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Interactions between C-C chemokine receptor types 2 (CCR2) and 5 (CCR5) and their ligands, including CCL2 and CCL5, mediate fibrogenesis by promoting monocyte/macrophage recruitment and tissue infiltration, as well as hepatic stellate cell activation. Cenicriviroc (CVC) is an oral, dual CCR2/CCR5 antagonist with nanomolar potency against both receptors. CVC's anti-inflammatory and antifibrotic effects were evaluated in a range of preclinical models of inflammation and fibrosis. Monocyte/macrophage recruitment was assessed in vivo in a mouse model of thioglycollate-induced peritonitis. CCL2-induced chemotaxis was evaluated ex vivo on mouse monocytes. CVC's antifibrotic effects were evaluated in a thioacetamide-induced rat model of liver fibrosis and mouse models of diet-induced non-alcoholic steatohepatitis (NASH) and renal fibrosis. Study assessments included body and liver/kidney weight, liver function test, liver/kidney morphology and collagen deposition, fibrogenic gene and protein expression, and pharmacokinetic analyses. CVC significantly reduced monocyte/macrophage recruitment in vivo at doses ≥20 mg/kg/day (p < 0.05). At these doses, CVC showed antifibrotic effects, with significant reductions in collagen deposition (p < 0.05), and collagen type 1 protein and mRNA expression across the three animal models of fibrosis. In the NASH model, CVC significantly reduced the non-alcoholic fatty liver disease activity score (p < 0.05 vs. controls). CVC treatment had no notable effect on body or liver/kidney weight. CVC displayed potent anti-inflammatory and antifibrotic activity in a range of animal fibrosis models, supporting human testing for fibrotic diseases. Further experimental studies are needed to clarify the underlying mechanisms of CVC's antifibrotic effects. A Phase 2b study in adults with NASH and liver fibrosis is fully enrolled (CENTAUR Study 652-2-203; NCT02217475).

Transplantation of exogenous dopaminergic neuron （DA neurons） is a promising approach for treating Parkin- son＇s disease （PD）. However, a major stumbling block has been the lack of a reliable source of donor DA neurons. Here we show that a combination of five transcriptional factors Mashl, Ngn2, Sox2, Nurrl, and Pitx3 can directly and effectively reprogram human fibroblasts into DA neuron-like cells. The reprogrammed cells stained positive for various markers for DA neurons. They also showed characteristic DA uptake and production properties. Moreover, they exhibited DA neuron-specific electrophysiological profiles. Finally, they provided symptomatic relief in a rat PD model. Therefore, our directly reprogrammed DA neuron-like cells are a promising source of cell-replacement thera- py for PD.

New teachers, or those within their first 5 years of teaching, have an attrition rate of 40% compared to the experienced teacher attrition rate of 8% (NCES, 2012; Taie & Goldring, 2020). Induction programs with organizational supports for novice teachers are in many districts, it is important to conduct program evaluations to review the perceived helpfulness of the programs (Davis & Higdon, 2008). The purposes of this mixed methods sequential explanatory study are to determine (a) the fidelity to which the district induction program was implemented, (b) which components of the district induction program novice teachers describe as most useful to their professional growth, and (c) the ways in which the district mentoring process was useful to novice teachers’ professional growth. Participants were 33 novice teachers in one Middle Tennessee school district during the 2018–2019, 2019–2020, and 2020–2021 school years. Most participants identified as White, non-Hispanic (n = 30), 21–25 years old (n = 18), and attended a traditional 4-year teacher preparation program (n = 20). Thirty-three novice teachers completed Likert-type surveys, which were analyzed using descriptive statistics. Five participants completed semistructured interviews, which were analyzed manually using thematic coding. Findings indicated that attendance at the novice teacher induction program was inconsistent, due to unclear administration expectations, timing and location of meetings, and late hiring dates. Participants spoke about the induction program and district-assigned mentors related to classroom management, lesson planning, expectations of administration, and the role of mentor. Implications for research include investigating differing perceptions and needs of traditional certification and alternative certification teachers, the correlation between program attendance and teacher attrition, and effective novice teacher supports in rural or fringe districts. Implications for practice include training mentors on constructive feedback and the use of the evaluation system, updating program content annually based on participant feedback, providing late hires and conflicting work schedules alternate ways to receive program content, and having consistent expectations from the district and school-based administration regarding program attendance.

