Optimal management of seizures associated with tuberous sclerosis complex: current and emerging options.

Seizures are clinically significant manifestations associated with 79%-90% of patients with tuberous sclerosis complex. Often occurring within the first year of life in the form of infantile spasms, seizures interfere with neuropsychiatric, social, and cognitive development and carry significant individual and societal consequences. Prompt identification and treatment of seizures is an important focus in the overall management of tuberous sclerosis complex patients. Medical management, either after seizure onset or prophylactically in infants with electroencephalographic abnormalities, is considered first-line therapy. Vigabatrin and adrenocorticotropic hormone have emerged over the past few decades as mainstay pharmacologic modalities. Furthermore, emerging research on mammalian target of rapamycin inhibitors demonstrated promise for the management of seizures and subependymal giant cell astrocytoma. For appropriate surgical candidates with an epileptogenic zone associated with one or more glioneuronal hamartomas, ideally in noneloquent cortex, resective surgery can be considered, which provides a cure in 56% of patients. For medically refractory patients who do not meet criteria for curative surgery, palliative surgical approaches focused on reducing seizure burden, in the form of corpus callosotomy and vagus nerve stimulation, are alternative management options. Lastly, the ketogenic diet, a reemerging therapy based on the anticonvulsant effects of ketone bodies, can be utilized independently or in conjunction with other treatment modalities for the management of difficult-to-treat seizures

Security and Ownership Verification in Deep Reinforcement Learning

Deep reinforcement learning (DRL) has seen many successes in complex tasks such as robot manipulation, autonomous driving, and competitive games. However, there are few studies on the security threats against DRL systems. In this thesis, we focus on two security concerns in DRL. The first security concern is adversarial perturbation attacks against DRL agents. % Adversarial perturbation attacks mislead DRL agents into taking sub-optimal actions by applying a small imperceptible perturbation to the states of the environment. Adversarial perturbation attacks mislead DRL agents into taking sub-optimal actions. These attacks apply small imperceptible perturbations to the agent's observations of the environment. Prior work shows that DRL agents are vulnerable to adversarial perturbation attacks. However, prior attacks are difficult to deploy in real-time settings. We show that universal adversarial perturbations (UAPs) are effective in reducing a DRL agent's performance in their tasks and are fast enough to be mounted in real-time. We propose three variants of UAPs. We evaluate the effectiveness of UAPs against different DRL agents (DQN, A2C, and PPO) in three different Atari 2600 games (Pong, Freeway, and Breakout). We show that UAPs can degrade agent performance by 100\%, in some cases even for a perturbation bound as small as $l_{\infty} = 0.01$. We also propose a technique for detecting adversarial perturbation attacks. An effective detection technique can be used in DRL tasks with potentially negative outcomes (such as the agents failing in a task or accumulating negative rewards) by suspending the task before the negative result manifests due to adversarial perturbation attacks. Our experiments found that this detection method works best for Pong with perfect precision and recall against all adversarial perturbation attacks but is less robust for Breakout and Freeway. The second security concern is theft and unauthorized distribution of DRL agents. As DRL agents gain success in complex tasks, there is a growing interest to monetize them. However, the possibility of theft could jeopardize the profitability of deploying these agents. Robust ownership verification techniques can deter malicious parties from stealing these agents, and in the event where theft cannot be prevented, ownership verification techniques can be used to track down and prosecute perpetrators. There are two prior works on ownership verification of DRL agents using watermarks. However, these two techniques require the verifier to deploy the suspected stolen agent in an environment where the verifier has complete control over the environment states. We propose a new fingerprint technique where the verifier compares the percentage of action agreement between the suspect agent and the owner's agent in environments where UAPs are applied. Our experimental results show that there is a significant difference in the percentage of action agreement (up to $50\%$ in some cases) when the suspect agent is a copy of the owner's agent versus when the suspect agent is an independently trained agent

Interaction of the oncoprotein transcription factor MYC with its chromatin cofactor WDR5 is essential for tumor maintenance.

