Background: SMA is characterized by reduced levels of survival of motor neuron (SMN) protein from deletions and/or mutations of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces low levels of functional SMN protein. Risdiplam (RG7916/RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates pre-mRNA splicing of SMN2 to increase SMN protein levels. Methods: FIREFISH (NCT02913482) is an ongoing, multicenter, open-label operationally seamless study of risdiplam in infants aged 1–7 months with Type 1 SMA and two SMN2 gene copies. Exploratory Part 1 (n=21) assesses the safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Confirmatory Part 2 (n=40) is assessing the safety and efficacy of risdiplam. Results: In a Part 1 interim analysis (data-cut 09/07/18), 93% (13/14) of babies had ≥4-point improvement in CHOP-INTEND total score from baseline at Day 245, with a median change of 16 points. The number of infants meeting HINE-2 motor milestones (baseline to Day 245) increased. To date (data-cut 09/07/18), no drug-related safety findings have led to patient withdrawal. No significant ophthalmological findings have been observed. Conclusions: In FIREFISH Part 1, risdiplam improved motor function in infants with Type 1 SMA.

The Chinese white pine beetle Dendroctonus armandi (Coleoptera: Scolytinae) typically displays bivoltinism at altitudes below 1700 m in the Qinling Mountains, China. The periods of host colonization and larval overwintering are two important phases in the life cycle of bark beetles, as it is during these periods that they have to contend with host plant defences and periods of intense cold, respectively. Although during different seasons, the females and males of Chinese white pine beetles show varying tolerances to host plant terpenoids, the sex ratio and survival physiology condition of the two beetle generations are unknown. We investigated the sex ratio of individuals, and also examined the body mass, energy stores, and detoxication enzymes of males and females in each of the two generations in order to determine the overall population stability of each generation. We identified a female-biased sex ratio among adults in both generations. Furthermore, patterns of body mass, energy stores, and detoxication enzymes were found to differ between the two sexes and two seasons. Compared with the males, the females have a larger body mass and higher amounts of stored lipids, which are assumed to be adaptations designed to overcome host resistance and facilitate subsequent oviposition.

Cucumber powdery mildew is a destructive foliar disease caused by Podosphaera xanthii (formerly known as Sphaerotheca fuliginea) that substantially damages the yield and quality of crops. The control of this disease primarily involves the use of chemical pesticides that cause serious environmental problems. Currently, numerous studies have indicated that some plant extracts or products potentially have the ability to act as natural pesticides to control plant diseases. It has been reported that turmeric (Curcuma longa L.) and its extract can be used in agriculture due to their insecticidal and fungicidal properties. However, the most effective fungicidal component of this plant is still unknown. In the current study, the crude extract of C. longa L. was found to have a fungicidal effect against P. xanthii. Afterwards, eight fractions (Fr.1–Fr.8) were gradually separated from the crude extract by column chromatography. Fraction 1 had the highest fungicidal effect against this pathogen among the eight fractions. The active compound, (+)-(S)-ar-turmerone, was separated from Fr 1 by semi-preparative high-performance liquid chromatography and identified based on its 1H nuclear magnetic resonance (NMR) and 13C NMR spectrum data. The EC50 value of (+)-(S)-ar-turmerone was found to be 28.7 µg/ml. The compound also proved to have a curative effect. This is the first study to report that the compound (+)-(S)-ar-turmerone has an effect on controlling this disease. These results provide a basis for developing a new phytochemical fungicide from C. longa L. extract.

In vivo and in vitro trials were conducted to assess the effects of tributyrin (TB) supplementation on short-chain fatty acid (SFCA) concentrations, fibrolytic enzyme activity, nutrient digestibility and methanogenesis in adult sheep. Nine 12-month-old ruminally cannulated Small Tail ewes (initial body weight 55 ± 5.0 kg) without pregnancy were used for the in vitro trial. In vitro substrate made to offer TB at 0, 2, 4, 6 and 8 g/kg on a dry matter (DM) basis was incubated by ruminal microbes for 72 h at 39°C. Forty-five adult Small Tail ewes used for the in vivo trial were randomly assigned to five treatments with nine animals each for an 18-d period according to body weight (55 ± 5.0 kg). Total mixed ration fed to ewes was also used to offer TB at 0, 2, 4, 6 and 8 g/kg on a DM basis. The in vitro trial showed that TB supplementation linearly increased apparent digestibility of DM, crude protein, neutral detergent fibre and acid detergent fibre, and enhanced gas production and methane emissions. The in vivo trial showed that TB supplementation decreased DM intake, but enhanced ruminal fermentation efficiency. Both in vitro and in vivo trials showed that TB supplementation enhanced total SFCA concentrations and carboxymethyl cellulase activity. The results indicate that TB supplementation might exert advantage effects on rumen microbial metabolism, despite having an enhancing effect on methanogenesis.

