Assessing Deep Generative Models in Chemical Composition Space

The computational discovery of novel materials has been one of the main motivations behind research in theoretical chemistry for several decades. Despite much effort, this is far from a solved problem, however. Among other reasons, this is due to the enormous space of possible structures and compositions that could potentially be of interest. In the case of inorganic materials, this is exacerbated by the combinatorics of the periodic table since even a single-crystal structure can in principle display millions of compositions. Consequently, there is a need for tools that enable a more guided exploration of the materials design space. Here, generative machine learning models have recently emerged as a promising technology. In this work, we assess the performance of a range of deep generative models based on reinforcement learning, variational autoencoders, and generative adversarial networks for the prototypical case of designing Elpasolite compositions with low formation energies. By relying on the fully enumerated space of 2 million main-group Elpasolites, the precision, coverage, and diversity of the generated materials are rigorously assessed. Additionally, a hyperparameter selection scheme for generative models in chemical composition space is developed

Current clinician perspective on non-vitamin K antagonist oral anticoagulant use in challenging clinical cases.

OBJECTIVE: The evolution of non-vitamin K antagonist anticoagulants (NOACs) has changed the horizon of stroke prevention in atrial fibrillation (SPAF). All 4 NOACs have been tested against dose-adjusted warfarin in well-designed, pivotal, phase III, randomized, controlled trials (RCTs) and were approved by regulatory authorities for an SPAF indication. However, as traditional RCTs, these trials have important weaknesses, largely related to their complex structure and patient participation, which was limited by strict inclusion and extensive exclusion criteria. In the real world, however, clinicians are often faced with complex, multimorbid patients who are underrepresented in these RCTs. This article is based on a meeting report authored by 12 scientists studying atrial fibrillation (AF) in diverse ways who discussed the management of challenging AF cases that are underrepresented in pivotal NOAC trials. METHODS: An advisory board panel was convened to confer on management strategies for challenging AF cases. The article is derived from a summary of case presentations and the collaborative discussions at the meeting. CONCLUSION: This expert consensus of cardiologists aimed to define management strategies for challenging cases with patients who underrepresented in pivotal trials using case examples from their routine practice. Although strong evidence is lacking, exploratory subgroup analysis of phase III pivotal trials partially informs the management of these patients. Clinical trials with higher external validity are needed to clarify areas of uncertainty. The lack of clear evidence about complex AF cases has pushed clinicians to manage patients based on clinical experience, including rare situations of off-label prescriptions

Protective effects of curcumin on antioxidant status, body weight gain, and reproductive parameters in male rats exposed to subchronic 2,3,7,8-tetrachlorodibenzo-p-dioxin

The aim of this study was to investigate the effects of curcumin (CUR) on antioxidant status, body weight (BW) gains, and some reproductive parameters in male rats exposed to subchronic doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Thirtytwo rats were divided into four groups. The first group was kept as control. The second group (TCDD group) was given TCDD at a dose of 50 ng kg 1 BW per day; the third group (CUR group) was treated with CUR at a dose of 80 mg kg 1 BW per day. The fourth group (TCDD þ CUR group) was given TCDD and CUR at the same doses simultaneously. Malondialdehyde (MDA) levels were significantly increased in the TCDD group. In addition, TCDD exposure decreased liver superoxide dismutase (SOD) activity, catalase (CAT) activities of kidney and brain, glutathione peroxidase (GSH-Px) activities of liver, kidney, and brain, and glutathione levels of liver, kidney, and heart. However, CUR treatment with TCDD exposure decreased MDA levels in all tissues and increased SOD activities of liver, kidney, and brain, CAT activity of heart, and GSH-Px activities of heart and brain. TCDD caused a decrease in BW gain, and CUR partially eliminated this effect of TCDD. In addition, while reproductive organ weights, sperm concentration, and sperm motility tended to decrease with TCDD exposure, these effects tended to be close to normal levels by CUR treatment. In conclusion, CUR was seen to be effective in the treatment and prevention of toxicity induced by subchronic TCDD exposure

