Translational insights and overall survival in the U31402-A-U102 study of patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC.

BACKGROUND: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd. PATIENTS AND METHODS: Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC. RESULTS: In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% [95% confidence interval (CI) 30.0% to 52.7%], median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified. CONCLUSIONS: In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy.

Whole-genome sequencing analysis of molecular epidemiology and silent transmissions causing meticillin-resistant Staphylococcus aureus bloodstream infections in a university hospital.

BACKGROUND: The emergence of novel genomic-type clones, such as community-associated meticillin-resistant Staphylococcus aureus (MRSA) and livestock-associated MRSA, and their invasion into hospitals have become major concerns worldwide; however, little information is available regarding the prevalence of MRSA in Japan. Whole-genome sequencing (WGS) has been conducted to analyse various pathogens worldwide. Therefore, it is important to establish a genome database of clinical MRSA isolates available in Japan. AIM: A molecular epidemiological analysis of MRSA strains isolated from bloodstream-infected patients in a Japanese university hospital was conducted using WGS and single-nucleotide polymorphism (SNP) analysis. Additionally, through a review of patients' clinical characteristics, the effectiveness of SNP analysis as a tool for detecting silent nosocomial transmission that may be missed by other methods was evaluated in diverse settings and various time points of detection. METHODS: Polymerase-chain-reaction-based staphylococcal cassette chromosome mec (SCCmec) typing was performed using 135 isolates obtained between 2014 and 2018, and WGS was performed using 88 isolates obtained between 2015 and 2017. FINDINGS: SCCmec type II strains, prevalent in 2014, became rare in 2018, whereas the prevalence of SCCmec type IV strains increased from 18.75% to 83.87% of the population, and became the dominant clones. Clonal complex (CC) 5 CC8 and CC1 were detected between 2015 and 2017, with CC1 being dominant. In 88 cases, SNP analyses revealed nosocomial transmissions among 20 patients which involved highly homologous strains. CONCLUSIONS: Routine monitoring of MRSA by whole-genome analysis is effective not only for gaining knowledge regarding molecular epidemiology, but also for detecting silent nosocomial transmission.

Efficacy of a "provisional incision" for longitudinal flap division after free-flap surgery.

Fix and flap surgery for severe open limb fractures is already a standard treatment. In cases where the fracture is complicated or accompanied by bone defects, secondary surgery is required for fracture sites covered with a myocutaneous flap after the soft tissue condition has stabilized. We applied the delayed procedure concept used for distant flaps and attempted to prevent postoperative myocutaneous flap necrosis by performing a provisional incision prior to the longitudinal incision of the flap. We report the course of five cases of the longitudinal division of the myocutaneous flap using "provisional incision" after free-flap surgery for severe open fracture and verify its usefulness. In this case series, five patients with severe open limb fractures treated from 2020 to 2021 who underwent longitudinal incision of the myocutaneous flap using provisional incision after free-flap surgery were included. The types of flaps used for soft tissue reconstruction in the acute phase, the reasons for the need for secondary surgery, the period from soft tissue reconstruction to additional surgery, and the healing status of soft tissue after secondary surgery were all investigated retrospectively. The types of flaps used for soft tissue reconstruction were latissimus dorsi myocutaneous flap in four cases and anterolateral thigh flap in one case. The breakdown of secondary surgery was osteosynthesis in one case, plate removal in one case, and bone cement removal and autologous bone grafting in three cases. The period from soft tissue reconstruction to secondary surgery ranged from 6 weeks to 4 months. In all cases, the wound healed without necrosis of the myocutaneous flap. For the treatment of severe open limb fractures, longitudinal division of the myocutaneous flap using "provisional incision" is a safer approach to the necessary secondary surgery and reduces the possibility of necrosis of the flap.

High-power laser experiment on developing supercritical shock propagating in homogeneously magnetized plasma of ambient gas origin.

A developing supercritical collisionless shock propagating in a homogeneously magnetized plasma of ambient gas origin having higher uniformity than the previous experiments is formed by using high-power laser experiment. The ambient plasma is not contaminated by the plasma produced in the early time after the laser shot. While the observed developing shock does not have stationary downstream structure, it possesses some characteristics of a magnetized supercritical shock, which are supported by a one-dimensional full particle-in-cell simulation taking the effect of finite time of laser-target interaction into account.

