Identification of neural networks that contribute to motion sickness through principal components analysis of fos labeling induced by galvanic vestibular stimulation

Motion sickness is a complex condition that includes both overt signs (e.g., vomiting) and more covert symptoms (e.g., anxiety and foreboding). The neural pathways that mediate these signs and symptoms are yet to identified. This study mapped the distribution of c-fos protein (Fos)-like immunoreactivity elicited during a galvanic vestibular stimulation paradigm that is known to induce motion sickness in felines. A principal components analysis was used to identify networks of neurons activated during this stimulus paradigm from functional correlations between Fos labeling in different nuclei. This analysis identified five principal components (neural networks) that accounted for greater than 95% of the variance in Fos labeling. Two of the components were correlated with the severity of motion sickness symptoms, and likely participated in generating the overt signs of the condition. One of these networks included neurons in locus coeruleus, medial, inferior and lateral vestibular nuclei, lateral nucleus tractus solitarius, medial parabrachial nucleus and periaqueductal gray. The second included neurons in the superior vestibular nucleus, precerebellar nuclei, periaqueductal gray, and parabrachial nuclei, with weaker associations of raphe nuclei. Three additional components (networks) were also identified that were not correlated with the severity of motion sickness symptoms. These networks likely mediated the covert aspects of motion sickness, such as affective components. The identification of five statistically independent component networks associated with the development of motion sickness provides an opportunity to consider, in network activation dimensions, the complex progression of signs and symptoms that are precipitated in provocative environments. Similar methodology can be used to parse the neural networks that mediate other complex responses to environmental stimuli. © 2014 Balaban et al

Time-resolved single-crystal X-ray crystallography

In this chapter the development of time-resolved crystallography is traced from its beginnings more than 30 years ago. The importance of being able to “watch” chemical processes as they occur rather than just being limited to three-dimensional pictures of the reactant and final product is emphasised, and time-resolved crystallography provides the opportunity to bring the dimension of time into the crystallographic experiment. The technique has evolved in time with developments in technology: synchrotron radiation, cryoscopic techniques, tuneable lasers, increased computing power and vastly improved X-ray detectors. The shorter the lifetime of the species being studied, the more complex is the experiment. The chapter focusses on the results of solid-state reactions that are activated by light, since this process does not require the addition of a reagent to the crystalline material and the single-crystalline nature of the solid may be preserved. Because of this photoactivation, time-resolved crystallography is often described as “photocrystallography”. The initial photocrystallographic studies were carried out on molecular complexes that either underwent irreversible photoactivated processes where the conversion took hours or days. Structural snapshots were taken during the process. Materials that achieved a metastable state under photoactivation and the excited (metastable) state had a long enough lifetime for the data from the crystal to be collected and the structure solved. For systems with shorter lifetimes, the first time-resolved results were obtained for macromolecular structures, where pulsed lasers were used to pump up the short lifetime excited state species and their structures were probed by using synchronised X-ray pulses from a high-intensity source. Developments in molecular crystallography soon followed, initially with monochromatic X-ray radiation, and pump-probe techniques were used to establish the structures of photoactivated molecules with lifetimes in the micro- to millisecond range. For molecules with even shorter lifetimes in the sub-microsecond range, Laue diffraction methods (rather than using monochromatic radiation) were employed to speed up the data collections and reduce crystal damage. Future developments in time-resolved crystallography are likely to involve the use of XFELs to complete “single-shot” time-resolved diffraction studies that are already proving successful in the macromolecular crystallographic field.</p

Turner syndrome and sexual differentiation of the brain: implications for understanding male-biased neurodevelopmental disorders

Turner syndrome (TS) is one of the most common sex chromosome abnormalities. Affected individuals often show a unique pattern of cognitive strengths and weaknesses and are at increased risk for a number of other neurodevelopmental conditions, many of which are more common in typical males than typical females (e.g., autism and attention-deficit hyperactivity disorder). This phenotype may reflect gonadal steroid deficiency, haploinsufficiency of X chromosome genes, failure to express parentally imprinted genes, and the uncovering of X chromosome mutations. Understanding the contribution of these different mechanisms to outcome has the potential to improve clinical care for individuals with TS and to better our understanding of the differential vulnerability to and expression of neurodevelopmental disorders in males and females. In this paper, we review what is currently known about cognition and brain development in individuals with TS, discuss underlying mechanisms and their relevance to understanding male-biased neurodevelopmental conditions, and suggest directions for future research

Guidelines to Evaluate Human Observational Studies for Quantitative Risk Assessment

BACKGROUND: Careful evaluation of the quality of human observational studies (HOS) is required to assess the suitability of HOS for quantitative risk assessment (QRA). In particular, the quality of quantitative exposure assessment is a crucial aspect of HOS to be considered for QRA. OBJECTIVE: We aimed to develop guidelines for the evaluation of HOS for QRA and to apply these guidelines to case–control and cohort studies on the relation between exposure to benzene and acute myeloid leukemia (AML). METHODS: We developed a three-tiered framework specific for the evaluation of HOS for QRA and used it to evaluate HOS on the relation between exposure to benzene and AML. RESULTS: The developed framework consists of 20 evaluation criteria. A specific focus of the framework was on the quality of exposure assessment applied in HOS. Seven HOS on the relation of benzene and AML were eligible for evaluation. Of these studies, five were suitable for QRA and were ranked based on the quality of the study design, conduct, and reporting on the study. CONCLUSION: The developed guidelines facilitate a structured evaluation that is transparent in its application and harmonizes the evaluation of HOS for QRA. With the application of the guidelines, it was possible to identify studies suitable for QRA of benzene and AML and rank these studies based on their quality. Application of the guidelines in QRA will be a valuable addition to the assessment of the weight of evidence of HOS for QRA