Sr Surface Enrichment in Solid Oxide Cells – Approaching the Limits of EDX Analysis by Multivariate Statistical Analysis and Simulations

In solid oxide cells, Sr segregation has been correlated with degradation. Yet, the atomistic mechanism remains unknown. Here we begin to localize the origin of Sr surface nucleation by combining force field based simulations, energy dispersive X-ray spectroscopy (EDX), and multi-variate statistical analysis. We find increased ion mobility in the complexion between yttria-stabilized zirconia and strontium-doped lanthanum manganite. Furthermore, we developed a robust and automated routine to detect localized nucleation seeds of Sr at the complexion surface. This hints at a mechanism originating at the complexion and requires in-depth studies at the atomistic level, where the developed routine can be beneficial for analyzing large hyperspectral EDX datasets

A dietary carbohydrate–gut Parasutterella–human fatty acid biosynthesis metabolic axis in obesity and type 2 diabetes

Recent rodent microbiome experiments suggest that besides Akkermansia, Parasutterella sp. are important in type 2 diabetes and obesity development. In the present translational human study, we aimed to characterize Parasutterella in our European cross-sectional FoCus cohort (n = 1,544) followed by validation of the major results in an independent Canadian cohort (n = 438). In addition, we examined Parasutterella abundance in response to a weight loss intervention (n = 55). Parasutterella was positively associated with BMI and type 2 diabetes independently of the reduced microbiome α/β diversity and low-grade inflammation commonly found in obesity. Nutritional analysis revealed a positive association with the dietary intake of carbohydrates but not with fat or protein consumption. Out of 126 serum metabolites differentially detectable by untargeted HPLC-based MS-metabolomics, L-cysteine showed the strongest reduction in subjects with high Parasutterella abundance. This is of interest, since Parasutterella is a known high L-cysteine consumer and L-cysteine is known to improve blood glucose levels in rodents. Furthermore, metabolic network enrichment analysis identified an association of high Parasutterella abundance with the activation of the human fatty acid biosynthesis pathway suggesting a mechanism for body weight gain. This is supported by a significant reduction of the Parasutterella abundance during our weight loss intervention. Together, these data indicate a role for Parasutterella in human type 2 diabetes and obesity, whereby the link to L-cysteine might be relevant in type 2 diabetes development and the link to the fatty acid biosynthesis pathway for body weight gain in response to a carbohydrate-rich diet in obesity development

Emergent versus delayed lithotripsy for obstructing ureteral stones: a cumulative analysis of comparative studies

Objective To analyze the current evidence on the use of ureteroscopy (URS) and extracorporeal shock wave lithotripsy (ESWL) for the management of obstructing ureteral stones in emergent setting. Methods A systematic literature review was performed up to June 2016 using Pubmed and Ovid databases to identify pertinent studies. The PRISMA criteria were followed for article selection. Separate searches were done using a combinations of several search terms: "laser lithotripsy", "ureteroscopy", "extracorporeal shock wave lithotripsy", "ESWL", "rapid", "immediate", "early", "delayed", "late", "ureteral stones", "kidney stones", "renal stones". Only titles related to emergent/rapid/immediate/early (as viably defined in each study) versus delayed/late treatment of ureteral stones with either URS and/or ESWL were considered for screening. Demographics and operative outcomes were compared between emergent and delayed lithotripsy. RevMan review manager software was used to perform data analysis. Results Four studies comparing emergent (n = 526) versus delayed (n = 987) URS and six studies comparing emergent (n = 356) versus delayed (n = 355) SWL were included in the analysis. Emergent URS did not show any significant difference in terms of stone-free rate (91.2 versus 90.9%; OR 1.04; CI 0.71, 1.52; p = 0.84), complication rate (8.7% for emergent versus 11.5% for delayed; OR 0.94; CI 0.65, 1.36; p = 0.74) and need for auxiliary procedures (OR 0.85; CI 0.42, 1.7; p = 0.85) when compared to delayed URS. Emergent ESWL was associated with a higher likelihood of stone free status (OR 2.2; CI 1.55, 3.17; p < 0.001) and a lower likelihood of need for auxiliary maneuvers (OR 0.49; CI 0.33, 0.72; p < 0.001) than the delayed procedure. No differences in complication rates were noticed between the emergent and delayed ESWL (p = 0.37). Conclusions Emergent lithotripsy, either ureteroscopic or extracorporeal, can be offered as an effective and safe treatment for patients with symptomatic ureteral stone. If amenable to ESWL, based on stone and patient characteristics, an emergent approach should be strongly considered. Ureteroscopy in the emergent setting is mostly reserved for distally located stones. The implementation of these therapeutic approaches is likely to be dictated by their availability.info:eu-repo/semantics/publishedVersio