Characterization of the oral and faecal microbiota associated with atopic dermatitis in dogs selected from a purebred Shiba Inu colony.

Atopic dermatitis (AD) is a chronic and relapsing multifactorial inflammatory skin disease that also affects dogs. The oral and gut microbiota are associated with many disorders, including allergy. Few studies have addressed the oral and gut microbiota in dogs, although the skin microbiota has been studied relatively well in these animals. Here, we studied the AD-associated oral and gut microbiota in 16 healthy and 9 AD dogs from a purebred Shiba Inu colony. We found that the diversity of the oral microbiota was significantly different among the dogs, whereas no significant difference was observed in the gut microbiota. Moreover, a differential abundance analysis detected the Family_XIII_AD3011_group (Anaerovoracaceae) in the gut microbiota of AD dogs; however, no bacterial taxa were detected in the oral microbiota. Third, the comparison of the microbial co-occurrence patterns between AD and healthy dogs identified differential networks in which the bacteria in the oral microbiota that were most strongly associated with AD were related to human periodontitis, whereas those in the gut microbiota were related to dysbiosis and gut inflammation. These results suggest that AD can alter the oral and gut microbiota in dogs.

Antibody-like proteins that capture and neutralize SARS-CoV-2.

To combat severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) and any unknown emerging pathogens in the future, the development of a rapid and effective method to generate high-affinity antibodies or antibody-like proteins is of critical importance. We here report high-speed in vitro selection of multiple high-affinity antibody-like proteins against various targets including the SARS-CoV-2 spike protein. The sequences of monobodies against the SARS-CoV-2 spike protein were successfully procured within only 4 days. Furthermore, the obtained monobody efficiently captured SARS-CoV-2 particles from the nasal swab samples of patients and exhibited a high neutralizing activity against SARS-CoV-2 infection (half-maximal inhibitory concentration, 0.5 nanomolar). High-speed in vitro selection of antibody-like proteins is a promising method for rapid development of a detection method for, and of a neutralizing protein against, a virus responsible for an ongoing, and possibly a future, pandemic.

Dominant effect of relative tropical Atlantic warming on major hurricane occurrence.

Here we explore factors potentially linked to the enhanced major hurricane activity in the Atlantic Ocean during 2017. Using a suite of high-resolution model experiments, we show that the increase in 2017 major hurricanes was not primarily caused by La Niña conditions in the Pacific Ocean but rather triggered mainly by pronounced warm sea surface conditions in the tropical North Atlantic. Further, we superimpose a similar pattern of North Atlantic surface warming on data for long-term increasing sea surface temperature (a product of increases in greenhouse gas concentrations and decreases in aerosols) to show that this warming trend will likely lead to even higher numbers of major hurricanes in the future. The key factor controlling Atlantic major hurricane activity appears to be the degree to which the tropical Atlantic warms relative to the rest of the global ocean.

Long-term patient survival after the surgical treatment of bone and soft-tissue metastases from renal cell carcinoma.

Aims: The aims of this study were to evaluate the long-term outcome of surgery for bone or soft-tissue metastases from renal cell carcinoma (RCC) and to determine factors that affect prognosis. Patients and Methods: Between 1993 and 2014, 58 patients underwent surgery for bone or soft-tissue metastases from RCC at our hospital. There were 46 men and 12 women with a mean age of 60 years (25 to 84). The mean follow-up period was 52 months (1 to 257). The surgical sites included the spine (33 patients), appendicular skeleton (ten patients), pelvis (eight patients), thorax (four patients), and soft tissue (three patients). The surgical procedures were en bloc metastasectomy in 46 patients (including 33 patients of total en bloc spondylectomy (TES)) and intralesional curettage in 12 patients. These patients were retrospectively evaluated for factors associated with prognosis. Results: The one-, three-, five-, ten-, and 15-year overall survival (OS) rates were 89%, 75%, 62%, 48%, and 25%, respectively. The median survival time (MST) was 127 months for en bloc metastasectomy and 54 months for intralesional curettage and bone grafting. The median survival time was 127 months for the spine, 140 months for lesions of the appendicular skeleton, and 54 months for the pelvis. Multivariate analysis showed that non-clear cell type RCC and metastases to more than two sites were independent risk factors for a poor prognosis. Conclusion: Patients with bone or soft-tissue metastases from a RCC have a reasonable prognosis, making surgical resection a viable option even in patients in whom the metastases are advanced. Cite this article: Bone Joint J 2018;100-B:1241-8.

