Because angiotensin-converting enzyme (ACE) activity is implicated widely in biological systems, we aimed to identify its novel quantitative trait loci for the purposes of understanding ACE activity ...regulation and pharmacogenetics relating to ACE inhibitor (ACEI). We performed a two-stage genome-wide association study: (1) from 400 young-onset hypertension (YOH) subjects and (2) a confirmation study with an additional 623 YOH subjects. In the first stage, eight single nucleotide polymorphisms (SNPs) of the ACE structural gene and one SNP of ABO genes were significantly associated with ACE activity. SNP rs4343 in exon17 near the well-known insertion/deletion polymorphism had the strongest association. We confirmed in the second stage that three SNPs: rs4343 in ACE gene (P=3.0 x 10⁻²⁵), rs495828 (P=3.5 x 10⁻⁸) and rs8176746 (P=9.3 x 10⁻⁵) in ABO gene were significantly associated with ACE activity. We further replicated the association between ABO genotype/blood types and ACE activity in an independent YOH family study (428 hypertension pedigrees), and showed a potential differential blood pressure response to ACEI in subjects with varied numbers of ACE-activity-raising alleles. These findings may broaden our understanding of the mechanisms controlling ACE activity and advance our pharmacogenetic knowledge on ACEI.
Abstract
We present the second release of value-added catalogues of the LAMOST Spectroscopic Survey of the Galactic Anticentre (LSS-GAC DR2). The catalogues present values of radial velocity Vr, ...atmospheric parameters – effective temperature Teff, surface gravity log g, metallicity Fe/H, α-element to iron (metal) abundance ratio α/Fe (α/M), elemental abundances C/H and N/H and absolute magnitudes MV and $M_{K_{\rm s}}$ deduced from 1.8 million spectra of 1.4 million unique stars targeted by the LSS-GAC since 2011 September until 2014 June. The catalogues also give values of interstellar reddening, distance and orbital parameters determined with a variety of techniques, as well as proper motions and multiband photometry from the far-UV to the mid-IR collected from the literature and various surveys. Accuracies of radial velocities reach 5 km s−1 for the late-type stars, and those of distance estimates range between 10 and 30 per cent, depending on the spectral signal-to-noise ratios. Precisions of Fe/H, C/H and N/H estimates reach 0.1 dex, and those of α/Fe and α/M reach 0.05 dex. The large number of stars, the contiguous sky coverage, the simple yet non-trivial target selection function and the robust estimates of stellar radial velocities and atmospheric parameters, distances and elemental abundances make the catalogues a valuable data set to study the structure and evolution of the Galaxy, especially the solar-neighbourhood and the outer disc.
HLJ1 (DNAJB4), a DNAJ/Hsp40 chaperone, has emerged as a novel prognostic marker in lung cancers; however, the molecular contribution and functionality in neoplastic diseases remain to be established. ...This study demonstrated that HLJ1 inhibits epithelial-mesenchymal transition in vitro and reduces lung cancer metastasis in vivo. Using shRNA silencing and ectopic expression of HLJ1, we found that HLJ1 not only suppresses catalytic activity of Src but also downregulates the formation of oncogenic complexes associated with the EGFR, FAK and STAT3 signaling pathways. A screen of specimens from HLJ1-knockout mice and lung cancer patients validated that HLJ1 expression is inversely correlated with Src activity. Mechanistically, HLJ1 protein directly bound to catalytic and protein-binding domains of Src through its amino acid Y172 and the P301/P304 motif. Following Src-induced HLJ1 phosphorylation at Y172, HLJ1-Src interaction was elevated, resulting in Src inhibition and malignancy suppression. Interestingly, both Src-binding regions also occurred in other DNAJB family members and contributed to anti-invasive activities of DNAJB proteins. We conclude that HLJ1 is an endogenous Src inhibitor that can suppress cancer metastasis through complex interacting mechanisms. This HLJ1-Src complex might provide a promising molecular model for developing new anticancer strategies.
Background
International guidelines on clinical staging of gastric cancer recommend the use of chest CT for the detection of pulmonary metastases. This study assessed the clinical value of routine ...chest CT in the staging of gastric cancer.
Methods
This retrospective study included patients identified from the gastric cancer registry of Chang Gung Memorial Hospital, Linkou, Taiwan. All patients who underwent clinical staging between 2008 and 2014 were included. The pattern, site and number of metastases at initial presentation and after surgery with curative intent were evaluated. Pulmonary metastases were defined as multiple small round pulmonary nodules with a random distribution or of variable size.
