Enchanced levels of apolipoprotein M during HBV infection feedback suppresses HBV replication

<p>Abstract</p> <p>Background</p> <p>Chronic liver diseases can interfere with hepatic metabolism of lipoproteins, apolipoproteins. Hepatitis B virus (HBV) is a major etiological agent causing acute and chronic liver diseases. Apolipoprotein M (ApoM) is a high-density lipoprotein (HDL) apolipoprotein and exclusively expressed in the liver parenchyma cells and in the tubular cells of the kidney. This study was to determine the correlation between HBV infection and ApoM expression.</p> <p>Materials and methods</p> <p>Serum ApoM levels in patients with HBV infection and in healthy individuals were measured by ELISA, ApoM mRNA expression were determined by RT-PCR, and the expression of S and E proteins of HBV, as well as the synthesis of viral DNA were measured by ELISA and real-time PCR.</p> <p>Results</p> <p>The levels of serum ApoM was significantly elevated in patients as compared to healthy individuals (<it>P </it>< 0.001), ApoM promoter activity, mRNA and protein expression were all stimulated in cells transfected with infectious HBV clone. In addition, ApoM decreases the expression of S and E proteins of HBV and the synthesis of viral DNA.</p> <p>Conclusion</p> <p>Raised ApoM levels in HBV infection may in turn suppress HBV replication, one of the protective mechanisms of nature.</p

Multi-node Acceleration for Large-scale GCNs

Limited by the memory capacity and compute power, singe-node graph convolutional neural network (GCN) accelerators cannot complete the execution of GCNs within a reasonable amount of time, due to the explosive size of graphs nowadays. Thus, large-scale GCNs call for a multi-node acceleration system (MultiAccSys) like TPU-Pod for large-scale neural networks. In this work, we aim to scale up single-node GCN accelerators to accelerate GCNs on large-scale graphs. We first identify the communication pattern and challenges of multi-node acceleration for GCNs on large-scale graphs. We observe that (1) coarse-grained communication patterns exist in the execution of GCNs in MultiAccSys, which introduces massive amount of redundant network transmissions and off-chip memory accesses; (2) overall, the acceleration of GCNs in MultiAccSys is bandwidth-bound and latency-tolerant. Guided by these two observations, we then propose MultiGCN, the first MultiAccSys for large-scale GCNs that trades network latency for network bandwidth. Specifically, by leveraging the network latency tolerance, we first propose a topology-aware multicast mechanism with a one put per multicast message-passing model to reduce transmissions and alleviate network bandwidth requirements. Second, we introduce a scatter-based round execution mechanism which cooperates with the multicast mechanism and reduces redundant off-chip memory accesses. Compared to the baseline MultiAccSys, MultiGCN achieves 4~12x speedup using only 28%~68% energy, while reducing 32% transmissions and 73% off-chip memory accesses on average. It not only achieves 2.5~8x speedup over the state-of-the-art multi-GPU solution, but also scales to large-scale graphs as opposed to single-node GCN accelerators.Comment: To appear in T

Enhanced Delivery of Rituximab Into Brain and Lymph Nodes Using Timed-Release Nanocapsules in Non-Human Primates.

Tumor metastasis into the central nervous system (CNS) and lymph nodes (LNs) is a major obstacle for effective therapies. Therapeutic monoclonal antibodies (mAb) have revolutionized tumor treatment; however, their efficacy for treating metastatic tumors-particularly, CNS and LN metastases-is poor due to inefficient penetration into the CNS and LNs following intravenous injection. We recently reported an effective delivery of mAb to the CNS by encapsulating the anti-CD20 mAb rituximab (RTX) within a thin shell of polymer that contains the analogs of choline and acetylcholine receptors. This encapsulated RTX, denoted as n-RTX, eliminated lymphoma cells systemically in a xenografted humanized mouse model using an immunodeficient mouse as a recipient of human hematopoietic stem/progenitor cells and fetal thymus more effectively than native RTX; importantly, n-RTX showed notable anti-tumor effect on CNS metastases which is unable to show by native RTX. As an important step toward future clinical translation of this technology, we further analyzed the properties of n-RTX in immunocompetent animals, rats, and non-human primates (NHPs). Our results show that a single intravenous injection of n-RTX resulted in 10-fold greater levels in the CNS and 2-3-fold greater levels in the LNs of RTX, respectively, than the injection of native RTX in both rats and NHPs. In addition, we demonstrate the enhanced delivery and efficient B-cell depletion in lymphoid organs of NHPs with n-RTX. Moreover, detailed hematological analysis and liver enzyme activity tests indicate n-RTX treatment is safe in NHPs. As this nanocapsule platform can be universally applied to other therapeutic mAbs, it holds great promise for extending mAb therapy to poorly accessible body compartments

Heating of multi‐species upflowing ion beams observed by Cluster on March 28, 2001

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149495/1/epp320083.pd

Assessing the concentration and potential health risk of heavy metals in China's main deciduous fruits