Subpopulation Primers Essential for Exhaustive Detection of Diverse Hemagglutinin Genes of H5 Subtype Avian Influenza Viruses by Loop-Mediated Isothermal Amplification Method.

Loop-mediated isothermal amplification (LAMP) is a potential screening test for avian influenza (AI), but its narrow detection spectrum limits its applications. To improve this narrow detection spectrum, 3 types of primers were compared for detection of diverse H5 subtype hemagglutinin (HA) genes. Four and 6 genes, of 10 genetically different H5 HA genes tested, were detected with S primers specific for A/duck/Tsukuba/9/2005 (H5N2) and with M primers (which contained mixed bases), respectively. In contrast, all 10 HA genes became positive with population primers (P primers) (a mixture of primers designed for each subpopulation of 2,202 HA genes). Our study indicated that the P primers for the forward inner primer (FIP) and backward inner primer (BIP) sites were essential for exhaustive detection, whereas those for the F3, forward loop (FL), backward loop (BL), and B3 sites were exchangeable with M primers. A base mismatch experiment demonstrated that HA genes with ≤2 base mismatches per primer site and ≤10 base mismatches per HA gene were amplifiable. Reverse transcription-LAMP was broadly reactive, specific for H5 subtype HA genes, and applicable to field samples, with the sensitivity of real-time PCR. The in silico analysis suggested that most H5 HA genes (2,586 positive genes/2,588 genes tested) registered in the GenBank database might be amplifiable. These results indicate that the use of subpopulation primers in LAMP allows exhaustive detection of diverse HA genes and H5 LAMP can be used as a reliable AI screening test in general diagnostic laboratories.

Evaluation of the effect of lanthanum carbonate hydrate on the pharmacokinetics of roxadustat in non-elderly healthy adult male subjects.

WHAT IS KNOWN AND OBJECTIVE: Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor currently being investigated for the treatment of anemia in chronic kidney disease. Lanthanum carbonate is a phosphate binder that is commonly used to treat hyperphosphatemia in patients with chronic kidney disease. This study investigated the effect of lanthanum carbonate on the pharmacokinetics, safety and tolerability of a single oral dose of roxadustat in healthy non-elderly adult male subjects. METHODS: This was an open-label, randomized, two-period, two-sequence crossover study in non-elderly healthy adult males. Subjects randomized to Group 1 received roxadustat alone during Period 1 and roxadustat concomitantly with lanthanum carbonate during Period 2; subjects randomized to Group 2 received roxadustat concomitantly with lanthanum carbonate during Period 1 and roxadustat alone during Period 2. All subjects received a single oral dose of 100 mg roxadustat on Day 1 in both periods. Subjects receiving concomitant lanthanum carbonate received 750 mg lanthanum carbonate three times daily on Days 1 and 2. Pharmacokinetic assessments were conducted on Days 1-4 in both periods. The primary study outcomes were the area under the concentration-time curve from the time of dosing extrapolated to infinity (AUCinf ), and maximum concentration (Cmax ); the geometric least squares mean ratio (GMR; roxadustat + lanthanum carbonate/roxadustat alone) and corresponding 90% confidence interval (CI) was calculated for AUCinf and Cmax . Safety was assessed by the occurrence of treatment-emergent adverse events (TEAEs), laboratory test results, vital signs and standard 12-lead electrocardiogram. RESULTS AND DISCUSSION: A total of 18 subjects were enrolled (Group 1, n = 9; Group 2, n = 9); no subjects discontinued from the study. Roxadustat was rapidly absorbed, reaching maximum plasma concentration between 1 and 4 hours. The GMRs for AUCinf and Cmax were 88.00% (90% CI: 84.01, 92.17) and 98.58% (90% CI: 92.92, 104.58), respectively. The 90% CIs for both parameters were within the no-effect boundaries of 80% and 125%, indicating a lack of effect of lanthanum carbonate on roxadustat absorption. No deaths or serious TEAEs occurred. WHAT IS NEW AND CONCLUSIONS: Concomitant administration of a single oral dose of 100 mg roxadustat and 750 mg lanthanum carbonate three times daily did not impact the AUCinf or Cmax of roxadustat and was considered safe and well tolerated in non-elderly healthy adult male Japanese subjects.

