A Model for the Acrosome Reaction in Mammalian Sperm.

The acrosome reaction is a complex, calcium-dependent reaction that results in an exocytotic event required for successful fertilization of the egg. It has long been thought that the acrosome reaction occurs upon sperm binding to the zona pellucida, a viscoelastic layer surrounding the oocyte. Recent studies have suggested that the reaction may even occur before the sperm encounters the zona, perhaps mediated by progesterone or some other agonist. It has been particularly difficult to understand differences between progesterone-induced and zona-induced reactions experimentally and whether one substance is the more biologically relevant trigger. Until this present work, there has been little effort to mathematically model the acrosome reaction in sperm as a whole. Instead, attention has been paid to modeling portions of the pathways involved in other cell types. Here we present a base model for the acrosome reaction which characterizes the known biochemical reactions and behaviors of the system. Our model allows us to analyze several pathways that may act as a stabilizing mechanism for avoiding sustained oscillatory calcium responses often observed in other cell types. Such an oscillatory regime might otherwise prevent acrosomal exocytosis and therefore inhibit fertilization. Results indicate that the acrosome reaction may rely upon multiple redundant mechanisms to avoid entering an oscillatory state and instead maintain a high resting level of calcium, known to be required for successful acrosomal exocytosis and, ultimately, fertilization of the oocyte.

A fully three-dimensional model of the interaction of driven elastic filaments in a Stokes flow with applications to sperm motility.

In many animals, sperm flagella exhibit primarily planar waveforms. An isolated sperm with a planar flagellar beat in a three-dimensional unbounded fluid domain would remain in a plane. However, because sperm must navigate through complex, three-dimensional confined spaces along with other sperm, forces that bend or move the flagellum out of its current beat plane develop. Here we present an extension of previous models of an elastic sperm flagellar filament whose shape change is driven by the pursuit of a preferred curvature wave. In particular, we extend the energy of the generalized elastica to include a term that penalizes out-of-plane motion. We are now able to study the interaction of free-swimmers in a 3D Stokes flow that do not start out beating in the same plane. We demonstrate the three-dimensional nature of swimming behavior as neighboring sperm swim close to each other and affect each others' trajectories via fluid-structure coupling.

The dynamics of sperm detachment from epithelium in a coupled fluid-biochemical model of hyperactivated motility.

Hyperactivation in mammalian sperm is characterized by a high-amplitude, asymmetric flagellar waveform. A mechanical advantage of this hyperactivated waveform has been hypothesized to be the promotion of flagellar detachment from oviductal epithelium. In order to investigate the dynamics of a free-swimming sperm׳s binding and escaping from a surface, we present an integrative model that couples flagellar force generation and a viscous, incompressible fluid. The elastic flagellum is actuated by a preferred curvature model that depends upon an evolving calcium profile along its length. In addition, forces that arise due to elastic bonds that form and break between the flagellar head and the surface are accounted for. As in recent laboratory experiments, we find that a hyperactive waveform does result in frequent detaching and binding dynamics that is not observed for symmetric flagellar beats. Moreover, we demonstrate that flagellar behavior depends strongly on the assumptions of the bond model, suggesting the need for more experimental investigation of the biochemistry of epithelial bonding and the shedding of binding proteins on the sperm head.

Predictive value of near-infrared spectroscopy on neurodevelopmental outcome after surgery for congenital heart disease in infancy.

OBJECTIVE: To explore the relationship between intraoperative regional cerebral oxygen saturation (rSO(2)) measured by near-infrared spectroscopy (NIRS) and neurodevelopmental outcome in children after cardiac surgery. METHODS: Cross-sectional neurodevelopmental evaluation at 2 years of age was performed in a cohort of young infants who had surgery for congenital heart disease in 2007. The third edition of Bayley Scales of Infant and Toddler Development (Bayley-III) was used to assess cognitive, language, and motor functioning. Clinical and perioperative data were collected, including intraoperative rSO(2) nadir, rSO(2) percent decrease from baseline, and cumulative minutes of at least 20%, 30%, and 40% decrease from baseline. RESULTS: Twenty-seven patients without chromosomal abnormality were included in analyses. Mean Bayley-III scores fell within 1 standard deviation of the normative mean. Stepwise regression analyses of patient- and procedure-related variables, including rSO(2), demonstrated that cognitive ability was predicted by length of hospital stay and premature birth (58.1% of variance), receptive communication was predicted by length of hospital stay and rSO(2) nadir (40.2% of variance), expressive communication was predicted by birth weight (26.2% of variance), fine motor functioning was predicted by duration of cardiac intensive care unit stay (41.4% of variance), and gross motor functioning was predicted by the presence of a significant comorbidity (43.5% of variance). CONCLUSIONS: In a contemporary cohort of infants undergoing surgery for congenital heart disease, neurodevelopmental outcomes at 2 years of age are largely influenced by patient-related characteristics. Although receptive communication appears to be influenced by rSO(2) nadir, the predictive value of NIRS remains unclear.

Intermediate neurodevelopmental outcome after repair of ventricular septal defect.

