Multivariate Longitudinal Shape Analysis of Human Lateral Ventricles during the First Twenty-Four Months of Life

Background

Little is known about the temporospatial shape characteristics of human lateral ventricles (LVs) during the first two years of life. This study aimed to delineate the morphological growth characteristics of LVs during early infancy using longitudinally acquired MR images in normal healthy infants.

Methods

24 healthy infants were MR imaged starting from 2 weeks old every 3 months during the first and every 6 months during the second year. Bilateral LVs were segmented and longitudinal morphological and shape analysis were conducted using longitudinal mixed effect models.

Results

A significant bilateral ventricular volume increase (p<0.0001) is observed in year one (Left: 126±51% and Right: 145±62%), followed by a significant reduction (p<0.02) during the second year of life (Left: −24±27% and Right: −20±18%) despite the continuing increase of intracranial volume. Morphological analysis reveals that the ventricular growth is spatially non-uniform, and that the most significant growth occurs during the first 6 months. The first 3 months of life exhibit a significant (p<0.01) bilateral lengthening of the anterior lateral ventricle and a significant increase of radius (p<0.01) and area (p<0.01) at the posterior portion of the ventricle. Shape analysis shows that the horns exhibit a faster growth rate than the mid-body. Finally, bilateral significant age effects (p<0.01) are observed for the growth of LVs whereas gender effects are more subtle and significant effects (p<0.01) only present at the left anterior and posterior horns. More importantly, both the age and gender effects are growth directionally dependent.

Conclusions

We have demonstrated the temporospatial shape growth characteristics of human LVs during the first two years of life using a unique longitudinal MR data set. A temporally and spatially non-uniform growth pattern was reported. These normative results could provide invaluable information to discern abnormal growth patterns in patients with neurodevelopmental disorders.     

Knockdown of CDK5 down-regulates PD-L1 via the ubiquitination-proteasome pathway and improves antitumor immunity in lung adenocarcinoma

Although immunotherapy (anti-PD-1/PD-L1 antibodies) has been approved for clinical treatment of lung cancer, only a small proportion of patients respond to monotherapy. Hence, understanding the regulatory mechanism of PD-L1 is particularly important to identify optimal combinations. In this study, we found that inhibition of CDK5 induced by shRNA or CDK5 inhibitor leads to reduced expression of PD-L1 protein in human lung adenocarcinoma cells, while the mRNA level is not substantially altered. The PD-L1 protein degradation is mediated by E3 ligase TRIM21 via ubiquitination-proteasome pathway. Subsequently, we studied the function of CDK5/PD-L1 axis in LUAD. In vitro, the absence of CDK5 in mouse Lewis lung cancer cell (LLC) has no effect on cell proliferation. However, the attenuation of CDK5 or combined with anti-PD-L1 greatly suppresses tumor growth in LLC implanted mouse models in vivo. Disruption of CDK5 elicits a higher level of CD3⁺, CD4⁺ and CD8⁺ T cells in spleens and lower PD-1 expression in CD4⁺ and CD8⁺ T cells. Our findings highlight a role for CDK5 in promoting antitumor immunity, which provide a potential therapeutic target for combined immunotherapy in LUAD.     

Crystal structure of chalcone synthase,a key enzyme for isoflavonoid biosynthesis in soybean

Isoflavonoid is one of the groups of flavonoids that play pivotal roles in the survival of land plants. Chalcone synthase (CHS), the first enzyme of the isoflavonoid biosynthetic pathway, catalyzes the formation of a common isoflavonoid precursor. We have previously reported that an isozyme of soybean CHS (termed GmCHS1) is a key component of the isoflavonoid metabolon, a protein complex to enhance efficiency of isoflavonoid production. Here, we determined the crystal structure of GmCHS1 as a first step of understanding the metabolon structure, as well as to better understand the catalytic mechanism of GmCHS1.     

NLRP3 Inflammasome Activation Enhances ADK Expression to Accelerate Epilepsy in Mice

Epilepsy (SE) is a common and serious neurological disease. NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome participates in the pathogenesis of SE, while its underlying mechanism is still unclear. Here, we attempted to explore the mechanism of action of NLRP3 inflammasome in SE. SE mouse model was constructed by administration of kainic acid (KA). Astrocytes were treated with KA to mimic SE cell model. MCC950 (NLRP3 inhibitor) and Z-YVAD-FMK (Caspase-1 inhibitor) were used to treat astrocytes to inhibit the activity of NLRP3 and Caspase-1. Nissl staining was performed to examine the morphology of neuron. Western blot, enzyme-linked immunosorbent assay and immunofluorescence staining were performed to assess protein expression. SE mouse model exhibited an increase of neuronal loss, and an up-regulation of Cleaved-Caspase-1, IL-1β and IL-18 in hippocampus. The levels of GFAP⁺ADK⁺ cells were significantly increased in SE mice. MCC950 or Z-YVAD-FMK abolished these impacts conferred by KA in SE mice. Moreover, KA treatment enhanced the expression of NLRP3, Cleaved-Caspase-1, IL-1β and IL-18 in astrocytes, which was rescued by knockdown of NLRP3 or Caspase-1. Additionally, CREB, p-CREB, REST were up-regulated, and SP1 was down-regulated in the KA-treated SE mice and KA-treated astrocytes. Inhibition of NLRP3 or Caspase-1 rescued these proteins expression in KA-treated astrocytes. CREB or REST silencing reduced adenosine kinase (ADK) expression, while SP1 knockdown enhanced ADK expression in KA-treated astrocytes. In conclusion, NLRP3 inflammasome activation enhances ADK expression to accelerate SE in mice through regulating CREB/REST/SP1 signaling pathway. Thus, inhibition of NLRP3 inflammasome may be a treatment for SE.