Peptidylarginine deiminase is involved in maintaining the cornified oral mucosa of rats.

BACKGROUND AND OBJECTIVE: Epithelial cells derived from different regions exhibit marked differences in their differentiation capacity, allowing them to provide a suitable protective barrier. We aimed to clarify the role of peptidylarginine deiminase (PAD) in modifying the key epidermal proteins filaggrin (FLG) and keratin 1 (K1) during stratification of the rat palate and buccal mucosa. MATERIAL AND METHODS: We performed immunofluorescence, immunoblotting, PAD activity assays and 2-dimensional electrophoresis, and developed an organotypic culture model. RESULTS: PAD1 expression was highest in the palate, whereas PAD2, PAD3 and PAD4 expression was highest in the skin, suggesting the tissue-specific expression of PAD isozymes that leads to differences in calcium dependency. Immunoblotting showed that the FLG monomer, as well as its degradation products and precursor (proFLG), were most abundantly expressed in the skin but had low expression in the palate, whereas only faint proFLG expression was detected in the buccal mucosa. FLG and K1 were colocalized with PAD1 and were likely to be citrullinated in the cornified layers of the skin; this colocalization was not detected on the palatal surface, and dot-like presence of proFLG that might be citrullinated and that of PAD1 were found in the granules of the palate. Organotypic models derived from the rat palate revealed that PAD inhibition reduced the breakdown of FLG, increased its association with K1 together with epithelial compaction, and decreased permeability in a dye permeability assay. Conversely, PAD stimulation had the opposite effects. CONCLUSION: Citrullination is likely a protein modification that plays an important role in maintaining the structure and function of oral cornified mucosa in a way that is distinctly different from that of the skin.

Heritability estimates of endurance-related phenotypes: A systematic review and meta-analysis.

The aim of this study was to clarify heritability estimates for endurance-related phenotypes and the underlying factors affecting these estimates. A systematic literature search was conducted for studies reporting heritability estimates of endurance-related phenotypes using the PubMed database (up to 30 September 2016). Studies that estimated the heritability of maximal oxygen uptake (V˙O2max), submaximal endurance phenotypes, and endurance performance were selected. The weighted mean heritability for endurance-related phenotypes was calculated using a random-effects model. A total of 15 studies were selected via a systematic review. Meta-analysis revealed that the weighted means of the heritability of V˙O2max absolute values and those adjusted for body weight and for fat-free mass were 0.68 (95% CI: 0.59-0.77), 0.56 (95% CI: 0.47-0.65), and 0.44 (95% CI: 0.13-0.75), respectively. There was a significant difference in the weighted means of the heritability of V˙O2max across these different adjustment methods (P < .05). Moreover, there was evidence of statistical heterogeneity in the heritability estimates among studies. Meta-regression analysis revealed that sex could partially explain the heterogeneity in the V˙O2max heritability estimates adjusted by body weight. For submaximal endurance phenotypes and endurance performance, the weighted mean heritabilities were 0.49 (95% CI: 0.33-0.65) and 0.53 (95% CI: 0.27-0.78), respectively. There was statistically significant heterogeneity in the heritability estimates reported among the studies, and we could not identify the specific factors explaining the heterogeneity. Although existing studies indicate that genetic factors account for 44%-68% of the variability in endurance-related phenotypes, further studies are necessary to clarify these values.

Factors affecting the potential for posterior bony impingement after total hip arthroplasty.

