A Method to Create Directed Acyclic Graphs from Cycles of Transmission of Zoonotic and Vector-Borne Infectious Agents.

Background: The life cycles of zoonotic and vector-borne diseases can be complex. This complexity makes it challenging to identify factors that confound the association between an exposure of interest and infection in one of the susceptible hosts. In epidemiology, directed acyclic graphs (DAGs) can be used to visualize the relationships between exposures and outcomes and also to identify which factors confound the association between exposure and the outcome of interest. However, DAGs can only be used in situations where no cycle exists in the causal relationships being represented. This is problematic for infectious agents that cycle between hosts. Zoonoses and vector-borne diseases pose additional challenges with DAG construction since multiple required or optional hosts of different species may be part of the cycle. Methods: We review the existing examples of DAGs created for nonzoonotic infectious agents. We then demonstrate how to cut the transmission cycle to create DAGs where infection of a specific host species is the outcome of interest. We adapt our method to create DAGs using examples of transmission and host characteristics common to many zoonotic and vector-borne infectious agents. Results: We demonstrate our method using the transmission cycle of West Nile virus to create a simple transmission DAG that lacks a cycle. Conclusions: Using our work, investigators can create DAGs to help identify confounders of the relationships between modifiable risk factors and infection. Ultimately, a better understanding and control of confounding in measuring the impact of such risk factors can be used to inform health policy, guide public health and animal health interventions, and uncover gaps needing further research attention.

Imaging correlates of serum enzyme-linked immunoelectrotransfer blot (EITB) positivity in patients with parenchymal neurocysticercosis: results from 521 patients.

BACKGROUND: The presence of perilesional edema among patients with parenchymal neurocysticercosis (pNCC) of various lesion subtypes has not been correlated with results of serum enzyme-linked immunotransfer blot (EITB) for cysticercal antibodies. METHODS: In total, 521 patients with pNCC were classified into solitary cysticercus granuloma (SCG), multiple lesions, at least one of which was an enhancing granuloma (GMNCC), solitary calcified cysticercal lesion (SCC) and multiple calcified cysticercal lesions (CMNCC). The proportion of EITB positivity among each lesion subtype and its association with perilesional edema were determined. RESULTS: There were significantly higher positive EITB results in patients with GMNCC (90/111, 81.1%) compared with other lesion types. Perilesional edema was associated with positive EITB in patients with CMNCC. On univariate analysis, perilesional edema and GMNCC were associated with EITB positivity. On multivariate analysis, only GMNCC (OR 7.5; 95% CI 3.5 to 16.2) was significantly associated with EITB positivity. CONCLUSIONS: In patients with pNCC, the presence of perilesional edema is associated with a higher probability of a positive EITB result in patients with CMNCC, suggesting a synchronicity in the mechanisms associated with formation of perilesional edema and the antibody response in this subtype. In patients with enhancing granulomas, edema is not an independent predictor of a positive EITB, suggesting that the enhancement itself is associated with a strong antibody response.

Breaking through the glioblastoma micro-environment via extracellular vesicles.

Glioblastoma (GBM) is the most common and most aggressive brain tumour. Prognosis remains poor, despite the combined treatment of radio- and chemotherapy following surgical removal. GBM cells coexist with normal non-neoplastic cells, including endothelial cells, astrocytes and immune cells, constituting a complex and dynamic tumour micro-environment (TME). Extracellular vesicles (EVs) provide a critical means of bidirectional inter-cellular communication in the TME. Through delivery of a diverse range of genomic, lipidomic and proteomic cargo to neighbouring and distant cells, EVs can alter the phenotype and function of the recipient cell. As such, EVs have demonstrated their role in promoting angiogenesis, immune suppression, invasion, migration, drug resistance and GBM recurrence. Moreover, EVs can reflect the phenotype of the cells within the TME. Thus, in conjunction with their accessibility in biofluids, they can potentially serve as a biomarker reservoir for patient prognosis, diagnosis and predictive therapeutic response as well as treatment follow-up. Furthermore, together with the ability of EVs to cross the blood-brain barrier undeterred and through the exploitation of their cargo, EVs may provide an effective mean of drug delivery to the target site. Unveiling the mechanisms by which EVs within the GBM TME are secreted and target recipient cells may offer an indispensable understanding of GBM that holds the potential to provide a better prognosis and overall quality of life for GBM patients.

Loss of Toll-Like Receptor 4 Function Partially Protects against Peripheral and Cardiac Glucose Metabolic Derangements During a Long-Term High-Fat Diet.

Diabetes is a chronic inflammatory disease that carries a high risk of cardiovascular disease. However, the pathophysiological link between these disorders is not well known. We hypothesize that TLR4 signaling mediates high fat diet (HFD)-induced peripheral and cardiac glucose metabolic derangements. Mice with a loss-of-function mutation in TLR4 (C3H/HeJ) and age-matched control (C57BL/6) mice were fed either a high-fat diet or normal diet for 16 weeks. Glucose tolerance and plasma insulin were measured. Protein expression of glucose transporters (GLUT), AKT (phosphorylated and total), and proinflammatory cytokines (IL-6, TNF-α and SOCS-3) were quantified in the heart using Western Blotting. Both groups fed a long-term HFD had increased body weight, blood glucose and insulin levels, as well as impaired glucose tolerance compared to mice fed a normal diet. TLR4-mutant mice were partially protected against long-term HFD-induced insulin resistance. In control mice, feeding a HFD decreased cardiac crude membrane GLUT4 protein content, which was partially rescued in TLR4-mutant mice. TLR4-mutant mice fed a HFD also had increased expression of GLUT8, a novel isoform, compared to mice fed a normal diet. GLUT8 content was positively correlated with SOCS-3 and IL-6 expression in the heart. No significant differences in cytokine expression were observed between groups, suggesting a lack of inflammation in the heart following a HFD. Loss of TLR4 function partially restored a healthy metabolic phenotype, suggesting that TLR4 signaling is a key mechanism in HFD-induced peripheral and cardiac insulin resistance. Our data further suggest that TLR4 exerts its detrimental metabolic effects in the myocardium through a cytokine-independent pathway.

Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation.

Histone acetylation plays important roles in gene regulation, DNA replication, and the response to DNA damage, and it is frequently deregulated in tumors. We postulated that tumor cell histone acetylation levels are determined in part by changes in acetyl coenzyme A (acetyl-CoA) availability mediated by oncogenic metabolic reprogramming. Here, we demonstrate that acetyl-CoA is dynamically regulated by glucose availability in cancer cells and that the ratio of acetyl-CoA:coenzyme A within the nucleus modulates global histone acetylation levels. In vivo, expression of oncogenic Kras or Akt stimulates histone acetylation changes that precede tumor development. Furthermore, we show that Akt's effects on histone acetylation are mediated through the metabolic enzyme ATP-citrate lyase and that pAkt(Ser473) levels correlate significantly with histone acetylation marks in human gliomas and prostate tumors. The data implicate acetyl-CoA metabolism as a key determinant of histone acetylation levels in cancer cells.