Temporal encoding in deep reinforcement learning agents.

Neuroscientists have observed both cells in the brain that fire at specific points in time, known as "time cells", and cells whose activity steadily increases or decreases over time, known as "ramping cells". It is speculated that time and ramping cells support temporal computations in the brain and carry mnemonic information. However, due to the limitations in animal experiments, it is difficult to determine how these cells really contribute to behavior. Here, we show that time cells and ramping cells naturally emerge in the recurrent neural networks of deep reinforcement learning models performing simulated interval timing and working memory tasks, which have learned to estimate expected rewards in the future. We show that these cells do indeed carry information about time and items stored in working memory, but they contribute to behavior in large part by providing a dynamic representation on which policy can be computed. Moreover, the information that they do carry depends on both the task demands and the variables provided to the models. Our results suggest that time cells and ramping cells could contribute to temporal and mnemonic calculations, but the way in which they do so may be complex and unintuitive to human observers.

PTGR1 is involved in cell proliferation in thoracic ossification of the ligamentum flavum.

Thoracic ossification of the ligamentum flavum (TOLF) is a heterotopic ossification of spinal ligaments, leading to serious myelopathy. TOLF underlying mechanisms are not well understood. Our iTRAQ analysis have identified ten inflammatory factors related to TOLF, including l. We found that PTGR1 expressions increased in TOLF by RT-PCR and western blot in this study. Both cell proliferation and differentiation are important for the process of bone formation. In our previous study, we demonstrated that TOLF primary cells grew faster than control cells. It was reported that knockdown of PTGR1 inhibited cell proliferation. We hypothesize that PTGR1 may participate in cell proliferation in TOLF. To test this hypothesis, TOLF primary cells were treated for 24h with PTGR1. We observed that PTGR1 increased cell proliferation. The effect of PTGR1 on cell proliferation related genes was examined in TOLF primary cells. Our results showed that PTGR1 was able to activate expressions of c-Myc and CyclinD1. Moreover, blocking JNK pathway by selective JNK inhibitor SP600125 eliminated the positive effect of PTGR1 on c-Myc expression, indicating that PTGR1 activated the expression of c-Myc via JNK pathway. Our new findings suggest that PTGR1 is involved in cell proliferation of TOLF.

Individuals with Autism Spectrum Disorders and Developmental Disorders in Oman: An Overview of Current Status.

This paper offers an overview of the current status of individuals with autism spectrum disorders (ASD) and developmental disorders (DD) in Oman. A review of demographic and background information about Oman is first presented, followed by an overview of the current status of individuals with autism and developmental disorders, in terms of disability-related legislation, prevalence and diagnosis, as well as treatment and education. In the last section of the paper, major challenges faced in the field are addressed, including lack of autism awareness, lack of healthcare and educational programs or related services, lack of highly qualified professionals to implement evidence-based practices, issues regarding early identification and early intervention, as well as issues pertaining secondary transition, independent living and employment. Corresponding recommendation is proposed at the end of each challenge.

Identification of kaempferol as an OSX upregulator by network pharmacology-based analysis of qianggu Capsule for osteoporosis.

