Despite decades of trials, the prognosis for diffuse intrinsic pontine gliomas (DIPG) remains dismal. DIPG is inoperable and standard treatment is radiation alone, as the addition of chemotherapeutic agents, such as temozolomide, have not improved survival. In addition to inherent chemoresistance, treatment of DIPG is impeded by an intact blood-brain barrier (BBB). VAL-083 is a structurally unique bi-functional DNA-targeting agent that readily crosses the BBB. VAL-083 forms interstrand DNA crosslinks at N7-guanine, resulting in DNA double-strand breaks (DSB), S/G2-phase cell-cycle arrest, and ultimately cancer cell death. We have previously demonstrated that VAL-083 is able to overcome temozolomide-resistance in vitro and in vivo, and that its cytotoxicity is independent of the DNA-repair enzyme O6-methylguanine DNA-methyltransferase (MGMT). MGMT is almost universally expressed in DIPG and its expression is strongly correlated with temozolomide-resistance. VAL-083’s distinct mechanism-of-action suggests the potential for combination with inhibitors of DNA DSB repair or S/G2 cell-cycle progression (e.g. Wee1 inhibitor AZD1775). Here, we investigated the effects of VAL-083 in combination with radiation, AZD1775 or irinotecan (topoisomerase inhibitor) in three DIPG cell-lines: SF10693 (H3.1), SF8628 (H3.3) and NEM157 (H3.3). VAL-083 showed activity at low uM-concentration in all three cell-lines. In addition, VAL-083 showed synergy with AZD1775 in all three cell-lines. Combined with its ability to cross the BBB, accumulate in brain tumor tissue and overcome MGMT-related chemoresistance, these results suggest VAL-083 as a potentially attractive treatment option for DIPG as single agent or in combination with AZD1775. Combination studies with radiation are ongoing and will be presented at the meeting.

We prove that, for $C^{1}$ -generic diffeomorphisms, if a homoclinic class is not hyperbolic, then there is a non-trivial non-hyperbolic ergodic measure supported on it. This proves a conjecture by Díaz and Gorodetski.

For underwater vehicle navigation sensors, the output signal periods are different and time-varying. This would result in the decline of precision, and even wrong results. To deal with the problem, this paper puts forward a multi-sensor, adjustable-period integrated navigation method based on multi-stage signal trigger. This method considers the valid signals of a Doppler Velocity Log (DVL) as the trigger signals of a Dead-Reckoning (DR) navigation program. It also considers the valid signals of an acoustic positioning sensor as the trigger signals of the integrated navigation program. In this method, it can adjust the filtering period in real time. According to the time label of signals, this method actualises the time-space alignment of sensors. Then it conducts DR navigation and integrated navigation. The method can not only utilise the valid signals of each sensor sufficiently but also fuses the data based on time-space alignment efficiently. Sea trial data shows that when the output signal periods are certain, navigation precision of the method in this paper is better than a non-adjustable-period filtering method. Moreover, in poor conditions, it can also attain a high precision.

Formation of a nanometer-scale oxide surface layer is common when a material is exposed to oxygen-containing environment. Employing aberration-corrected analytical transmission electron microscopy and using single crystal SnSe as an example, we show that for an alloy, a second thin amorphous layer can appear underneath the outmost oxide layer. This inner amorphous layer is not oxide based, but instead originates from solid-state amorphization of the base alloy when its free energy rises to above that of the metastable amorphous state; which is a result of the composition shift due to the preferential depletion of the oxidizing species, in our case, the outgoing Sn reacting with the oxygen atmosphere.

In this paper, a diffuse-interface immersed boundary method (IBM) is proposed to treat three different thermal boundary conditions (Dirichlet, Neumann, Robin) in thermal flow problems. The novel IBM is implemented combining with the lattice Boltzmann method (LBM). The present algorithm enforces the three types of thermal boundary conditions at the boundary points. Concretely speaking, the IBM for the Dirichlet boundary condition is implemented using an iterative method, and its main feature is to accurately satisfy the given temperature on the boundary. The Neumann and Robin boundary conditions are implemented in IBM by distributing the jump of the heat flux on the boundary to surrounding Eulerian points, and the jump is obtained by applying the jump interface conditions in the normal and tangential directions. A simple analysis of the computational accuracy of IBM is developed. The analysis indicates that the Taylor-Green vortices problem which was used in many previous studies is not an appropriate accuracy test example. The capacity of the present thermal immersed boundary method is validated using four numerical experiments: (1) Natural convection in a cavity with a circular cylinder in the center; (2) Flows over a heated cylinder; (3) Natural convection in a concentric horizontal cylindrical annulus; (4) Sedimentation of a single isothermal cold particle in a vertical channel. The numerical results show good agreements with the data in the previous literatures.

