Using an economic simulation model to identify key drivers of profitability and estimate the environmental sustainability impact of immunization against gonadotropin-releasing factor (GnRF) in male and female pigs intended for market.

An existing model was used to identify key drivers of profitability and estimate the impact on environmental sustainability when immunizing finishing pigs against GnRF with Improvac®. The model estimated performance and economic differences between immunized (IM) and non-IM pigs from the perspective of producers and packers, based on two recent meta-analyses in male and female pigs. It was populated with data from 9 countries in four continents (Europe, Asia, North and Latin-America). One-way sensitivity analyses (OWSA) were used to define key drivers of profitability. When changing the country specific input data over a range of ±20%, most OWSA did not reverse the mathematical sign of incremental net return between IM and non-IM pigs as calculated in base case analyses. Only the difference in feed conversion rate between IM and untreated female pigs was a key driver of profitability. The parameters with the highest impact on outcomes were similar across countries and expectable (feed costs), or explainable (parameters with statistical differences between IM and non-IM pigs in meta-analyses). In both single-gender herds, Improvac® reduced the environmental impact of pig production by improving feed efficiency (FE), the key driver of environmental burden. In a 50/50 mixed gender herd, IM pigs consumed less feed and gained more weight in 7 out of 9 countries; in the other two countries the FE calculated for the additional weight gain in IM pigs was >1.00, i.e., each additional kilogram of weight gain was associated with less than one additional kilogram of feed consumed.

Examining gender differences in adolescent exposure to food and beverage marketing through go-along interviews.

This study explores how adolescents engage with unhealthy food and beverage marketing in online settings, from a gender perspective. Employing an online ethnography approach and using go-along interviews, we explored the experiences of adolescent boys and girls aged 13-17 as they navigated their online experiences with digital food and beverage marketing. Notable themes emerged, including the identification of predatory actions by food companies, the role of protective factors such as family, and the influence of social media influencers in shaping adolescent dietary preferences. Importantly, this research unearthed gender disparities in the participants' responses. Girls, in particular, exhibited a heightened awareness of the protective role played by their families, emphasized the influence of color in marketing strategies, recognized the significance of gender in marketing, and reported exposure to alcohol advertisements-findings that boys less frequently echoed. The study underscores the importance of adolescence as a critical phase in development, during which food companies target these impressionable individuals, driven by their independence and potential for brand loyalty. Moreover, it highlights the potential avenue of gender-specific marketing, offering valuable insights into the gendered dimensions of adolescents' food marketing experiences. By examining the interplay between digital food marketing and gender, this research addresses a critical gap in the literature, shedding light on how gender influences adolescents' perceptions, responses, and behaviors in the context of food marketing strategies. These findings have the potential to inform adolescents of the marketing techniques that target them and guide policymakers in developing and implementing evidence-based regulations aimed at safeguarding adolescents from exposure to unhealthy food marketing.

Understanding the tool influence function during sub-aperture belt-on-wheel glass polishing.

The tool influence function (TIF) during sub-aperture belt-on-wheel polishing has been evaluated as a function of various process conditions (belt use/wear, dwell time, displacement, belt velocity, and wheel modulus and diameter) on fused silica glass workpieces using C e O 2 polishing media. TIF spots are circular or elliptical in shape with a largely flat bottom character. The volumetric removal rate varies significantly with belt use (or wear), stabilizing after ∼15m i n of use. A modified Preston model, where the pressure dependence is adjusted using a different scaling of the wheel modulus (E w0.5), largely predicts the volumetric removal rate over the range of process conditions evaluated. The relatively high volumetric removal rate of 30-60m m 3/h using a fixed C e O 2-in-resin-host belt offers a rapid, and hence, more economical, initial polish of aspheric and freeform optics.

The efficacy of a modified live virus vaccine Fostera® PRRS against heterologous strains of porcine reproductive and respiratory syndrome virus: A meta-analysis.