Advanced Technologies for Oral Controlled Release: Cyclodextrins for oral controlled release

Cyclodextrins (CDs) are used in oral pharmaceutical formulations, by means of inclusion complexes formation, with the following advantages for the drugs: (1) solubility, dissolution rate, stability and bioavailability enhancement; (2) to modify the drug release site and/or time profile; and (3) to reduce or prevent gastrointestinal side effects and unpleasant smell or taste, to prevent drug-drug or drug-additive interactions, or even to convert oil and liquid drugs into microcrystalline or amorphous powders. A more recent trend focuses on the use of CDs as nanocarriers, a strategy that aims to design versatile delivery systems that can encapsulate drugs with better physicochemical properties for oral delivery. Thus, the aim of this work was to review the applications of the CDs and their hydrophilic derivatives on the solubility enhancement of poorly water soluble drugs in order to increase their dissolution rate and get immediate release, as well as their ability to control (to prolong or to delay) the release of drugs from solid dosage forms, either as complexes with the hydrophilic (e.g. as osmotic pumps) and/ or hydrophobic CDs. New controlled delivery systems based on nanotechonology carriers (nanoparticles and conjugates) have also been reviewed

Organometallic iridium(III) anticancer complexes with new mechanisms of action: NCI-60 screening, mitochondrial targeting, and apoptosis

Platinum complexes related to cisplatin, cis-[PtCl2(NH3)2], are successful anticancer drugs; however, other transition metal complexes offer potential for combating cisplatin resistance, decreasing side effects, and widening the spectrum of activity. Organometallic half-sandwich iridium (IrIII) complexes [Ir(Cpx)(XY)Cl]+/0 (Cpx = biphenyltetramethylcyclopentadienyl and XY = phenanthroline (1), bipyridine (2), or phenylpyridine (3)) all hydrolyze rapidly, forming monofunctional G adducts on DNA with additional intercalation of the phenyl substituents on the Cpx ring. In comparison, highly potent complex 4 (Cpx = phenyltetramethylcyclopentadienyl and XY = N,N-dimethylphenylazopyridine) does not hydrolyze. All show higher potency toward A2780 human ovarian cancer cells compared to cisplatin, with 1, 3, and 4 also demonstrating higher potency in the National Cancer Institute (NCI) NCI-60 cell-line screen. Use of the NCI COMPARE algorithm (which predicts mechanisms of action (MoAs) for emerging anticancer compounds by correlating NCI-60 patterns of sensitivity) shows that the MoA of these IrIII complexes has no correlation to cisplatin (or oxaliplatin), with 3 and 4 emerging as particularly novel compounds. Those findings by COMPARE were experimentally probed by transmission electron microscopy (TEM) of A2780 cells exposed to 1, showing mitochondrial swelling and activation of apoptosis after 24 h. Significant changes in mitochondrial membrane polarization were detected by flow cytometry, and the potency of the complexes was enhanced ca. 5× by co-administration with a low concentration (5 μM) of the γ-glutamyl cysteine synthetase inhibitor L-buthionine sulfoximine (L-BSO). These studies reveal potential polypharmacology of organometallic IrIII complexes, with MoA and cell selectivity governed by structural changes in the chelating ligands