BACKGROUND: Children with congenital heart disease are at risk for impaired neurodevelopmental outcome. Despite the high prevalence of ventricular septal defects relative to other cardiac defects, few studies have specifically examined this population. The purpose of this study was to provide data on the intermediate neurodevelopmental outcome for children after repair of a ventricular septal defect. METHODS: Neurodevelopmental outcome was assessed for 31 children using standardized tests of IQ, memory, visual-motor ability, and academic achievement. Standardized parent and teacher reports of behavioral and psychosocial functioning were also examined. Patients were grouped into younger (less than 6 years old; n = 18) and older (6 years and older; n = 13) cohorts. RESULTS: Full-scale IQ scores were within the normal range. Although most other domains of neurodevelopmental and behavioral functioning were comparable to normative data, patient functioning was lower than population norms in the areas of performance IQ for the younger cohort (90.6 ± 16.1; p = 0.023), visual memory for the older cohort (84.5 ± 15.3; p = 0.003), and visual-motor ability (87.9 ± 14.2; p < 0.001) and adaptive behavior (94.3 ± 15.3; p = 0.050) for the entire cohort. CONCLUSIONS: After repair of ventricular septal defects, children function within the normal range in most areas. Three of the four domains in which lower functioning was observed tap into visual cognitive abilities rather than verbal abilities. Lower mean scores in these areas were, however, generally within one standard deviation of the population mean, suggesting mild weaknesses rather than significant impairments.

Improved protection of mice against lethal respiratory infection with Coccidioides posadasii using two recombinant antigens expressed as a single protein.

Two recombinant antigens which individually protect mice from lethal intranasal infection were studied in combination, either as a mixture of two separately expressed proteins or as a single chimeric expression product. Mice vaccinated with either combination survived longer than mice given single antigens. Immunized mice also exhibited specific IgG immunoglobulins and yielded splenocytes which produced interferon-gamma in response to either antigen. The chimeric antigen has the practical advantage of offering enhanced protection from multiple components without increasing production costs.

Couple power dynamics, systemic family functioning, and child adjustment: a test of a mediational model in a multiethnic sample.

Power dynamics in the marital dyad and systemic elements of whole-family functioning (cohesion, subsystem boundary formations) were examined in relation to each other and also in relation to child adjustment in a multiethnic sample of families. Support was found for a mediational model, such that family functioning was found to mediate the relationship between marital power dynamics and children's internalizing and externalizing behavior. Some support also was found for ethnicity as a moderator of the association between systemic family processes and children's adjustment. Disturbances in family cohesion and subsystem boundaries were more strongly related to internalizing symptomatology for children in European American families compared to children in Hispanic American families.

Impacting re-arrest rates among youth sentenced in adult court: an epidemiological examination of the Juvenile Sentencing Advocacy Project.

Examines the impact of a program aimed at reducing re-offending among juveniles transferred to adult court in Miami-Dade County, Florida. Initiated in 1998, the Juvenile Sentencing Advocacy Project (JSAP) worked to increase the degree to which defense lawyers, prosecutors, judges, and police officers considered the developmental status of youth charged with crimes, as well as the contextual basis for their behavior and their potential for rehabilitation. Through such activities, the goal was to increase the use of juvenile sanctions, rather than traditional adult sentences. Based on previous research, it was predicted that increased use of juvenile sanctions would be associated with fewer youth re-offending. This article examines 162 youth who were transferred to and sentenced in adult court during 1999. Re-offense patterns were monitored through June 2001. Analyses using epidemiological measures of effect found that the use of juvenile sanctions significantly increased following implementation of JSAP and that youth receiving adult probation or boot camp were 1.74 to 2.29 times more likely to re-offend than were youth receiving juvenile sanctions. The increased use of juvenile sanctions following implementation of JSAP corresponded to an 11.2% to 15.3% decrease in the number of youth one would have anticipated would re-offend had previous patterns of sentencing continued.

Localization within a proline-rich antigen (Ag2/PRA) of protective antigenicity against infection with Coccidioides immitis in mice.

Subunits of a proline-rich coccidioidal antigen (Ag2/PRA) of Coccidioides immitis were analyzed by comparison as vaccines in mice. The optimal dose of plasmid vaccine encoding full-length Ag2/PRA was determined to be between 10 and 100 microg. Mice vaccinated with plasmids encoding amino acids (aa) 1 to 106 were as protective as full-length Ag2/PRA (aa 1 to 194). The subunit from aa 27 to 106 was significantly but less protective. Plasmids encoding aa 90 to 151 or aa 90 to 194 were not protective. Analogous results were obtained with recombinant vaccines of the same amino acid sequences. In addition, mixtures of aa 90 to 194 with either aa 1 to 106 or aa 27 to 106 did not enhance protection compared to the active single-recombinant subunits alone. Humoral response of total immunoglobulin G (IgG) and subclasses IgG1 and IgG2a were detectable in subunit vaccinations but at significantly (100-fold) lower concentrations than after vaccination with plasmids encoding full-length Ag2/PRA. Since virtually all protection by vaccination with full-length Ag2/PRA can be accounted for in the first half of the protein (aa 1 to 106), this subunit could make a multicomponent vaccine more feasible by reducing the quantity of protein per dose and the possibility of an untoward reactions to a foreign protein.

Protection of mice against Coccidioides immitis intranasal infection by vaccination with recombinant antigen 2/PRA.

Subcutaneous vaccination with recombinant antigen 2/PRA (rAg2/PRA) protected BALB/c mice against intranasal infection with Coccidioides immitis. Subcutaneously vaccinated C57BL/6 mice and intranasally vaccinated BALB/c mice were protected against larger numbers of infecting spores. Weight loss correlated with lethality, but histologic appearance did not. These studies support rAg2/PRA vaccination to prevent coccidioidomycosis.