AbstractTo assess levels of contamination and human health risk, we analyzed the concentrations of the heavy metals lead (Pb), cadmium (Cd), chromium (Cr), and nickel (Ni) in China's main deciduous fruits — apple, pear, peach, grape, and jujube. The concentration order of the heavy metals was Ni>Cr>Pb>Cd. In 97.5% of the samples, heavy metal concentrations were within the maximum permissible limits. Among the fruits studied, the heavy metal concentrations in jujube and peach proved to be the highest, and those in grape proved to be the lowest. Only 2.2% of the samples were polluted by Ni, only 0.4% of the samples were polluted by Pb, and no samples were polluted by Cd or Cr. Compared with the other fruits, the combined heavy metal pollution was significantly higher (P<0.05) in peach and significantly lower (P<0.05) in grape. For the combined heavy metal pollution, 96.9% of the samples were at safe level, 2.32% at warning level, 0.65% at light level, and 0.13% at moderate level. In the fruits studied, the contribution of heavy metals to the daily intake rates (DIR) followed the order of Ni>Cr>Pb>Cd. The highest DIR came from apple, while the lowest DIR came from grape. For each of the heavy metals, the total DIR from five studied fruits corresponded to no more than 1.1% of the tolerable daily intake, indicating that no significant adverse health effects are expected from the heavy metals and the fruits studied. The target hazard quotients and the total target hazard quotients demonstrated that none of the analyzed heavy metals may pose risk to consumers through the fruits studied. The highest risk was posed by apple, followed in decreasing order by peach and pear, jujube, and grape. We suggest that the main deciduous fruits (apple, pear, peach, grape, and jujube) of China's main producing areas are safe to eat

Discovery of novel SOS1 inhibitors using machine learning

Overactivation of the rat sarcoma virus (RAS) signaling is responsible for 30% of all human malignancies. Son of sevenless 1 (SOS1), a crucial node in the RAS signaling pathway, could modulate RAS activation, offering a promising therapeutic strategy for RAS-driven cancers. Applying machine learning (ML)-based virtual screening (VS) on small-molecule databases, we selected a random forest (RF) regressor for its robustness and performance. Screening was performed with the L-series and EGFR-related datasets, and was extended to the Chinese National Compound Library (CNCL) with more than 1.4 million compounds. In addition to a series of documented SOS1-related molecules, we uncovered nine compounds that have an unexplored chemical framework and displayed inhibitory activity, with the most potent achieving more than 50% inhibition rate in the KRAS G12C/SOS1 PPI assay and an IC50 value in the proximity of 20 μg mL−1. Compared with the manner that known inhibitory agents bind to the target, hit compounds represented by CL01545365 occupy a unique pocket in molecular docking. An in silico drug-likeness assessment suggested that the compound has moderately favorable drug-like properties and pharmacokinetic characteristics. Altogether, our findings strongly support that, characterized by the distinctive binding modes, the recognition of novel skeletons from the carboxylic acid series could be candidates for developing promising SOS1 inhibitors

雷公藤红素通过靶向核受体Nur77促进损伤线粒体自噬而抑制炎症反应

文章简介线粒体在细胞死亡、自噬、免疫和炎症中起着不可或缺的作用。前期研究发现,孤儿核受体Nur77通过靶向线粒体诱导细胞凋亡。本文报道了Nur77作为具有抗炎作用的雷公藤红素的直接靶点,介导雷公藤红素通过自噬清除损伤线粒体,抑制炎症反应而达到治疗炎症疾病包括肥胖症的功能。研究人员发现,雷公藤红素的结合

Serological surveillance of GI norovirus reveals persistence of blockade antibody in a Jidong community-based prospective cohort, 2014–2018

IntroductionHerd immunity against norovirus (NoV) is poorly understood in terms of its serological properties and vaccine designs. The precise neutralizing serological features of genotype I (GI) NoV have not been studied.MethodsTo expand insights on vaccine design and herd immunity of NoVs, seroprevalence and seroincidence of NoV genotypes GI.2, GI.3, and GI.9 were determined using blockade antibodies based on a 5-year longitudinal serosurveillance among 449 residents in Jidong community.ResultsCorrelation between human histo-blood group antigens (HBGAs) and GI NoV, and dynamic and persistency of antibodies were also analyzed. Seroprevalence of GI.2, GI.3, and GI.9 NoV were 15.1%–18.0%, 35.0%–38.8%, and 17.6%–22.0%; seroincidences were 10.0, 21.0, and 11.0 per 100.0 person-year from 2014 to 2018, respectively. Blockade antibodies positive to GI.2 and GI.3 NoV were significantly associated with HBGA phenotypes, including blood types A, B (excluding GI.3), and O+; Lewis phenotypes Leb+/Ley+ and Lea+b+/Lex+y+; and secretors. The overall decay rate of anti-GI.2 antibody was -5.9%/year (95% CI: -7.1% to -4.8%/year), which was significantly faster than that of GI.3 [-3.6%/year (95% CI: -4.6% to -2.6%/year)] and GI.9 strains [-4.0%/year (95% CI: -4.7% to -3.3%/year)]. The duration of anti-GI.2, GI.3, and GI.9 NoV antibodies estimated by generalized linear model (GLM) was approximately 2.3, 4.2, and 4.8 years, respectively.DiscussionIn conclusion, enhanced community surveillance of GI NoV is needed, and even one-shot vaccine may provide coast-efficient health benefits against GI NoV infection