The Endangered giant panda Ailuropoda melanoleuca is one of the most threatened mammals. The species has experienced declines in its population and habitat as a result of human disturbance. We investigated the influence of human disturbance on habitat use by giant pandas in the Daxiangling Mountains, in China's Sichuan Province. We mapped all signs of giant panda and all locations of seven types of human disturbance in the study area. We used correlation analysis, generalized linear models, and Akaike information criteria to analyse the influence of the various types of human disturbances on habitat use by the giant panda. Our results showed that habitat use was positively correlated with elevation and distance from roads, residences, hydropower stations and logging or tree-felling sites, but negatively correlated with distance from bamboo shoot collection sites and trap sites. We found that the road-effect zone spanned a distance of c. 1,200 m and that human residence could affect the intensity of habitat use by giant pandas at distances > 2,500 m. The effect of roads on habitat use was probably influenced by the association of roads with residences, hydropower stations and mines. In the area occupied by giant pandas, we recommend increased regulation to minimize the expansion and impact of roads, residences, hydropower stations and logging activities.

Epilepsy is now recognized as the second most common neurological disease in China. To determine the genetic cause of epileptic encephalopathy, we performed a multiomics study using mouse models of controls, anticonvulsant mice treated with five drugs and epileptic mice. Based on genome-wide profiling analysis, we discovered four genes in the epileptic mouse group with differentially-expressed mRNA. After isobaric tags for relative and absolute quantification (iTRAQ) validation, only one gene, SNCA, remained, which was associated with apoptotic response of neuronal cells, and regulation of dopamine release and transport. We also identified three miRNAs targeting SNCA, out of which mmu-miR-21a-3p demonstrated a seven-fold change in expression between control and epileptic mice.

The distribution of the Critically Endangered tree Manglietia longipedunculata, of which there are only 11 known wild individuals, is restricted to the Nankunshan Nature Reserve in South China. The species is threatened with extinction because of its small number of individuals and the impediments to its reproduction (a combination of protogyny, a short period of stigma receptivity, and a lack of efficient pollinators). To reduce the risk of extinction we conducted two conservation translocation trials: one to augment the sole extant population, and the other 202 km north of the current range. The latter trial was a conservation introduction in which the goals were to increase the population and to buffer against the effects of climate change. We used emerged and grafted seedlings as translocation materials. We compared the survival, growth, and eco-physiological properties of emerged and grafted seedlings at the two sites. The survival rate and growth were higher for grafted seedlings than for emerged seedlings at both sites. Eco-physiological data indicated that grafted seedlings at both sites were as efficient or more so in light and water usage than wild individuals, whereas emerged seedlings were less efficient. Grafted seedlings attained the flowering stage sooner than emerged seedlings. Our study suggests that grafting can facilitate the augmentation and establishment of new populations of M. longipedunculata and perhaps of new populations of other threatened species facing reproductive difficulties and climate change.

Non-shared parenting and deviant peer affiliation are linked to differences in externalizing behaviors between twins. However, few studies have examined these two non-shared environments simultaneously. The present study examined the transactional roles of differential parenting (i.e., warmth and hostility) and deviant peer affiliation on monozygotic (MZ) twin differences in externalizing behaviors using a two-wave longitudinal study of twins and their parents. The sample consisted of 520 pairs of MZ twins (46.5% males, 53.5% females), with a mean age of 13.86 years (SD = 2.10) at the T1 assessment, residing in Beijing, China. The association between non-shared hostility in parenting and adolescent externalizing behaviors was mainly explained by a child-driven effect whereby the twin with a higher level of externalizing behaviors than his or her co-twin was more likely to receive more hostility from the parents. Similarly, the relationship between deviant peer affiliation and adolescent externalizing behaviors supported the selection effect whereby the twin with a higher level of externalizing behaviors than his or her co-twin was more likely to affiliate with deviant peers. The theoretical and practical implications of these findings are discussed.

Rates of emotional and behavioral problems among children and adolescents in China are increasing and represent a major public health concern. To investigate the etiology of such problems, including the effects and interplay of genes and environment, the Beijing Twin Study (BeTwiSt) was established. A representative sample of adolescent twins in Beijing (N = 1,387 pairs of adolescent twins, mostly between the ages of 10 and 18 years) was recruited and assessed longitudinally. Data collection included the following: emotional and behavioral problems (e.g., depressive symptoms, anxiety, delinquency, drinking, and smoking); family, peer, and school environments; stress; social and academic competence; cognitive traits (e.g., emotion suppression, rumination, and effortful control); and saliva samples for DNA genotyping and sequencing. The combination of quantitative and molecular genetic approaches and the timeliness of the project, with the sample residing in a region with a rapidly changing economic and cultural climate, are particular strengths of this study. Findings from this study are expected to help understanding of the etiological mechanisms underlying child and adolescent normal and abnormal development in regions undergoing substantial social, cultural, and economic changes.