Vestibular CCK signaling drives motion sickness-like behavior in mice.

Travel can induce motion sickness (MS) in susceptible individuals. MS is an evolutionary conserved mechanism caused by mismatches between motion-related sensory information and past visual and motion memory, triggering a malaise accompanied by hypolocomotion, hypothermia, hypophagia, and nausea. Vestibular nuclei (VN) are critical for the processing of movement input from the inner ear. Motion-induced activation of VN neurons recapitulates MS-related signs. However, the genetic identity of VN neurons mediating MS-related autonomic and aversive responses remains unknown. Here, we identify a central role of cholecystokinin (CCK)-expressing VN neurons in motion-induced malaise. Moreover, we show that CCK VN inputs onto the parabrachial nucleus activate Calca-expressing neurons and are sufficient to establish avoidance to novel food, which is prevented by CCK-A receptor antagonism. These observations provide greater insight into the neurobiological regulation of MS by identifying the neural substrates of MS and providing potential targets for treatment.

Reevaluation of the Toxoplasma gondii and Neospora caninum genomes reveals misassembly, karyotype differences, and chromosomal rearrangements.

Neospora caninum primarily infects cattle, causing abortions, with an estimated impact of a billion dollars on the worldwide economy annually. However, the study of its biology has been unheeded by the established paradigm that it is virtually identical to its close relative, the widely studied human pathogen Toxoplasma gondii By revisiting the genome sequence, assembly, and annotation using third-generation sequencing technologies, here we show that the N. caninum genome was originally incorrectly assembled under the presumption of synteny with T. gondii We show that major chromosomal rearrangements have occurred between these species. Importantly, we show that chromosomes originally named Chr VIIb and VIII are indeed fused, reducing the karyotype of both N. caninum and T. gondii to 13 chromosomes. We reannotate the N. caninum genome, revealing more than 500 new genes. We sequence and annotate the nonphotosynthetic plastid and mitochondrial genomes and show that although apicoplast genomes are virtually identical, high levels of gene fragmentation and reshuffling exist between species and strains. Our results correct assembly artifacts that are currently widely distributed in the genome database of N. caninum and T. gondii and, more importantly, highlight the mitochondria as a previously oversighted source of variability and pave the way for a change in the paradigm of synteny, encouraging rethinking the genome as basis of the comparative unique biology of these pathogens.

Defined neuronal populations drive fatal phenotype in a mouse model of Leigh syndrome.

Mitochondrial deficits in energy production cause untreatable and fatal pathologies known as mitochondrial disease (MD). Central nervous system affectation is critical in Leigh Syndrome (LS), a common MD presentation, leading to motor and respiratory deficits, seizures and premature death. However, only specific neuronal populations are affected. Furthermore, their molecular identity and their contribution to the disease remains unknown. Here, using a mouse model of LS lacking the mitochondrial complex I subunit Ndufs4, we dissect the critical role of genetically-defined neuronal populations in LS progression. Ndufs4 inactivation in Vglut2-expressing glutamatergic neurons leads to decreased neuronal firing, brainstem inflammation, motor and respiratory deficits, and early death. In contrast, Ndufs4 deletion in GABAergic neurons causes basal ganglia inflammation without motor or respiratory involvement, but accompanied by hypothermia and severe epileptic seizures preceding death. These results provide novel insight in the cell type-specific contribution to the pathology, dissecting the underlying cellular mechanisms of MD.

Salivary Biomarker Responses to Two Final Matches in Women's Professional Football.

The aim of this study was to examine the link between salivary concentrations of cortisol, testosterone, immunoglobulin A (IgA) and the rate of perceived exertion (RPE) as a measure of internal load after two final matches played 3 days apart by professional women football players. Saliva samples were taken before and after the two matches (M1, M2). RPE was used to monitor the exercise intensity after each match. Testosterone concentrations increased after each match (M1: +42%, p = 0.002; M2: +50%, p < 0.001) while cortisol increased only after M1 (+116%, p < 0.001). The testosterone-to-cortisol ratio decreased only after M1 (-32.4%, p < 0.001). IgA concentration did not change after any match. Testosterone concentrations were correlated with IgA concentrations after each match (M1: R = 0.59, p = 0.008; M2: R=0.51, p = 0.02). RPE was correlated with cortisol concentrations after M1 (R = 0.57; p = 0.01), but not after M2 (R = 0.38; p = 0.07). All these results suggest that salivary cortisol and testosterone concentrations increase especially after the first match of a final, without affecting IgA levels. We speculate that increased testosterone concentration in women after football matches may play a protecting role against immune suppression usually observed after intense exercise. Key pointsIn our sample space, IgA concentrations did not change for teams even, before and after separated match. Suggesting that salivary IgA determinations after physical activities remain under debate.Testosterone concentrations were the only one hormone showing a consequent increase in both matches after physical activity carrying.The T/C ratio decrease only after M1 according with a higher cortisol level reach after M1 get-together, suggesting a differential impact over anxiety-associated team performance. So M2 play gives a more stable psychological state.

Optimization of antitrypanosomatid agents: identification of nonmutagenic drug candidates with in vivo activity.

Chagas disease, caused by Trypanosoma cruzi parasite, was described thousands of years ago. Currently, it affects millions of people, mostly in Latin America, and there are not suitable drugs for treating it. As an attempt to find appropriate drugs to deal with this problem, we report here on the design, synthesis, and characterization of 82 new compounds. Trypanosomicidal behavior in vitro showed more than 20 outstanding derivatives with anti-Trypanosoma cruzi activity. Furthermore, we studied the nonspecific toxicity against mammalian cells determining their selectivity and also performed mutagenicity studies. Proof of concept, in vivo studies, was conducted with two of the most promising derivatives (77 and 80). They were identified as candidates because they have (i) very simple and cost-effective syntheses; (ii) activity against different stages and strains of the parasite showing excellent in vivo behavior during the acute phase of Chagas disease; and (iii) neither nonspecific toxicity nor mutagenic activity.

Functional grading of mineral and collagen in the attachment of tendon to bone.

Attachment of dissimilar materials is a major challenge because high levels of localized stress may develop at their interfaces. An effective biologic solution to this problem exists at one of nature's most extreme interfaces: the attachment of tendon (a compliant, structural "soft tissue") to bone (a stiff, structural "hard tissue"). The goal of our study was to develop biomechanical models to describe how the tendon-to-bone insertion derives its mechanical properties. We examined the tendon-to-bone insertion and found two factors that give the tendon-to-bone transition a unique grading in mechanical properties: 1), a gradation in mineral concentration, measured by Raman spectroscopy; and 2), a gradation in collagen fiber orientation, measured by polarized light microscopy. Our measurements motivate a new physiological picture of the tissue that achieves this transition, the tendon-to-bone insertion, as a continuous, functionally graded material. Our biomechanical model suggests that the experimentally observed increase in mineral accumulation within collagen fibers can provide significant stiffening of the partially mineralized fibers, but only for concentrations of mineral above a "percolation threshold" corresponding to formation of a mechanically continuous mineral network within each collagen fiber (e.g., the case of mineral connectivity extending from one end of the fiber to the other). Increasing dispersion in the orientation distribution of collagen fibers from tendon to bone is a second major determinant of tissue stiffness. The combination of these two factors may explain the nonmonotonic variation of stiffness over the length of the tendon-to-bone insertion reported previously. Our models explain how tendon-to-bone attachment is achieved through a functionally graded material composition, and provide targets for tissue engineered surgical interventions and biomimetic material interfaces.