The aggressive nature and poor prognosis of lung cancer led us to explore the mechanisms driving disease progression. Utilizing our invasive cell‐based model, we identified methylthioadenosine ...phosphorylase (MTAP) and confirmed its suppressive effects on tumorigenesis and metastasis. Patients with low MTAP expression display worse overall and progression‐free survival. Mechanistically, accumulation of methylthioadenosine substrate in MTAP‐deficient cells reduce the level of protein arginine methyltransferase 5 (PRMT5)‐mediated symmetric dimethylarginine (sDMA) modification on proteins. We identify vimentin as a dimethyl‐protein whose dimethylation levels drop in response to MTAP deficiency. The sDMA modification on vimentin reduces its protein abundance but trivially affects its filamentous structure. In MTAP‐deficient cells, lower sDMA modification prevents ubiquitination‐mediated vimentin degradation, thereby stabilizing vimentin and contributing to cell invasion. MTAP and PRMT5 negatively correlate with vimentin in lung cancer samples. Taken together, we propose a mechanism for metastasis involving vimentin post‐translational regulation.
Synopsis
Repression of MTAP‐dependent symmetric dimethylation mediated by PRMT5 increases vimentin protein stability and leads to invasion and metastasis in MTAP‐deficient lung cancer.
MTAP loss promotes lung cancer metastasis.
MTA accumulation in MTAP‐deficient cancer cells inhibits PRMT5‐mediated symmetric dimethylation on arginine residues of vimentin.
Vimentin is destabilized by PRMT5‐mediated symmetric dimethylation.
Reduced dimethylation and stabilization of vimentin in MTAP‐deficient cancer cells contributes to invasion and metastasis.
Repression of MTAP‐dependent symmetric dimethylation mediated by PRMT5 increases vimentin protein stability and leads to invasion and metastasis in MTAP‐deficient lung cancer.
Some oral probiotics have been shown to prevent necrotizing enterocolitis (NEC) and decrease mortality effectively in preterm very low birth weight (PVLBW) infants. However, it is unclear whether a ...single probiotic or a mixture of probiotics is most effective for the prevention of NEC.
A meta-analysis was conducted by reviewing the most up to date literature to investigate whether multiple strains probiotics are more effective than a single strain in reducing NEC and death in PVLBW infants.
Relevant studies were identified by searches of the MEDLINE, EMBASE, and Cochrane CENTRAL databases, from 2001 to 2016.
The inclusion criteria were randomized controlled trials of any enteral probiotic supplementation that was initiated within the first 7 days and continued for at least 14 days in preterm infants (≤ 34 weeks' gestation) and/or those of a birth weight ≤1500 g.
A total of 25 trials (n = 7345 infants) were eligible for inclusion in the meta-analysis using a fixed-effects model. Multiple strains probiotics were associated with a marked reduction in the incidence of NEC, with a pooled OR of 0.36 (95% CI, 0.24-0.53; P < .00001). Single strain probiotic using Lactobacillus species had a borderline effect in reducing NEC (OR of 0.60; 95% CI 0.36-1.0; P = .05), but not mortality. Multiple strains probiotics had a greater effectiveness in reducing mortality and were associated with a pooled OR of 0.58 (95% CI, 0.43-0.79; P = .0006). Trials using single strain of Bifidobacterium species and Saccharomyces boulardii did not reveal any beneficial effects in terms of reducing NEC or mortality.
This updated report found that multiple strains probiotics appear to be the most feasible and effective strategy for the prevention of NEC and reduction of mortality in PVLBW neonates. Further clinical trials should focus on which probiotic combinations are most effective.
