As the criteria for liver donation have been extended to include marginal donors, liver grafts are becoming particularly vulnerable to hepatic ischemia–reperfusion injury (IRI). However, no specific ...measures have been validated to ameliorate hepatic IRI. In this article, we explored whether everolimus has protective effects against hepatic IRI in relation with autophagy. The effects of everolimus were investigated in both in vitro and in vivo hepatic IRI models. Mouse hepatocyte AML12 cells and BALB/c mice were utilized for the establishment of each model. In the IRI‐induced AML12 cells, everolimus treatment increased the expressions of autophagic markers (microtubule‐associated protein 1 light chain 3 and p62) and decreased pro‐apoptotic proteins (cleaved caspase 3 and cleaved poly‐ADP ribose polymerase). The blockage of autophagy, using either bafilomycin A1 or si‐autophagy‐related protein 5, abrogated these anti‐apoptosis effects of everolimus. Subsequently, everolimus administration to the hepatic IRI‐induced mice provided hepatoprotective effects in terms of (1) decreasing the expressions of pro‐apoptotic proteins, (2) inhibiting the release of pro‐inflammatory cytokines (IL‐6 and tumor necrosis factor‐α), (3) reducing elevated liver enzymes (aspartate transaminase, alanine transaminase, and ammonia), and (4) restoring liver histopathology. These findings suggest that everolimus protects the liver against hepatic IRI by way of activating autophagy, and thus could be a potential therapeutic agent for hepatic IRI.
This experimental study suggests that everolimus protects the liver against hepatic ischemia–reperfusion injury by way of activating autophagy, and thus could be a potential therapeutic agent.
The genome of soybean (Glycine max), a commercially important crop, has recently been sequenced and is one of six crop species to have been sequenced. Here we report the genome sequence of G. soja, ...the undomesticated ancestor of G. max (in particular, G. soja var. IT182932). The 48.8-Gb Illumina Genome Analyzer (Illumina-GA) short DNA reads were aligned to the G. max reference genome and a consensus was determined for G. soja. This consensus sequence spanned 915.4 Mb, representing a coverage of 97.65% of the G. max published genome sequence and an average mapping depth of 43-fold. The nucleotide sequence of the G. soja genome, which contains 2.5 Mb of substituted bases and 406 kb of small insertions/deletions relative to G. max, is ∼0.31% different from that of G. max. In addition to the mapped 915.4-Mb consensus sequence, 32.4 Mb of large deletions and 8.3 Mb of novel sequence contigs in the G. soja genome were also detected. Nucleotide variants of G. soja versus G. max confirmed by Roche Genome Sequencer FLX sequencing showed a 99.99% concordance in single-nucleotide polymorphism and a 98.82% agreement in insertion/deletion calls on Illumina-GA reads. Data presented in this study suggest that the G. soja/G. max complex may be at least 0.27 million y old, appearing before the relatively recent event of domestication (6,000∼9,000 y ago). This suggests that soybean domestication is complicated and that more in-depth study of population genetics is needed. In any case, genome comparison of domesticated and undomesticated forms of soybean can facilitate its improvement.
We assessed the association of herpes zoster (HZ) with stroke/transient ischaemic attack (TIA) in the general population according to age with controlling risk factors for stroke, using a nationwide ...representative cohort. The study was based on a prospective dynamic cohort consisting of 1 million Koreans representing all age groups, genders and geographical areas in the Korea Health Insurance Database. New events of stroke/TIA and HZ were identified using the diagnostic codes in the International Classification of Diseases, tenth revision. The risk for stroke/TIA after HZ was compared with HZ-free stroke/TIA individuals according to age group. A total of 766 179 adults were followed up for 11 years from 2003. The incidence of the first-diagnosed HZ cases was 9.40 per 1000 person-years, and that of the first-diagnosed stroke/TIA cases was 9.77 per 1000 person-years. The risk for stroke/TIA was higher in patients who had previous HZ episodes than in those who had never experienced HZ (incidence rate ratio 1.90; 95% CI 1.85–1.95). In addition, this risk persisted for several years after HZ. The risk of stroke/TIA after HZ gradually decreased with age; adjusted hazard ratio (HR) 2.04 in 18- to 30-year-olds, HR 1.74 in 30- to 40-year-olds, HR 1.43 in 40- to 50-year-olds, HR 1.23 in 50- to 60-year-olds, HR 1.24 in 60- to 70-year-olds, and HR 1.29 in those >70 years old, after controlling risk factors for stroke/TIA. Our findings provide evidence that HZ carries an increased risk of stroke or TIA and that the effect of HZ on stroke decreases with increasing age.
This paper is concerned with the problem of stability and stabilization for Takagi-Sugeno (T-S) fuzzy systems with time-varying delays. By constructing a suitable Lyapunov-Krasovskii functional, ...sufficient conditions for ensuring the asymptotic stability and stabilization of the concerned fuzzy systems have been derived within the framework of linear matrix inequalities (LMIs). The advantage and effectiveness of the proposed criteria will be shown through the comparison of maximum delay bounds with some results obtained by recently published papers via four numerical examples.
The association of a broad spectrum of infectious diseases with cardiovascular outcomes remains unclear.
We aim to provide the cardiovascular risk profiles associated with a wide range of infectious ...diseases and explore the extent to which infections reduce life expectancy.
We ascertained exposure to 900+ infectious diseases before cardiovascular disease (CVD) onset in 453,102 participants from the UK Biobank study. Time-varying Cox proportional hazard models were used. Life table was used to estimate the life expectancy of individuals aged ≥50 with different levels of infection burden (defined as the number of infection episodes over time and the number of co-occurring infections).