Detecting ancient codispersals and host shifts by double dating of host and parasite phylogenies: Application in proctophyllodid feather mites associated with passerine birds

Inferring cophylogeographic events requires matching the timing of these events on both host and symbiont (e.g., parasites) phylogenies because divergences of hosts and their symbionts may not temporally coincide, and host switches may occur. We investigate a large radiation of birds (Passeriformes) and their permanent symbionts, the proctophyllodid feather mites (117 species from 116 bird species; six genes, 11,468 nt aligned) using two time‐calibration strategies for mites: fossils only and host phylogeography only. Out of 10 putative cophylogeographic events 4 agree in timing for both symbiont and host events being synchronous co‐origins or codispersals; three were based on host shifts, but agree in timing being very close to the origin of modern hosts; two disagree; and one large basal mite split was seemingly independent from host phylogeography. Among these events was an ancient (21–25.3 Mya), synchronous codispersal from the Old World leading to the origin and diversifications of New World emberizoid passerids and their mites, the thraupis + quadratus species groups of Proctophyllodes. Our framework offers a more robust detection of host and symbiont cophylogeographic events (as compared to host‐symbiont reconciliation analysis and using host phylogeography for time‐calibration) and provides independent data for testing alternative hypotheses on timing of host diversification and dispersal.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138927/1/evo13309-sup-0003-figureS3.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138927/2/evo13309.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138927/3/evo13309-sup-0006-figureS6.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138927/4/evo13309_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138927/5/evo13309-sup-0009-figureS9.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138927/6/evo13309-sup-0005-figureS5.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138927/7/evo13309-sup-0004-figureS4.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138927/8/evo13309-sup-0002-figureS2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138927/9/evo13309-sup-0008-figureS8.pd

Comparison of the marginal adaptation of direct and indirect composite inlay restorations with optical coherence tomography

OBJECTIVE: The purpose of the study was to use the photonic imaging modality of optical coherence tomography (OCT) to compare the marginal adaptation of composite inlays fabricated by direct and indirect techniques. MATERIAL AND METHODS: Class II cavities were prepared on 34 extracted human molar teeth. The cavities were randomly divided into two groups according to the inlay fabrication technique. The first group was directly restored on cavities with a composite (Esthet X HD, Dentsply, Germany) after isolating. The second group was indirectly restored with the same composite material. Marginal adaptations were scanned before cementation with an invisible infrared light beam of OCT (Thorlabs), allowing measurement in 200 µm intervals. Restorations were cemented with a self-adhesive cement resin (SmartCem2, Dentsply), and then marginal adaptations were again measured with OCT. Mean values were statistically compared by using independent-samples t-test and paired samples t-test (p<0.05), before and after cementation. RESULTS: Direct inlays presented statistically smaller marginal discrepancy values than indirect inlays, before (p=0.00001442) and after (p=0.00001466) cementation. Marginal discrepancy values were increased for all restorations after cementation (p=0.00008839, p=0.000000952 for direct and indirect inlays, respectively). The mean marginal discrepancy value of the direct group increased from 56.88±20.04 µm to 91.88±31.7 µm, whereas the indirect group increased from 107.54±35.63 µm to 170.29±54.83 µm. Different techniques are available to detect marginal adaptation of restorations, but the OCT system can give quantitative information about resin cement thickness and its interaction between tooth and restoration in a nondestructive manner. CONCLUSIONS: Direct inlays presented smaller marginal discrepancy than indirect inlays. The marginal discrepancy values were increased for all restorations that refer to cement thickness after cementation