Mismatch Negativity (MMN) in Freely-Moving Rats with Several Experimental Controls

Mismatch negativity (MMN) is a scalp-recorded electrical potential that occurs in humans in response to an auditory stimulus that defies previously established patterns of regularity. MMN amplitude is reduced in people with schizophrenia. In this study, we aimed to develop a robust and replicable rat model of MMN, as a platform for a more thorough understanding of the neurobiology underlying MMN. One of the major concerns for animal models of MMN is whether the rodent brain is capable of producing a human-like MMN, which is not a consequence of neural adaptation to repetitive stimuli. We therefore tested several methods that have been used to control for adaptation and differential exogenous responses to stimuli within the oddball paradigm. Epidural electroencephalographic electrodes were surgically implanted over different cortical locations in adult rats. Encephalographic data were recorded using wireless telemetry while the freely-moving rats were presented with auditory oddball stimuli to assess mismatch responses. Three control sequences were utilized: the flip-flop control was used to control for differential responses to the physical characteristics of standards and deviants; the many standards control was used to control for differential adaptation, as was the cascade control. Both adaptation and adaptation-independent deviance detection were observed for high frequency (pitch), but not low frequency deviants. In addition, the many standards control method was found to be the optimal method for observing both adaptation effects and adaptation-independent mismatch responses in rats. Inconclusive results arose from the cascade control design as it is not yet clear whether rats can encode the complex pattern present in the control sequence. These data contribute to a growing body of evidence supporting the hypothesis that rat brain is indeed capable of exhibiting human-like MMN, and that the rat model is a viable platform for the further investigation of the MMN and its associated neurobiology.     

Establishment of a Wolbachia Superinfection in Aedes aegypti Mosquitoes as a Potential Approach for Future Resistance Management

Wolbachia pipientis is an endosymbiotic bacterium estimated to chronically infect between 40–75% of all arthropod species. Aedes aegypti, the principle mosquito vector of dengue virus (DENV), is not a natural host of Wolbachia. The transinfection of Wolbachia strains such as wAlbB, wMel and wMelPop-CLA into Ae. aegypti has been shown to significantly reduce the vector competence of this mosquito for a range of human pathogens in the laboratory. This has led to wMel-transinfected Ae. aegypti currently being released in five countries to evaluate its effectiveness to control dengue disease in human populations. Here we describe the generation of a superinfected Ae. aegypti mosquito line simultaneously infected with two avirulent Wolbachia strains, wMel and wAlbB. The line carries a high overall Wolbachia density and tissue localisation of the individual strains is very similar to each respective single infected parental line. The superinfected line induces unidirectional cytoplasmic incompatibility (CI) when crossed to each single infected parental line, suggesting that the superinfection would have the capacity to replace either of the single constituent infections already present in a mosquito population. No significant differences in fitness parameters were observed between the superinfected line and the parental lines under the experimental conditions tested. Finally, the superinfected line blocks DENV replication more efficiently than the single wMel strain when challenged with blood meals from viremic dengue patients. These results suggest that the deployment of superinfections could be used to replace single infections and may represent an effective strategy to help manage potential resistance by DENV to field deployments of single infected strains.     

Bromus tectorum (Poaceae) in midcontinental United States: Population genetic analysis of an ongoing invasion

Biological invasions can be substantially influenced by the genetic sampling associated with a species' introduction. As a result, we assessed the genetic and evolutionary consequences of the entry and spread of the invasive grass Bromus tectorum (cheatgrass) across the United States midcontinent through an analysis of 54 populations, using enzyme electrophoresis. On average, these populations display 1.04 alleles per locus (A), 4.1% percent polymorphic loci per population (%P) and an expected mean heterozygosity (H(exp)) value of 0.009. Heterozygotes, which have been rarely reported for B. tectorum in North America, occur in three populations in the midcontinent and are likely novel multilocus genotypes that arose postimmigration. The midcontinent distribution of multilocus genotypes suggests that plant immigrants came directly from either the native range or the eastern United States, or both. Continued dispersal of preadapted genotypes and the assembly of populations that are genetic admixtures may enhance this invasion by increasing both the genetic diversity within populations and the selection of novel genotypes arising from occasional outcrossing. The potential for postimmigration evolution in most species points to the largely unrecognized need to block the introduction of new, potentially aggressive genotypes of an alien species already in the United States.     

Congenital amusia: all the songs sound the same

Recent evidence from individuals born with a profound musical impairment suggests that the ability to process pitch information is normally present from birth. This finding supports the idea that the perception and appreciation of music, both of which critically depend on pitch processing, have a biological basis in the brain.     

