Although acute exacerbation of idiopathic pulmonary fibrosis (IPF) has become well recognised, the reported incidence and outcomes are highly variable, and risk factors are unknown. The aim of this ...study was to estimate the incidence, risk factors and impact of acute exacerbations, and other known causes of rapid deterioration. This was a retrospective review of 461 patients with IPF (269 cases were biopsy-proven). The median follow-up period was 22.9 months. Rapid deterioration requiring hospitalisation occurred in 163 (35.4%) patients, with multiple episodes in 42 patients. Acute exacerbation was the most frequent cause (55.2%), followed by infection. The 1- and 3-yr incidences of acute exacerbation were 14.2 and 20.7%, respectively. Never having smoked and low forced vital capacity (FVC) were significant risk factors. The in-hospital mortality rate was 50.0%, and the 1- and 5-yr survival rates from the initial diagnosis were 56.2 and 18.4%, respectively. Acute exacerbation was a significant predictor of poor survival after the initial diagnosis, along with increased age, low FVC and diffusing capacity of the lung for carbon monoxide, and steroid use with or without cytotoxic therapy. 1- and 3-yr incidences of acute exacerbation were 14.2 and 20.7%, respectively. Never having smoked and low FVC were risk factors. Acute exacerbation had a serious impact on the overall survival of the patients with IPF.
Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal disorder that can be caused by mutations in the superoxide dismutase 1 (SOD1) gene. Although ALS is currently incurable, CRISPR base ...editors hold the potential to treat the disease through their ability to create nonsense mutations that can permanently disable the expression of the mutant SOD1 gene. However, the restrictive carrying capacity of adeno-associated virus (AAV) vectors has limited their therapeutic application. In this study, we establish an intein-mediated trans-splicing system that enables in vivo delivery of cytidine base editors (CBEs) consisting of the widely used Cas9 protein from Streptococcus pyogenes. We show that intrathecal injection of dual AAV particles encoding a split-intein CBE engineered to trans-splice and introduce a nonsense-coding substitution into a mutant SOD1 gene prolonged survival and markedly slowed the progression of disease in the G93A-SOD1 mouse model of ALS. Adult animals treated by this split-intein CRISPR base editor had a reduced rate of muscle atrophy, decreased muscle denervation, improved neuromuscular function, and up to 40% fewer SOD1 immunoreactive inclusions at end-stage mice compared to control mice. This work expands the capabilities of single-base editors and demonstrates their potential for gene therapy.
Lim et al. establish a trans-splicing system to deliver CRISPR base editors in vivo that enables treatment of a mouse model of ALS. They show that base editing can increase survival and slow the progression of disease.
Claudins (CLDNs) are a family of integral membrane proteins central to the formation of tight junctions, structures that are involved in paracellular transport and cellular growth and ...differentiation, and are critical for the maintenance of cellular polarity. Recent studies have provided evidence that CLDNs are aberrantly expressed in diverse types of human cancers, including hepatocellular carcinomas (HCCs). However, little is known about how CLDN expression is involved in cancer progression. In this study, we show that CLDN1 has a causal role in the epithelial-mesenchymal transition (EMT) in human liver cells, and that the c-Abl-Ras-Raf-1-ERK1/2 signaling axis is critical for the induction of malignant progression by CLDN1. Overexpression of CLDN1 induced expression of the EMT-regulating transcription factors Slug and Zeb1, and thereby led to repression of E-cadherin, β-catenin expression, enhanced expression of N-cadherin and Vimentin, a loss of cell adhesion, and increased cell motility in normal liver cells and HCC cells. In line with these findings, inhibition of either c-Abl or ERK clearly attenuated CLDN1-induced EMT, as evidenced by a reversal of N-cadherin and E-cadherin expression patterns, and restored normal motility. Collectively, these results indicate that CLDN1 is necessary for the induction of EMT in human liver cells, and that activation of the c-Abl-Ras-Raf-1-ERK1/2 signaling pathway is required for CLDN1-induced acquisition of the malignant phenotype. The present observations suggest that CLDN1 could be exploited as a biomarker for liver cancer metastasis and might provide a pivotal point for therapeutic intervention in HCC.
