Electrochemical reduction of CO
using Cu catalysts enables the synthesis of C
products including C
H
and C
H
OH. In this study, Cu catalysts were fabricated using plasma-enhanced atomic layer ...deposition (PEALD), achieving conformal deposition of catalysts throughout 3-D gas diffusion electrode (GDE) substrates while maintaining tunable control of Cu nanoparticle size and areal loading. The electrochemical CO
reduction at the Cu surface yielded a total Faradaic efficiency (FE) > 75% for C
products. Parasitic hydrogen evolution was minimized to a FE of ∼10%, and a selectivity of 42.2% FE for C
H
was demonstrated. Compared to a line-of-sight physical vapor deposition method, PEALD Cu catalysts show significant suppression of C
products compared to C
, which is associated with improved control of catalyst morphology and conformality within the porous GDE substrate. Finally, PEALD Cu catalysts demonstrated a stable performance for 15 h with minimal reduction in the C
H
production rate.
Industrialization has impacted the human gut ecosystem, resulting in altered microbiome composition and diversity. Whether bacterial genomes may also adapt to the industrialization of their host ...populations remains largely unexplored. Here, we investigate the extent to which the rates and targets of horizontal gene transfer (HGT) vary across thousands of bacterial strains from 15 human populations spanning a range of industrialization. We show that HGTs have accumulated in the microbiome over recent host generations and that HGT occurs at high frequency within individuals. Comparison across human populations reveals that industrialized lifestyles are associated with higher HGT rates and that the functions of HGTs are related to the level of host industrialization. Our results suggest that gut bacteria continuously acquire new functionality based on host lifestyle and that high rates of HGT may be a recent development in human history linked to industrialization.
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•Thousands of gut bacterial genomes from worldwide human populations were sequenced•HGT occurs at high frequency in the gut microbiome of individual persons•HGT occurs more frequently in the microbiome of industrialized and urban populations•Transferred gene functions in the microbiome reflect the lifestyle of the host
A worldwide microbiome analysis from 15 populations along the industrialization gradient reveals that horizontal gene transfer occurs on short timescales and that microbiomes continuously acquire new functionality based on host lifestyle.
Rhabdoid tumors are devastating pediatric cancers in need of improved therapies. We sought to identify small molecules that exhibit
and
efficacy against preclinical models of rhabdoid tumor.
We ...screened eight rhabdoid tumor cell lines with 481 small molecules and compared their sensitivity with that of 879 other cancer cell lines. Genome-scale CRISPR-Cas9 inactivation screens in rhabdoid tumors were analyzed to confirm target vulnerabilities. Gene expression and CRISPR-Cas9 data were queried across cell lines and primary rhabdoid tumors to discover biomarkers of small-molecule sensitivity. Molecular correlates were validated by manipulating gene expression. Subcutaneous rhabdoid tumor xenografts were treated with the most effective drug to confirm
results.
Small-molecule screening identified the protein-translation inhibitor homoharringtonine (HHT), an FDA-approved treatment for chronic myelogenous leukemia (CML), as the sole drug to which all rhabdoid tumor cell lines were selectively sensitive. Validation studies confirmed the sensitivity of rhabdoid tumor to HHT was comparable with that of CML cell lines. Low expression of the antiapoptotic gene
, which encodes Bcl-XL, was the strongest predictor of HHT sensitivity, and HHT treatment consistently depleted Mcl-1, the synthetic-lethal antiapoptotic partner of Bcl-XL. Rhabdoid tumor cell lines and primary-tumor samples expressed low
, and overexpression of
induced resistance to HHT in rhabdoid tumor cells. Furthermore, HHT treatment inhibited rhabdoid tumor cell line and patient-derived xenograft growth
.
Rhabdoid tumor cell lines and xenografts are highly sensitive to HHT, at least partially due to their low expression of
. HHT may have therapeutic potential against rhabdoid tumors.
Objectives/Hypothesis
To assess balloon dilation of the Eustachian tube with Eustachian tube balloon catheter in conjunction with medical management as treatment for Eustachian tube dilatory ...dysfunction.
Study Design
In this prospective, multicenter, randomized, controlled trial, we assigned, in a 2:1 ratio, patients age 22 years and older with Eustachian tube dilatory dysfunction refractory to medical therapy to undergo balloon dilation of the Eustachian tube with balloon catheter in conjunction with medical management or medical management alone.
Methods
The primary endpoint was normalization of tympanogram at 6 weeks. Additional endpoints were normalization of Eustachian Tube Dysfunction Questionaire‐7 symptom scores, positive Valsalva maneuver, mucosal inflammation, and safety.
