Machine Learning and Artificial Intelligence in PK-PD Modeling: Fad, Friend, or Foe?

Developing pharmacokinetic-pharmacodynamic (PK-PD) models requires a significant amount of time from highly skilled scientists and the demand for this expertise far outstrips the current supply. The use of machine learning (ML) and artificial intelligence (AL) in PK-PD modeling promises to reduce the number human supervision hours and improve predictive performance, but in its current form it suffers from various limitations. In this perspective, we aimed to structure the main trends and define boundaries and opportunities

Partition-based K-space Synthesis for Multi-contrast Parallel Imaging

Multi-contrast magnetic resonance imaging is a significant and essential medical imaging technique.However, multi-contrast imaging has longer acquisition time and is easy to cause motion artifacts. In particular, the acquisition time for a T2-weighted image is prolonged due to its longer repetition time (TR). On the contrary, T1-weighted image has a shorter TR. Therefore,utilizing complementary information across T1 and T2-weighted image is a way to decrease the overall imaging time. Previous T1-assisted T2 reconstruction methods have mostly focused on image domain using whole-based image fusion approaches. The image domain reconstruction method has the defects of high computational complexity and limited flexibility. To address this issue, we propose a novel multi-contrast imaging method called partition-based k-space synthesis (PKS) which can achieve super reconstruction quality of T2-weighted image by feature fusion. Concretely, we first decompose fully-sampled T1 k-space data and under-sampled T2 k-space data into two sub-data, separately. Then two new objects are constructed by combining the two sub-T1/T2 data. After that, the two new objects as the whole data to realize the reconstruction of T2-weighted image. Finally, the objective T2 is synthesized by extracting the sub-T2 data of each part. Experimental results showed that our combined technique can achieve comparable or better results than using traditional k-space parallel imaging(SAKE) that processes each contrast independently

Levels of Vascular Endothelial Growth Factor-A165b (VEGF-A165b) are Elevated in Experimental Glaucoma

Purpose: Although ischemia has previously been suggested to contribute to the pathogenesis of glaucoma, neovascularization is not implicated in glaucoma. Because vascular endothelial growth factor-A (VEGF-A) is a key mediator in neovascularization response, we investigated the levels of the major pro-angiogenic (VEGF-A164) and anti-angiogenic VEGF-A subtypes (VEGF-A165b) in the retina during experimental glaucoma. Methods: Glaucoma was induced unilaterally in rats by injecting 1.9 M hypertonic saline solution in the episcleral veins. The contralateral eye served as the control. The intraocular pressure (IOP) of each eye was measured via Tonopen in conscious rats. Eyes were enucleated either on the 5th or the 10th day of elevated IOP. Whole retinal lysates were separated by SDS–PAGE and transferred to PVDF membranes. Levels of VEGF-A164 and VEGF-A165b were analyzed by western blotting using specific antibodies. In a different group of rats, retinal ganglion cells were retrogradely labeled by injecting Fluorogold in the superior colliculus a week before the induction of glaucoma. After the eyes were enucleated on the fifth day of elevated IOP, posterior eye cups were sectioned using a cryostat. Levels and localization of VEGF-A164 and VEGF-A165b were examined in retinal sections by immunohistochemistry. Results: VEGF-A164 levels remained unchanged between the control and glaucomatous retinas after five days (p=0.341) and 10 days of elevated IOP (p=0.117). The presence of the anti-angiogenic VEGF-A isoform has not been previously reported in the rat. An antibody specific to VEGF-A165b detected the anti-angiogenic protein in the rat retina. VEGF-A165b levels were significantly increased (2.33±0.44 fold, p=0.014) in the glaucomatous retinas compared to those in controls after five days of elevated IOP. VEGF-A165b levels were not different (p=0.864) between the control and glaucomatous retinas following 10 days of elevated IOP. Expression of both VEGF-A164 and VEGF-A165b were observed in the retinal ganglion cells (RGC) and inner nuclear layer (INL). Conclusions: Five day elevation of IOP leads to an increase in the anti-angiogenic VEGF-A165b levels but not in the pro-angiogenic VEGF-A164 levels in the glaucomatous retina. VEGF-A165b levels return to baseline after 10 days of elevated IOP, and VEGF-A164 levels remain unchanged. We speculate that the short-term elevation of VEGF-A165b levels and/or the unchanged levels of VEGF-A164 contribute to the lack of neovascularization in the glaucomatous retina

Three Pairs of New Spirocyclic Alkaloid Enantiomers From the Marine-Derived Fungus Eurotium sp. SCSIO F452

Three pairs of new spirocyclic alkaloid enantiomers eurotinoids A–C (1–3), as well as a known biogenetically related racemate dihydrocryptoechinulin D (4) were isolated from a marine-derived fungus Eurotium sp. SCSIO F452. Their structures were determined by spectroscopic analyses and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 represent the first two “meta” products from a non-stereoselective [4 + 2] Diels-Alder cycloaddition presumably between an enone group of a diketopiperazine alkaloid and a diene group of a benzaldehyde derivative via a new head-to-tail coupling mode biosynthetically, while 3 and 4 were “ortho” products. Their enantiomers exhibited different antioxidative and cytotoxic activities. The modes of action were investigated by a preliminary molecular docking study

Open burning of rice, corn and wheat straws: primary emissions, photochemical aging, and secondary organic aerosol formation

