Inspired by the exquisite helices in Nature, fabrication of helical materials with controlled handedness has attracted considerable attention. Herein, we report on precis synthesis of single left‐ ...and right‐handed helical polyisocyanides through living polymerization of achiral monomers using chiral palladium catalysts under helix‐sense‐selective manner. Mechanism study revealed that the yielded helices with opposite handedness showed different activity of the living chain end. The helix with unfavored handedness was self‐terminated, while the one with favored handedness showed high activity and could undergo chain propagation to form a high molecular weight polymer with maintained single‐handed helicity.
Living polymerization of achiral isocyanide by chiral PdII‐catalyst yielded a mixture of right‐ and left‐handed helices with great bias. The helix with preferred handedness has an active chain end and can undergo chain propagation. While the opposite handed helix was self‐terminated due to the inactive chain end. The mechanism study will pave an avenue for the development of new catalysts for synthesis of chiral materials.
•Different types of middle cerebral artery stenosis are identified by HRMRI.•The differences between MMD and intracranial atherosclerotic stenosis are elucidated by HRMRI.•Outer diameter and wall ...thickness of the MCAs in different MRA stages are compared.•The possible mechanism of arterial progressive stenosis in MMD is analyzed.
High resolution magnetic resonance imaging (HRMRI) has been developed as an emerging tool for evaluating intracranial arterial disease. We aimed to analyze the progression of diseased arterial walls in moyamoya disease (MMD) and further elucidate differences compared to intracranial atherosclerotic stenosis using HRMRI. The population of this HRMRI study consisted of 21 patients with MMD and 44 patients with atherosclerotic middle cerebral artery (MCA) stenosis. The cross-sectional images of the MCA wall on HRMRI were compared between the two groups based on outer diameter, wall thickness, luminal stenotic morphology, signal intensity, collateral vascular structures adjacent to stenotic position. In addition, stage classification based on MRA finding was used to depict the course of moyamoya disease. We compared outer diameter and wall thickness of the MCAs in different MRA stages. As a result, the outer diameter and wall thickness of MCAs were significantly smaller in the MMD group than in the atherosclerosis group (outer diameter: MMD 2.01±0.31mm vs. atherosclerosis 3.31±0.37mm, p<0.001 and wall thickness: MMD 0.39±0.19mm vs. atherosclerosis 1.64±0.38mm, p<0.001). The concentric stenosis (91.4% in MMD vs. 36.9% in atherosclerosis group, p<0.001), homogeneous signal intensity (85.7% in MMD vs. 32.6% in atherosclerosis group, p<0.001) and collateral vascular structures (54.3% in MMD vs. 8.7% in atherosclerosis group, p<0.001) were more common in MMD patients. In addition, the outer diameter of MCAs in MMD was significantly different between MRA stage 1 and MRA stage 3 or 4 (MRA stage 1 vs. MRA stage 3, Nemenyi test p=0.005 and MRA stage 1 vs. MRA stage 4, Nemenyi test p=0.009). But the wall thickness of MCAs was no significantly different in different MRA stages (Kruskal–wallis H test, p=0.074). We conclude that HRMRI may be used to identify different types of middle cerebral artery stenosis. MMD was characterized by concentric stenosis, homogeneous signal intensity, and collateral vascular structures in the affected MCA segments by HRMRI. Pathological shrinkage of MCA was an important phenomenon in MMD progression.
Background and Aims
Although NASH can lead to severe clinical consequences, including cirrhosis and hepatocellular carcinoma, no effective treatment is currently available for this disease. ...Increasing evidence indicates that LSECs play a critical role in NASH pathogenesis; however, the mechanisms involved in LSEC‐mediated NASH remain to be fully elucidated.
