Significance: Particulate matter exposure causes infant respiratory morbidity and mortality, but the role of ultrafine particles (UFPs) with an aerodynamic diameter of less than 0.1 μm in asthma and respiratory tract infections is unclear. Limited mechanistic information is available concerning UFP influence on the etiology of childhood asthma or susceptibility to respiratory infections. Here we exposed two strains of mice (sensitive to oxidative stress or allergen exposure) to UFPs throughout gestation at concentrations relevant to human exposures. Our results reveal a window of pulmonary immunosuppression in offspring following in utero UFP exposure. A dampened host immune response during early development underlies increased childhood susceptibility to respiratory infections, highlighting the necessity to develop strategies to protect the fetus during this vulnerable period.

Metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) is a long non-coding RNA (lncRNA) that is a negative prognostic factor for patients with pancreatic cancer and several other tumors. In this study, we show that knockdown of MALAT-1 in Panc1 and other pancreatic cancer cell lines decreases cell proliferation, survival and migration. We previously observed similar results for the lncRNAs HOTTIP and HOTAIR in Panc1 cells; however, RNAseq comparison of genes regulated by MALAT-1 shows minimal overlap with HOTTIP/HOTAIR-regulated genes. Analysis of changes in gene expression after MALAT-1 knockdown shows that this lncRNA represses several tumor suppressor-like genes including N-myc downregulated gene-1 (NDRG-1), a tumor suppressor in pancreatic cancer that is also corepressed by EZH2 (a PRC2 complex member). We also observed that Specificity proteins Sp1, Sp3 and Sp4 are overexpressed in Panc1 cells and Sp knockdown or treatment with small molecules that decrease Sp proteins expression also decrease MALAT-1 expression. We also generated Kras-overexpressing p53L/L;LSL-Kras^G12DL/+;p48Cre+/- (p53^L/L/Kras^G12D) and p53L/+;LSLKras^G12DL/+;p48Cre+/- (p53^L/+/Kras^G12D) mice which are p53 homo- and heterozygous, respectively. These mice rapidly develop pancreatic ductal adenocarcinoma-like tumors and were crossed with MALAT-1^-/- mice. We observed that the loss of one or two MALAT-1 alleles in these Ras overexpressing mice does not significantly affect the time to death; however, the loss of MALAT-1 in the p53^-/+ (heterozygote) mice slightly increases their lifespan.

Clostridium chauvoei causes blackleg in cattle. The disease has been reported worldwide, and although it can be prevented by vaccination, sporadic cases and occasional outbreaks still occur. We describe a case of blackleg in a 2-y-old, pregnant Gyr cow with in utero transmission to the fetus. The cow had characteristic gross and microscopic lesions of blackleg including widespread necrohemorrhagic and emphysematous skeletal and myocardial myositis, and fibrinous pericarditis. Her uterus contained a near-term, markedly emphysematous fetus with skeletal muscle and myocardial lesions similar to those seen in the dam. Histopathology of dam and fetal tissues revealed numerous gram-positive bacilli, many of them with sub-terminal spores, in multiple tissues. These bacilli were identified as C. chauvoei by immunohistochemistry. Anaerobic culture and fluorescent antibody tests performed on skeletal muscle from both the dam and fetus were positive for C. chauvoei, confirming a diagnosis of blackleg. Blackleg is a so-called endogenous infection, and the currently accepted pathogenesis involves ingestion of spores that are transported to muscle tissues where they lie dormant until anaerobiosis prompts germination. Germinating bacteria are histotoxic, producing severe, local necrosis and ultimately lethal toxemia. This model, however, has not been confirmed experimentally and also fails to explain some cases of the disease. A presumptive diagnosis of blackleg is based on clinical, gross, and histologic findings. Diagnostic confirmation necessitates the detection of C. chauvoei by culture, PCR, or immunodetection methods.

Parrot bornaviruses (PaBVs) are the causative agents of proventricular dilatation disease, however key aspects of its pathogenesis, such as route of infection, viral spread and distribution, and target cells remain unclear. Our study aimed to track the viral spread and lesion development at 5, 10, 20, 25, 35, 40, 60, 80, 95 and 114 dpi using histopathology, immunohistochemistry, and RT-PCR. After intramuscular inoculation of parrot bornavirus 2 (PaBV-2) in the pectoral muscle of cockatiels, this virus was first detected in macrophages and lymphocytes in the inoculation site and adjacent nerves, then reached the brachial plexus, centripetally spread to the thoracic segment of the spinal cord, and subsequently invaded the other spinal segments and brain. After reaching the central nervous system (CNS), PaBV-2 centrifugally spread out the CNS to the ganglia in the gastrointestinal (GI) system, adrenal gland, heart, and kidneys. At late points of infection, PaBV-2 was not only detected in nerves and ganglia but widespread in the smooth muscle and/or scattered epithelial cells of tissues such as crop, intestines, proventriculus, kidneys, skin, and vessels. Despite the hallmark lesion of PaBVs infection being the dilation of the proventriculus, our results demonstrate PaBV-2 first targets the CNS, before migrating to peripheral tissues such as the GI system.

Neurotropism is a striking characteristic of bornaviruses, including parrot bornavirus 2 (PaBV-2). Our study evaluated the distribution of inflammatory foci and viral nucleoprotein (N) antigen in the brain and spinal cord of 27 cockatiels (Nymphicus hollandicus) following experimental infection with PaBV-2 by injection into the pectoral muscle. Tissue samples were taken at 12 timepoints between 5 and 114 days post-inoculation (dpi). Each experimental group had approximately 3 cockatiels per group and usually 1 negative control. Immunolabeling was first observed within the ventral horns of the thoracic spinal cord at 20 dpi and in the brain (thalamic nuclei and hindbrain) at 25 dpi. Both inflammation and viral antigen were restricted to the central core of the brain until 40 dpi. The virus then spread quickly at 60 dpi to both gray and white matter of all analyzed sections of the central nervous system (CNS). Encephalitis was most severe in the thalamus and hindbrain, while myelitis was most prominent in the gray matter and equally distributed in the cervical, thoracic, and lumbosacral spinal cord. Our results demonstrate a caudal to rostral spread of virus in the CNS following experimental inoculation of PABV-2 into the pectoral muscle, with the presence of viral antigen and inflammatory lesions first in the spinal cord and progressing to the brain.