Multiple human immunodeficiency virus (HIV)-1 genotypes in China were first discovered in Yunnan Province before disseminating throughout the country. As the HIV-1 epidemic continues to expand in Yunnan, genetic characteristics and transmitted drug resistance (TDR) should be further investigated among the recently infected population. Among 2828 HIV-positive samples newly reported in the first quarter of 2014, 347 were identified as recent infections with BED-captured enzyme immunoassay (CEIA). Of them, 291 were successfully genotyped and identified as circulating recombinant form (CRF)08_BC (47.4%), unique recombinant forms (URFs) (18.2%), CRF01_AE (15.8%), CRF07_BC (14.4%), subtype C (2.7%), CRF55_01B (0.7%), subtype B (0.3%) and CRF64_BC (0.3%). CRF08_BC and CRF01_AE were the predominant genotypes among heterosexual and homosexual infections, respectively. CRF08_BC, URFs, CRF01_AE and CRF07_BC expanded with higher prevalence in central and eastern Yunnan. The recent common ancestor of CRF01_AE, CRF07_BC and CRF08_BC dated back to 1983.1, 1992.1 and 1989.5, respectively. The effective population sizes (EPS) for CRF01_AE and CRF07_BC increased exponentially during 1991–1999 and 1994–1999, respectively. The EPS for CRF08_BC underwent two exponential growth phases in 1994–1998 and 2001–2002. Lastly, TDR-associated mutations were identified in 1.8% of individuals. These findings not only enhance our understanding of HIV-1 evolution in Yunnan but also have implications for vaccine design and patient management strategies.

By introducing the concept of forming springback anti-coupled systems and considering the influence of the self damping effect, meanwhile establishing higher-order geometrical nonlinear equation of a high strength and low alloy (HSLA) steel plate, then a set of nonlinear dynamic springback governing equations of the plate are obtained. The finite difference method, Newmark method and iterative method are applied to solve the whole problem. Numerical results denote that the boundary conditions, thickness-length ratio of the plate and initial impact velocity of the impactor have great influence on the springback amount of the rectangular HSLA steel plate, besides the natural frequency is affected a lot by the boundary conditions and thickness-length ratio. The effect of higher-order geometrical nonlinearity on the springback amount of the plate can be ignored, considering the first-order geometrical nonlinearity is enough accurate for such similar nonlinear dynamic problems.

In this paper, the dynamical behavior and stability of hanging micropipes conveying fluid with pinned-free boundary conditions are investigated. For a pinned-free rigid micropipe, the dynamical system is found to be stable for various flow velocities. Particular emphasis is placed on the effects of flow velocity, mass ratio and gravity on the dynamics and flutter instability of flexible micropipe system with pinned-free boundary conditions. The governing equations for flexible micropipes are discretized using the differential quadrature method (DQM), yielding a generalized eigenvalue problem which is then solved for various flow velocities, mass ratios and gravity parameters. It is shown that, with increasing flow velocity, the flexible micropipe with pinned-free boundary conditions is stable until it becomes unstable via a Hopf bifurcation leading to flutter. The system may lose stability first in the second or third mode, mainly depending on the selected value of mass ratio. The existence of mode exchange between the second and third modes is possible. The gravity parameter of positive values causes additional restoring force and hence enhances the stability of the micropipe system; however, it can generate the complexity of stability diagrams.

Background: Ataluren is the first drug to treat the underlying cause of nmDMD. Methods: Phase 2 and 3 studies of ataluren in nmDMD were reviewed, with efficacy and safety/tolerability findings summarized. Results: Ataluren nmDMD trials include: a Phase 2a proof-of-concept study (N=38); a Phase 2b randomized controlled trial (RCT) (N=174); an ongoing US-based open-label safety extension study (N=108); an ongoing non-US-based open-label safety/efficacy extension study (N=94); and a Phase 3 RCT, ACT DMD (N=228), whose primary endpoint was change in six-minute walk distance (6MWD) over 48 weeks. The proof-of-concept study demonstrated increased dystrophin production in post-treatment muscle biopsies from ataluren-treated patients with nmDMD. The Phase 2b results demonstrated an ataluren treatment effect in 6MWD, timed function tests, and other measures of physical functioning, The Phase 3 ACT DMD results demonstrated an ataluren treatment effect in patients with nmDMD in both primary and secondary endpoints, particularly in those with a baseline 6MWD of 300-400m. Ataluren was consistently well-tolerated in all three trials, as well as in the ongoing extension studies. Trial findings will be presented in detail. Conclusions: The totality of the results demonstrates that ataluren enables nonsense mutation readthrough in the dystrophin mRNA, producing functional dystrophin and slowing disease progression.