AIMS: Our aim was to evaluate the radiographic characteristics of patients undergoing total hip arthroplasty (THA) for the potential of posterior bony impingement using CT simulations. PATIENTS AND METHODS: Virtual CT data from 112 patients who underwent THA were analysed. There were 40 men and 72 women. Their mean age was 59.1 years (41 to 76). Associations between radiographic characteristics and posterior bony impingement and the range of external rotation of the hip were evaluated. In addition, we investigated the effects of pelvic tilt and the neck/shaft angle and femoral offset on posterior bony impingement. RESULTS: The range of external rotation and the ischiofemoral length were significantly lower, while femoral anteversion, the ischial ratio, and ischial angle were significantly higher in patients with posterior bony impingement compared with those who had implant impingement (p < 0.05). The range of external rotation positively correlated with ischiofemoral length (r = 0.49, p < 0.05), and negatively correlated with ischial length (r = -0.49, p < 0.05), ischial ratio (r =- 0.49, p < 0.05) and ischial angle (r = -0.55, p < 0.05). The range of external rotation was lower in patients with posterior pelvic tilt (p < 0.05) and in those with a high offset femoral component (p < 0.05) due to posterior bony impingement. CONCLUSION: Posterior bony impingement after THA is more likely in patients with a wider ischium and a narrow ischiofemoral space. A high femoral offset and posterior pelvic tilt are also risk factors for this type of impingement. Cite this article: Bone Joint J 2017;99-B:1140-6.

Heritability estimates of muscle strength-related phenotypes: A systematic review and meta-analysis.

The purpose of this study was to clarify the heritability estimates of human muscle strength-related phenotypes (H2 -msp). A systematic literature search was conducted using PubMed (through August 22, 2016). Studies reporting the H2 -msp for healthy subjects in a sedentary state were included. Random-effects models were used to calculate the weighted mean heritability estimates. Moreover, subgroup analyses were performed based on phenotypic categories (eg, grip strength, isotonic strength, jumping ability). Sensitivity analyses were also conducted to investigate potential sources of heterogeneity of H2 -msp, which included age and sex. Twenty-four articles including 58 measurements were included in the meta-analysis. The weighted mean H2 -msp for all 58 measurements was 0.52 (95% confidence intervals [CI]: 0.48-0.56), with high heterogeneity (I2 =91.0%, P<.001). Subgroup analysis showed that the heritability of isometric grip strength, other isometric strength, isotonic strength, isokinetic strength, jumping ability, and other power measurements was 0.56 (95% CI: 0.46-0.67), 0.49 (0.47-0.52), 0.49 (0.32-0.67), 0.49 (0.37-0.61), 0.55 (0.45-0.65), and 0.51 (0.31-0.70), respectively. The H2 -msp decreased with age (P<.05). In conclusion, our results indicate that the influence of genetic and environmental factors on muscle strength-related phenotypes is comparable. Moreover, the role of environmental factors increased with age. These findings may contribute toward an understanding of muscle strength-related phenotypes.

The Association Between MCT1 T1470A Polymorphism and Power-Oriented Athletic Performance.

The purpose of this study was to investigate the effects of the MCT1 T1470A polymorphism (rs1049434) on power-oriented performance and lactate concentration during or after cycling sprints in Japanese wrestlers. Participants (199 wrestlers and 649 controls) were genotyped for the MCT1 T1470A genotype (rs1049434) using the TaqMan® Assay. All wrestlers were international (n=77) or national (n=122) level athletes. Among them, 46 wrestlers performed 2 anaerobic performance tests, a 30-s Wingate Anaerobic test (WAnT) and a series of 10 maximal effort 10-s sprints on a cycle ergometer. Blood lactate levels were measured before, during, and after the tests. In the A-allele recessive model (AA vs. TA+TT), the frequency of the AA genotype was significantly higher in all wrestlers than in controls (p=0.037). Wrestlers with AA genotype had lower blood lactate concentrations than those with TA+TT genotype at 10 min after the WAnT and following the 5th and the final set of repeated cycling sprints (p<0.05). The AA genotype of the MCT1 T1470A polymorphism is over-represented in wrestlers compared with controls and is associated with lower blood lactate concentrations after 30-s WAnT and during intermittent sprint tests in Japanese wrestlers.

Inducement of tissue regeneration of harvested hamstring tendons in a rabbit model.

