Anal intraepithelial neoplasia and squamous cell carcinoma in HIV‐infected adults

Anal cancer is one of the most common non‐AIDS‐defining malignancies in the era of combination antiretroviral therapy. Its precursor lesion, anal intraepithelial neoplasia (AIN), is highly prevalent in HIV‐infected populations. More than 90% of anal squamous cell cancers are attributable to human papillomavirus (HPV). While the biology of HPV‐related intraepithelial neoplasia is consistent across lower anogenital sites, the natural history of AIN is not well established and cannot be assumed to be identical to that of cervical intraepithelial neoplasia. Screening strategies to prevent anal cancer should be developed based on robust natural history data in HIV‐infected and uninfected populations. Likewise, treatments need to be tested in randomized clinical trials, and reserved for those at significant risk of progression to cancer. This review covers the epidemiology, pathogenesis and immunology of HPV infection, AIN and anal cancer, and summarizes the current diagnosis, screening and treatment strategies in HIV‐infected adults.     

Spontaneous bacterial peritonitis due to carbapenemase-producing Enterobacteriaceae: Etiology and antibiotic treatment

Carbapenem antibiotics were first introduced in the 1980s and have long been considered the most active agents for the treatment of multidrug-resistant gram-negative bacteria. Over the last decade, carbapenem-resistant Enterobacteriaceae (CRE) have emerged as organisms causing spontaneous bacterial peritonitis. Infections caused by CRE have shown a higher mortality rate than those caused by bacteria sensitive to carbapenem antibiotics. Current antibiotic guidelines for the treatment of spontaneous bacterial peritonitis are insufficient, and rapid de-escalation of empiric antibiotic treatment is not widely recognized. This review summarizes the molecular characteristics, epidemiology and possible treatment of spontaneous bacterial peritonitis caused by CRE.     

uPA‐uPAR molecular complex is involved in cell signaling during neuronal migration and neuritogenesis

Background: In the development of the central nervous system (CNS), neuronal migration and neuritogenesis are crucial processes for establishing functional neural circuits. This relies on the regulation exerted by several signaling molecules, which play important roles in axonal growth and guidance. The urokinase‐type plasminogen activator (uPA)—in association with its receptor—triggers extracellular matrix proteolysis and other cellular processes through the activation of intracellular signaling pathways. Even though the uPA‐uPAR complex is well characterized in nonneuronal systems, little is known about its signaling role during CNS development. Results : In response to uPA, neuronal migration and neuritogenesis are promoted in a dose‐dependent manner. After stimulation, uPAR interacts with α₅‐ and β₁‐integrin subunits, which may constitute an αβ‐heterodimer that acts as a uPA‐uPAR coreceptor favoring the activation of multiple kinases. This interaction may be responsible for the uPA‐promoted phosphorylation of focal adhesion kinase (FAK) and its relocation toward growth cones, triggering cytoskeletal reorganization which, in turn, induces morphological changes related to neuronal migration and neuritogenesis. Conclusions : uPA has a key role during CNS development. In association with its receptor, it orchestrates both proteolytic and nonproteolytic events that govern the proper formation of neural networks. Developmental Dynamics 243:676–689, 2014. © 2014 Wiley Periodicals, Inc.     

Neglected Parasitic Infections in the United States: Toxoplasmosis

Toxoplasma gondii is a leading cause of severe foodborne illness in the United States. Population-based studies have found T. gondii infection to be more prevalent in racial/ethnic minority and socioeconomically disadvantaged groups. Soil contaminated with cat feces, undercooked meat, and congenital transmission are the principal sources of infection. Toxoplasmosis-associated illnesses include congenital neurologic and ocular disease; acquired illness in immunocompetent persons, most notably ocular disease; and encephalitis or disseminated disease in immunosuppressed persons. The association of T. gondii infection with risk for mental illness is intriguing and requires further research. Reduction of T. gondii in meat, improvements in hygiene and food preparation practices, and reduction of environmental contamination can prevent toxoplasmosis, but more research is needed on how to implement these measures. In addition, screening and treatment may help prevent toxoplasmosis or reduce the severity of disease in some settings.     

Steroidogenic gene expression following D-aspartate treatment in frog testis

Previous studies have provided evidence that D-Asp plays a role in steroid-mediated reproductive biology in amphibians, reptiles, birds and mammals. To examine the molecular involvement of D-Asp on steroidogenic pathway regulation, we analysed the expression of StAR, P450 aromatase and 5αRed2 mRNAs in Pelophylax esculentus testis, either in relation to the reproductive cycle or D-Asp treatment. Basal StAR mRNA levels, as well as D-Asp and testosterone concentrations, were higher in reproductive than in post-reproductive frogs. D-Asp treatment increased StAR mRNA expression and immunolocalisation in both the reproductive and post-reproductive periods. In control testis, aromatase mRNA levels were higher in the post-reproductive period, but following D-Asp administration, they increased only in the reproductive period. The level of 5αRed2 mRNA was higher in reproductive frogs than in post-reproductive frogs, and it increased after D-Asp treatment only in the post-reproductive phase. Our results suggest that, in P. esculentus testis, D-Asp increases StAR mRNA in both periods, and P450 aromatase and 5αRed2 mRNAs at different points during the reproductive cycle.     

Entropic origin of Mg2+-facilitated RNA folding

Mg(2+) is essential for the proper folding and function of RNA, though the effect of Mg(2+) concentration on the free energy, enthalpy, and entropy landscapes of RNA folding is unknown. This work exploits temperature-controlled single-molecule FRET methods to address the thermodynamics of RNA folding pathways by probing the intramolecular docking/undocking kinetics of the ubiquitous GAAA tetraloop-receptor tertiary interaction as a function of [Mg(2+)]. These measurements yield the barrier and standard state enthalpies, entropies, and free energies for an RNA tertiary transition, in particular, revealing the thermodynamic origin of [Mg(2+)]-facilitated folding. Surprisingly, these studies reveal that increasing [Mg(2+)] promotes tetraloop-receptor interaction by reducing the entropic barrier (-TΔS(++)(dock)) and the overall entropic penalty (-TΔS(+) (dock)) for docking, with essentially negligible effects on both the activation enthalpy (ΔH(++)(dock)) and overall exothermicity (ΔH(+)(dock)). These observations contrast with the conventional notion that increasing [Mg(2+)] facilitates folding by minimizing electrostatic repulsion of opposing RNA helices, which would incorrectly predict a decrease in ΔH(++)(dock)) and ΔH(+)(dock)) with [Mg(2+)]. Instead we propose that higher [Mg(2+)] can aid RNA folding by decreasing the entropic penalty of counterion uptake and by reducing disorder of the unfolded conformational ensemble.