Accelerated multi-contrast high isotropic resolution 3D intracranial vessel wall MRI using a tailored k-space undersampling and partially parallel reconstruction strategy

Objective

To develop a 3D multi-contrast IVW protocol with 0.5-mm isotropic resolution and a scan time of 5 min per sequence.

Materials and methods

Pre-contrast T1w VISTA, DANTE prepared PDw VISTA, SNAP, and post-contrast T1w VISTA were accelerated using cartesian undersampling with target ordering method (CUSTOM) and self-supporting tailored k-space estimation for parallel imaging reconstruction (STEP). CUSTOM + STEP IVW was compared to full-sample IVW, SENSE-accelerated IVW, and CUSTOM + zero-filled Fourier reconstruction in normal volunteers and subjects with intracranial atherosclerotic disease (ICAD). Image quality, vessel delineation, CSF suppression, and blood suppression were compared.

Results

CUSTOM + STEP vessel wall delineation was comparable to full-sample IVW and better than SENSE IVW for vessel wall delineation on T1w VISTA and luminal contrast on SNAP. Average image quality and wall depiction were significantly improved using STEP reconstruction compared with zero-filled Fourier reconstruction, with no significant difference in CSF or blood suppression.

Conclusions

CUSTOM + STEP allowed multi-contrast 3D 0.5-mm isotropic IVW within 30 min. Although some quantitative and qualitative scores for CUSTOM − STEP were lower than fully sampled IVW, CUSTOM + STEP provided comparable vessel wall delineation as full-sample IVW and was superior to SENSE. CUSTOM + STEP IVW was well tolerated by patients and showed good delineation of ICAD plaque.

     

A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877

Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation.     

Supramolecular Assembly of Aminoethylene‐Lipopeptide PMO Conjugates into RNA Splice‐Switching Nanomicelles

Phosphorodiamidate morpholino oligomers (PMOs) are oligonucleotide analogs that can be used for therapeutic modulation of pre‐mRNA splicing. Similar to other classes of nucleic acid‐based therapeutics, PMOs require delivery systems for efficient transport to the intracellular target sites. Here, artificial peptides based on the oligo(ethylenamino) acid succinyl‐tetraethylenpentamine (Stp), hydrophobic modifications, and an azide group are presented, which are used for strain‐promoted azide‐alkyne cycloaddition conjugation with splice‐switching PMOs. By systematically varying the lead structure and formulation, it is determined that the type of contained fatty acid and supramolecular assembly have a critical impact on the delivery efficacy. A compound containing linolenic acid with three cis double bonds exhibits the highest splice‐switching activity and significantly increases functional protein expression in pLuc/705 reporter cells in vitro and after local administration in vivo. Structural and mechanistic studies reveal that the lipopeptide PMO conjugates form nanoparticles, which accelerate cellular uptake and that the content of unsaturated fatty acids enhances endosomal escape. In an in vitro Duchenne muscular dystrophy exon skipping model using H2K‐mdx52 dystrophic skeletal myotubes, the highly potent PMO conjugates mediate significant splice‐switching at very low nanomolar concentrations. The presented aminoethylene‐lipopeptides are thus a promising platform for the generation of PMO‐therapeutics with a favorable activity/toxicity profile.     

Microstructures and mechanical properties of B4C-TiB2-SiC composites fabricated by ball milling and hot pressing

B₄C-TiB₂-SiC composites were fabricated via hot pressing using ball milled B₄C, TiB₂, and SiC powder mixtures as the starting materials. The impact of ball milling on the densification behaviors, mechanical properties, and microstructures of the ceramic composites were investigated. The results showed that the refinement of the powder mixtures and the removal of the oxide impurities played an important role in the improvement of densification and properties. Moreover, the formation of the liquid phases during the sintering was deemed beneficial for densification. The typical values of relative density, hardness, bending strength, and fracture toughness of the composites reached 99.20%, 32.84?GPa, 858?MPa and 8.21?MPa?m^1/2, respectively. Crack deflection, crack bridging, crack branching, and microcracking were considered to be the potential toughening mechanisms in the composites. Furthermore, numerous nano-sized intergranular/intragranular phases and twin structures were observed in the B₄C-TiB₂-SiC composite.     

Effect of Supports and Promoters on the Performance of Ni-Based Catalysts in Ethanol Steam Reforming

Ethanol steam reforming (ESR) is one of the potential processes to convert ethanol into valuable products. Hydrogen produced from ESR is considered as green energy for the future and can be an excellent alternative to fossil fuels with the aim of mitigating the greenhouse gas effect. The ESR process has been well studied, using transition metals as catalysts coupled with both acidic and basic oxides as supports. Among various reported transition metals, Ni is an inexpensive material with activity comparable to that of noble metals, showing promising ethanol conversion and hydrogen yields. Additionally, different promoters and supports were utilized to enhance the hydrogen yield and the catalyst stability. This review summarizes and discusses the influences of the supports and promoters of Ni-based catalysts on the ESR process.     

Group sequential crossover trial designs with strong control of the familywise error rate

Crossover designs are an extremely useful tool to investigators, and group sequential methods have proven highly proficient at improving the efficiency of parallel group trials. Yet, group sequential methods and crossover designs have rarely been paired together. One possible explanation for this could be the absence of a formal proof of how to strongly control the familywise error rate in the case when multiple comparisons will be made. Here, we provide this proof, valid for any number of initial experimental treatments and any number of stages, when results are analyzed using a linear mixed model. We then establish formulae for the expected sample size and expected number of observations of such a trial, given any choice of stopping boundaries. Finally, utilizing the four-treatment, four-period TOMADO trial as an example, we demonstrate that group sequential methods in this setting could have reduced the trials expected number of observations under the global null hypothesis by over 33%.     

关于当前钢材市场形势的看法

从今年3月初以来,钢材市场行情呈现明显恢复性上扬态势。据中国钢铁工业协会财务资产部和冶金价格信息中心发布的钢材价格指数,5月15日-5月19日板材平均已恢复到110.34点,比去年末上升17.92点,价格恢复性上涨19.38%,但比去年5月份的146.1点仍低24.5%;长材价格指数略有同升,在94.37点,比去年末只回升3.56点,价格只恢复性上涨3.92%,比去年5月份的102.19点仍低7.65。掘国家统计局数据,一季度全国规模以上工业企业销售收入同比增长25.3%,实现利润同比增长21.3%,但钢铁企业由于去年下半年价格大幅度下降,今年一季度钢协会员企业(钢产量占全国81.8%)销售收入同比下降5.18%,实现利润同比下降