Results
Primary efficacy results demonstrated superiority of balloon dilation of the Eustachian tube with balloon catheter + medical management compared to medical management alone. Tympanogram normalization at 6‐week follow‐up was observed in 51.8% (72/139) of investigational patients versus 13.9% (10/72) of controls (P < .0001). Tympanogram normalization in the treatment group was 62.2% after 24 weeks. Normalization of Eustachian Tube Dysfunction Questionaire‐7 Symptom scores at 6‐week follow‐up was observed in 56.2% (77/137) of investigational patients versus 8.5% (6/71) controls (P < .001). The investigational group also demonstrated substantial improvement in both mucosal inflammation and Valsalva maneuver at 6‐week follow‐up compared to controls. No device‐ or procedure‐related serious adverse events were reported for those who underwent balloon dilation of the Eustachian tube.
Conclusions
This study demonstrated superiority of balloon dilation of the Eustachian tube with balloon catheter + medical management compared to medical management alone to treat Eustachian tube dilatory dysfunction in adults.
Level of Evidence
1b. Laryngoscope, 128:1200–1206, 2018
Disruption of antagonism between SWI/SNF chromatin remodelers and polycomb repressor complexes drives the formation of numerous cancer types. Recently, an inhibitor of the polycomb protein EZH2 was ...approved for the treatment of a sarcoma mutant in the SWI/SNF subunit SMARCB1, but resistance occurs. Here, we performed CRISPR screens in SMARCB1-mutant rhabdoid tumor cells to identify genetic contributors to SWI/SNF-polycomb antagonism and potential resistance mechanisms. We found that loss of the H3K36 methyltransferase NSD1 caused resistance to EZH2 inhibition. We show that NSD1 antagonizes polycomb via cooperation with SWI/SNF and identify co-occurrence of NSD1 inactivation in SWI/SNF-defective cancers, indicating in vivo relevance. We demonstrate that H3K36me2 itself has an essential role in the activation of polycomb target genes as inhibition of the H3K36me2 demethylase KDM2A restores the efficacy of EZH2 inhibition in SWI/SNF-deficient cells lacking NSD1. Together our data expand the mechanistic understanding of SWI/SNF and polycomb interplay and identify NSD1 as the key for coordinating this transcriptional control.
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A genome-wide CRISPR screen reveals that NSD1 loss causes resistance to EZH2 inhibitionExpression of EZH2 targets requires H3K27me3 loss plus NSD1-driven H3K36me2 gainNSD1 cooperates with SWI/SNF to antagonize polycomb complexesInhibiting the H3K36me2 eraser KDM2A sensitizes NSD1-deficient cells to the EZH2 inhibitor
Drosos et al. performed a CRISPR-depletion screen in SWI/SNF-mutant rhabdoid tumors to identify mutants conferring resistance to EZH2 inhibition. NSD1 was a top hit. They found that gene activation following EZH2 inhibition depends on the H3K36 methyltransferase activity of NSD1. Inhibition of the KDM2A demethylase re-sensitizes NSD1 null cells to EZH2 inhibition.
A large set of genome-wide markers and a high-throughput genotyping platform can facilitate the genetic dissection of complex traits and accelerate molecular breeding applications. Previously, we ...identified about 0.9 million SNP markers by sequencing transcriptomes of 27 diverse alfalfa genotypes. From this SNP set, we developed an Illumina Infinium array containing 9,277 SNPs. Using this array, we genotyped 280 diverse alfalfa genotypes and several genotypes from related species. About 81% (7,476) of the SNPs met the criteria for quality control and showed polymorphisms. The alfalfa SNP array also showed a high level of transferability for several closely related Medicago species. Principal component analysis and model-based clustering showed clear population structure corresponding to subspecies and ploidy levels. Within cultivated tetraploid alfalfa, genotypes from dormant and nondormant cultivars were largely assigned to different clusters; genotypes from semidormant cultivars were split between the groups. The extent of linkage disequilibrium (LD) across all genotypes rapidly decayed to 26 Kbp at r(2) = 0.2, but the rate varied across ploidy levels and subspecies. A high level of consistency in LD was found between and within the two subpopulations of cultivated dormant and nondormant alfalfa suggesting that genome-wide association studies (GWAS) and genomic selection (GS) could be conducted using alfalfa genotypes from throughout the fall dormancy spectrum. However, the relatively low LD levels would require a large number of markers to fully saturate the genome.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A Leadless Intracardiac Transcatheter Pacing System Reynolds, Dwight; Duray, Gabor Z; Omar, Razali ...
New England journal of medicine/The New England journal of medicine,
02/2016, Letnik:
374, Številka:
6
Journal Article
Recenzirano
Odprti dostop
A series of 725 patients underwent attempted implantation of a leadless transcatheter pacemaker. At 6 months, 96.0% of patients had no major device-related complications, and 98.3% had a low and ...stable pacing capture threshold.
For more than half a century, permanent cardiac pacing for symptomatic bradycardia has been achieved with systems that consist of a surgically implanted subcutaneous electrical generator connected to one or more transvenous leads that deliver the pacing therapy to the heart. Although these devices are effective, approximately one in eight patients has an early complication, frequently related to the lead or leads or to the subcutaneous “pocket.”