Results
Some 1669 patients were included, of whom 478 (28·6 per cent) had metastatic disease at clinical presentation. The majority of metastases were to the peritoneum (75·7 per cent of patients) or liver (30·5 per cent), and only 27 patients (5·6 per cent) had pulmonary metastases at presentation, none of which were isolated to the lung. Of these 27 patients, 11 had primary lesions located at the cardia/fundus. In 19 patients the lung metastases were also detected on the staging chest X‐ray. After surgery there were 196 cancer recurrences. Some 15 patients (7·6 per cent) had lung metastasis and this was not the only site of metastases in any patient. The prevalence of lung metastasis at presentation of the disease and after surgery was 1·6 and 1·5 per cent respectively.
Conclusion
This study does not support the routine use of chest CT for staging of gastric cancer as isolated pulmonary metastasis in the absence of other metastatic sites could not be detected.
Routine inclusion of chest CT in gastric cancer staging is not necessary because of the rarity of pulmonary metastasis at initial presentation and at recurrence following surgery with curative intent, and the absence of isolated pulmonary metastasis. The incidence of lung metastasis was 1·6 per cent. LN, lymph nodes.
Not needed
Infectious viruses so precisely fit their hosts that the study of natural viral infection depends on host-specific mechanisms that affect viral infection. For human parainfluenza virus 3, a prevalent ...cause of lower respiratory tract disease in infants, circulating human viruses are genetically different from viruses grown in standard laboratory conditions; the surface glycoproteins that mediate host cell entry on circulating viruses are suited to the environment of the human lung and differ from those of viruses grown in cultured cells. Polarized human airway epithelium cultures have been used to represent the large, proximal airways of mature adult airways. Here we modeled respiratory virus infections that occur in children or infect the distal lung using lung organoids that represent the entire developing infant lung. These 3D lung organoids derived from human pluripotent stem cells contain mesoderm and pulmonary endoderm and develop into branching airway and alveolar structures. Whole-genome sequencing analysis of parainfluenza viruses replicating in the organoids showed maintenance of nucleotide identity, suggesting that no selective pressure is exerted on the virus in this tissue. Infection with parainfluenza virus led to viral shedding without morphological changes, while respiratory syncytial virus infection induced detachment and shedding of infected cells into the lung organoid lumens, reminiscent of parainfluenza and respiratory syncytial virus in human infant lungs. Measles virus infection, in contrast, induced syncytium formation. These human stem cell-derived lung organoids may serve as an authentic model for respiratory viral pathogenesis in the developing or infant lung, recapitulating respiratory viral infection in the host.
Respiratory viruses are among the first pathogens encountered by young children, and the significant impact of these viral infections on the developing lung is poorly understood. Circulating viruses are suited to the environment of the human lung and are different from those of viruses grown in cultured cells. We modeled respiratory virus infections that occur in children or infect the distal lung using lung organoids that represent the entire developing infant lung. These 3D lung organoids, derived from human pluripotent stem cells, develop into branching airway and alveolar structures and provide a tissue environment that maintains the authentic viral genome. The lung organoids can be genetically engineered prior to differentiation, thereby generating tissues bearing or lacking specific features that may be relevant to viral infection, a feature that may have utility for the study of host-pathogen interaction for a range of lung pathogens.
ABSTRACT We present high-resolution (0 16) 870 m Atacama Large Millimeter/submillimeter Array (ALMA) imaging of 16 luminous ( ) submillimeter galaxies (SMGs) from the ALESS survey of the Extended ...Chandra Deep Field South. This dust imaging traces the dust-obscured star formation in these galaxies on ∼1.3 kpc scales. The emission has a median effective radius of Re = 0 24 0 02, corresponding to a typical physical size of 1.8 0.2 kpc. We derive a median Sérsic index of n = 0.9 0.2, implying that the dust emission is remarkably disk-like at the current resolution and sensitivity. We use different weighting schemes with the visibilities to search for clumps on 0 12 (∼1.0 kpc) scales, but we find no significant evidence for clumping in the majority of cases. Indeed, we demonstrate using simulations that the observed morphologies are generally consistent with smooth exponential disks, suggesting that caution should be exercised when identifying candidate clumps in even moderate signal-to-noise ratio interferometric data. We compare our maps to comparable-resolution Hubble Space Telescope -band images, finding that the stellar morphologies appear significantly more extended and disturbed, and suggesting that major mergers may be responsible for driving the formation of the compact dust disks we observe. The stark contrast between the obscured and unobscured morphologies may also have implications for SED fitting routines that assume the dust is co-located with the optical/near-IR continuum emission. Finally, we discuss the potential of the current bursts of star formation to transform the observed galaxy sizes and light profiles, showing that the descendants of these SMGs are expected to have stellar masses, effective radii, and gas surface densities consistent with the most compact massive ( 1-2 × 1011 ) early-type galaxies observed locally.
