Mouse models for human intestinal microbiota research: a critical evaluation

Since the early days of the intestinal microbiota research, mouse models have been used frequently to study the interaction of microbes with their host. However, to translate the knowledge gained from mouse studies to a human situation, the major spatio-temporal similarities and differences between intestinal microbiota in mice and humans need to be considered. This is done here with specific attention for the comparative physiology of the intestinal tract, the effect of dietary patterns and differences in genetics. Detailed phylogenetic and metagenomic analysis showed that while many common genera are found in the human and murine intestine, these differ strongly in abundance and in total only 4% of the bacterial genes are found to share considerable identity. Moreover, a large variety of murine strains is available yet most of the microbiota research is performed in wild-type, inbred strains and their transgenic derivatives. It has become increasingly clear that the providers, rearing facilities and the genetic background of these mice have a significant impact on the microbial composition and this is illustrated with recent experimental data. This may affect the reproducibility of mouse microbiota studies and their conclusions. Hence, future studies should take these into account to truly show the effect of diet, genotype or environmental factors on the microbial composition.     

The impact of HIV-1 on neurogenesis: implications for HAND

HIV-1 infection, in addition to its destructive effects on the immune system, plays a role in the development of neurocognitive deficits. Indeed up to 50 % of long-term HIV infected patients suffer from HIV-associated neurocognitive disorders (HAND). These deficits have been well characterized and defined clinically according to a number of cognitive parameters. HAND is often accompanied by atrophy of the brain including inhibition of neurogenesis, especially in the hippocampus.  Many mechanisms have been proposed as contributing factors to HAND including induction of oxidative stress in the central nervous system (CNS), chronic microglial-mediated neuroinflammation, amyloid-beta (Aβ) deposition, hyperphosphorylated tau protein, and toxic effects of combination antiretroviral therapy (cART). In these review we focus solely on recent experimental evidence suggesting that disturbance by HIV-1 results in impairment of neurogenesis as one contributing factor to HAND. Impaired neurogenesis has been linked to cognitive deficits and other neurodegenerative disorders. This article will highlight recently identified pathological mechanisms which potentially contribute to the development of impaired neurogenesis by HIV-1 or HIV-1-associated proteins from both animal and human studies.     

Retrocyclins and their activity against HIV-1

Primate theta-defensins are physically distinguished as the only known fully-cyclic peptides of animal origin. Humans do not produce theta-defensin peptides due to a premature stop codon present in the signal sequence of all six theta-defensin pseudogenes. Instead, since the putative coding regions of human theta-defensin pseudogenes have remained remarkably intact, their corresponding peptides, called “retrocyclins”, have been recreated using solid-phase synthetic approaches. Retrocyclins exhibit an exceptional therapeutic index both as inhibitors of HIV-1 entry and as bactericidal agents, which makes retrocyclins promising candidates for further development as topical microbicides to prevent sexually transmitted diseases. This review presents the evolution, antiretroviral mechanism of action, and potential clinical applications of retrocyclins to prevent sexual transmission of HIV-1.     

Distribution of HIV-1 in the genomes of AIDS patients

The localization of HIV-1 proviruses in compositional DNA fractions from 27 AIDS patients during the chronic phase of the disease with depletion of CD4+ and different levels of viremia showed the following. (1) At low viremia, proviruses are predominantly localized in the GC-richest isochores, which are characterized by an open chromatin structure; this result mimics findings on HIV-1 integration in early infected cells in culture. (2) At higher viremia, an increased distribution of proviruses in GC-poor isochores (which match the GC poorness of HIV-1) was found; this suggests a selection of cells in which the isopycnic localization leads to a higher expression of proviruses and, in turn, to higher viremia. (3) At the highest viremia, integrations in GC-rich isochores are often predominant again, but generally not at the same level as in (1); this may be the consequence of new integrations from the extremely abundant RNA copies.Received 21 November 2003; received after revision 13 January 2004: accepted 15 January 2004     

Activation of GCN2 upon HIV-1 infection and inhibition of translation

Higher eukaryotic organisms have a variety of specific and nonspecific defense mechanisms against viral invaders. In animal cells, viral replication may be limited through the decrease in translation. Some viruses, however, have evolved mechanisms that counteract the response of the host. We report that infection by HIV-1 triggers acute decrease in translation. The human protein kinase GCN2 (eIF2AK4) is activated by phosphorylation upon HIV-1 infection in the hours following infection. Thus, infection by HIV-1 constitutes a stress that leads to the activation of GCN2 with a resulting decrease in protein synthesis. We have shown that GCN2 interacts with HIV-1 integrase (IN). Transfection of IN in amino acid-starved cells, where GCN2 is activated, increases the protein synthesis level. These results point to an as yet unknown role of GCN2 as an early mediator in the cellular response to HIV-1 infection, and suggest that the virus is able to overcome the involvement of GCN2 in the cellular response by eliciting methods to maintain protein synthesis.     