Osteoporosis is the most common metabolic disease of skeleton with reduced bone density and weaker bone. Qianggu Capsule as a traditional chinese medicine has been widely used to treat osteoporosis. The potential pharmacological mechanism of its active ingredient Gusuibu is not well understood. The purpose of this work is to analyze the anti-osteoporosis function of Gusuibu based on network pharmacology, and further explore the potential mechanism of Qianggu Capsule. The active compounds and their corresponding targets of Gusuibu were obtained from TCMSP, TCMID, and BATMAN-TCM databases. Potential therapeutic targets for osteoporosis were obtained through DisGeNET, TTD, GeneCards, MalaCards, CTD, and OMIM databases. The overlapping targets of Gusuibu and osteoporosis were obtained. GO and KEGG pathway enrichment analysis were performed. The "Gusuibu-active compounds-target genes-osteoporosis" network and protein-protein interaction (PPI) network were constructed, and the top hub genes were screened by using the plug-in CytoHubba. Molecular docking was used to verify the binding activity of hub genes and key compounds. We identified 21 active compounds and 140 potential therapeutic targets that may be related to Gusuibu and 10 hub genes (AKT1, IL6, JUN, TNF, MAPK3, VEGFA, EGFR, MAPK1, CASP3, PTGS2). Molecular docking analysis demonstrated that four key active small molecules in Gusuibu (including Luteolin, Naringenin, Kaempferol, and Beta-sitosterol) have excellent binding affinity to the target proteins encoded by the top 10 hub genes. Our new findings indicated that one key active compound kaempferol activated the expression of osteoblast specific transcription factor OSX through JNK kinase pathway.

IL-6 is involved in thoracic ossification of the ligamentum flavum.

Thoracic ossification of the ligamentum flavum (TOLF) is a heterotopic ossification of spinal ligaments. TOLF is the major cause of thoracic spinal canal stenosis and myelopathy, and its underlying mechanisms are not clear. Bone formation is a complex developmental process involving the differentiation of mesenchymal stem cells to osteoblasts, and regulated by BMP2, RUNX2, Osterix (OSX), etc. In this study, we continue to further characterize properties of TOLF. Our immunohistochemistry experiments showed that expressions of osteoblastic factors such as BMP2 and RUNX2 increased in TOLF. According to flow cytometry analysis the proportion of S phase of cell cycle in primary TOLF cells was 9% higher than the control. Alizarin red staining and ALP staining observations were consistent with immunohistochemistry results. It was also observed that inflammatory cytokine IL-6 level dramatically increased in the culture supernatant of primary TOLF cells. We propose the hypothesis that IL-6 is involved in TOLF. To testify the hypothesis, we examined the effect of IL-6. Our results showed that IL-6 was able to activate expressions of osteoblastic factors such as BMP2, RUNX2, OSX, OCN and ALP, and that expressions of cell proliferation factors cyclin D1 and cyclin C increased in the presence of IL-6. Moreover, IL-6-induced BMP2 expression was inhibited by p38 inhibitor SB203580, indicating that IL-6 regulated the osteogenic BMP2 activation through p38 MAPK pathway. These data suggest that IL-6 is involved in TOLF.

Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series.

Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. These compounds have improved physicochemical properties over prior series frontrunners and they show no time-dependent CYP inhibition, characteristic of earlier compounds. Frontrunners have potent antimalarial activity in vitro against blood and liver schizont stages and show good efficacy in Plasmodium falciparum SCID mouse models. They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes.

Weakened portfolio effects constrain management effectiveness for population aggregates.

Population diversity can reduce temporal variability in aggregate population abundances in a process known as the portfolio effect. Portfolio effects may weaken, however, due to greater synchrony among component populations. While weakened portfolio effects have been previously documented, the consequences of reduced stability on meeting conservation goals for population aggregates that are harvested (e.g., stock aggregates in fisheries) are rarely quantified. Here, we demonstrate how changes in variability within components, synchrony among components, and population productivity interact to influence the probability of achieving an array of management objectives for Fraser River sockeye salmon: a stock aggregate of high economic, ecological, and cultural value. We first present evidence that component variability and synchrony have increased over the last two decades, consistent with a weakening portfolio effect. We then parameterize a stochastic, closed-loop model that simulates the population dynamics of each stock, the fishery that harvests the stock aggregate, and the management framework used to establish mixed-stock exploitation rates. We find that while median aggregate abundance and catch through time were relatively insensitive to greater aggregate variability, catch stability and performance metrics associated with achieving management targets generally declined as component variability and synchrony increased. A notable exception we observed is that harvest control means that scale exploitation rates based on aggregate abundance may be more effective as synchrony increases. Reductions in productivity led to broad declines in performance, but also moderated the impacts of component variability and synchrony on the proportion of component stocks above management targets and catch stability. Our results suggest that even precautionary management strategies that account for declines in productivity may underestimate risk, particularly to socioeconomic objectives, if they fail to consider changes in aggregate variability. Adequately incorporating changes in portfolio effect strength may be particularly relevant when developing recovery strategies that are robust to climate change, which is likely to increase synchrony and component variability.