Porcine reproductive and respiratory syndrome virus (PRRSV) is currently one of the most economically important health challenges in the global swine industry. The primary aim of this study was to evaluate the overall efficacy of a modified live virus vaccine Fostera® PRRS (F-PRRS) compared to no vaccination as reported in published studies, using meta-analytic techniques. Additionally, we aimed to evaluate the potential impact of age at vaccination and F-PRRS cross-protection against different genetically distanced PRRS strains. In total, 20 papers fulfilled the predefined inclusion criteria. Vaccinated pigs had on average 38.52 g/d higher daily weight gain and a 65% lower mortality (relative risk = 0.35) compared to non-vaccinates. F-PRRS reduced the maximum macroscopic lung lesion score on average by 16.82% points and the maximum viral load in serum by 1.36 log10 PRRSV RNA copies. Vaccination at 1 day and 21 days of age was similarly effective, and the pathogenic PRRS strain(s) used for challenge or being endemic in field studies (PRRSV-1, PRRSV-2, or PRRSV-1 & -2) did not significantly influence the outcomes. Our findings confirm the effectiveness of F-PRRS against heterologous PRRSV infection.

Immunization against gonadotropin-releasing factor (GnRF) in market gilts: Effect on growth and carcass parameters, and impact of immunization timing.

Reproductive cycling in fattening gilts can be associated with undesirable effects, such as estrus-related aggressive behavior, reduced feed intake and, in production systems where gilts are co-housed with entire males, unwanted pregnancy. Immunization against Gonadotrophin Releasing Factor (IM) can temporarily suppress ovarian activity, including related negative consequences on animal welfare and productivity. Feed intake has been shown to be higher after IM, resulting in both increased growth and increased carcass fat. A series of studies was conducted to confirm these effects on production and look at their dynamics over time. Three trials were performed to a similar design, each involving 240 gilts divided into 4 experimental groups at 12 weeks of age. One group remained untreated while the others had the two dose, IM course completed 8, 6 or 4 weeks before harvest, which was on a single day at 24, 25 or 26 weeks of age depending on the study. Feed intake was measured daily and bodyweight weekly, allowing growth parameters to be calculated on a weekly basis and for specific longer periods. Carcass weight, backfat depth and lean meat percentage were recorded at harvest. No effects were observed before the second application of the immunological product (V2) and completion of the IM course. Starting in the second week after V2 all IM groups showed a marked and consistent increase in Average Daily Feed Intake (ADFI), typically peaking at over 120% of the control group 3 to 4 weeks after V2 and then slowly declining, but still remaining elevated at 8 weeks. Weekly Average Daily Gain (ADG) showed a similar pattern but with a faster decline, resulting in the initially favorable impact on feed efficiency becoming less favorable as the V2 to harvest interval (V2H) progressed. Carcass weights were higher in IM gilts and backfat depths were greater, with the effects increasing with increasing V2H. Correspondingly, carcass lean meat percentage tended to decrease, although the higher carcass weights meant that the absolute weight of lean meat remained similar or higher. Carcass yield was generally unaffected by IM, but some between-group differences were statistically significant, and it is possible that different factors predominated at different times after V2, creating a complex relationship with V2H duration. The optimum IM protocol will depend on local conditions and production objectives but, as a generalization and assuming ad libitum feeding, a shorter V2H will favor efficient growth, while a longer duration will maximize carcass changes, such as increased fat coverage. It is suggested that the growth performance changes seen after IM in gilts might be viewed as a process of adjustment to a heavier and fatter target body type.

Evaluation of commercially available aroA delated gene E. coli O78 vaccine in commercial broiler chickens under Middle East simulating field conditions.

The broiler industry in the Middle East (ME) faces many challenges related to bacterial infections, including M. gallisepticum, M. synoviae, E. coli, and other gram-negative bacteria, exacerbated by various errors in the brooding process. Antibiotics use in the first three days of life, such as Linco-Spectin 100 SP, tilmicosin, enrofloxacin, tylosin, colistin, and doxycycline, is the trend in the market to control such challenges. This study aimed to evaluate the efficacy of the newly introduced aroA E. coli vaccine (Poulvac E. coli) and its ability to reduce over-reliance on the heavy use of antibiotics in the ME. The study was conducted on 160 broiler chicks, divided into eight even groups. Each group was treated differently in terms of antibiotic therapy and ages at the time of Poulvac E. coli administration and the challenge of virulent avian pathogenic E. coli (APEC), serotype O78. Spray application of Poulvac E. coli at seven days of age plus Linco-Spectin 100 SP during the first three days provided the best results for zero mortality after challenge with APEC, while Poulvac E. coli at seven days with enrofloxacin during the early three days resulted in 10% mortality. Poulvac E. coli hatchery vaccination protected birds against mortality but reduced body weight gain compared to the 7-day group vaccinated with Linco-Spectin 100 SP during the first three days. Poulvac E. coli given on day one or day seven did not affect the immune response to concurrent respiratory viral vaccines and, in some cases, improved response. This study shows that Poulvac E. coli at seven days of age, together with Linco-Spectin 100 during the first three days, has produced the best results in terms of protection and performance in the ME high presence of avian pathogenic E. coli field challenge.