Psychostimulant sensitization is a phenomenon whereby repeated, intermittent drug treatment produces responses of a greater magnitude than a single dose. Sensitization to psychostimulants, stressors, electrical stimuli, or chemicals is hypothesized to contribute to the etiology of addiction and neuropsychiatric disorders such as obsessive compulsive disorder (OCD) and psychosis. In order to focus on the elucidation of dopamine receptor-mediated mechanisms underlying sensitization, quinpirole, a highly specific, direct dopamine agonist at D2 and D3 receptors, was selected as the sensitizing agent in these studies. This model is of particular interest as it produces repetitive behaviors in rats that suggest that it may represent an animal model of OCD. Thus, the objectives of this dissertation were to determine the anatomical substrates altered by quinpirole-induced sensitization, to examine in detail the behavioral manifestations of quinpirole-induced sensitization, and to ascertain how both of these parameters are changed after modification of quinpirole-induced sensitization by co-administration of clorgyline, a drug that changes the behavioral manifestation of quinpirole sensitization. Briefly, the present studies found that neuronal activity was consistently decreased in the nucleus accumbens, ventral pallidum, and medial/ventral orbital cortex of quinpirole-sensitized subjects compared to saline controls whereas these regions were not significantly changed in subjects receiving a single dose of quinpirole. Secondly, quinpirole-sensitized subjects with and without clorgyline pretreatment had similar alterations in neuronal activity associated with the limbic motive circuitry but differed in the locus coeruleus, piriform cortex, raphe magnus nucleus, and septal area. Finally, the present studies found that quinpirole-induced sensitization of locomotor activity was transformed into a form of focused stereotypy consisting of licking/stroking behavior by clorgyline pretreatment. Altogether, studies described in this dissertation provide novel contributions to the field of psychostimulant sensitization in terms of expanding the current description of the behavioral manifestations of quinpirole-induced sensitization and its modification by clorgyline pretreatment, determining brain regions that may be integral to the expression of sensitization, and identifying novel anterior cortical regions that may be involved. Brain regions that might be involved in the switch in behavior observed in quinpirole-sensitized subjects with clorgyline pretreatment were also identified. Furthermore, these brain regions may be new targets for the treatment of OCD, and perhaps, other neuropsychiatric disorders and addiction.

This paper describes a procedure used to link Medicaid claims data to California vital statistics records for very low birthweight infants. The linkage involved about 53,000 infants born from 1980 to 1987 and 1.46 million claims for delivery/birth-related hospital admissions during the same period. Because the two data files did not share a unique identifier, record linkage required combining evidence across several linking variables: delivery hospital, delivery/birth date or hospitalization period, names, mother's age, and zip code. To combine the various pieces of evidence, we used record linkage theory to compute scores that measure the likelihood of a match, i.e., that two records correspond to the same delivery. These scores appropriately weight the various pieces of evidence for or against a match. Implementation required dealing with large amounts of missing data in one of the files, errors and variations in reported names, and the need to minimize the number of incorrect links. The approach applies to a wide range of linkage problems. The ability to combine existing datasets to form new datasets containing analysis variables from each facilitates analyses that would otherwise be impossible, or prohibitively expensive.

This paper analyzes short-run fluctuations in national time series of vital events for France in the period 1740 to 1909. Fertility, mortality, and nuptiality form a simultaneous system which interacts with economic and meteorological conditions. In the short run, the demographic variables are endogenous. Economic and meteorological conditions are exogenous. Our indicator of economic conditions is the price of wheat, the principal food crop. Biometric models of fertility and empirical research on the biologically-based interrelations of fertility and mortality provide insight into the expected timing of events. We combine these results with empirical research on the effects of nutrition on fertility and mortality, research in medical biometeorology, and French historical demographic and economic research to formulate our model. The resultant distributed lag system is estimated. We find that the economic/nutritional effects are more likely to be statistically significant in predicting the time path of vital events than are the demographic variables or the effects of meteorological conditions.

A nonparametric strategy proposed by J. Heckman & B. Singer (see \"A Method for Minimizing the Impact of Distributional Assumptions in Econometric Models for Duration Data,\" Econometrica, 1984, 52, 271-320) for correcting for unobserved heterogeneity in hazard models is described & used to examine the covariates of child mortality & birth interval length in Korea. Apart from the primary aim of illustrating the application of the Heckman-Singer strategy in an actual demographic analysis, other goals of the analysis include: to discover whether the specific allowance for heterogeneity alters covariate effects estimates & conclusions that would have been reached in hazard models that ignore unobserved heterogeneity; to examine the sensitivity of covariate effects estimates to the imposition of a specific parametric form on the hazard & the sensitivity to different choices of parametric hazards; to offer suggestions about actually estimating such models to the investigator who is concerned about correcting for heterogeneity; & to offer an evaluation about the wisdom of pursuing the strategy suggested by Heckman & Singer. The research presented here can offer only tentative answers to the questions posed; however, the findings demonstrate that the Heckman-Singer strategy is sensitive to the choice for the parametric form. 5 Tables, 3 Figures, 34 References. Modified AA

A re-analysis of Knodel's data provides some new results for the fertility decline in Germany and a new approach to testing hypotheses about the demographic transition. Two formulations of transition theory are compared: one emphasizing the importance of changing social and economic structure for fertility decline; the other, the changing relationships between fertility and its determinants over time. To evaluate these formulations, multivariate time series cross-sectional models are developed. The statistical models permit the estimation of relationships both cross-sectionally and over time. As a consequence, the ability of the independent variables to explain cross-sectional as against temporal differences is evaluated. Industrialization, urbanization, religious composition, migration, infant mortality and marriage patterns satisfactorily explain the fertility decline once regional differences have been taken into account. Persisting characteristics of regional units account for much of the unexplained variance. Industrialization is the main explanatory variable of fertility decline in Germany. In the period considered, its impact on fertility increased substantially.