Effects of Apolipoprotein E on Neurite Outgrowth from Adult Mice Cortical Neurons

Apolipoprotein (apo) E4, one of the three common isoforms of apoE, has been implicated in Alzheimer\u27s disease (AD). The mechanism whereby apoE4 leads to the pathogenesis of AD is unknown. In the present study, I examined the effects of apoE on neurite outgrowth from adult mice cortical neurons (AMC) in culture. I found that neurite outgrowth from AMC neurons derived from apoE deficient/apoE gene knockout (apoE KO) mice is significantly shorter than that from age-, sex-, and strain-matched wild-type control mice. Furthermore, I present evidence for the differential effects of two isoforms of human apoE, apoE3 and apoE4, on neurite outgrowth from apoE KO neurons. Human apoE3 enhances neurite outgrowth whereas human apoE4 inhibits outgrowth. The differential effects of apoE3 and apoE4 on neurite outgrowth appear to be mediated by the low-density lipoprotein receptor related protein (LRP). Blocking of the LRP pathway of lipoprotein uptake with lactoferrin and receptor associated protein (RAP) abolished the differential effects of apoE isoforms on neurite outgrowth. Further understanding of the isoform specific cell biological processes mediated by apoE-LRP interactions in AMC culture may provide insight into AD pathogenesis

Effects of Apolipoprotein E on Neurite Outgrowth from Adult Mice Cortical Neurons

Apolipoprotein (apo) E4, one of the three common isoforms of apoE, has been implicated in Alzheimer\u27s disease (AD). The mechanism whereby apoE4 leads to the pathogenesis of AD is unknown. In the present study, I examined the effects of apoE on neurite outgrowth from adult mice cortical neurons (AMC) in culture. I found that neurite outgrowth from AMC neurons derived from apoE deficient/apoE gene knockout (apoE KO) mice is significantly shorter than that from age-, sex-, and strain-matched wild-type control mice. Furthermore, I present evidence for the differential effects of two isoforms of human apoE, apoE3 and apoE4, on neurite outgrowth from apoE KO neurons. Human apoE3 enhances neurite outgrowth whereas human apoE4 inhibits outgrowth. The differential effects of apoE3 and apoE4 on neurite outgrowth appear to be mediated by the low-density lipoprotein receptor related protein (LRP). Blocking of the LRP pathway of lipoprotein uptake with lactoferrin and receptor associated protein (RAP) abolished the differential effects of apoE isoforms on neurite outgrowth. Further understanding of the isoform specific cell biological processes mediated by apoE-LRP interactions in AMC culture may provide insight into AD pathogenesis

The C. elegans PUM1, 2-like RNA binding protein PUF-8 is required for robustness of the cell death fate

During C. elegans development, 1090 somatic cells are generated of which 959 survive and 131 die, many through apoptosis. We present evidence that PUF-8, a C. elegans ortholog of the mammalian RNA binding proteins PUM1 and PUM2, is required for the robustness of this 'survival and death' pattern. We found that PUF-8 prevents the inappropriate death of cells that normally survive, and we present evidence that this anti-apoptotic activity of PUF-8 is dependent on PUF-8's ability to interact with ced-3caspase mRNA thereby repressing the activity of the pro-apoptotic ced-3caspase gene. PUF-8 also promotes the death of cells that are programmed to die, and we propose that this pro-apoptotic activity of PUF-8 may depend on PUF-8's ability to repress the expression of the anti-apoptotic ced-9Bcl-2 gene. Our results suggest that stochastic differences in the expression of genes within the apoptosis pathway can disrupt the highly reproducible and robust survival and death pattern during C. elegans development, and that PUF-8PUM1, 2 acts at the post-transcriptional level to level out these differences, thereby ensuring proper cell number homeostasis

Solid-surface vitrification is an appropriate and convenient method for cryopreservation of isolated rat follicles