The effect of immunization against gonadotropin-releasing factor in market gilts: Meta-analyses of parameters relevant for pig producers, pork packers and retailers/consumers.

The vaccine against gonadotropin releasing factor (GnRF), Improvac®, has recently emerged as an option for rearing market gilts up to heavier harvest weights. Improvac's® temporary suppression of the ovarian function and gonadal hormones results in greater feed intake and better welfare from avoidance of sexual behavioral problems. Based on 22 published articles, our meta-analysis has quantified the effect of immunizing gilts against GnRF on parameters relevant for pig producers, pork packers and retailers/consumers. The meta-analyses included growth performance and final harvest parameters, general carcass traits and yield of valuable meat, meat and fat quality parameters. Primary analyses considered studies without ractopamine, subgroup and additional analyses assessed the impact of co-variates. From the perspective of pig producers, primary analyses showed that immunized (IM) gilts have significantly (P < 0.001) increased average daily gain (+45.1 g/day) and daily feed intake (+0.19 kg/day), higher final live weight (+4.0 kg) and more backfat (+2.8 mm). From the perspective of the pork packers, IM gilts have heavier carcasses (+3.2 kg; P < 0.001), whereas dressing percentage is similar. IM gilts are less lean (-1.5% units; P < 0.001) and have 0.21% units more intramuscular fat (P = 0.001). The yield of ham, shoulder, and loin is similar, whereas the yield of belly is significantly higher (+0.28 kg; P < 0.001). There are no differences in meat quality parameters (color, pH24, and drip loss) between IM gilts and untreated gilts, whereas a lower iodine value in IM gilts indicates an improved fat quality. Further subgroup and additional analyses confirmed the validity of our meta-analysis.

Streamlined MRM method transfer between instruments assisted with HRMS matching and retention-time prediction.

Multiple reaction monitoring (MRM) mode using liquid-chromatography tandem mass spectrometry (e.g., LC-QqQ-MS/MS) has been extensively employed in the small molecule analysis with trace levels in complex samples owing to its high sensitivity. However, most of the reported MRM methods are developed using authentic standards, which are often costly yet not readily available. To address this question, a practical platform for the MRM method transfer between different LC-QqQ-MS/MS instruments, assisted by the high-resolution mass spectrometry (LC-HRMS) and retention time (RT) prediction, has been developed in this study. The reported platform can take advantage of both the high sensitivity of LC-MRM method and ion transition pairs from the previous publications. LC-HRMS can provide the accurate mass measurement of the compounds, though high-quality MS/MS fragments are usually difficult to obtain for chemicals at trace levels. Retention time matching and peaks matching between both instrumental platforms rule out isobaric candidates. With an additional retention time prediction filter from quantitative structure retention relationship (QSRR) model based on random forest feature selection (Pearson r2 = 0.63), identification of small molecules is achieved at a high confidence level without using authentic standards. The developed platform has been validated with robustness by examining spiked environmental chemicals in sludge water samples, biological urine, and cell extracts.

The effect of immunization against gonadotropin-releasing factor on growth performance, carcass characteristics and boar taint relevant to pig producers and the pork packing industry: A meta-analysis.

