Daily Sampling of an HIV-1 Patient with Slowly Progressing Disease Displays Persistence of Multiple env Subpopulations Consistent with Neutrality

The molecular evolution of HIV-1 is characterized by frequent substitutions, indels and recombination events. In addition, a HIV-1 population may adapt through frequency changes of its variants. To reveal such population dynamics we analyzed HIV-1 subpopulation frequencies in an untreated patient with stable, low plasma HIV-1 RNA levels and close to normal CD4+ T-cell levels. The patient was intensively sampled during a 32-day period as well as approximately 1.5 years before and after this period (days −664, 1, 2, 3, 11, 18, 25, 32 and 522). 77 sequences of HIV-1 env (approximately 3100 nucleotides) were obtained from plasma by limiting dilution with 7–11 sequences per time point, except day −664. Phylogenetic analysis using maximum likelihood methods showed that the sequences clustered in six distinct subpopulations. We devised a method that took into account the relatively coarse sampling of the population. Data from days 1 through 32 were consistent with constant within-patient subpopulation frequencies. However, over longer time periods, i.e. between days 1…32 and 522, there were significant changes in subpopulation frequencies, which were consistent with evolutionarily neutral fluctuations. We found no clear signal of natural selection within the subpopulations over the study period, but positive selection was evident on the long branches that connected the subpopulations, which corresponds to >3 years as the subpopulations already were established when we started the study. Thus, selective forces may have been involved when the subpopulations were established. Genetic drift within subpopulations caused by de novo substitutions could be resolved after approximately one month. Overall, we conclude that subpopulation frequencies within this patient changed significantly over a time period of 1.5 years, but that this does not imply directional or balancing selection. We show that the short-term evolution we study here is likely representative for many patients of slow and normal disease progression

Chondroitin sulfates and their binding molecules in the central nervous system

Chondroitin sulfate (CS) is the most abundant glycosaminoglycan (GAG) in the central nervous system (CNS) matrix. Its sulfation and epimerization patterns give rise to different forms of CS, which enables it to interact specifically and with a significant affinity with various signalling molecules in the matrix including growth factors, receptors and guidance molecules. These interactions control numerous biological and pathological processes, during development and in adulthood. In this review, we describe the specific interactions of different families of proteins involved in various physiological and cognitive mechanisms with CSs in CNS matrix. A better understanding of these interactions could promote a development of inhibitors to treat neurodegenerative diseases

Working across species down on the farm: Howard S Liddell and the development of comparative psychopathology, c. 1923 to 1962

Seeking a scientific basis for understanding and treating mental illness, and inspired by the work of Ivan Pavlov, American physiologists, psychiatrists and psychologists in the 1920s turned to nonhuman animals. This paper examines how new constructs such as “experimental neurosis” emerged as tools to enable psychiatric comparison across species. From 1923 to 1962, the Cornell “Behavior Farm” was a leading interdisciplinary research center pioneering novel techniques to experimentally study nonhuman psychopathology. Led by the psychobiologist Howard Liddell, work at the Behavior Farm formed part of an ambitious program to develop new preventative and therapeutic techniques and bring psychiatry into closer relations with physiology and medicine. At the heart of Liddell’s activities were a range of nonhuman animals, including pigs, sheep, goats and dogs, each serving as a proxy for human patients. We examine how Pavlov’s conceptualization of ‘experimental neurosis’ was used by Liddell to facilitate comparison across species and communication between researchers and clinicians. Our close reading of his experimental system demonstrates how unexpected animal behaviors and emotions were transformed into experimental virtues. However, to successfully translate such behaviors from the animal laboratory into the field of human psychopathology, Liddell increasingly reached beyond, and, in effect, redefined, the Pavlovian method to make it compatible and compliant with an ethological approach to the animal laboratory. We show how the resultant Behavior Farm served as a productive “hybrid” place, containing elements of experiment and observation, laboratory and field. It was through the building of close and more naturalistic relationships with animals over extended periods of time, both normal and pathological, and within and outside of the experimental space, that Liddell could understand, manage, and make useful the myriad behavioral complexities that emerged from the life histories of experimental animals, the researchers who worked with them, and their shared relationships to the wider physical and social environments