Liver transplantation is the only definitive treatment for end‐stage cirrhosis and fulminant liver failure, but the lack of available donor livers is a major obstacle to liver transplantation. ...Recently, induced pluripotent stem cells (iPSCs) derived from the reprogramming of somatic fibroblasts, have been shown to resemble embryonic stem (ES) cells in that they have pluripotent properties and the potential to differentiate into all cell lineages in vitro, including hepatocytes. Thus, iPSCs could serve as a favorable cell source for a wide range of applications, including drug toxicity testing, cell transplantation, and patient‐specific disease modeling. Here, we describe an efficient and rapid three‐step protocol that is able to rapidly generate hepatocyte‐like cells from human iPSCs. This occurs because the endodermal induction step allows for more efficient and definitive endoderm cell formation. We show that hepatocyte growth factor (HGF), which synergizes with activin A and Wnt3a, elevates the expression of the endodermal marker Foxa2 (forkhead box a2) by 39.3% compared to when HGF is absent (14.2%) during the endodermal induction step. In addition, iPSC‐derived hepatocytes had a similar gene expression profile to mature hepatocytes. Importantly, the hepatocyte‐like cells exhibited cytochrome P450 3A4 (CYP3A4) enzyme activity, secreted urea, uptake of low‐density lipoprotein (LDL), and possessed the ability to store glycogen. Moreover, the hepatocyte‐like cells rescued lethal fulminant hepatic failure in a nonobese diabetic severe combined immunodeficient mouse model. Conclusion: We have established a rapid and efficient differentiation protocol that is able to generate functional hepatocyte‐like cells from human iPSCs. This may offer an alternative option for treatment of liver diseases. (Hepatology 2012)
Gold has always been regarded as a symbol of nobility, and its shiny golden appearance has always attracted the attention of many people. Gold has good ductility, molecular recognition properties, ...and good biocompatibility. At present, gold is being used in many fields. When gold particles are as small as several nanometers, their physical and chemical properties vary with their size in nanometers. The surface area of a nano-sized gold surface has a special effect. Therefore, gold nanoparticles can, directly and indirectly, give rise to different biological activities. For example, if the surface of the gold is sulfided. Various substances have a strong chemical reactivity and are easy to combine with sulfhydryl groups; hence, nanogold is often used in biomedical testing, disease diagnosis, and gene detection. Nanogold is easy to bind to proteins, such as antibodies, enzymes, or cytokines. In fact, scientists use nanogold to bind special antibodies, as a tool for targeting cancer cells. Gold nanoparticles are also directly cytotoxic to cancer cells. For diseases caused by inflammation and oxidative damage, gold nanoparticles also have antioxidant and anti-inflammatory effects. Based on these unique properties, gold nanoparticles have become the most widely studied metal nanomaterials. Many recent studies have further demonstrated that gold nanoparticles are beneficial for humans, due to their functional pharmacological properties in a variety of diseases. The content of this review will be the application of gold nanoparticles in treating or diagnosing pressing diseases, such as cancers, retinopathy, neurological diseases, skin disorders, bowel diseases, bone cartilage disorders, cardiovascular diseases, infections, and metabolic syndrome. Gold nanoparticles have shown very obvious therapeutic and application potential.
Electronic device versions of the neural functions of the human retina have high potential for use in artificial vision. This study demonstrates halide perovskite artificial human photoreceptors with ...specific photoresponses to red, green, and blue colors, which are consistent with human retinal photoreceiving cones and rods. In contrast to the current programmable spectral‐response technologies, a novel microcavity structure is combined in this study with a perovskite absorber to achieve a targeted spectrum without using external optical filters. The fabricated artificial photoreceptors exhibit excellent performance including a high detectivity of more than 1013 Jones, a large linear dynamic range of 154 dB, and a short response time of 580 ns. These values are equal to or better than those of the natural human retina. These devices can easily be monolithically integrated on a single flexible substrate by using vacuum deposition, and a true proof‐of‐concept full‐color image reconstruction is demonstrated.
Microcavity‐integrated monolithic flexible perovskite artificial human photoreceptors are demonstrated. The artificial cones and rods exhibit a true similarity with the natural human retina and exhibit excellent specific detectivity, large linear dynamic range, short response time, and low noise current. The potential of these versatile structures is manifested by reproducing a realistic full‐color image.
