Phthalates can leach into indoor and outdoor airborne particulate matter and dust, which can then be ingested or absorbed and induce lung injury. Dermal phthalate levels can be used as a matrix for ...exposure direct absorption from air, particle deposition, and contact with contaminated products. However, the association between dermal phthalate levels in skin wipes and lung function tests remains unknown. A total of 397 participants were included. Spirometry measurements of forced expiratory volume in 1 s (FEV1, L) and forced vital capacity (FVC, L) were calculated. Dermal phthalate levels of diethyl phthalate (DMP), diethyl phthalate (DEP), di(n-butyl) phthalate (DnBP), butyl benzyl phthalate (BBzP), di(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DiNP), and diisodecyl phthalate (DiDP) on forehead skin wipes were detected. The one-unit increases in logarithm (log) dermal DnBP (
β
= − 0.08; 95% CI − 0.16, − 0.003,
p
= 0.041), BBzP (
β
= − 0.09; 95% CI − 0.16, − 0.02,
p
= 0.009), DEHP (
β
= − 0.07; 95% CI − 0.14, − 0.003,
p
= 0.042), and DiNP (
β
= − 0.08; 95% CI − 0.15, − 0.02,
p
= 0.017) were significantly associated with decreases in FVC. For elderly participants, one-unit increases in log dermal DnBP (
β
= − 0.25; 95% CI − 0.46, − 0.04,
p
= 0.021), BBzP (
β
= − 0.17; 95% CI − 0.33, − 0.01,
p
= 0.042), and DiDP (
β
= − 0.19; 95% CI − 0.39, < 0.01,
p
= 0.052) were associated with decreases in FEV1. In conclusion, dermal phthalate levels were significantly associated with decreases in lung function tests.
Epidermal growth factor receptor (EGFR)-targeted therapy in non-small cell lung cancer represents a breakthrough in the field of precision medicine. Previously, we have identified a lead compound, ...furanopyrimidine 2, which contains a (S)-2-phenylglycinol structure as a key fragment to inhibit EGFR. However, compound 2 showed high clearance and poor oral bioavailability in its pharmacokinetics studies. In this work, we optimized compound 2 by scaffold hopping and exploiting the potent inhibitory activity of various warhead groups to obtain a clinical candidate, 78 (DBPR112), which not only displayed a potent inhibitory activity against EGFRL858R/T790M double mutations but also exhibited tenfold potency better than the third-generation inhibitor, osimertinib, against EGFR and HER2 exon 20 insertion mutations. Overall, pharmacokinetic improvement through lead-to-candidate optimization yielded fourfold oral AUC better that afatinib along with F = 41.5%, an encouraging safety profile, and significant antitumor efficacy in in vivo xenograft models. DBPR112 is currently undergoing phase 1 clinical trial in Taiwan.
Stenotrophomonas maltophilia, a gram-negative bacterium, has increasingly emerged as an important nosocomial pathogen. It is well-known for resistance to a variety of antimicrobial agents including ...cationic antimicrobial polypeptides (CAPs). Resistance to polymyxin B, a kind of CAPs, is known to be controlled by the two-component system PhoPQ. To unravel the role of PhoPQ in polymyxin B resistance of S. maltophilia, a phoP mutant was constructed. We found MICs of polymyxin B, chloramphenicol, ampicillin, gentamicin, kanamycin, streptomycin and spectinomycin decreased 2-64 fold in the phoP mutant. Complementation of the phoP mutant by the wild-type phoP gene restored all of the MICs to the wild type levels. Expression of PhoP was shown to be autoregulated and responsive to Mg2+ levels. The polymyxin B and gentamicin killing tests indicated that pretreatment of low Mg2+ can protect the wild-type S. maltophilia from killing but not phoP mutant. Interestingly, we found phoP mutant had a decrease in expression of SmeZ, an efflux transporter protein for aminoglycosides in S. maltophilia. Moreover, phoP mutant showed increased permeability in the cell membrane relative to the wild-type. In summary, we demonstrated the two-component regulator PhoP of S. maltophilia is involved in antimicrobial susceptibilities and low Mg2+ serves as a signal for triggering the pathway. Both the alteration in membrane permeability and downregulation of SmeZ efflux transporter in the phoP mutant contributed to the increased drug susceptibilities of S. maltophilia, in particular for aminoglycosides. This is the first report to describe the role of the Mg2+-sensing PhoP signaling pathway of S. maltophilia in regulation of the SmeZ efflux transporter and in antimicrobial susceptibilities. This study suggests PhoPQ TCS may serve as a target for development of antimicrobial agents against multidrug-resistant S. maltophilia.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Learning-based presimulation (i.e., layout-to-fabrication) models have been proposed to predict the fabrication-induced shape deformation from an IC layout to its fabricated circuit. Such models are ...usually driven by pairwise learning, involving a training set of layout patterns and their reference shape images after fabrication. However, it is expensive and time consuming to collect the reference shape images of all layout clips for model training and updating. To address the problem, we propose a deep-learning-based layout novelty detection scheme to identify novel (unseen) layout patterns, which cannot be well predicted by a pretrained presimulation model. We devise a global-local novelty scoring mechanism to assess the potential novelty of a layout by exploiting two subnetworks: 1) an autoencoder and 2) a pretrained presimulation model. The former characterizes the global structural dissimilarity between a given layout and training samples, whereas the latter extracts a latent code representing the fabrication-induced local deformation. By integrating the global dissimilarity with the local deformation boosted by a self-attention mechanism, our model can accurately detect novelties without the ground-truth circuit shapes of test samples. Based on the detected novelties, we further propose two active-learning strategies to sample a reduced amount of representative layouts most worthy to be fabricated for acquiring their ground-truth circuit shapes. Experimental results demonstrate: 1) the effectiveness of our layout novelty detection algorithm and 2) the ability of our active-learning strategies in selecting representative novel layouts for keeping a learning-based presimulation model updated.
