Quantitative trait loci for bone traits segregating independently of those for growth in an F-2 broiler X layer cross

An F broiler-layer cross was phenotyped for 18 skeletal traits at 6, 7 and 9 weeks of age and genotyped with 120 microsatellite markers. Interval mapping identified 61 suggestive and significant QTL on 16 of the 25 linkage groups for 16 traits. Thirty-six additional QTL were identified when the assumption that QTL were fixed in the grandparent lines was relaxed. QTL with large effects on the lengths of the tarsometatarsus, tibia and femur, and the weights of the tibia and femur were identified on GGA4 between 217 and 249 cM. Six QTL for skeletal traits were identified that did not co-locate with genome wide significant QTL for body weight and two body weight QTL did not coincide with skeletal trait QTL. Significant evidence of imprinting was found in ten of the QTL and QTL x sex interactions were identified for 22 traits. Six alleles from the broiler line for weight- and size-related skeletal QTL were positive. Negative alleles for bone quality traits such as tibial dyschondroplasia, leg bowing and tibia twisting generally originated from the layer line suggesting that the allele inherited from the broiler is more protective than the allele originating from the layer

Assortment optimisation under a general discrete choice model: A tight analysis of revenue-ordered assortments

The assortment problem in revenue management is the problem of deciding which subset of products to offer to consumers in order to maximise revenue. A simple and natural strategy is to select the best assortment out of all those that are constructed by fixing a threshold revenue $\pi$ and then choosing all products with revenue at least $\pi$. This is known as the revenue-ordered assortments strategy. In this paper we study the approximation guarantees provided by revenue-ordered assortments when customers are rational in the following sense: the probability of selecting a specific product from the set being offered cannot increase if the set is enlarged. This rationality assumption, known as regularity, is satisfied by almost all discrete choice models considered in the revenue management and choice theory literature, and in particular by random utility models. The bounds we obtain are tight and improve on recent results in that direction, such as for the Mixed Multinomial Logit model by Rusmevichientong et al. (2014). An appealing feature of our analysis is its simplicity, as it relies only on the regularity condition. We also draw a connection between assortment optimisation and two pricing problems called unit demand envy-free pricing and Stackelberg minimum spanning tree: These problems can be restated as assortment problems under discrete choice models satisfying the regularity condition, and moreover revenue-ordered assortments correspond then to the well-studied uniform pricing heuristic. When specialised to that setting, the general bounds we establish for revenue-ordered assortments match and unify the best known results on uniform pricing.Comment: Minor changes following referees' comment

Home advantage in the Winter Paralympic Games 1976–2014

Purpose: There is a limited amount of home advantage research concerned with winter sports. There is also a distinct lack of studies that investigate home advantage in the context of para-sport events. This paper addresses this gap in the knowledge by examining home advantage in the Winter Paralympic Games. Methods: Using a standardised measure of success, we compared the performances of host nations at home with their own performances away from home between 1976 and 2014. Both country level and individual sport level analysis is conducted for this time period. Comparisons are also drawn with the Winter Olympic Games since 1992, the point from which both the Winter Olympic Games and the Winter Paralympic Games have been hosted by the same nations and in the same years. Results: Clear evidence of a home advantage effect in the Winter Paralympic Games was found at country level. When examining individual sports, only alpine skiing and cross country skiing returned a significant home advantage effect. When comparing home advantage in the Winter Paralympic Games with the Winter Olympic Games for the last seven host nations (1992–2014), we found that home advantage was generally more pronounced (although not a statistically significant difference) in the case of the former. Conclusion: The causes of home advantage in the Winter Paralympic Games are unclear and should be investigated further

Human papillomavirus 16 is an aetiological factor of scrotal cancer

Background: Squamous cell scrotal carcinoma (SCSC) is an infrequent skin cancer associated historically with occupational carcinogens. Human papillomavirus (HPV) DNA has been associated with SCSC but there is no definitive proof of its oncogenic role. Methods: Human papillomavirus-DNA and -E6*I mRNA were analysed in six invasive histologically typed SCSC. LCM-PCR was used to localise HPV DNA to tumour cells. P16(INK4a)and p53 expression were studied by immunohistochemistry. Results: In three warty or basaloid SCSC HPV16-DNA and E6*I-mRNA were detected. LCM-PCR confirmed HPV16 was in p16(INK4a)-positive malignant cells. However, of three usual-type SCSC, all were HPV-negative and two expressed p53 protein but not p16(INK4a). Conclusions: Human papillomavirus 16 was present in tumour cells and oncogenically active in basaloid and warty SCSC, whereas usual SCSC was HPV-negative and showed immunostaining, suggesting p53 mutation. The dual pathways of oncogenesis and relation between histological type of SCSC and HPV are similar to that in penile cancers

Preclinical Assessment of the Treatment of Second-Stage African Trypanosomiasis with Cordycepin and Deoxycoformycin

There is an urgent need to substitute the highly toxic arsenic compounds still in use for treatment of the encephalitic stage of African trypanosomiasis, a disease caused by infection with Trypanosoma brucei. We exploited the inability of trypanosomes to engage in de novo purine synthesis as a therapeutic target. Cordycepin was selected from a trypanocidal screen of a 2200-compound library. When administered together with the adenosine deaminase inhibitor deoxycoformycin, cordycepin cured mice inoculated with the human pathogenic subspecies T. brucei rhodesiense or T. brucei gambiense even after parasites had penetrated into the brain. Successful treatment was achieved by intraperitoneal, oral or subcutaneous administration of the compounds. Treatment with the doublet also diminished infection-induced cerebral inflammation. Cordycepin induced programmed cell death of the parasites. Although parasites grown in vitro with low doses of cordycepin gradually developed resistance, the resistant parasites lost virulence and showed no cross-resistance to trypanocidal drugs in clinical use. Our data strongly support testing cordycepin and deoxycoformycin as an alternative for treatment of second-stage and/or melarsoprol-resistant HAT

A novel miniature in-line load-cell to measure in-situ tensile forces in the tibialis anterior tendon of rats.