Angiopoietin-2 promotes osteogenic differentiation of thoracic ligamentum flavum cells via modulating the Notch signaling pathway.

Thoracic ossification of the ligamentum flavum (TOLF) is heterotopic ossification of spinal ligaments, which may cause serious thoracic spinal canal stenosis and myelopathy. However, the underlying etiology remains inadequately understood. In this study, the ossification patterns of TOLF were analyzed by micro-computer tomography (micro-CT). The expression profile of genes associated with angiogenesis was analyzed in thoracic ligamentum flavum cells at sites of different patterns of ossification using RNA sequencing. Significant differences in the expression profile of several genes were identified from Gene Ontology (GO) analysis. Angiopoietin-2 (ANGPT2) was significantly up-regulated in primary thoracic ligamentum flavum cells during osteogenic differentiation. To address the effect of ANGPT2 on Notch signaling and osteogenesis, ANGPT2 stimulation increased the expression of Notch2 and osteogenic markers of primary thoracic ligamentum flavum cells of immature ossification, while inhibition of ANGPT2 exhibited opposite effect on Notch pathway and osteogenesis of cells of mature ossification. These findings provide the first evidence for positive regulation of ANGPT2 on osteogenic differentiation in human thoracic ligamentum flavum cells via modulating the Notch signaling pathway.

MiR-490-3p inhibits osteogenic differentiation in thoracic ligamentum flavum cells by targeting FOXO1.

Thoracic ossification of the ligamentum flavum (TOLF) is a rare heterotopic ossification of spinal ligaments, which is the major cause of thoracic spinal canal stenosis and myelopathy. In this study, the roles of miR-490-3p and forkhead box O1 (FOXO1) in osteogenesis of human thoracic ligamentum flavum cells were investigated. MiR-490-3p was found to be down-regulated during osteogenic differentiation of thoracic ligamentum flavum cells, while their overexpression inhibited osteogenic differentiation. In addition, the analysis of target prediction and dual luciferase reporter assays supported that miR-490-3p directly targeted FOXO1 and suppressed the expression of FOXO1. Moreover, FOXO1 knockdown was displayed to attenuate the effect of miR-490-3p inhibition. ChIP assays showed that miR-490-3p negatively regulated the interaction of FOXO1 and RUNX2. These findings suggest that miR-490-3p performs an inhibitory role in osteogenic differentiation of thoracic ligamentum flavum cells by potentially targeting FOXO1.

Understanding the Self in Individuals with Autism Spectrum Disorders (ASD): A Review of Literature.

When the system of self is explored in individuals with Autism Spectrum Disorders (ASDs), it is important to measure it via both their own perceptions of the self and their understanding of others' perceptions on themselves at a multidimensional level. This paper reviews existing research in this area using a three-dimension approach. Researchers have found that impairments in the self-system are usually correlated with these individuals' social and cognitive functioning levels: high functioning individuals with ASD who have higher IQ are found to have better awareness of their limitations in social and communication domains than those with lower IQ. Many researchers believe that there are impairments in the psychological (but not physical) self in individuals with ASD, such as theory of mind deficits due to social and communicative impairments. On the other hand, some researchers argue that individuals with ASD have selective rather than global impairments in the self. In other words, the impairment usually lies in a specific aspect of functioning in individuals with ASD. Insights from the review of existing literature on this topic may be able to shed some lights on the development of effective intervention programs to improve social communication deficits in this population.