Cardiac amyloidosis is one form of systemic amyloidosis caused by abnormal amyloid fibrils deposited in the extracellular space of the myocardium causing heart failure because of restrictive ...cardiomyopathy and conduction disturbances. The incidence and prevalence of cardiac amyloidosis are higher than previously noted, particularly among special populations. The most common forms of cardiac amyloidosis are light chain and transthyretin amyloid cardiomyopathy. Even though more than 70% of patients with systemic amyloidosis have cardiac amyloidosis, the diagnosis is often delayed, suggesting significant gaps in the knowledge of cardiac amyloidosis and a lack of multidisciplinary teamwork in our daily practice. The Taiwan Society of Cardiology Heart Failure Committee organized experts to draft the ＂Expert Consensus on the diagnosis and treatment of cardiac amyloidosis.＂ This statement aims to help clinicians and healthcare professionals improve early diagnosis and management of cardiac amyloidosis in Taiwan. The expert panel met virtually to review the data and discuss the consensus statements. Our review provided practical information about diagnostic methods and algorithms, clinical clues and red-flag signs, cardiac amyloidosis per se and its comorbidities treatment modalities, and follow-up plans for asymptomatic transthyretin gene carriers. We especially innovate two acronyms, ＂HFpEF MUTED CALL＂ and ＂HFmrEF MUST COUNT＂, to help in the early diagnosis and screening of transthyretin amyloid cardiomyopathy as shown in the Central Illustration.
The prevalence of chronic kidney disease (CKD) is increasing annually in Taiwan. In addition to traditional risk factors, heavy metals contribute to the development of CKD. The aim of this study was ...to investigate associations among heavy metals and proteinuria and CKD in the general population in Southern Taiwan. We also explored the interaction and synergetic effects among heavy metals on proteinuria.
We conducted a health survey in the general population living in Southern Taiwan between June 2016 and September 2018. Seven heavy metals were measured: blood lead (Pb) and urine nickel (Ni), chromium (Cr), manganese (Mn), arsenic (As), copper (Cu), and cadmium (Cd). Proteinuria was measured using reagent strips. CKD was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m
.
The mean age of the 2447 participants was 55.1 ± 13.2 years and included 977 males and 1470 females. Participants with high blood Pb and high urine Ni, Mn, Cu, and Cd were significantly associated with proteinuria. Interactions between blood Pb and urine Cr, and between urine Cd and Cu, had significant effects on proteinuria. The participants with high blood Pb and high urine Cu were significantly associated with an eGFR of <60 mL/min/1.73 m
.
High blood Pb and high urine Cu may be associated with proteinuria and an eGFR of <60 mL/min/1.73 m
. High urine Ni, Mn, and Cd were significantly associated with proteinuria. Co-exposure to Cd and Cu, and Pb and Cr, may have synergistic effects on proteinuria.