The prognostic significance of the relapse interval in patients with resected oral cavity squamous cell carcinoma (OCSCC) is a matter of ongoing debate. In this large-scale, registry-based, ...nationwide study, we examined whether the time interval between surgery and the first disease relapse may affect survival outcomes in Taiwanese patients with OCSCC.
Data made available by the Taiwan Health Promotion Administration as of 2004 were obtained. The study cohort consisted of patients who were included in the registry between 2011 and 2017. Disease staging was performed according to the American Joint Committee on Cancer (AJCC) Staging Manual, Eight Edition. We retrospectively reviewed the clinical records of 13,789 patients with OCSCC who received surgical treatment. A total of 2327 (16.9%) patients experienced a first disease relapse. The optimal cutoff value for the relapse interval was 330 days when both 5-year disease-specific survival (DSS) and overall survival (OS) (≤ 330/>330 days, n = 1630/697) were taken into account. In addition, we undertook a propensity score (PS)-matched analysis of patients (n = 654 each) with early (≤ 330 days) versus late (> 330 days) relapse.
The median follow-up time in the entire study cohort was 702 days (433 and 2001 days in the early and late relapse groups, respectively). Compared with patients who experienced late relapse, those with early relapse showed a higher prevalence of the following adverse prognostic factors: pT4, pN3, pStage IV, poor differentiation, depth of invasion ≥ 10 mm, and extra-nodal extension. Multivariable analysis revealed that early relapse was an independent adverse prognostic factor for both 5-year DSS and OS (average hazard ratios AHRs: 3.24 and 3.91, respectively). In the PS-matched cohort, patients who experienced early relapse showed less favorable 5-year DSS: 58% versus 30%, p < 0.0001 (AHR: 3.10 2.69 - 3.57) and OS: 49% versus 22%, p < 0.0001 (AHR: 3.32 2.89 - 3.81).
After adjustment for potential confounders and PS matching, early relapse was an adverse prognostic factor for survival outcomes in patients with OCSCC. Our findings may have significant implications for risk stratification.
Beneficial Bacillus subtilis (BS) symbiosis could combat root pathogenesis, but it relies on root‐secreted sugars. Understanding the molecular control of sugar flux during colonization would benefit ...biocontrol applications. The SWEET (Sugar Will Eventually Be Exported Transporter) uniporter regulates microbe‐induced sugar secretion from roots; thus, its homologs may modulate sugar distribution upon BS colonization. Quantitative polymerase chain reaction revealed that gene transcripts of SWEET2, but not SWEET16 and 17, were significantly induced in seedling roots after 12 h of BS inoculation. Particularly, SWEET2‐β‐glucuronidase fusion proteins accumulated in the apical mature zone where BS abundantly colonized. Yet, enhanced BS colonization in sweet2 mutant roots suggested a specific role for SWEET2 to constrain BS propagation, probably by limiting hexose secretion. By employing yeast one‐hybrid screening and ectopic expression in Arabidopsis protoplasts, the transcription factor AHL29 was identified to function as a repressor of SWEET2 expression through the AT‐hook motif. Repression occurred despite immunity signals. Additionally, enhanced SWEET2 expression and reduced colonies were specifically detected in roots of BS‐colonized ahl29 mutant. Taken together, we propose that BS colonization may activate repression of AHL29 on SWEET2 transcription that would be enhanced by immunity signals, thereby maintaining adequate sugar secretion for a beneficial Bacillus association.
Summary statement
Arabidopsis vacuolar SWEET2 transporter limits root sugar secretion upon colonization with beneficial Bacillus subtilis. The AT‐hook protein AHL29 binds to the SWEET2 promoter to repress its immunity‐induced expression, thereby promoting adequate carbon for a mutualistic association with Bacillus.
