Gene Network Disruptions and Neurogenesis Defects in the Adult Ts1Cje Mouse Model of Down Syndrome

Background: Down syndrome (DS) individuals suffer mental retardation with further cognitive decline and early onset Alzheimer's disease. Methodology/Principal Findings: To understand how trisomy 21 causes these neurological abnormalities we investigated changes in gene expression networks combined with a systematic cell lineage analysis of adult neurogenesis using the Ts1Cje mouse model of DS. We demonstrated down regulation of a number of key genes involved in proliferation and cell cycle progression including Mcm7, Brca2, Prim1, Cenpo and Aurka in trisomic neurospheres. We found that trisomy did not affect the number of adult neural stem cells but resulted in reduced numbers of neural progenitors and neuroblasts. Analysis of differentiating adult Ts1Cje neural progenitors showed a severe reduction in numbers of neurons produced with a tendency for less elaborate neurites, whilst the numbers of astrocytes was increased. Conclusions/Significance: We have shown that trisomy affects a number of elements of adult neurogenesis likely to result in a progressive pathogenesis and consequently providing the potential for the development of therapies to slow progression of, or even ameliorate the neuronal deficits suffered by DS individuals.Chelsee A. Hewitt, King-Hwa Ling, Tobias D. Merson, Ken M. Simpson, Matthew E. Ritchie, Sarah L. King, Melanie A. Pritchard, Gordon K. Smyth, Tim Thomas, Hamish S. Scott and Anne K. Vos

Hepatitis B virus modulates store-operated calcium entry to enhance viral replication in primary hepatocytes

Many viruses modulate calcium (Ca2+) signaling to create a cellular environment that is more permissive to viral replication, but for most viruses that regulate Ca2+ signaling, the mechanism underlying this regulation is not well understood. The hepatitis B virus (HBV) HBx protein modulates cytosolic Ca2+ levels to stimulate HBV replication in some liver cell lines. A chronic HBV infection is associated with life-threatening liver diseases, including hepatocellular carcinoma (HCC), and HBx modulation of cytosolic Ca2+ levels could have an important role in HBV pathogenesis. Whether HBx affects cytosolic Ca2+ in a normal hepatocyte, the natural site of an HBV infection, has not been addressed. Here, we report that HBx alters cytosolic Ca2+ signaling in cultured primary hepatocytes. We used single cell Ca2+ imaging of cultured primary rat hepatocytes to demonstrate that HBx elevates the cytosolic Ca2+ level in hepatocytes following an IP3-linked Ca2+ response; HBx effects were similar when expressed alone or in the context of replicating HBV. HBx elevation of the cytosolic Ca2+ level required extracellular Ca2+ influx and store-operated Ca2+ (SOC) entry and stimulated HBV replication in hepatocytes. We used both targeted RT-qPCR and transcriptome-wide RNAseq analyses to compare levels of SOC channel components and other Ca2+ signaling regulators in HBV-expressing and control hepatocytes and show that the transcript levels of these various proteins are not affected by HBV. We also show that HBx regulation of SOC-regulated Ca2+ accumulation is likely the consequence of HBV modulation of a SOC channel regulatory mechanism. In support of this, we link HBx enhancement of SOC-regulated Ca2+ accumulation to Ca2+ uptake by mitochondria and demonstrate that HBx stimulates mitochondrial Ca2+ uptake in primary hepatocytes. The results of our study may provide insights into viral mechanisms that affect Ca2+ signaling to regulate viral replication and virus-associated diseases

Early Placement of Optional Vena Cava Filter in High-Risk Patients with Traumatic Brain Injury

Objectives: Patients sustaining severe trauma are at high risk for the development of venous thromboembolic events (VTE). Pharmacologic VTE prophylaxis may be contraindicated early after trauma due to potential bleeding complications. The purpose of this study was to evaluate safety and feasibility of early prophylactic vena cava filter (VCF) placement and subsequent retrieval in multiple injured patients with traumatic brain injury (TBI). Methods: Analysis of single-institution case series of consecutive patients who received a prophylactic VCF after severe TBI (Abbreviated Injury Scale, AiS ‡ 3) between August 2003 and October 2006. Results: A total of 34 optional VCF were prophylactically placed with a median delay of 1 day after trauma (range, 0–7 days). All patients had sustained multiple injuries (median Injury Severity Score 41, range, 18–59) with severe TBI (median AiS 4, range 3–5). Median age was 41 years (range, 17–67 years). Two patients had succumbed before potential filter retrieval. Of the remaining patients, 27 (84%) had their filters uneventfully retrieved between 11 and 32 days (median, 18 days) after placement with no retrieval-related morbidity. Five VCF (16%) were left permanently. In one patient (3%) early inferior vena cava occlusion and deep venous thrombosis occurred 14 days after VCF placement. Symptomatic pulmonary embolism was observed in one patient (3%) 5 days after VCF retrieval. Overall trauma-related mortality was 9%. Conclusions: Early VCF placement may be of benefit for multiple injured patients with TBI when pharmacologic VTE prophylaxis is contraindicated. VCF retrieval is safe and feasible. Filter placement- and retrieval-related morbidity is low