Meta-analysis was used to compare pigs immunocastrated (IC) with Improvac® versus physically castrated (PC) or entire male (EM) pigs. Performance and carcass data as most relevant for producers and packers were analyzed and the risk of boar taint was assessed by comparing the number of pigs exceeding the consumer thresholds of detection (ToD) for skatole and androstenone. A total of 78 articles fulfilled pre-defined inclusion criteria. Compared to PC pigs, IC pigs have a higher average daily gain (ADG; +32.54 g/day, P < 0.0001) and more favorable feed conversion ratio (FCR; -0.234 kg/kg, P < 0.0001), higher live weight and percentage lean, and lower hot carcass weight (HCW) and dressing percentage. Compared to EM pigs, IC pigs have a higher ADG (+65.04 g/day, P < 0.0001), FCR (+0.075 kg/kg, P < 0.0001), live weight and HCW, and a similar dressing percentage. Conventionally raised IC pigs yield more valuable meat compared to PC (+0.628 kg) and EM (+1.385 kg) pigs. Heavy IC pigs (HCW > 97.7 kg) destined for the production of high-quality cured products gain approximately 0.3 kg more ham than their PC counterparts, with backfat and intramuscular fat still fulfilling the requirements for high-quality cured products. The risk of exceeding the ToD for skatole and androstenone is similar in IC and PC pigs, but significantly higher in EM pigs. Results from our meta-analyses confirm growth performance advantages of IC pigs compared with PC or EM pigs, and reveal a higher gain of valuable meat and a similar risk of boar taint as estimated for PC pigs.

New vaccine administration practice recommendations from the Canadian Immunization Guide.

BACKGROUND: The Canadian Immunization Guide (CIG) is published online by the Public Health Agency of Canada and summarizes guidance on vaccines for human use into a single resource. Chapters are reviewed and updated on a regular basis. Vaccine administration is a critical part of any immunization program. Recently, the CIG chapter on vaccine administration practices was updated. OBJECTIVE: To provide highlights of recent changes to the Vaccine Administration Practices chapter of the CIG. APPROACH: Vaccine-specific guidance in the CIG is based on National Committee on Immunization (NACI) and Committee to Advise on Tropical Medicine and Travel (CATMAT) recommendations as well as new recommendations developed by the CIG Working Group members and NACI Secretariat technical staff. New recommendations are based on a review of the literature, including systematic reviews when available, a review of guidance provided by other National Immunization Technical Advisory Groups and expert opinion. The revisions are approved by the Working Group chair, as well as NACI. RESULTS: Highlights of new recommendations include the following: vaccine providers should adhere to jurisdictional or organizational policies and procedures regarding combining the contents of multi-dose vials; clinical judgement should be used when selecting needle length for intramuscular injections that takes into account the vaccine recipient's weight, gender and age; filter needles are not recommended for vaccine administration as they may filter out active ingredients such as adjuvants; an injection site other than in an area where lymphatic drainage may be impaired should be considered; there is no evidence or theoretical rationale for avoiding injection through a tattoo or superficial birthmark; and immunization pain management strategies have now been developed for all ages. CONCLUSION: Recommendations in vaccine administration practices have recently been changed in some important ways. The Public Health Agency of Canada is committed to providing information on immunization in an easily accessible, reader-friendly format for healthcare providers and policy-makers.

Eating well with Canada's food guide? Authoritative knowledge about food and health among newcomer mothers.

PROBLEM: Current versions of Canada's Food Guide (CFG) aim to inform a culturally diverse population, but it is not known how intended audiences from different cultural and linguistic groups within Canada's diverse population understand and apply its messages. METHODS: We analyzed data from qualitative interviews conducted with 32 newcomer mothers of children aged 1-5 years to explore how conceptions of food and health change with migration to Canada among Spanish-speaking Latin American and Tamil Speaking Sri Lankan newcomers and may influence the appropriateness and applicability of Canada's Food Guide (CFG) as a nutrition education tool. We applied Jordan's model of authoritative knowledge to identify different forms of newcomer maternal nutrition knowledge, how they influence child feeding practices, and shifts causing some forms of knowledge to be devalued in favor of others. RESULTS: Awareness of CFG differed between groups, with all Latin American and only half of Tamil participants familiar with it. Three distinct, overlapping ways of knowing about the relationship between food and health are identified within both groups of mothers: "natural" foods as healthy; influence of foods on illness susceptibility, and the nutritional components of food. CFG was found to be limited in its representations of recommended foods and its exclusive utilization of biomedical concepts of nutrition. CONCLUSIONS: Development of new, culturally competent versions of CFG that depict a variety of ethno-culturally meaningful diets and encompass both non-biomedical conceptualizations of food and health has the potential to enhance effective knowledge translation of CFG's key messages to an increasingly cosmopolitan Canadian population.