The involvement and possible mechanism of pro-inflammatory tumor necrosis factor alpha (TNF-α) in thoracic ossification of the ligamentum flavum.

Thoracic ossification of the ligamentum flavum (TOLF) is characterized by ectopic bone formation in the ligamentum flavum and is considered to be a leading cause of thoracic spinal canal stenosis and myelopathy. However, the underlying etiology is not well understood. An iTRAQ proteomics was used to reveal the involvement of inflammation factors in TOLF. TNF-α is a pro-inflammatory cytokine implicated in the pathogenesis of many human diseases. Protein profiling analysis showed that the protein level of TNF-α increased in the ossified ligamentum flavum of TOLF, which was confirmed by western blot. The effects of TNF-α on primary ligamentum flavum cells was examined. Cell proliferation assay demonstrated that primary cells from the ossified ligamentum flavum of TOLF grew faster than the control. Flow cytometry assay indicated that the proportions of cells in S phase of cell cycle of primary cells increased after TNF-α stimulation. To address the effect of TNF-α on gene expression, primary cells were derived from ligamentum flavum of TOLF patients. Culture cells were stimulated by TNF-α. RNA was isolated and analyzed by quantitative RT-PCR. G1/S-specific proteins cyclin D1 and c-Myc were upregulated after TNF-α stimulation. On the other hand, osteoblast differentiation related genes such as Bmp2 and Osterix (Osx) were upregulated in the presence of TNF-α. TNF-α activated Osx expression in a dose-dependent manner. Interestingly, a specific mitogen-activated protein kinase ERK inhibitor U0126, but not JNK kinase inhibitor SP600125, abrogated TNF-α activation of Osx expression. This suggests that TNF-α activates Osx expression through the mitogen-activated protein kinase ERK pathway. Taken together, we provide the evidence to support that TNF-α involves in TOLF probably through regulating cell proliferation via cyclin D1 and c-Myc, and promoting osteoblast differentiation via Osx.

Bortezomib congeners induce apoptosis of hepatocellular carcinoma via CIP2A inhibition.

CIP2A is an oncoprotein that upregulates p-Akt and promotes cancer cell proliferation and survival. The proteasome inhibitor bortezomib has been shown to reduce CIP2A and lead to cell apoptosis. Here; we modified the functional group of bortezomib to generate a series of novel compounds and conducted a structure-activity relationship (SAR) study. The results showed that compound 1 was able to repress CIP2A expression and cell apoptosis in the same manner as bortezomib, but with less potency in inhibition of proteasome activity. This finding provides a new direction for the design of CIP2A inhibitors.

Maltreatment and depression in adolescent sexual offenders with an autism spectrum disorder.

This study examined the self-reported presence and severity of abuse, neglect, and depressive symptoms for 43 adolescents adjudicated delinquent due to a sexual offense. Twenty-seven of the adolescent sexual offenders were also diagnosed with an autism spectrum disorder, and 16 did not carry an autism spectrum disorder diagnosis. Both groups reported moderate to high levels of abuse and neglect. Adolescent sexual offenders with an autism spectrum disorder reported significantly higher depressive symptoms than those without an autism spectrum disorder. Furthermore, of the group with an autism spectrum disorder, those reporting severe levels of emotional abuse and/or emotional neglect were more likely to also have depressive symptoms. Results suggest a need to tailor treatment programs to match the unique needs of sexual offenders.

Children with autism in the People's Republic of China: diagnosis, legal issues, and educational services.

Since the late 1970s, special education in the People's Republic of China has experienced significant reform and fast development. However, education for children with severe developmental disabilities, especially autism spectrum disorders (ASDs), is still the greatest challenge in the field. This paper aims to give readers an overview of what is happening to children with ASDs in China. We first address the issue of prevalence of ASDs, and then offer an introduction to the diagnostic process. After that, a review of disability-related legislation is provided, followed by a description of current treatment options and available educational services. Finally we introduce all extent service providers and their roles.