Publications

No concrete, causal, mechanistic theory is available to explain how different hepatic zonation patterns of P450 isozyme levels and hepatotoxicity emerge following dosing with different compounds. We used the synthetic method of modeling and simulation to discover, explore, and experimentally challenge concrete mechanisms that show how and why biomimetic zonation patterns can emerge and change within agent-based analogues, expecting that those mechanisms may have counterparts in rats. Mobile objects map to compounds. One analogue represents a cross-section through a lobule. It is comprised of 460 identical, quasi-autonomous functional units called sinusoidal segments (SSs). SSs detect and respond to compound-generated response signals and the local level of an endogenous gradient. Each SS adapts by using those signals to adjust (or not) the probability that it will clear a detected compound during the next simulation cycle. The adjustment decision is based on the value of a biomimetic algorithm that is based on an assumed, evolution imposed, genetic mandate that normal hepatocytes resist increasing the cost of their actions. The algorithm estimates the long-term, discounted cost to a given SS of continuing to use its current clearance effort. Upon compound exposure, lobular analogues developed a variety of clearance and hepatotoxicity patterns that were strikingly similar to those reported in the literature. A degree of quantitative validation was achieved against data on hepatic zonation of CYP1A2 mRNA expression caused by three different doses of TCDD (2,3,7,8-tetracholorodibenzo-p-dioxone).

Intermuscular adipose tissue (IMAT) is associated with metabolic abnormalities similar to those associated with visceral adipose tissue (VAT). Increased IMAT has been found in obese human immunodeficiency virus (HIV)-infected women. We hypothesized that IMAT, like VAT, would be similar or increased in HIV-infected persons compared with healthy controls, despite decreases in subcutaneous adipose tissue (SAT) found in HIV infection. In the second FRAM (Study of Fat Redistribution and Metabolic Change in HIV infection) exam, we studied 425 HIV-infected subjects and 211 controls (from the Coronary Artery Risk Development in Young Adults study) who had regional AT and skeletal muscle (SM) measured by magnetic resonance imaging (MRI). Multivariable linear regression identified factors associated with IMAT and its association with metabolites. Total IMAT was 51% lower in HIV-infected participants compared with controls (P = 0.003). The HIV effect was attenuated after multivariable adjustment (to -28%, P < 0.0001 in men and -3.6%, P = 0.70 in women). Higher quantities of leg SAT, upper-trunk SAT, and VAT were associated with higher IMAT in HIV-infected participants, with weaker associations in controls. Stavudine use was associated with lower IMAT and SAT, but showed little relationship with VAT. In multivariable analyses, regional IMAT was associated with insulin resistance and triglycerides (TGs). Contrary to expectation, IMAT is not increased in HIV infection; after controlling for demographics, lifestyle, VAT, SAT, and SM, HIV(+) men have lower IMAT compared with controls, whereas values for women are similar. Stavudine exposure is associated with both decreased IMAT and SAT, suggesting that IMAT shares cellular origins with SAT.

This article describes the submucosal injection technique applied in the endoscopic resection of non-polypoid colorectal neoplasms, with an emphasis on a particular technique, the dynamic submucosal injection technique.

The Vif protein of HIV is essential for the effective propagation of this pathogenic retrovirus in vivo. Vif acts by preventing virion encapsidation of two potent antiviral factors, the APOBEC3G and APOBEC3F cytidine deaminases. Decreased encapsidation in part involves Vif-mediated recruitment of a ubiquitin E3 ligase complex that promotes polyubiquitylation and proteasome-mediated degradation of APOBEC3G/F. The resultant decline in intracellular levels of these enzymes leads to decreased encapsidation of APOBECG/F into budding virions. This review discusses recent advances in our understanding of the dynamic interplay of Vif with the antiviral APOBEC3 enzymes.

Endoscopic mucosal resection (EMR) is preferred to standard polypectomy for the resection of non-polypoid lesions because these lesions can be technically difficult to capture with a snare; furthermore, without submucosal injection the underlying muscularis propria may be excessively coagulated or even inadvertently resected. Because the resection plane of EMR is in the middle or deeper part of the submucosa, EMR allows the precise depth of the lesion to be evaluated. Although the majority of non-polypoid lesions are adenomatous, non-polypoid colorectal neoplasm has a high association with advanced pathology, irrespective of size. Using EMR, a complete pathologic specimen is obtained, the risk of lymph node metastasis can be accurately assessed based on the depth of invasion, and patients can be suitably managed. Used according to its indications, EMR provides curative resection, and obviates the higher morbidity, mortality, and cost associated with surgical treatment.

BACKGROUND

Methionine-choline-deficient (MCD) diets cause steatohepatitis in rodents and are used to model fatty liver disease in human beings. Recent studies have identified sucrose as a major contributor to MCD-related liver disease through its ability to promote hepatic de novo lipogenesis.

AIMS

To determine whether glucose and fructose, the two constitutents of sucrose, differ in their capacity to provoke steatohepatitis when incorporated individually into MCD formulas.

MATERIALS & METHODS

MCD and control formulas prepared with either glucose or fructose as the sole source of carbohydrate were fed to mice for 21 days. Liver injury was assessed biochemically and histologically together with hepatic gene expression and fatty acid analysis.

RESULTS

Mice fed MCD formulas developed similar degrees of hepatic steatosis whether they contained glucose or fructose. By contrast, mice fed MCD-fructose developed significantly more hepatocellular injury than mice fed MCD-glucose, judged by histology, apoptosis staining and serum alanine aminotransferase. Liver injury in MCD-fructose mice coincided with an exaggerated rise in the ratio of long-chain saturated to unsaturated fatty acids in the liver. Notably, hepatic inflammation was not enhanced in mice fed MCD-fructose, correlating instead with hepatic lipid peroxidation, which was equivalent in the two MCD groups.

DISCUSSION

Fructose is more cytotoxic than glucose when used as the source of carbohydrate in MCD formulas.

CONCLUSION

The data suggest the enhanced cytotoxicity of fructose in the MCD model is related to its ability to stimulate de novo lipogenesis, which yields harmful long-chain saturated fatty acids.

Over the course of infection, the human immunodeficiency virus type 1 (HIV-1) continuously adapts in part to evade the host's neutralizing antibody response. Antibodies often target the HIV envelope proteins that mediate HIV fusion to its cellular targets. HIV virions pseudotyped with primary envelopes have often been used to explore the fusogenic properties of these envelopes. Unfortunately, these pseudotyped virions fuse with greatly reduced efficiency to primary cells. Here, we describe a relatively simple strategy to clone primary envelopes into a provirus and increase the sensitivity of the virion-based fusion assay.