The Shikani optical stylet as an alternative to the GlideScope® videolaryngoscope in simulated difficult intubations--a randomised controlled trial.

The GlideScope(®) videolaryngoscope is widely utilised in the management of the difficult airway. However, complications such as mucosal injury, palatal and tonsillar perforations have been reported with its use. The Shikani optical stylet has shown promise in aiding difficult intubations. This randomised controlled trial evaluates the Shikani optical stylet as an alternative to the GlideScope videolaryngoscope in patients undergoing anaesthesia, with a simulated difficult airway. Sixty patients were randomised to undergo tracheal intubation with either the GlideScope videolaryngoscope (n = 30) or the Shikani optical stylet (n = 30). All patients had rigid cervical collars applied to simulate a difficult airway. Tracheal intubation was successful in all patients, with first attempt success rates of 97% (29/30) the GlideScope group compared with 93% (28/30) in the Shikani group compared with 93% (28/30) in the Shikani group (p = 0.5). The mean (SD) time to intubation was 64 (37) s when using the GlideScope and 58 (26) s in the Shikani group (p = 0.48). A higher incidence of airway mucosal injury was noted in patients intubated with the GlideScope videolaryngoscope, compared with the Shikani optical stylet (5 vs 0, respectively, p = 0.05). This trial suggests that the Shikani optical stylet is a viable alternative to the GlideScope videolaryngoscope in the management of the difficult airway.

Induction of tolerance to factor VIII by transient co-administration with rapamycin.

BACKGROUND: Formation of inhibitory antibodies is a frequent and serious complication of factor (F) VIII replacement therapy for the X-linked bleeding disorder hemophilia A. Similarly, hemophilia A mice develop high-titer inhibitors to recombinant human FVIII after a few intravenous injections. OBJECTIVE: Using the murine model, the study sought to develop a short regimen capable of inducing tolerance to FVIII. METHODS: A 1-month immunomodulatory protocol, consisting of FVIII administration combined with oral delivery of rapamycin, was developed. RESULTS: The protocol effectively prevented formation of inhibitors to FVIII upon subsequent intravenous treatment (weekly for 3.5 months). Control mice formed high-titer inhibitors and had CD4(+) T effector cell responses characterized by expression of IL-2, IL-4 and IL-6. Tolerized mice instead had a CD4(+)CD25(+)FoxP3(+) T cell response to FVIII that suppressed antibody formation upon adoptive transfer, indicating a shift from Th2 to Treg if FVIII antigen was introduced to T cells during inhibition with rapamycin. CD4(+) T cells from tolerized mice also expressed TGF-ß1 and CTLA4, but not IL-10. The presence of FVIII antigen during the time of rapamycin administration was required for specific tolerance induction. CONCLUSIONS: The study shows that a prophylactic immune tolerance protocol for FVIII can be developed using rapamycin, a drug that is already widely in clinical application. Immune suppression with rapamycin was mild and highly transient, as the mice regained immune competence within a few weeks.

Indoleamine 2,3-dioxygenase attenuates inhibitor development in gene-therapy-treated hemophilia A mice.

A serious impediment to gene and protein replacement therapy in hemophilia A is the development of inhibitors. Mechanisms responsible for inhibitor development include T-cell-dependent adaptive immune responses and the CD28-B7 signaling pathway that eventually leads to the formation of antibodies directed against factor VIII (FVIII). Indoleamine 2,3-dioxygenase (IDO) is a potent immunosuppressive enzyme that can inhibit T-cell responses and induce T-cell apoptosis by regulation of tryptophan metabolism. Kynurenine, one of the metabolites of tryptophan, has been implicated as an immune modulator. Here we hypothesize that co-delivery of the genes for FVIII and IDO can attenuate inhibitor formation. Using transposon-based gene delivery, we observed long-term therapeutic FVIII expression and significantly reduced inhibitor titers when the genes were co-delivered. Co-expression of FVIII and IDO in the liver was associated with increased plasma kynurenine levels, an inhibition of T-cell infiltration and increased apoptosis of T cells within the liver. These experiments suggest that modulation of tryptophan catabolism through IDO expression provides a novel strategy to reduce inhibitor development in hemophilia gene/protein therapy.