The identification of high-redshift, massive galaxies with old stellar populations may pose challenges to some models of galaxy formation. However, to securely classify a galaxy as quiescent, it is ...necessary to exclude significant ongoing star formation, something that can be challenging to achieve at high redshifts. In this Letter, we analyze deep ALMA/870 m and SCUBA-2/450 m imaging of the claimed "post-starburst" galaxy ZF 20115 at z = 3.717 that exhibits a strong Balmer break and absorption lines. The rest-frame far-infrared imaging identifies a luminous starburst 0 4 0 1 (∼3 kpc in projection) from the position of the ultraviolet/optical emission and is consistent with lying at the redshift of ZF 20115. The star-forming component, with an obscured star formation rate of , is undetected in the rest-frame ultraviolet but contributes significantly to the lower angular resolution photometry at rest-frame wavelengths 3500 . This contribution from the obscured starburst, especially in the Spitzer/IRAC wavebands, significantly complicates the determination of a reliable stellar mass for the ZF 20015 system, and we conclude that this source does not pose a challenge to current models of galaxy formation. The multi-wavelength observations of ZF 20115 unveil a complex system with an intricate and spatially varying star formation history. ZF 20115 demonstrates that understanding high-redshift obscured starbursts will only be possible with multi-wavelength studies that include high-resolution observations, available with the James Webb Space Telescope, at mid-infrared wavelengths.
Although there is robust evidence linking childhood adversities (CAs) and an increased risk for psychotic experiences (PEs), little is known about whether these associations vary across the ...life-course and whether mental disorders that emerge prior to PEs explain these associations.
We assessed CAs, PEs and DSM-IV mental disorders in 23 998 adults in the WHO World Mental Health Surveys. Discrete-time survival analysis was used to investigate the associations between CAs and PEs, and the influence of mental disorders on these associations using multivariate logistic models.
Exposure to CAs was common, and those who experienced any CAs had increased odds of later PEs odds ratio (OR) 2.3, 95% confidence interval (CI) 1.9-2.6. CAs reflecting maladaptive family functioning (MFF), including abuse, neglect, and parent maladjustment, exhibited the strongest associations with PE onset in all life-course stages. Sexual abuse exhibited a strong association with PE onset during childhood (OR 8.5, 95% CI 3.6-20.2), whereas Other CA types were associated with PE onset in adolescence. Associations of other CAs with PEs disappeared in adolescence after adjustment for prior-onset mental disorders. The population attributable risk proportion (PARP) for PEs associated with all CAs was 31% (24% for MFF).
Exposure to CAs is associated with PE onset throughout the life-course, although sexual abuse is most strongly associated with childhood-onset PEs. The presence of mental disorders prior to the onset of PEs does not fully explain these associations. The large PARPs suggest that preventing CAs could lead to a meaningful reduction in PEs in the population.
The purpose of this paper is to extend the single-subject Eve atlas from Johns Hopkins University, which currently contains diffusion tensor and T1-weighted anatomical maps, by including contrast ...based on quantitative susceptibility mapping. The new atlas combines a “deep gray matter parcellation map” (DGMPM) derived from a single-subject quantitative susceptibility map with the previously established “white matter parcellation map” (WMPM) from the same subject's T1-weighted and diffusion tensor imaging data into an MNI coordinate map named the “Everything Parcellation Map in Eve Space,” also known as the “EvePM.” It allows automated segmentation of gray matter and white matter structures. Quantitative susceptibility maps from five healthy male volunteers (30 to 33years of age) were coregistered to the Eve Atlas with AIR and Large Deformation Diffeomorphic Metric Mapping (LDDMM), and the transformation matrices were applied to the EvePM to produce automated parcellation in subject space. Parcellation accuracy was measured with a kappa analysis for the left and right structures of six deep gray matter regions. For multi-orientation QSM images, the Kappa statistic was 0.85 between automated and manual segmentation, with the inter-rater reproducibility Kappa being 0.89 for the human raters, suggesting “almost perfect” agreement between all segmentation methods. Segmentation seemed slightly more difficult for human raters on single-orientation QSM images, with the Kappa statistic being 0.88 between automated and manual segmentation, and 0.85 and 0.86 between human raters. Overall, this atlas provides a time-efficient tool for automated coregistration and segmentation of quantitative susceptibility data to analyze many regions of interest. These data were used to establish a baseline for normal magnetic susceptibility measurements for over 60 brain structures of 30- to 33-year-old males. Correlating the average susceptibility with age-based iron concentrations in gray matter structures measured by Hallgren and Sourander (1958) allowed interpolation of the average iron concentration of several deep gray matter regions delineated in the EvePM.
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•We added a Quantitative Susceptibility Mapping (QSM) template to the Eve atlas.•We utilized MRI Studio software to coregister QSM images to the Eve atlas.•Automated segmentation took less than 24h for over sixty brain regions.•We derived a susceptibility-iron calibration curve based on known iron values.•This curve was used to determine iron concentration in other gray matter regions.