<p>Abstract</p> <p>Background</p> <p>Cryopreservation of isolated follicles may be a potential option to restore fertility in young women with cancer, because it can prevent the risks of cancer transmission. Several freezing protocols are available, including slow-rate freezing, open-pulled straws vitrification (OPS) and solid-surface vitrification (SSV, a new freezing technique). The purpose of our study was to investigate the effects of these freezing procedures on viability, ultrastructure and developmental capacity of isolated rat follicles.</p> <p>Methods</p> <p>Isolated follicles from female Sprague-Dawley rats were randomly assigned to SSV, OPS and slow-rate freezing groups for cryopreservation. Follicle viability assessment and ultrastructural examination were performed after thawing. In order to study the developmental capacity of thawed follicles, we performed <it>in vitro </it>culture with a three-dimensional (3D) system by alginate hydrogels.</p> <p>Results</p> <p>Our results showed that the totally viable rate of follicles vitrified by SSV (64.76%) was slightly higher than that of the OPS group (62.38%) and significantly higher than that of the slow-rate freezing group (52.65%; <it>P </it>< 0.05). The ultrastructural examination revealed that morphological alterations were relatively low in the SSV group compared to the OPS and slow-rate freezing groups. After <it>in vitro </it>culture within a 3D system using alginate hydrogels, we found the highest increase (28.90 ± 2.21 μm) in follicle diameter in follicles from the SSV group. The estradiol level in the SSV group was significantly higher than those in the OPS and slow-rate freezing groups at the end of a 72-hr culture period (<it>P </it>< 0.05).</p> <p>Conclusions</p> <p>Our results suggest that the SSV method is an appropriate and convenient method for cryopreservation of isolated rat follicles compared with the conventional slow-rate freezing method and the OPS method.</p

PGformer: Proxy-Bridged Game Transformer for Multi-Person Extremely Interactive Motion Prediction

Multi-person motion prediction is a challenging task, especially for real-world scenarios of densely interacted persons. Most previous works have been devoted to studying the case of weak interactions (e.g., hand-shaking), which typically forecast each human pose in isolation. In this paper, we focus on motion prediction for multiple persons with extreme collaborations and attempt to explore the relationships between the highly interactive persons' motion trajectories. Specifically, a novel cross-query attention (XQA) module is proposed to bilaterally learn the cross-dependencies between the two pose sequences tailored for this situation. Additionally, we introduce and build a proxy entity to bridge the involved persons, which cooperates with our proposed XQA module and subtly controls the bidirectional information flows, acting as a motion intermediary. We then adapt these designs to a Transformer-based architecture and devise a simple yet effective end-to-end framework called proxy-bridged game Transformer (PGformer) for multi-person interactive motion prediction. The effectiveness of our method has been evaluated on the challenging ExPI dataset, which involves highly interactive actions. We show that our PGformer consistently outperforms the state-of-the-art methods in both short- and long-term predictions by a large margin. Besides, our approach can also be compatible with the weakly interacted CMU-Mocap and MuPoTS-3D datasets and achieve encouraging results. Our code will become publicly available upon acceptance