Codon usage biases are found in all eukaryotic and prokaryotic genomes, and preferred codons are more frequently used in highly expressed genes. The effects of codon usage on gene expression were ...previously thought to be mainly mediated by its impacts on translation. Here, we show that codon usage strongly correlates with both protein and mRNA levels genome-wide in the filamentous fungus Neurospora. Gene codon optimization also results in strong up-regulation of protein and RNA levels, suggesting that codon usage is an important determinant of gene expression. Surprisingly, we found that the impact of codon usage on gene expression results mainly from effects on transcription and is largely independent of mRNA translation and mRNA stability. Furthermore, we show that histone H3 lysine 9 trimethylation is one of the mechanisms responsible for the codon usage-mediated transcriptional silencing of some genes with nonoptimal codons. Together, these results uncovered an unexpected important role of codon usage in ORF sequences in determining transcription levels and suggest that codon biases are an adaptation of protein coding sequences to both transcription and translation machineries. Therefore, synonymous codons not only specify protein sequences and translation dynamics, but also help determine gene expression levels.
The use of photovoltaic cells with an organometallic perovskite as the active layer for indoor dim‐light energy harvesting is evaluated. By designing the electron‐transporting materials and ...fabrication processes, the traps in the perovskite active layers and carrier dynamics can be controlled, and efficient devices are demonstrated. The best‐performing small‐area perovskite photovoltaics exhibit a promising high power conversion efficiency up to ≈27.4%, no hysteresis behavior, and an exceptionally low maximum power point voltage variation of ≈0.1 V under fluorescent lamp illumination at 100–1000 lux. The 5.44 cm2 large‐area device also shows a high efficiency of 20.4% and a promising long‐term stability. Compared with the most efficient inorganic and organic solar cells nowadays, the competitive efficiency, low fabrication cost, and low raw material costs make perovskite photovoltaics ideal for indoor light harvesting and as Internet of Things power provider.
Device engineering of perovskite photovoltaics dedicated to indoor dim‐light applications is reported. The trap density in the perovskite layer is effectively eliminated by judiciously controlling the fabrication of the electron‐transporting layers. Small‐area lab cell and 5.44 cm2 large‐area device attain maximum efficiencies up to 27.4% and 20.4% under indoor illumination, respectively.
TP53 alterations are frequent relapse‐acquired mutations in childhood acute lymphoblastic leukemia (ALL). The present study evaluated the clinical significance of relapsed childhood ALL in Taiwan. ...Diagnostic and/or relapsed bone marrow or peripheral blood was obtained from 111 children with relapsed ALL who were initially treated by using Taiwan Pediatric Oncology Group (TPOG) ALL protocols from January 1997 to May 2018. Mutations were detected by PCR and sequencing, as well as by multiplex ligation‐dependent probe amplification to detect copy number alterations. Copy number and/or sequence alterations of TP53 were detected in 29% (28 of 98) and in 46% (6 of 13) of patients with relapsed B‐cell and T‐cell ALL, respectively. This incidence was much higher than that in several similar studies conducted in Caucasian populations. Seventy percent of all TP53 alterations were gained at relapse in 67 matched samples by back‐tracking matched diagnostic samples. TP53 alterations were associated with lower 5‐year event‐free survival (EFS) and overall survival (OS) rates (P = .013 and P = .0002, respectively). Multivariate analysis confirmed the prognostic significance of TP53 alterations. Forty‐five patients received hematopoietic stem‐cell transplantations post‐relapse. Patients with TP53 alterations (14/45) had inferior 5‐year EFS and OS than patients without TP53 alterations after transplantation (P = .002 and P = .001, respectively). The significance of these TP53 alterations for patients who received transplantations was confirmed by multivariate analysis. In conclusion, TP53 alterations were enriched and useful as prognostic markers in relapsed childhood ALL.
Relapsed pediatric ALL patients with TP53 alterations had inferior 5‐year EFS and OS. TP53 alterations were enriched and useful as prognostic markers in relapsed childhood ALL.
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