Improved spread of transduction in the central nervous system (CNS) was achieved from intravenous administration of adeno-associated virus serotype-9 (AAV9) to neonatal rats. Spinal lower motor neuron transduction efficiency was estimated to be 78% using the highest vector dose tested at a 12-week interval. The widespread expression could aid studying diseases that affect both the spinal cord and brain, such as amyotrophic lateral sclerosis (ALS). The protein most relevant to neuropathology in ALS is transactive response DNA-binding protein 43 (TDP-43). When expressed in rats, human wild-type TDP-43 rapidly produced symptoms germane to ALS including paralysis of the hindlimbs and muscle wasting, and mortality over 4 weeks that did not occur in controls. The hindlimb atrophy and weakness was evidenced by assessments of rotarod, rearing, overall locomotion, muscle mass, and histology. The muscle wasting suggested denervation, but there was only 14% loss of motor neurons in the TDP-43 rats. Tissues were negative for ubiquitinated, cytoplasmic TDP-43 pathology, suggesting that altering TDP-43's nuclear function was sufficient to cause the disease state. Other relevant pathology in the rats included microgliosis and degenerating neuronal perikarya positive for phospho-neurofilament. The expression pattern encompassed the distribution of neuropathology of ALS, and could provide a rapid, relevant screening assay for TDP-43 variants and other disease-related proteins.

We have developed a tetracycline-regulatable adenoviral transfection system that mediates efficient long-term transfer of genes into neuronal cells in vivo. This system allows gene expression to be switched on, then off, and back on again simply by administering or removing doxycycline from the animals' drinking water. This regulatable adenoviral vector system should be of value in behavioral studies and in vivo studies of neuronal gene function, and may further the development of effective gene therapy strategies in the brain.

No abstract

The transporter associated with antigen processing (TAP) and the major histocompatibility complex class I (MHC-I), two important components of the MHC-I antigen presentation pathway, are often deficient in tumor cells. The restoration of their expression has been shown to restore the antigenicity and immunogenicity of tumor cells. However, it is unclear whether TAP and MHC-I expression in tumor cells can affect the induction phase of the T cell response. To address this issue, we expressed viral antigens in tumors that are either deficient or proficient in TAP and MHC-I expression. The relative efficiency of direct immunization or immunization through cross-presentation in promoting adaptive T cell responses was compared. The results demonstrated that stimulation of animals with TAP and MHC-I proficient tumor cells generated antigen specific T cells with greater killing activities than those of TAP and MHC-I deficient tumor cells. This discrepancy was traced to differences in the ability of dendritic cells (DCs) to access and sample different antigen reservoirs in TAP and MHC-I proficient versus deficient cells and thereby stimulate adaptive immune responses through the process of cross-presentation. In addition, our data suggest that the increased activity of T cells is caused by the enhanced DC uptake and utilization of MHC-I/peptide complexes from the proficient cells as an additional source of processed antigen. Furthermore, we demonstrate that immune-escape and metastasis are promoted in the absence of this DC ‘arming’ mechanism. Physiologically, this novel form of DC antigen sampling resembles trogocytosis, and acts to enhance T cell priming and increase the efficacy of adaptive immune responses against tumors and infectious pathogens.

No abstract

Education researchers have been impacted by COVID-19 as school closures interrupted ongoing education research, including clinical trials, case study and ethnographic inquiry in schools, and longitudinal studies using federal, state, or district administrative data. The recommendations we present here focus on immediate and future actions education researchers can take to support public health and educational institutions dealing with a pandemic. Clearly not exhaustive, our recommendations are intended to prompt the education research community to collectively consider how the field’s efforts can both inform the knowledge base and support frontline educators and health care researchers dealing with COVID-19.

SUMMARYWe investigated the effects of catecholamines and sympathetic nerve stimulation in the feline pulmonary vascular bed under conditions of controlled pulmonary blood flow. Norepinephrine and nerve stimulation caused dose-and stimulus frequency-dependent increases in pulmonary vascular resistance. However, when pulmonary vascular tone was enhanced and a receptors blocked, norepinephrine and nerve stimulation caused dose-and frequency-dependent decreases in pulmonary vascular resistance. The decreases in pulmonary vascular resistance were blocked with propranolol and were of greater magnitude than were constrictor responses observed under basal conditions. Vasodilator responses to nerve stimulation were not modified by atropine. Epinephrine and isoproterenol had marked vasodilator activity in the pulmonary vascular bed when pulmonary vascular tone was elevated. When o receptors were blocked, isoproterenol and epinephrine had similar vasodilator activity, and when fi receptors were blocked, epinephrine and norepinephrine had marked vasoconstrictor activity. Selective /8-1 receptor antagonists had little effect on vasodilator responses to isoproterenol, whereas responses to this substance were blocked by propranolol. These results suggest the presence of a-and f}-2 adrenoreceptors in the feline pulmonary vascular bed and that both types of adrenergic receptors are innervated by the sympathetic nervous system. Circ Res 48: [407][408][409][410][411][412][413][414][415] 1981

Sound public financial management is a key concern of Pacific island country governments and their development partners. Public Expenditure and Financial Accountability assessments have become a ubiquitous tool for assessing public financial management performance in the region. This paper summarizes Pacific island country performance using global data and identifies a relationship between small population size and lower scores in Public Expenditure and Financial Accountability assessments. This relationship reflects capacity constraints to successful implementation of capacity-intensive public financial management functions measured in such assessments. The analysis suggests that high scores may be an unrealistic and inappropriate goal for Pacific governments and development partners. Greater account should be taken of population-related capacity constraints when designing and implementing public financial management reforms. Scarce capacity should be prioritized towards binding constraints to service delivery and macroeconomic management, rather than dispersed in attempts to improve assessment scores through adopting capacity-intensive 'best-practice' systems.