Characterization of a novel murine retrovirus mixture that facilitates hematopoiesis

A new virus previously arose in BALB/c females mated repeatedly to C57BL/6 (B6) males and then injected with fixed, activated B6 male spleen cells (V. S. Ter-Grigorov, O. Krifuks, E. Liubashevsky, A. Nyska, Z. Trainin, and V. Toder, Nat. Med. 3:37-41, 1997). In the present study, BALB/cJ mice inoculated with virus-containing plasma from affected mice developed splenomegaly, which was caused by increased numbers of Sca-1(+) Lin(-) hematopoietic stem cells (HSC) and their differentiated progeny. Biological and molecular analyses of a new virus revealed a mixture of murine leukemia viruses (MuLVs). These MuLVs comprised ecotropic and mink lung cell focus-forming (MCF) virus classes and are termed Rauscher-like MuLVs because they bear numerous similarities to the ecotropic and MCF viruses of the Rauscher MuLV complex but do not include a spleen focus-forming virus. The ecotropic virus component alone transferred some disease characteristics, while MCF virus alone did not. Thus, we have described a novel virus mixture, termed Rauscher-like MuLV, that causes an increase in hematopoiesis due to activation of pluripotent HSC. Experiments using mice and a protocol that replicated the pregnancy and immunization strategy of the original experiment demonstrated that endogenous BALB/c mouse ecotropic and xenotropic MuLVs are activated by these treatments. Emv1 was expressed in the spleens of multiparous mice but not in those of virgin mice, and Bxv1Emv1-pseudotyped MuLVs were recovered following injection of fixed, activated B6 cells. Thus, multiple pregnancies and allostimuli appear to have provided the signals required for activation of and recombination among endogenous viruses and could have resulted in generation of the Rauscher-like MuLV mixture.     

Cost-Effectiveness Analysis of Risk-Factor Guided and Birth-Cohort Screening for Chronic Hepatitis C Infection in the United States

Background

No consensus exists on screening to detect the estimated 2 million Americans unaware of their chronic hepatitis C infections. Advisory groups differ, recommending birth-cohort screening for baby boomers, screening only high-risk individuals, or no screening. We assessed one-time risk assessment and screening to identify previously undiagnosed 40–74 year-olds given newly available hepatitis C treatments.

Methods and Findings

A Markov model evaluated alternative risk-factor guided and birth-cohort screening and treatment strategies. Risk factors included drug use history, blood transfusion before 1992, and multiple sexual partners. Analyses of the National Health and Nutrition Examination Survey provided sex-, race-, age-, and risk-factor-specific hepatitis C prevalence and mortality rates. Nine strategies combined screening (no screening, risk-factor guided screening, or birth-cohort screening) and treatment (standard therapy–peginterferon alfa and ribavirin, Interleukin-28B-guided (IL28B) triple-therapy–standard therapy plus a protease inhibitor, or universal triple therapy). Response-guided treatment depended on HCV genotype. Outcomes include discounted lifetime costs (2010 dollars) and quality adjusted life-years (QALYs).Compared to no screening, risk-factor guided and birth-cohort screening for 50 year-olds gained 0.7 to 3.5 quality adjusted life-days and cost $168 to $568 per person. Birth-cohort screening provided more benefit per dollar than risk-factor guided screening and cost $65,749 per QALY if followed by universal triple therapy compared to screening followed by IL28B-guided triple therapy. If only 10% of screen-detected, eligible patients initiate treatment at each opportunity, birth-cohort screening with universal triple therapy costs $241,100 per QALY. Assuming treatment with triple therapy, screening all individuals aged 40–64 years costs less than $100,000 per QALY.

Conclusions

The cost-effectiveness of one-time birth-cohort hepatitis C screening for 40–64 year olds is comparable to other screening programs, provided that the healthcare system has sufficient capacity to deliver prompt treatment and appropriate follow-on care to many newly screen-detected individuals.     

The conservation status and population decline of the African penguin deconstructed in space and time

Understanding changes in abundance is crucial for conservation, but population growth rates often vary over space and time. We use 40 years of count data (1979–2019) and Bayesian state‐space models to assess the African penguin Spheniscus demersus population under IUCN Red List Criterion A. We deconstruct the overall decline in time and space to identify where urgent conservation action is needed. The global African penguin population met the threshold for Endangered with a high probability (97%), having declined by almost 65% since 1989. An historical low of ~17,700 pairs bred in 2019. Annual changes were faster in the South African population (?4.2%, highest posterior density interval, HPDI: ?7.8 to ?0.6%) than the Namibian one (?0.3%, HPDI: ?3.3 to +2.6%), and since 1999 were almost ?10% at South African colonies north of Cape Town. Over the 40‐year period, the Eastern Cape colonies went from holding ~25% of the total penguin population to ~40% as numbers decreased more rapidly elsewhere. These changes coincided with an altered abundance and availability of the main prey of African penguins. Our results underline the dynamic nature of population declines in space as well as time and highlight which penguin colonies require urgent conservation attention.     

Palmitoylated Proteins in Plasmodium falciparum-Infected Erythrocytes: Investigation with Click Chemistry and Metabolic Labeling

The examination of the complex cell biology of the human malaria parasite Plasmodium falciparum usually relies on the time-consuming generation of transgenic parasites. Here, metabolic labeling and click chemistry are employed as a fast transfection-independent method for the microscopic examination of protein S-palmitoylation, an important post-translational modification during the asexual intraerythrocytic replication of P. falciparum. Applying various microscopy approaches such as confocal, single-molecule switching, and electron microscopy, differences in the extent of labeling within the different asexual developmental stages of P. falciparum and the host erythrocytes over time are observed.