Infectious diseases were associated with a greater risk of CVD events (adjusted HR aHR 1.79 95% confidence interval {CI} 1.74-1.83). For type-specific analysis, bacterial infection with sepsis had the strongest risk of CVD events aHR 4.76 (4.35-5.20). For site-specific analysis, heart and circulation infections posed the greatest risk of CVD events aHR 4.95 (95% CI 3.77-6.50), whereas noncardiac infections also showed excess risk 1.77 (1.72-1.81). Synergistic interactions were observed between infections and genetic risk score. A dose-response relationship was found between infection burden and CVD risks (p-trend <0.001). Infection burden >1 led to a CVD-related life loss at age 50 by 9.3 years 95% CI 8.6-10.3) for men and 6.6 years 5.5-7.8 for women.
The magnitude of the infection-CVD association showed specificity in sex, pathogen type, infection burden, and infection site. High genetic risk and infection synergistically increased the CVD risk.
Head and neck squamous cell carcinomas (HNSCCs) display cellular heterogeneity and contain cancer stem cells (CSCs). Sex-determining region Y SRY-box (SOX)2 is an important regulator of embryonic ...stem cell fate and is aberrantly expressed in several types of human tumours. Nonetheless, the role of SOX2 in HNSCC remains unclear.
We created cells ectopically expressing SOX2 from previously established HNSCC cells and examined the cell proliferation, self-renewal capacity, and chemoresistance of these cells compared with control cells. In addition, we knocked down SOX2 in primary spheres obtained from HNSCC tumour tissue and assessed the attenuation of stemness-associated traits in these cells in vitro and in vivo. Furthermore, we examined the clinical relevance of SOX2 expression in HNSCC patients.
SOX2 is aberrantly expressed in primary tissue of HNSCC patients but not in healthy tissue. SOX2 expression correlated with tumour recurrence and poor prognosis of HNSCC patients. Ectopic expression of SOX2 induced cell proliferation via cyclin B1 expression and stemness-associated features, such as self-renewal and chemoresistance. In addition, a knockdown of SOX2 in HNSCC CSCs attenuated their self-renewal capacity, chemoresistance (through ABCG2 suppression), invasion capacity (via snail downregulation), and in vivo tumorigenicity.
These results suggest that SOX2 may have important roles in the 'stemness' and progression of HNSCC. Targeting SOX2-positive tumour cells (CSCs) could be a new therapeutic strategy in HNSCCs.
Stacking fault energies (SFE) were determined in additively manufactured (AM) stainless steel (SS 316 L) and equiatomic CrCoNi medium-entropy alloys. AM specimens were fabricated via directed energy ...deposition and tensile loaded at room temperature. In situ neutron diffraction was performed to obtain a number of faulting-embedded diffraction peaks simultaneously from a set of (hkl) grains during deformation. The peak profiles diffracted from imperfect crystal structures were analyzed to correlate stacking fault probabilities and mean-square lattice strains to the SFE. The result shows that averaged SFEs are 32.8 mJ/m
for the AM SS 316 L and 15.1 mJ/m
for the AM CrCoNi alloys. Meanwhile, during deformation, the SFE varies from 46 to 21 mJ/m
(AM SS 316 L) and 24 to 11 mJ/m
(AM CrCoNi) from initial to stabilized stages, respectively. The transient SFEs are attributed to the deformation activity changes from dislocation slip to twinning as straining. The twinning deformation substructure and atomic stacking faults were confirmed by electron backscatter diffraction (EBSD) and transmission electron microscopy (TEM). The significant variance of the SFE suggests the critical twinning stress as 830 ± 25 MPa for the AM SS 316 L and 790 ± 40 MPa for AM CrCoNi, respectively.
With development of massively parallel sequencing technologies, there is a substantial need for developing powerful rare variant association tests. Common approaches include burden and non-burden ...tests. Burden tests assume all rare variants in the target region have effects on the phenotype in the same direction and of similar magnitude. The recently proposed sequence kernel association test (SKAT) (Wu, M. C., and others, 2011. Rare-variant association testing for sequencing data with the SKAT. The American Journal of Human Genetics 89, 82-93, an extension of the C-alpha test (Neale, B. M., and others, 2011. Testing for an unusual distribution of rare variants. PLoS Genetics 7, 161-165, provides a robust test that is particularly powerful in the presence of protective and deleterious variants and null variants, but is less powerful than burden tests when a large number of variants in a region are causal and in the same direction. As the underlying biological mechanisms are unknown in practice and vary from one gene to another across the genome, it is of substantial practical interest to develop a test that is optimal for both scenarios. In this paper, we propose a class of tests that include burden tests and SKAT as special cases, and derive an optimal test within this class that maximizes power. We show that this optimal test outperforms burden tests and SKAT in a wide range of scenarios. The results are illustrated using simulation studies and triglyceride data from the Dallas Heart Study. In addition, we have derived sample size/power calculation formula for SKAT with a new family of kernels to facilitate designing new sequence association studies.
A
bstract
Models of Dark Matter (DM) can leave unique imprints on the Universe’s small scale structure by boosting density perturbations on small scales. We study the capability of Pulsar Timing ...Arrays to search for, and constrain, subhalos from such models. The models of DM we consider are ordinary adiabatic perturbations in ΛCDM, QCD axion miniclusters, models with early matter domination, and vector DM produced during inflation. We show that ΛCDM, largely due to tidal stripping effects in the Milky Way, is out of reach for PTAs. Axion miniclusters may be within reach, although this depends crucially on whether the axion relic density is dominated by the misalignment or string contribution. Models where there is matter domination with a reheat temperature below 1 GeV may be observed with future PTAs. Lastly, vector DM produced during inflation can be detected if it is lighter than 10
−
16
GeV. We also make publicly available a Python Monte Carlo tool for generating the PTA time delay signal from any model of DM substructure.
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