Background and purpose
Restless legs syndrome (RLS) is an underestimated movement disorder in patients with end‐stage renal disease (ESRD). Several clinical and laboratory factors were inconsistently ...reported to associate with RLS. We aim to perform a large‐scale multicenter study to investigate the possible associated risk factors of RLS in patients with ESRD in Taiwan, a country with the highest incidence of uremia in the world.
Methods
From October 2009 to October 2011, we constitutively recruited 1130 patients with ESRD from 17 hemodialysis centers. Demographic, laboratory data, presence and severity of RLS were collected. Odds ratios (ORs) were estimated by logistic regression models.
Results
We found the prevalence of RLS to be 25.3% in patients with ESRD. Having type 2 diabetes OR = 3.61 (2.27–5.77), P < 0.01, low serum transferrin saturation OR = 1.42 (1.01–2.03), P < 0.05 and duration of dialysis OR = 1.09 (1.03–1.14), P < 0.01 were associated with RLS. In contrast, high serum hemoglobin level was inversely associated with RLS OR = 0.61 (0.40–0.89), P < 0.05. RLS has a significant impact on sleep quality in dialysis patients. Among patients with RLS, history of type 2 diabetes OR = 4.04 (1.65–10.79), P < 0.05, low serum hemoglobin level OR = 5.41 (2.43–13.12), P < 0.01 and duration of dialysis OR = 1.01 (1.01–1.02), P < 0.01 were associated with increased severity of RLS.
Conclusions
Our findings demonstrated that RLS is common in Taiwanese dialysis patients. Clinicians should have a high suspicion for the presence of RLS symptoms in patients with ESRD, especially those with type 2 diabetes, anemia, low serum iron status and long duration of dialysis.
Objective
To assess the efficacy of metformin in megestrol acetate (MA)‐based fertility‐sparing treatment for patients with atypical endometrial hyperplasia (AEH) and endometrioid endometrial cancer ...(EEC).
Design
A randomised, single‐centre, open‐label, controlled trial conducted between October 2013 and December 2017.
Setting
Shanghai OBGYN Hospital of Fudan University, China.
Population
A total of 150 patients (18–45 years old) with primary AEH or well‐differentiated EEC were randomised into an MA group (n = 74) and an MA plus metformin group (n = 76).
Methods
Patients with AEH or EEC were firstly stratified, then randomised to receive MA (160 mg orally, daily) or MA (160 mg orally, daily) plus metformin (500 mg orally, three times a day).
Main outcomes and measures
The primary efficacy parameter was the cumulate complete response (CR) rate within 16 weeks of treatment (16w‐CR rate); the secondary efficacy parameters were 30w‐CR rate and adverse events.
Results
The 16w‐CR rate was higher in the metformin plus MA group than in the MA‐only group (34.3 versus 20.7%, odds ratio OR 2.0, 95% confidence interval CI 0.89–4.51, P = 0.09) but the difference was more significant in 102 AEH patients (39.6 versus 20.4%, OR 2.56, 95% CI 1.06–6.21, P = 0.04). This effect of metformin was also significant in non‐obese (51.4 versus 24.3%, OR 3.28, 95% CI 1.22–8.84, P = 0.02) and insulin‐sensitive (54.8 versus 28.6%, OR 3.04, 95% CI 1.03–8.97, P = 0.04) subgroups of AEH women. No significant result was found in secondary endpoints.
Conclusion
As a fertility‐sparing treatment, metformin plus MA was associated with a higher early CR rate compared with MA alone in AEH patients.
Tweetable
For AEH patients, metformin plus MA might be a better fertility‐sparing treatment to achieve a higher early CR rate compared with MA alone.
Tweetable
For AEH patients, metformin plus MA might be a better fertility‐sparing treatment to achieve higher early CR rate compared with MA alone.
Human mitochondrial ribosomes are highly divergent from all other known ribosomes and are specialized to exclusively translate membrane proteins. They are linked with hereditary mitochondrial ...diseases and are often the unintended targets of various clinically useful antibiotics. Using single-particle cryogenic electron microscopy, we have determined the structure of its large subunit to 3.4 angstrom resolution, revealing 48 proteins, 21 of which are specific to mitochondria. The structure unveils an adaptation of the exit tunnel for hydrophobic nascent peptides, extensive remodeling of the central protuberance, including recruitment of mitochondrial valine transfer RNA (tRNAVal) to play an integral structural role, and changes in the tRNA binding sites related to the unusual characteristics of mitochondrial tRNAs.
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