1
Complications include problems with the subcutaneous pocket, such as hematomas and infections; lead-insertion problems, such as pneumothoraxes and hemothoraxes; lead dislodgements and integrity problems; infections, including septicemia and endocarditis; vascular obstructions; and reduced . . .
CRLF2 rearrangements, JAK1/2 point mutations, and JAK2 fusion genes have been identified in Philadelphia chromosome (Ph)–like acute lymphoblastic leukemia (ALL), a recently described subtype of ...pediatric high-risk B-precursor ALL (B-ALL) which exhibits a gene expression profile similar to Ph-positive ALL and has a poor prognosis. Hyperactive JAK/STAT and PI3K/mammalian target of rapamycin (mTOR) signaling is common in this high-risk subset. We, therefore, investigated the efficacy of the JAK inhibitor ruxolitinib and the mTOR inhibitor rapamycin in xenograft models of 8 pediatric B-ALL cases with and without CRLF2 and JAK genomic lesions. Ruxolitinib treatment yielded significantly lower peripheral blast counts compared with vehicle (P < .05) in 6 of 8 human leukemia xenografts and lower splenic blast counts (P < .05) in 8 of 8 samples. Enhanced responses to ruxolitinib were observed in samples harboring JAK-activating lesions and higher levels of STAT5 phosphorylation. Rapamycin controlled leukemia burden in all 8 B-ALL samples. Survival analysis of 2 representative B-ALL xenografts demonstrated prolonged survival with rapamycin treatment compared with vehicle (P < .01). These data demonstrate preclinical in vivo efficacy of ruxolitinib and rapamycin in this high-risk B-ALL subtype, for which novel treatments are urgently needed, and highlight the therapeutic potential of targeted kinase inhibition in Ph-like ALL.
Biallelic inactivation of SMARCB1, encoding a member of the SWI/SNF chromatin remodeling complex, is the hallmark genetic aberration of atypical teratoid rhabdoid tumors (ATRT). Here, we report how ...loss of SMARCB1 affects the epigenome in these tumors. Using chromatin immunoprecipitation sequencing (ChIP-seq) on primary tumors for a series of active and repressive histone marks, we identified the chromatin states differentially represented in ATRTs compared with other brain tumors and non-neoplastic brain. Re-expression of SMARCB1 in ATRT cell lines enabled confirmation of our genome-wide findings for the chromatin states. Additional generation of ChIP-seq data for SWI/SNF and Polycomb group proteins and the transcriptional repressor protein REST determined differential dependencies of SWI/SNF and Polycomb complexes in regulation of diverse gene sets in ATRTs.
•ATRT epigenomes display a global depletion of H3K27ac and H3K27me3•Neuronal genes bound by SMARCB1 in normal brain are repressed by EZH2 in ATRT•ATRT harbor many active genes occupied by EZH2 but without occupancy of H3K27me3•Residual SWI/SNF occupancy maintains genes active in the presence of Polycomb complex
Erkek et al. show that in atypical teratoid rhabdoid tumors (ATRT), which often lack the SWI/SNF complex component SMARCB1, a large fraction of SMARCB1 binding loci in normal brain is bound by EZH2 but without H3K27me3 and remains in an active state, and some of these genes are essential for ATRT survival.
There is growing recognition that reproductive factors are associated with increased risk of future cardiovascular disease. Infertility has been less well studied, although emerging data support its ...association with increased risk of cardiovascular disease. Whether infertility is associated with future risk of heart failure (HF) is not known.
This study sought to examine the development of HF and HF subtypes in women with and without history of infertility.
We followed postmenopausal women from the Women’s Health Initiative prospectively for the development of HF. Infertility was self-reported at study baseline. Multivariable cause-specific Cox models were used to evaluate the association of infertility with incident overall HF and HF subtypes (heart failure with preserved ejection fraction HFpEF: left ventricular ejection fraction of ≥50% vs heart failure with reduced ejection fraction HFrEF: left ventricular ejection fraction of <50%).
Among 38,528 postmenopausal women (mean age: 63 ± 7 years), 5,399 (14%) participants reported a history of infertility. Over a median follow-up of 15 years, 2,373 developed incident HF, including 807 with HFrEF and 1,133 with HFpEF. Infertility was independently associated with future risk of overall HF (HR: 1.16; 95% CI: 1.04-1.30; P = 0.006). Notably, when examining HF subtypes, infertility was associated with future risk of HFpEF (HR: 1.27; 95% CI: 1.09-1.48; P = 0.002) but not HFrEF (HR: 0.97; 95% CI: 0.80-1.18).
Infertility was significantly associated with incident HF. This was driven by increased risk of HFpEF, but not HFrEF, and appeared independent of traditional cardiovascular risk factors and other infertility-related conditions. Future research should investigate mechanisms that underlie the link between infertility and HFpEF.
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