Supported by: PTC Therapeutics Inc.

In this paper, transient response analysis of a circular sandwich plate with a functionally graded material (FGM) central disk and two piezoelectric layers is presented. Material properties of the FGM central disk for the circular sandwich plate are assumed to vary through the structural thickness according to a power law and the Poisson’s ratio is assumed as the same constant. Based on the first-order shear deformation theory and geometric nonlinear relationship, the nonlinear motion equations of the circular sandwich plate are formulated by using the Hamilton’s variational principle, then combining with the boundary and initial conditions, the whole problem is solved by adopting the finite difference method, Newmark method and iterative method. Numerical results are presented to illustrate that the volume fraction index, geometric parameters, mechanical and electrical loads have a great influence on transient response of the circular sandwich plate.

Both maternal 25-hydroxyvitamin D (25(OH)D) concentrations during pregnancy and placental amino acid transporter gene expression have been associated with development of the offspring in terms of body composition and bone structure. Several amino acid transporter genes have vitamin D response elements in their promoters suggesting the possible linkage of these two mechanisms. We aimed to establish whether maternal 25(OH)D and vitamin D-binding protein (VDBP) levels relate to expression of placental amino acid transporters. RNA was extracted from 102 placental samples collected in the Southampton Women's Survey, and gene expression was analysed using quantitative real-time PCR. Gene expression data were normalised to the geometric mean of three housekeeping genes, and related to maternal factors and childhood body composition. Maternal serum 25(OH)D and VDBP levels were measured by radioimmunoassay. Maternal 25(OH)D and VDBP levels were positively associated with placental expression of specific genes involved in amino acid transport. Maternal 25(OH)D and VDBP concentrations were correlated with the expression of specific placental amino acid transporters, and thus may be involved in the regulation of amino acid transfer to the fetus. The positive correlation of VDBP levels and placental transporter expression suggests that delivery of vitamin D to the placenta may be important. This exploratory study identifies placental amino acid transporters which may be altered in response to modifiable maternal factors and provides a basis for further studies.

This paper studies the buckling analysis for a ring-stiffened cylindrical shell consisted of functionally graded material (FGM) subjected to hydrostatic pressure and thermal loads. Material properties of the ring-stiffened FGM cylindrical shell are assumed to be temperature-dependent, and vary smoothly through the thickness direction of the structure according to a volume exponent. Based on the Donnell assumptions, buckling loads of the ring-stiffened FGM cylindrical shell are presented by utilizing the Galerkin method. Numerical results reveal that thermal loads, volume exponent and geometric parameters have significant effects on the buckling behavior of the ring-stiffened cylindrical shell.

This study evaluated whether exposure to maternal pre- or postnatal depression or anxiety symptoms predicted psychopathology in adolescent offspring. Growth mixture modeling was used to identify trajectories of pre- and postnatal depression and anxiety symptoms in 577 women of low socioeconomic status selected from a prenatal clinic. Logistic regression models indicated that maternal pre- and postnatal depression trajectory exposure was not associated with offspring major depression, anxiety, or conduct disorder, but exposure to the high depression trajectory was associated with lower anxiety symptoms in males. Exposure to medium and high pre- and postnatal anxiety was associated with the risk of conduct disorder among offspring. Male offspring exposed to medium and high pre- and postnatal anxiety had higher odds of conduct disorder than did males with low exposure levels. Females exposed to medium or high pre- and postnatal anxiety were less likely to meet conduct disorder criteria than were females with lower exposure. To the best of our knowledge, this is the first study to examine the effect of pre- and postnatal anxiety trajectories on the risk of conduct disorder in offspring. These results suggest new directions for investigating the etiology of conduct disorder with a novel target for intervention.

In the paper, nonlinear dynamic analysis of a circular plate composed of functionally graded material (FGM) is presented. Considering a transverse shear deformation and geometric nonlinearity, the von Karman geometric relation of the FGM circular plate is established. Based on the theory of the first-order shear deformation, a new set of equilibrium equations is developed by the principle of minimum total energy. Applying the finite difference method and Newmark scheme, the nonlinear transient problem is solved by the iterative method. To validate the presented method, the transient problem of the FGM circular plate is compared with those of the existed literature, and good agreement is observed. The effects of the volume fraction index, boundary conditions, mechanical load and the ratio of thickness to radius on the nonlinear transient problem of the FGM circular plate are investigated.