Strain prioritization and genome mining for enediyne natural products

The enediyne family of natural products has had a profound impact on modern chemistry, biology, and medicine, and yet only 11 enediynes have been structurally characterized to date. Here we report a genome survey of 3,400 actinomycetes, identifying 81 strains that harbor genes encoding the enediyne polyketide synthase cassettes that could be grouped into 28 distinct clades based on phylogenetic analysis. Genome sequencing of 31 representative strains confirmed that each clade harbors a distinct enediyne biosynthetic gene cluster. A genome neighborhood network allows prediction of new structural features and biosynthetic insights that could be exploited for enediyne discovery. We confirmed one clade as new C-1027 producers, with a significantly higher C-1027 titer than the original producer, and discovered a new family of enediyne natural products, the tiancimycins (TNMs), that exhibit potent cytotoxicity against a broad spectrum of cancer cell lines. Our results demonstrate the feasibility of rapid discovery of new enediynes from a large strain collection. IMPORTANCE Recent advances in microbial genomics clearly revealed that the biosynthetic potential of soil actinomycetes to produce enediynes is underappreciated. A great challenge is to develop innovative methods to discover new enediynes and produce them in sufficient quantities for chemical, biological, and clinical investigations. This work demonstrated the feasibility of rapid discovery of new enediynes from a large strain collection. The new C-1027 producers, with a significantly higher C-1027 titer than the original producer, will impact the practical supply of this important drug lead. The TNMs, with their extremely potent cytotoxicity against various cancer cells and their rapid and complete cancer cell killing characteristics, in comparison with the payloads used in FDA-approved antibody-drug conjugates (ADCs), are poised to be exploited as payload candidates for the next generation of anticancer ADCs. Follow-up studies on the other identified hits promise the discovery of new enediynes, radically expanding the chemical space for the enediyne family

Aberration in DNA Methylation in B-Cell Lymphomas Has a Complex Origin and Increases with Disease Severity

Despite mounting evidence that epigenetic abnormalities play a key role in cancer biology, their contributions to the malignant phenotype remain poorly understood. Here we studied genome-wide DNA methylation in normal B-cell populations and subtypes of B-cell non-Hodgkin lymphoma: follicular lymphoma and diffuse large B-cell lymphomas. These lymphomas display striking and progressive intra-tumor heterogeneity and also inter-patient heterogeneity in their cytosine methylation patterns. Epigenetic heterogeneity is initiated in normal germinal center B-cells, increases markedly with disease aggressiveness, and is associated with unfavorable clinical outcome. Moreover, patterns of abnormal methylation vary depending upon chromosomal regions, gene density and the status of neighboring genes. DNA methylation abnormalities arise via two distinct processes: i) lymphomagenic transcriptional regulators perturb promoter DNA methylation in a target gene-specific manner, and ii) aberrant epigenetic states tend to spread to neighboring promoters in the absence of CTCF insulator binding sites

Irradiation- Induced Extremes Create Hierarchical Face- /Body- Centered- Cubic Phases in Nanostructured High Entropy Alloys

A nanoscale hierarchical dual- phase structure is reported to form in a nanocrystalline NiFeCoCrCu high- entropy- alloy (HEA) film via ion irradiation. Under the extreme energy deposition and consequent thermal energy dissipation induced by energetic particles, a fundamentally new phenomenon is revealed, in which the original single- phase face- centered- cubic (FCC) structure partially transforms into alternating nanometer layers of a body- centered- cubic (BCC) structure. The orientation relationship follows the Nishiyama- Wasser- man relationship, that is, (011)BCC || (- 1¯1¯1)FCC and [100]BCC || [- 11¯0]FCC. Simulation results indicate that Cr, as a BCC stabilizing element, exhibits a tendency to segregate to the stacking faults (SFs). Furthermore, the high densities of SFs and twin boundaries in each nanocrystalline grain serve to accelerate the nucleation and growth of the BCC phase during irradiation. By adjusting the irradiation parameters, desired thicknesses of the FCC and BCC phases in the laminates can be achieved. This work demonstrates the controlled formation of an attractive dual- phase nanolaminate structure under ion irradiation and provides a strategy for designing new derivate structures of HEAs.A nanoscale hierarchical dual- phase structure is reported to form in a nanocrystalline NiFeCoCrCu high- entropy- alloy film via ion- irradiation- induced face- centered- cubic to body- centered- cubic phase transformation. Both kinetic and thermodynamic conditions for the phase transformation are explored. The results provide a new strategy for tailoring material structures on the nanometer or sub- nanometer scales.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162803/3/adma202002652_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162803/2/adma202002652.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162803/1/adma202002652-sup-0001-SuppMat.pd