Approach and Results
In the current study, we found that LSEC homeostasis was disrupted and LSEC‐specific gene profiles were altered in methionine–choline‐deficient (MCD) diet‐induced NASH mouse models. Importantly, Notch signaling was found to be activated in LSECs of NASH mice. To then investigate the role of endothelial Notch in NASH progression, we generated mouse lines with endothelial‐specific Notch intracellular domain (NICD) overexpression or RBP‐J knockout to respectively activate or inhibit Notch signaling in endothelial cells. Notably, endothelial‐specific overexpression of the NICD accelerated LSEC maladaptation and aggravated NASH, whereas endothelial cell–specific inhibition of Notch signaling restored LSEC homeostasis and improved NASH phenotypes. Furthermore, we demonstrated that endothelial‐specific Notch activation exacerbated NASH by inhibiting endothelial nitric oxide synthase (eNOS) transcription, whereas administration of the pharmacological eNOS activator YC‐1 alleviated hepatic steatosis and lipid accumulation resulting from Notch activation. Finally, to explore the therapeutic potential of using Notch inhibitors in NASH treatment, we applied two gamma‐secretase inhibitors—DAPT and LY3039478—in an MCD diet‐induced mouse model of NASH, and found that both inhibitors effectively ameliorated hepatic steatosis, inflammation, and liver fibrosis.
Conclusions
Endothelial‐specific Notch activation triggered LSEC maladaptation and exacerbated NASH phenotypes in an eNOS‐dependent manner. Genetic and pharmacological inhibition of Notch signaling effectively restored LSEC homeostasis and ameliorated NASH progression.
Background and Aims
Heparin‐binding epidermal growth factor (HB‐EGF), a member of the epidermal growth factor family, plays a pivotal role in the progression of several malignancies, but its role and ...regulatory mechanisms in hepatocellular carcinoma (HCC) remain obscure. Here, we report that transmembrane protease serine 4 (TMPRSS4) significantly enhanced the expression and proteolytic cleavage of HB‐EGF to promote angiogenesis and HCC progression.
Approach and Results
A mechanistic analysis revealed that TMPRSS4 not only increased the transcriptional and translational levels of HB‐EGF precursor, but also promoted its proteolytic cleavage by enhancing matrix metallopeptidase 9 expression through the EGF receptor/Akt/mammalian target of rapamycin/ hypoxia‐inducible factor 1 α signaling pathway. In addition, HB‐EGF promoted HCC proliferation and invasion by the EGF receptor/phosphoinositide 3‐kinase/Akt signaling pathway. The level of HB‐EGF in clinical samples of serum or HCC tissues from patients with HCC was positively correlated with the expression of TMPRSS4 and the microvessel density, and was identified as a prognostic factor for overall survival and recurrence‐free survival, which suggests that HB‐EGF can serve as a potential therapeutic target for HCC. More importantly, we provide a demonstration that treatment with the HB‐EGF inhibitor cross‐reacting material 197 alone or in combination with sorafenib can significantly suppress angiogenesis and HCC progression.
Conclusions
HB‐EGF can be regulated by TMPRSS4 to promote HCC proliferation, invasion, and angiogenesis, and the combination of the HB‐EGF inhibitor cross‐reacting material 197 with sorafenib might be used for individualized treatment of HCC.
Metabolic engineering of Saccharomyces cerevisiae for high‐level production of aromatic chemicals has received increasing attention in recent years. Tyrosol production from glucose by S. cerevisiae ...is considered an environmentally sustainable and safe approach. However, the production of tyrosol and salidroside by engineered S. cerevisiae has been reported to be lower than 2 g/L to date. In this study, S. cerevisiae was engineered with a push‐pull‐restrain strategy to efficiently produce tyrosol and salidroside from glucose. The biosynthetic pathways of ethanol, phenylalanine, and tryptophan were restrained by disrupting PDC1, PHA2, and TRP3. Subsequently, tyrosol biosynthesis was enhanced with a metabolic pull strategy of introducing PcAAS and EcTyrAM53I/A354V. Moreover, a metabolic push strategy was implemented with the heterologous expression of phosphoketolase (Xfpk), and then erythrose 4‐phosphate was synthesized simultaneously by two pathways, the Xfpk‐based pathway and the pentose phosphate pathway, in S. cerevisiae. Furthermore, the heterologous expression of Xfpk alone in S. cerevisiae efficiently improved tyrosol production compared with the coexpression of Xfpk and phosphotransacetylase. Finally, the tyrosol yield increased by approximately 135‐folds, compared with that of parent strain. The total amount of tyrosol and salidroside with glucose fed‐batch fermentation was over 10 g/L and reached levels suitable for large‐scale production.