Identifying US business cycle regimes using dynamic factors and neural network models

We use dynamic factors and neural network models to identify current and past states (instead of future) of the US business cycle. In the first step, we reduce noise in data by using a moving average filter. Dynamic factors are then extracted from a large-scale data set consisted of more than 100 variables. In the last step, these dynamic factors are fed into the neural network model for predicting business cycle regimes. We show that our proposed method follows US business cycle regimes quite accurately in-sample and out-of-sample without taking account of the historical data availability. Our results also indicate that noise reduction is an important step for business cycle prediction. Furthermore, using pseudo real time and vintage data, we show that our neural network model identifies turning points quite accurately and very quickly in real time.     

On estimation and prediction procedures for ar(1) models with power transformation

The power transformation of Box and Cox (1964) has been shown to be quite useful in short-term forecasting for the linear regression model with AR(1) dependence structure (see, for example, Lee and Lu, 1987, 1989). It is crucial to have good estimates of the power transformation and serial. correlation parameters, because they form the basis for estimating other parameters and predicting future observations. The prediction of future observations is the main focus of this paper. We propose to estimate these two parameters by minimizing the mean squared prediction errors. These estimates and the corresponding predictions compare favourably, via revs and simulated data, with those obtained by the maximum likelihood method. Similar results are also demonstrated in the repeated measurements setting.     

Retrocausal models for EPR

This paper takes up Huw Price׳s challenge to develop a retrocausal toy model of the Bell-EPR experiment. I develop three such models which show that a consistent, local, hidden-variables interpretation of the EPR experiment is indeed possible, and which give a feel for the kind of retrocausation involved. The first of the models also makes clear a problematic feature of retrocausation: it seems that we cannot interpret the hidden elements of reality in a retrocausal model as possessing determinate dispositions to affect the outcome of experiments. This is a feature which Price has embraced, but Gordon Belot has argued that this feature renders retrocausal interpretations “unsuitable for formal development”, and the lack of such determinate dispositions threatens to undermine the motivation for hidden-variables interpretations in the first place. But Price and Belot are both too quick in their assessment. I show that determinate dispositions are indeed consistent with retrocausation. What is more, I show that the ontological economy allowed by retrocausation holds out the promise of a classical understanding of spin and polarization.     

Protein intrinsic disorder as a flexible armor and a weapon of HIV-1

Many proteins and protein regions are disordered in their native, biologically active states. These proteins/regions are abundant in different organisms and carry out important biological functions that complement the functional repertoire of ordered proteins. Viruses, with their highly compact genomes, small proteomes, and high adaptability for fast change in their biological and physical environment utilize many of the advantages of intrinsic disorder. In fact, viral proteins are generally rich in intrinsic disorder, and intrinsically disordered regions are commonly used by viruses to invade the host organisms, to hijack various host systems, and to help viruses in accommodation to their hostile habitats and to manage their economic usage of genetic material. In this review, we focus on the structural peculiarities of HIV-1 proteins, on the abundance of intrinsic disorder in viral proteins, and on the role of intrinsic disorder in their functions.     

The implications of viral reservoirs on the elite control of HIV-1 infection

The mechanisms by which a small percentage of HIV-1 infected individuals known as elite suppressors or controllers are able to control viral replication are not fully understood. Early cases of viremic control were attributed to infection with defective virus, but subsequent work has demonstrated that infection with a defective virus is not the exclusive cause of control. Replication-competent virus has been isolated from patients who control viral replication, and studies have demonstrated that evolution occurs in plasma virus but not in virus isolates from the latent reservoir. Additionally, transmission pair studies have demonstrated that patients infected with similar viruses can have dramatically different outcomes of infection. An increased understanding of the viral factors associated with control is important to understand the interplay between viral replication and host control, and has implications for the design of an effective therapeutic vaccine that can lead to a functional cure of HIV-1 infection.