A randomised controlled trial on beneficial effects of early feeding post-Caesarean delivery under regional anaesthesia.

INTRODUCTION: We prospectively investigated the incidence of ileus, nausea/vomiting, and hospital course of non-labouring women fed immediately after Caesarean delivery under regional anaesthesia. METHODS: 196 patients were randomised into either the early-fed group (250 ml clear fruit juice 30 minutes postoperatively, and unlimited solid food thereafter) or the control group (clear feeds allowed after two hours, advanced to solids as tolerated). RESULTS: Both groups had similar baseline demographics and operative characteristics. Bowel sounds were present immediately postoperatively in 90.8 percent (early group) versus 95.9 percent (control). The early-fed group had reduced time to first drink (0.86 +/- 0.6 hours versus 14.4 +/- 18.2 hours) and solid food intake (4.2 +/- 2.7 hours versus 20.0 +/- 6.8 hours), earlier passage of flatus (14.4 +/- 9.4 hours versus 21.0 +/- 10.4 hours) and first stool (44.4 +/- 18.7 hours versus 65.6 +/- 25.4 hours), shorter duration of intravenous hydration (12.8 +/- 7.5 hours versus 22.4 +/- 5.8 hours), and earlier removal of intravenous cannulae (20.5 +/- 6.7 hours versus 24.7 +/- 7.8 hours), with all p-values less than 0.001. Early-fed mothers also mobilised (23.1 +/- 6.8 hours versus 27.4 +/- 7.6 hours), commenced breastfeeding (26.5 +/- 14.1 hours versus 38.8 +/- 21.8 hours), and were ready for discharge earlier (44.3 +/- 10.4 hours versus 62.0 +/- 12.7 hours), compared to the control group, with all p-values less than 0.001. There was no difference in mild ileus symptoms (3.1 percent). Earlier solid intake resulted in more nausea (10.2 percent versus 2 percent, p-value is 0.033), which was self-limiting. Maternal satisfaction rated higher in the early-fed group (90 versus 60, on visual analogue scale score 0-100, p-value is less than 0.001). CONCLUSION: This prospective randomised trial showed no increase in ileus with early feeding post-Caesarean delivery under spinal anaesthesia, with added benefits of earlier intravenous cannulae removal, ambulation, breastfeeding initiation and potential for shorter hospitalisation. Despite increased nausea in those taking solids earlier (but not feeds), maternal satisfaction rated higher in the early-fed group.

Sustained correction of glycogen storage disease type II using adeno-associated virus serotype 1 vectors.

Glycogen storage disease type II (GSDII) is caused by a lack of functional lysosomal acid alpha-glucosidase (GAA). Affected individuals store glycogen in lysosomes beginning during gestation, ultimately resulting in fatal hypertrophic cardiomyopathy and respiratory failure. We have assessed the utility of recombinant adeno-associated virus (rAAV) vectors to restore GAA activity in vivo in a mouse model of GSDII (Gaa(-/-)). A single systemic administration of a rAAV serotype 1 (rAAV1) vector to neonate animals resulted in restored cardiac GAA activity to 6.4 times the normal level (mean=641+/-190% of normal (Gaa(+/+)) levels with concomitant glycogen clearance) at 11 months postinjection. Greater than 20% of normal levels of GAA activity were also observed in the diaphragm and quadriceps muscles. Furthermore, functional correction of the soleus skeletal muscle was also observed compared to age-matched untreated Gaa(-/-) control animals. These results demonstrate that rAAV1 vectors can mediate sustained therapeutic levels of correction of both skeletal and cardiac muscles in a model of fatal cardiomyopathy and muscular dystrophy.

Mapping genes that regulate density of dopamine transporters and correlated behaviors in recombinant inbred mice.