Highest production of tyrosol and salidroside, obtained via introducing the Xfpk‐based pathway into S. cerevisiae, can pave a green, efficient and sustainable way for large‐scale production of tyrosol and salidroside.
We demonstrate sensitive detection of alpha protons of fully protonated proteins by solid‐state NMR spectroscopy with 100–111 kHz magic‐angle spinning (MAS). The excellent resolution in the Cα‐Hα ...plane is demonstrated for 5 proteins, including microcrystals, a sedimented complex, a capsid and amyloid fibrils. A set of 3D spectra based on a Cα–Hα detection block was developed and applied for the sequence‐specific backbone and aliphatic side‐chain resonance assignment using only 500 μg of sample. These developments accelerate structural studies of biomolecular assemblies available in submilligram quantities without the need of protein deuteration.
No deuterium: With new 111 kHz magic‐angle spinning probes, high‐resolution 1H‐detected NMR spectroscopy of insoluble, crystalline, or self‐assembled protein aggregates is now feasible without replacing side‐chain protons with deuterons. α‐Protons become sensitive and spectrally resolved NMR probes, which allow backbone and side‐chain resonance assignment in about one week of experimental time for proteins of about 20 kDa.
An efficient protocol for the ligand‐free and heterogeneous Pd/C‐catalyzed one‐pot, three‐component synthesis of aryl‐substituted benzimidazoles from benzyl alcohols by using water as the solvent was ...developed. The reaction involves hydrogen‐transfer and Suzuki reactions. This method is quite convenient and environmentally friendly.
An efficient protocol for the ligand‐free and heterogeneous Pd/C‐catalyzed one‐pot, three‐component synthesis of aryl‐substituted benzimidazoles from benzyl alcohols by using water as the solvent is developed. This method is quite convenient and environmentally friendly.
Background
The anterolateral thigh (ALT) free flap has been an extremely versatile flap. The purpose of this study was to propose comprehensive functional assessments of the donor site.
Methods
A ...total of 33 ALT flaps were enrolled prospectively. Objective assessments included isokinetic testing of the knee, and electromyographic examination of the lateral femoral cutaneous nerve (LFCN). The Patient and Observer Scar Assessment Scale (POSAS) was used to subjectively assess the donor‐site scar.
Results
On the donor side, a significant decrease in most isokinetic muscle strength values was obvious 1 year postoperatively (P < .01). The normal side showed a compensatory increase 1 year postoperatively in the majority of isokinetic muscle strength values (P < .05). The majority of patients (70%) showed decreased sensory conduction velocity of the LFCN or no response to the microcurrent stimulation postoperatively. The aesthetic outcome was satisfactory.
Conclusion
The decline in functional parameters at the donor‐site was common. However, much more research is needed.
A novel Ebola virus (EBOV) first identified in March 2014 has infected more than 25,000 people in West Africa, resulting in more than 10,000 deaths. Preliminary analyses of genome sequences of 81 ...EBOV collected from March to June 2014 from Guinea and Sierra Leone suggest that the 2014 EBOV originated from an independent transmission event from its natural reservoir followed by sustained human-to-human infections. It has been reported that the EBOV genome variation might have an effect on the efficacy of sequence-based virus detection and candidate therapeutics. However, only limited viral information has been available since July 2014, when the outbreak entered a rapid growth phase. Here we describe 175 full-length EBOV genome sequences from five severely stricken districts in Sierra Leone from 28 September to 11 November 2014. We found that the 2014 EBOV has become more phylogenetically and genetically diverse from July to November 2014, characterized by the emergence of multiple novel lineages. The substitution rate for the 2014 EBOV was estimated to be 1.23 × 10(-3) substitutions per site per year (95% highest posterior density interval, 1.04 × 10(-3) to 1.41 × 10(-3) substitutions per site per year), approximating to that observed between previous EBOV outbreaks. The sharp increase in genetic diversity of the 2014 EBOV warrants extensive EBOV surveillance in Sierra Leone, Guinea and Liberia to better understand the viral evolution and transmission dynamics of the ongoing outbreak. These data will facilitate the international efforts to develop vaccines and therapeutics.
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