Abstract
Aims
Epidemiological studies indicate that individuals with one type of mental disorder have an increased risk of subsequently developing other types of mental disorders. This study aimed to ...undertake a comprehensive analysis of pair-wise lifetime comorbidity across a range of common mental disorders based on a diverse range of population-based surveys.
Methods
The WHO World Mental Health (WMH) surveys assessed 145 990 adult respondents from 27 countries. Based on retrospectively-reported age-of-onset for 24 DSM-IV mental disorders, associations were examined between all 548 logically possible temporally-ordered disorder pairs. Overall and time-dependent hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Absolute risks were estimated using the product-limit method. Estimates were generated separately for men and women.
Results
Each prior lifetime mental disorder was associated with an increased risk of subsequent first onset of each other disorder. The median HR was 12.1 (mean = 14.4; range 5.2–110.8, interquartile range = 6.0–19.4). The HRs were most prominent between closely-related mental disorder types and in the first 1–2 years after the onset of the prior disorder. Although HRs declined with time since prior disorder, significantly elevated risk of subsequent comorbidity persisted for at least 15 years. Appreciable absolute risks of secondary disorders were found over time for many pairs.
Conclusions
Survey data from a range of sites confirms that comorbidity between mental disorders is common. Understanding the risks of temporally secondary disorders may help design practical programs for primary prevention of secondary disorders.
•EnergyPlus simulation tool produced energy benchmark in residential houses.•The three electrical load categories have been identified.•Verification of energy building simulation models against ...utility data and survey.•EUI for residential buildings in Brunei fluctuates from 47.8 to 64.2kWh/m2.
Energy performance of buildings is a highly important measure for Energy Efficiency and Conservation initiatives. The fundamental step toward the understanding of energy use is benchmarking. In this study, the EnergyPlus simulation tool is used to benchmark the energy performance of 400 residential buildings from which three types of buildings were classified. EnergyPlus models were developed for the three types of building designs typically found in the national housing scheme in Brunei Darussalam. The EnergyPlus models produced the energy use intensity (EUI) per year for these buildings, with values ranging from approximately 64.2 to 47.8kWh/m2. The EnergyPlus outputs were verified against the power consumption data, and data from selected door-to-door survey. This study demonstrates the capability of engineering models in producing benchmarking, and simulating conditions for the improvements of energy performance in buildings.
Initial performance of the COSINE-100 experiment Adhikari, G.; Adhikari, P.; de Souza, E. Barbosa ...
The European physical journal. C, Particles and fields,
02/2018, Letnik:
78, Številka:
2
Journal Article
Recenzirano
Odprti dostop
COSINE is a dark matter search experiment based on an array of low background NaI(Tl) crystals located at the Yangyang underground laboratory. The assembly of COSINE-100 was completed in the summer ...of 2016 and the detector is currently collecting physics quality data aimed at reproducing the DAMA/LIBRA experiment that reported an annual modulation signal. Stable operation has been achieved and will continue for at least 2 years. Here, we describe the design of COSINE-100, including the shielding arrangement, the configuration of the NaI(Tl) crystal detection elements, the veto systems, and the associated operational systems, and we show the current performance of the experiment.
Aims/hypothesis Insulin resistance (IR) is associated with obesity, but can also develop in individuals with normal body weight. We employed comprehensive profiling methods to identify metabolic ...events associated with IR, while controlling for obesity. Methods We selected 263 non-obese (BMI approximately 24 kg/m²) Asian-Indian and Chinese men from a large cross-sectional study carried out in Singapore. Individuals taking medication for diabetes or hyperlipidaemia were excluded. Participants were separated into lower and upper tertiles of IR based on HOMA indices of ≤1.06 or ≥1.93, respectively. MS-based metabolic profiling of acylcarnitines, amino acids and organic acids was combined with hormonal and cytokine profiling in all participants. Results After controlling for BMI, commonly accepted risk factors for IR, including circulating fatty acids and inflammatory cytokines, did not discriminate the upper and lower quartiles of insulin sensitivity in either Asian-Indian or Chinese men. Instead, IR was correlated with increased levels of alanine, proline, valine, leucine/isoleucine, phenylalanine, tyrosine, glutamate/glutamine and ornithine, and a cluster of branched-chain and related amino acids identified by principal components analysis. These changes were not due to increased protein intake by individuals in the upper quartile of IR. Increased abdominal adiposity and leptin, and decreased adiponectin and IGF-binding protein 1 were also correlated with IR. Conclusions/interpretation These findings demonstrate that perturbations in amino acid homeostasis, but not inflammatory markers or NEFAs, are associated with IR in individuals of relatively low body mass.
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