Binding of 3beta-(4-iodophenyl) tropane-2beta-carboxylic acid methyl ester ([125I]RTI-55) to the dopamine transporter (DAT) in neostriatum from C57BL/6J, DBA/2J, and 21 BXD recombinant inbred (RI) mouse strains indicated highly significant strain differences in DAT density (Bmax) but no significant differences in affinity (Kd) for this radioligand. Strain mean Bmax values and the known genomic locations of 1390 marker loci were used to carry out a genome-wide search for quantitative trait loci (QTLs), which are chromosomal sites containing genes that influence DAT expression. This search revealed an unusually large effect QTL on chromosome 19 in the region of the proopiomelanocortin pseudogene Pomc-ps1 (8-11 cM), homologous to regions of human chromosomes 9q21 and 11q12-13. This QTL (logarithm of the odds 4.7, df = 1, p = 3 x 10(-6)) by conservative estimates accounts for just over half of the genetic variation in DAT binding site density. The QTL is not the DAT gene itself (Dat1, chromosome 13), but a powerful modulator of DAT expression in neostriatum. Furthermore, DAT expression levels in 20 of the BXD RI strains and the chromosome 19 QTL were correlated with cocaine and methamphetamine-induced locomotor activation and thermic responses (hypo- or hyperthermia), but were not correlated with behaviors related to sensitization, reward, voluntary consumption, stereotypy, or seizures induced by these two psychostimulant drugs. The results suggest that there is a gene(s) on proximal chromosome 19 that strongly influences DAT expression in neostriatum and may influence psychostimulant-induced activity and thermal responses.

Spatial and temporal modulation of joint stiffness during multijoint movement.

Joint stiffness measurements during small transient perturbations have suggested that stiffness during movement is different from that observed during posture. These observations are problematic for theories like the classical equilibrium point hypothesis, which suggest that desired trajectories during movement are enforced by joint stiffness. We measured arm impedances during large, slow perturbations to obtain detailed information about the spatial and temporal modulation of stiffness and viscosity during movement. While our measurements of stiffness magnitudes during movement generally agreed with the results of measurements using fast perturbations, they revealed that joint stiffness undergoes stereotyped changes in magnitude and aspect ratio which depend on the direction of movement and show a strong dependence on joint angles. Movement simulations using measured parameters show that the measured modulation of impedance acts as an energy conserving force field to constrain movement. This mechanism allows for a computationally simplified account of the execution of multijoint movement. While our measurements do not rule out a role for afferent feedback in force generation, the observed stereotyped restoring forces can allow a dramatic relaxation of the accuracy requirements for forces generated by other control mechanisms, such as inverse dynamical models.

TBX5 transcription factor regulates cell proliferation during cardiogenesis.

Mutations in human TBX5, a member of the T-box transcription factor gene family, cause congenital cardiac septation defects and isomerism in autosomal dominant Holt-Oram syndrome. To determine the cellular function of TBX5 in cardiogenesis, we overexpressed wild-type and mutant human TBX5 isoforms in vitro and in vivo. TBX5 inhibited cell proliferation of D17 canine osteosarcoma cells and MEQC quail cardiomyocyte-like cells in vitro. Mutagenesis of the 5' end of the T-box but not the 3' end of the T-box abolished this effect. Overexpression of TBX5 in embryonic chick hearts showed that TBX5 inhibits myocardial growth and trabeculation. TBX5 effects in vivo were abolished by Gly80Arg missense mutation of the 5' end of the T-box. PCNA analysis in transgenic chick hearts revealed that TBX5 overexpression does suppress embryonic cardiomyocyte proliferation in vivo. Inhibitory effects of TBX5 on cardiomyocyte proliferation include a noncell autonomous process in vitro and in vivo. TBX5 inhibited proliferation of both nontransgenic cells cocultured with transgenic cells in vitro and nontransgenic cardiomyocytes in transgenic chick hearts with mosaic expression of TBX5 in vivo. Immunohistochemical studies of human embryonic tissues, including hearts, also demonstrated that TBX5 expression is inversely related to cellular proliferation. We propose that TBX5 can act as a cellular arrest signal during vertebrate cardiogenesis and thereby participate in modulation of cardiac growth and development.