS We found almost perfect agreement (κ = 0.829) between the visual scores by the 2 observers. The automated method showed strong correlation with the visual and manual evaluation techniques and its diagnostic accuracy (sensitivity = 97.0%; specificity = 93.3%) was also comparable to these methods. The automatically determined uptake parameters showed negative correlation with the clinical severity of parkinsonism. Based on ordinal regression modelling, the automated MRI-based method could reliably determine the visual grading scores. CONCLUSION The novel MRI-based evaluation of (123)I-FP-CIT SPECT images is useful for the differentiation of PS from ET

Ion acceleration with few cycle relativistic laser pulses from foil targets

Ion acceleration resulting from the interaction of 11 fs laser pulses of ~35 mJ energy with ultrahigh contrast (<10^-10), and 10^19 W/cm^2 peak intensity with foil targets made of various materials and thicknesses at normal (0-degree) and 45-degree laser incidence is investigated. The maximum energy of the protons accelerated from both the rear and front sides of the target was above 1 MeV. A conversion efficiency from laser pulse energy to proton beam is estimated to be as high as ~1.4 % at 45-degree laser incidence using a 51 nm-thick Al target. The excellent laser contrast indicates the predominance of vacuum heating via the Brunels effect as an absorption mechanism involving a tiny pre-plasma of natural origin due to the Gaussian temporal laser pulse shape. Experimental results are in reasonable agreement with theoretical estimates where proton acceleration from the target rear into the forward direction is well explained by a TNSA-like mechanism, while proton acceleration from the target front into the backward direction can be explained by the formation of a charged cavity in a tiny pre-plasma. The exploding Coulomb field from the charged cavity also serves as a source for forward-accelerated ions at thick targets.Comment: 12 pages, 7 figures

The Drug Candidate BGP-15 Delays the Onset of Diastolic Dysfunction in the Goto-Kakizaki Rat Model of Diabetic Cardiomyopathy

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Evidence for diagnosis of early chronic pancreatitis after three episodes of acute pancreatitis : a cross-sectional multicentre international study with experimental animal model

Chronic pancreatitis (CP) is an end-stage disease with no specific therapy; therefore, an early diagnosis is of crucial importance. In this study, data from 1315 and 318 patients were analysed from acute pancreatitis (AP) and CP registries, respectively. The population from the AP registry was divided into AP (n=983), recurrent AP (RAP, n=270) and CP (n=62) groups. The prevalence of CP in combination with AP, RAP2, RAP3, RAP4 and RAP5+was 0%, 1%, 16%, 50% and 47%, respectively, suggesting that three or more episodes of AP is a strong risk factor for CP. Laboratory, imaging and clinical biomarkers highlighted that patients with RAP3+do not show a significant difference between RAPs and CP. Data from CP registries showed 98% of patients had at least one AP and the average number of episodes was four. We mimicked the human RAPs in a mouse model and found that three or more episodes of AP cause early chronic-like morphological changes in the pancreas. We concluded that three or more attacks of AP with no morphological changes to the pancreas could be considered as early CP (ECP).The new diagnostic criteria for ECP allow the majority of CP patients to be diagnosed earlier. They can be used in hospitals with no additional costs in healthcare.Peer reviewe