Agricultural residues are among the most abundant biomass burned globally, especially in China. However, there is little information on primary emissions and photochemical evolution of agricultural residue burning. In this study, indoor chamber experiments were conducted to investigate primary emissions from open burning of rice, corn and wheat straws and their photochemical aging as well. Emission factors of NOx, NH3, SO2, 67 non-methane hydrocarbons (NMHCs), particulate matter (PM), organic aerosol (OA) and black carbon (BC) under ambient dilution conditions were determined. Olefins accounted for > 50% of the total speciated NMHCs emission (2.47 to 5.04 g kg(-1)), indicating high ozone formation potential of straw burning emissions. Emission factors of PM (3.73 to 6.36 g kg(-1)) and primary organic carbon (POC, 2.05 to 4.11 gC kg(-1)), measured at dilution ratios of 1300 to 4000, were lower than those reported in previous studies at low dilution ratios, probably due to the evaporation of semi-volatile organic compounds under high dilution conditions. After photochemical aging with an OH exposure range of (1.97-4.97) x 10(10) molecule cm(-3) s in the chamber, large amounts of secondary organic aerosol (SOA) were produced with OA mass enhancement ratios (the mass ratio of total OA to primary OA) of 2.4-7.6. The 20 known precursors could only explain 5.0-27.3% of the observed SOA mass, suggesting that the major precursors of SOA formed from open straw burning remain unidentified. Aerosol mass spectrometry (AMS) signaled that the aged OA contained less hydrocarbons but more oxygen-and nitrogen-containing compounds than primary OA, and carbon oxidation state (OSc) calculated with AMS resolved O / C and H / C ratios increased linearly (p < 0.001) with OH exposure with quite similar slopes

Blood Gene Expression and Immune Cell Subtypes Associated with Chronic Obstructive Pulmonary Disease Exacerbations.

Rationale: Acute exacerbations of chronic obstructive pulmonary disease (AE-COPDs) are associated with a significant disease burden. Blood immune phenotyping may improve our understanding of a COPD endotype at increased risk of exacerbations. Objective: To determine the relationship between the transcriptome of circulating leukocytes and COPD exacerbations. Methods: Blood RNA sequencing data (n = 3,618) from the COPDGene (Genetic Epidemiology of COPD) study were analyzed. Blood microarray data (n = 646) from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study were used for validation. We tested the association between blood gene expression and AE-COPDs. We imputed the abundance of leukocyte subtypes and tested their association with prospective AE-COPDs. Flow cytometry was performed on blood in SPIROMICS (Subpopulations and Intermediate Outcomes in COPD Study) (n = 127), and activation markers for T cells were tested for association with prospective AE-COPDs. Measurements and Main Results: Exacerbations were reported 4,030 and 2,368 times during follow-up in COPDGene (5.3 ± 1.7 yr) and ECLIPSE (3 yr), respectively. We identified 890, 675, and 3,217 genes associated with a history of AE-COPDs, persistent exacerbations (at least one exacerbation per year), and prospective exacerbation rate, respectively. In COPDGene, the number of prospective exacerbations in patients with COPD (Global Initiative for Chronic Obstructive Lung Disease stage ⩾2) was negatively associated with circulating CD8+ T cells, CD4+ T cells, and resting natural killer cells. The negative association with naive CD4+ T cells was replicated in ECLIPSE. In the flow-cytometry study, an increase in CTLA4 on CD4+ T cells was positively associated with AE-COPDs. Conclusions: Individuals with COPD with lower circulating lymphocyte counts, particularly decreased CD4+ T cells, are more susceptible to AE-COPDs, including persistent exacerbations

Widespread occurrence of distinct alkenones from Group I haptophytes in freshwater lakes: Implications for paleotemperature and paleoenvironmental reconstructions

Alkenones are C35-C42 polyunsaturated ketone lipids that are commonly employed to reconstruct changes in sea surface temperature. However, their use in coastal seas and saline lakes can be hindered by species-mixing effects. We recently hypothesized that freshwater lakes are immune to species-mixing effects because they appear to exclusively host Group I haptophyte algae, which produce a distinct distribution of alkenones with a relatively consistent response of alkenone unsaturation to temperature. To evaluate this hypothesis and explore the geographic extent of Group I haptophytes, we analyzed alkenones in sediment and suspended particulate matter samples from lakes distributed throughout the mid- and high latitudes of the Northern Hemisphere (n = 30). Our results indicate that Group I-type alkenone distributions are widespread in freshwater lakes from a range of different climates (mean annual air temperature range: -17.3-10.9 degrees C; mean annual precipitation range: 125-1657 mm yr(-1); latitude range: 40-81 degrees N), and are commonly found in neutral to basic lakes (pH > 7.0), including volcanic lakes and lakes with mafic bedrock. We show that these freshwater lakes do not feature alkenone distributions characteristic of Group II lacustrine haptophytes, providing support for the hypothesis that freshwater lakes are immune to species-mixing effects. In lakes that underwent temporal shifts in salinity, we observed mixed Group I/II alkenone distributions and the alkenone contributions from each group could be quantified with the RIK37 index. Additionally, we observed significant correlations of alkenone unsaturation (U-37(K)) with seasonal and mean annual air temperature with this expanded freshwater lakes dataset, with the strongest correlation occurring during the spring transitional season (U-37(K) = 0.029 * T - 0.49; r(2) = 0.60; p < 0.0001). We present new sediment trap data from two lakes in northern Alaska (Toolik Lake, 68.632 degrees N, 149.602 degrees W; lake E5, 68.643 degrees N, 149.458 degrees W) that demonstrate the highest sedimentary fluxes of alkenones in the spring transitional season, concurrent with the period of lake ice melt and isothermal mixing. Together, these data provide a framework for evaluating lacustrine alkenone distributions and utilizing alkenone unsaturation as a lake temperature proxy. (C) 2018 Elsevier B.V. All rights reserved