OBJECTIVES: The objective of this study was to determine if the use of fascia lata as a tendon regeneration guide (placed into the tendon canal following harvesting the semitendinosus tendon) would improve the incidence of tissue regeneration and prevent fatty degeneration of the semitendinosus muscle. MATERIALS AND METHODS: Bilateral semitendinosus tendons were harvested from rabbits using a tendon stripper. On the inducing graft (IG) side, the tendon canal and semitendinosus tibial attachment site were connected by the fascia lata, which was harvested at the same width as the semitendinosus tendon. On the control side, no special procedures were performed. Two groups of six rabbits were killed at post-operative weeks 4 and 8, respectively. In addition, three healthy rabbits were killed to obtain normal tissue. We evaluated the incidence of tendon tissue regeneration, cross-sectional area of the regenerated tendon tissue and proportion of fatty tissue in the semitendinosus muscle. RESULTS: At post-operative week 8, the distal end of the regenerated tissue reached the vicinity of the tibial insertion on the control side in two of six specimens. On the IG side, the regenerated tissue maintained continuity with the tibial insertion in all specimens. The cross-sectional area of the IG side was significantly greater than that of the control side. The proportion of fatty tissue in the semitendinosus muscle on the IG side was comparable with that of the control side, but was significantly greater than that of the normal muscle. CONCLUSIONS: Tendon tissue regenerated with the fascia lata graft was thicker than naturally occurring regenerated tissue. However, the proportion of fatty tissue in the semitendinosus muscle was greater than that of normal muscle.Cite this article: K. Tabuchi, T. Soejima, H. Murakami, K. Noguchi, N. Shiba, K. Nagata. Inducement of tissue regeneration of harvested hamstring tendons in a rabbit model. Bone Joint Res 2016;5:247-252. DOI: 10.1302/2046-3758.56.2000585.

Clustered regulatory interspaced short palindromic repeats (CRISPR)-mediated mutagenesis and phenotype rescue by piggyBac transgenesis in a nonmodel Drosophila species.

How behavioural diversity emerged in evolution is an unexplored subject in biology. To tackle this problem, genes and circuits for a behaviour need to be determined in different species for phylogenetic comparisons. The recently developed clustered regulatory interspaced short palindromic repeats/CRISPR associated protein9 (CRISPR/Cas9) system made such a challenge possible by providing the means to induce mutations in a gene of interest in any organism. Aiming at elucidating diversification in genetic and neural networks for courtship behaviour, we attempted to generate a genetic tool kit in Drosophila subobscura, a nonmodel species distantly related to the genetic model Drosophila melanogaster. Here we report the generation of yellow (y) and white mutations with the aid of the CRISPR/Cas9 system, and the rescue of the y mutant phenotype by germline transformation of the newly established y mutant fly line with a y(+) -marked piggyBac vector. This successful mutagenesis and transformation in D. subobscura open up an avenue for comprehensive genetic analyses of higher functions in this and other nonmodel Drosophila species, representing a key step toward systematic comparisons of genes and circuitries underlying behaviour amongst species.

CNTFR Genotype and Sprint/power Performance: Case-control Association and Functional Studies.

The aim of this study was to investigate whether rs41274853 in the 3'-untranslated region of the ciliary neurotrophic factor receptor gene (CNTFR) is associated with elite sprint/power athletic status and assess its functional significance. A total of 211 Japanese sprint/power track and field athletes (62 international, 72 national, and 77 regional athletes) and 814 Japanese controls were genotyped at rs41274853. Luciferase reporter assay was conducted to investigate whether this C-to-T polymorphism affects binding of microRNA miR-675-5p to this region. The TT genotype was significantly more frequent among international sprint/power athletes (19.4%) than in the controls after Bonferroni correction (7.9%, P=0.036, OR=2.81 [95% CI: 1.43-5.55]). Furthermore, in non-athletic young/middle-aged men (n=132), TT genotype carriers exhibited significantly greater leg extension power (26.6±5.4 vs. 24.0±5.4 W/kg BW, P=0.019) and vertical jump performance (50.1±6.9 vs. 47.9±7.5 cm, P=0.047) than the CC+CT genotype carriers. Reporter assays revealed that the miR-675-5p binds to this polymorphic region within the CNTFR mRNA, irrespective of the rs41274853 allele present. Although the functional significance of the rs41274853 polymorphism remains unclear, the CNTFR is one of the candidate genes contributing to sprint/power performance.