Direct measurements of muscular forces usually require a substantial rearrangement of the biomechanical system. To circumvent this problem, various indirect techniques have been used in the past. We introduce a novel direct method, using a lightweight (~0.5 g) miniature (3 x 3 x 7 mm) in-line load-cell to measure tension in the tibialis anterior tendon of rats. A linear motor was used to produce force-profiles to assess linearity, step-response, hysteresis and frequency behavior under controlled conditions. Sensor responses to a series of rectangular force-pulses correlated linearly (R2 = 0.999) within the range of 0-20 N. The maximal relative error at full scale (20 N) was 0.07% of the average measured signal. The standard deviation of the mean response to repeated 20 N force pulses was ± 0.04% of the mean response. The step-response of the load-cell showed the behavior of a PD2T2-element in control-engineering terminology. The maximal hysteretic error was 5.4% of the full-scale signal. Sinusoidal signals were attenuated maximally (-4 dB) at 200 Hz, within a measured range of 0.01-200 Hz. When measuring muscular forces this should be of minor concern as the fusion-frequency of muscles is generally much lower. The newly developed load-cell measured tensile forces of up to 20 N, without inelastic deformation of the sensor. It qualifies for various applications in which it is of interest directly to measure forces within a particular tendon causing only minimal disturbance to the biomechanical system

The SPINK gene family and celiac disease susceptibility

The gene family of serine protease inhibitors of the Kazal type (SPINK) are functional and positional candidate genes for celiac disease (CD). Our aim was to assess the gut mucosal gene expression and genetic association of SPINK1, -2, -4, and -5 in the Dutch CD population. Gene expression was determined for all four SPINK genes by quantitative reverse-transcription polymerase chain reaction in duodenal biopsy samples from untreated (n = 15) and diet-treated patients (n = 31) and controls (n = 16). Genetic association of the four SPINK genes was tested within a total of 18 haplotype tagging SNPs, one coding SNP, 310 patients, and 180 controls. The SPINK4 study cohort was further expanded to include 479 CD cases and 540 controls. SPINK4 DNA sequence analysis was performed on six members of a multigeneration CD family to detect possible point mutations or deletions. SPINK4 showed differential gene expression, which was at its highest in untreated patients and dropped sharply upon commencement of a gluten-free diet. Genetic association tests for all four SPINK genes were negative, including SPINK4 in the extended case/control cohort. No SPINK4 mutations or deletions were observed in the multigeneration CD family with linkage to chromosome 9p21-13 nor was the coding SNP disease-specific. SPINK4 exhibits CD pathology-related differential gene expression, likely derived from altered goblet cell activity. All of the four SPINK genes tested do not contribute to the genetic risk for CD in the Dutch population

A Novel ‘Gene Insertion/Marker Out’ (GIMO) Method for Transgene Expression and Gene Complementation in Rodent Malaria Parasites

Research on the biology of malaria parasites has greatly benefited from the application of reverse genetic technologies, in particular through the analysis of gene deletion mutants and studies on transgenic parasites that express heterologous or mutated proteins. However, transfection in Plasmodium is limited by the paucity of drug-selectable markers that hampers subsequent genetic modification of the same mutant. We report the development of a novel ‘gene insertion/marker out’ (GIMO) method for two rodent malaria parasites, which uses negative selection to rapidly generate transgenic mutants ready for subsequent modifications. We have created reference mother lines for both P. berghei ANKA and P. yoelii 17XNL that serve as recipient parasites for GIMO-transfection. Compared to existing protocols GIMO-transfection greatly simplifies and speeds up the generation of mutants expressing heterologous proteins, free of drug-resistance genes, and requires far fewer laboratory animals. In addition we demonstrate that GIMO-transfection is also a simple and fast method for genetic complementation of mutants with a gene deletion or mutation. The implementation of GIMO-transfection procedures should greatly enhance Plasmodium reverse-genetic research

The 3-methylglutaconic acidurias: what’s new?

The heterogeneous group of 3-methylglutaconic aciduria (3-MGA-uria) syndromes includes several inborn errors of metabolism biochemically characterized by increased urinary excretion of 3-methylglutaconic acid. Five distinct types have been recognized: 3-methylglutaconic aciduria type I is an inborn error of leucine catabolism; the additional four types all affect mitochondrial function through different pathomechanisms. We provide an overview of the expanding clinical spectrum of the 3-MGA-uria types and provide the newest insights into the underlying pathomechanisms. A diagnostic approach to the patient with 3-MGA-uria is presented, and we search for the connection between urinary 3-MGA excretion and mitochondrial dysfunction