Abstract
In 2018, Jewitt identified the “The Trojan Color Conundrum,” namely that Neptune's Trojan asteroids (NTs) had no ultrared members, unlike the the nearby Kuiper Belt. Since then, numerous ...ultrared NTs have been discovered, seemingly resolving this conundrum. However, it is still unclear whether or not the Kuiper Belt has a color distribution consistent with the NT population, as would be expected if it were the source population. In this work, we present a new photometric survey of 15 out of 31 NTs. We utilized the Sloan
g
′
r
′
i
′
z
′
filters on the IMACS f/4 instrument, which is mounted on the 6.5 m Baade telescope. In this survey, we identify four NTs as being ultrared using a principal component analysis. This result brings the ratio of red to ultrared NTs to 7.75:1, more consistent with the corresponding trans-Neptunian object ratio of 4–11:1. We also identify three targets as being blue (nearly solar) in color. Such objects may be C-type surfaces, but we see more of these blue NTs than has been observed in the Kuiper Belt. Finally, we show that there are hints of a color-absolute magnitude (H) correlation, with larger H (smaller sized, lower albedo) tending to be more red, but more data are needed to confirm this result. The origin of such a correlation remains an open question that will be addressed by future observations of the surface composition of these targets and their rotational properties.
Abstract We present the DECam Ecliptic Exploration Project (DEEP) survey strategy, including observing cadence for orbit determination, exposure times, field pointings and filter choices. The overall ...goal of the survey is to discover and characterize the orbits of a few thousand Trans-Neptunian objects (TNOs) using the Dark Energy Camera (DECam) on the Cerro Tololo Inter-American Observatory Blanco 4 m telescope. The experiment is designed to collect a very deep series of exposures totaling a few hours on sky for each of several 2.7 square degree DECam fields-of-view to achieve approximate depths of magnitude 26.2 using a wide V R filter that encompasses both the V and R bandpasses. In the first year, several nights were combined to achieve a sky area of about 34 square degrees. In subsequent years, the fields have been re-visited to allow TNOs to be tracked for orbit determination. When complete, DEEP will be the largest survey of the outer solar system ever undertaken in terms of newly discovered object numbers, and the most prolific at producing multiyear orbital information for the population of minor planets beyond Neptune at 30 au.
Abstract We present the methods and results from the discovery and photometric measurement of 26 bright VR > 24 trans-Neptunian objects (TNOs) during the first year (2019–20) of the DECam Ecliptic ...Exploration Project (DEEP). The DEEP survey is an observational TNO survey with wide sky coverage, high sensitivity, and a fast photometric cadence. We apply a computer vision technique known as a progressive probabilistic Hough transform to identify linearly moving transient sources within DEEP photometric catalogs. After subsequent visual vetting, we provide a photometric and astrometric catalog of our TNOs. By modeling the partial lightcurve amplitude distribution of the DEEP TNOs using Monte Carlo techniques, we find our data to be most consistent with an average TNO axis ratio b / a < 0.5, implying a population dominated by non-spherical objects. Based on ellipsoidal gravitational stability arguments, we find our data to be consistent with a TNO population containing a high fraction of contact binaries or other extremely non-spherical objects. We also discuss our data as evidence that the expected binarity fraction of TNOs may be size-dependent.
Twenty five novel chemical analogs of the previously reported Aurora kinase inhibitor BPR1K653 ...(1-(4-(2-((5-chloro-6-phenylfuro2,3-dpyrimidin-4-yl)amino)ethyl)phenyl)-3-(2-((dimethylamino)methyl)phenyl)urea) have been designed, synthesized, and evaluated by Aurora-A and Aurora-B enzymatic kinase activity assays. Similar to BPR1K653, analogs 3b-3h bear alkyl or tertiary amino group at the ortho position of the phenylurea, and showed equal or better inhibition activity for Aurora-B over Aurora-A. Conversely, preferential Aurora-A inhibition activity was observed when the same functional group was moved to the meta position of the phenylurea. Compounds 3m and 3n, both of which harbor a tertiary amino group at the meta position of the phenylurea, showed 10–16 fold inhibition selectivity for Aurora-A over Aurora-B. The in vitro kinase inhibition results were verified by Western blot analysis, and indicated that compounds 3m and 3n were more than 75-fold superior in inhibiting T-loop autophosphorylation of Aurora-A (Thr288), compared to Aurora-B (Thr232) in HCT116 colon carcinoma cells. The computational docking analysis suggested that the tertiary amine at the meta position of the phenylurea formed a more stable interaction with residues in the back pocket of Aurora-A than in Aurora-B, a possible explanation for the observed discrepancy in the selectivity. These results support an alternative small molecule design strategy targeting the back pocket of Aurora kinases for selective isoform inhibition.
Display omitted
•25 new furanopyrimidine analogs were designed and synthesized.•The designed compounds were evaluated for Aurora-A and Aurora-B inhibition activity.•Derivatization on the phenylurea modulates isoform-selective kinase inhibition.•Molecular docking studies were performed.
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