The oncoprotein transcription factor MYC is overexpressed in the majority of cancers. Key to its oncogenic activity is the ability of MYC to regulate gene expression patterns that drive and maintain the malignant state. MYC is also considered a validated anticancer target, but efforts to pharmacologically inhibit MYC have failed. The dependence of MYC on cofactors creates opportunities for therapeutic intervention, but for any cofactor this requires structural understanding of how the cofactor interacts with MYC, knowledge of the role it plays in MYC function, and demonstration that disrupting the cofactor interaction will cause existing cancers to regress. One cofactor for which structural information is available is WDR5, which interacts with MYC to facilitate its recruitment to chromatin. To explore whether disruption of the MYC-WDR5 interaction could potentially become a viable anticancer strategy, we developed a Burkitt\u27s lymphoma system that allows replacement of wild-type MYC for mutants that are defective for WDR5 binding or all known nuclear MYC functions. Using this system, we show that WDR5 recruits MYC to chromatin to control the expression of genes linked to biomass accumulation. We further show that disrupting the MYC-WDR5 interaction within the context of an existing cancer promotes rapid and comprehensive tumor regression in vivo. These observations connect WDR5 to a core tumorigenic function of MYC and establish that, if a therapeutic window can be established, MYC-WDR5 inhibitors could be developed as anticancer agents

Intracellular Disposition of Fludarabine Triphosphate in Human Natural Killer Cells

Purpose. Fludarabine is a key component of several reduced-intensity conditioning regimens for hematopoietic cell transplantation (HCT). Shortly after reduced-intensity conditioning, the percent of donor natural killer (NK) cells has been associated with progression-free survival. Insufficient suppression of the recipient’s NK cells by fludarabine may lead to lower donor chimerism; however, the effect of fludarabine upon NK cells is poorly understood. Thus, in purified human NK cells we evaluated the uptake and activation of fludarabine to its active metabolite, fludarabine triphosphate (F-ara-ATP), and assessed the degree of interindividual variability in F-ara-ATP accumulation. Methods. Intracellular F-ara-ATP was measured in purified NK cells isolated from healthy volunteers (n = 6) after ex vivo exposure to fludarabine. Gene expression levels of the relevant transporters and enzymes involved in fludarabine uptake and activation were also measured in these cells. Results. F-ara-ATP accumulation (mean ± s.d.) was 6.00 ± 3.67 pmol/1x106 cells/4 hours, comparable to average levels previously observed in CD4+ and CD8+ T-lymphocytes. We observed considerable variability in F-ara-ATP accumulation and mRNA expression of transporters and enzymes relevant to F-ara-ATP accumulation in NK cells from different healthy volunteers. Conclusions. Human NK cells have the ability to form F-ara-ATP intracellularly and large interindividual variability was observed in healthy volunteers. Further studies are needed to evaluate whether F-ara-ATP accumulation in NK cells are associated with apoptosis and clinical outcomes

Essential Points of a Support Network Approach for School Counselors Working with Children Diagnosed with Asperger’s

Asperger Syndrome (AS) presents unique challenges to both families and schools. Children diagnosed with Asperger’s possess unparalleled characteristics in cognitive functioning and behavioral pattern. These children need extra attention and assistance in schools. School counselors require a strategy to successfully engage and support these children and to deal with multiple phases of difficulties. A support network approach is proposed in this article to assist school counselors coordinating resources in schools, families, and the community. This approach is discussed with essential points that will help school counselors reach out to families and the community and create a friendly and supportive environment for children diagnosed with Asperger’s

Cross-National Emailing as Cultural Immersion in Multicultural Counselor Training: A Pilot Study

Multicultural counselor training has utilized cultural immersion to stimulate students’ multicultural competency development. This article discussed a pilot study which experimented with a new instructional strategy of cultural immersion in a multicultural counseling class. This strategy intended to study the effectiveness of a cross-national emailing project (CNE) on students’ multicultural competency development. Multicultural Counseling Inventory (MCI; Sodowsky, Taffe, Gutkin, & Wise, 1994) was used to measure the multicultural competencies of 13 female counseling students from the United States in this semester-long project. Both quantitative and qualitative results supported the positive development of multicultural competency in cross-national emailing

The π Complex of the Hydronium Ion Frozen on the Pathway of Electrophilic Aromatic Substitution

A very rare crystal was prepared consisting of a 2D aromatic (toluene) together with a weakly coordinating 3D aromatic (closo-1-CB11H12 –) and a hydronium ion, and this crystal was analyzed by using X-ray diffraction and high-level quantum-mechanical calculations. The nature of the crystal arrangement made it possible to detect the frozen π complex that would originate during protonation of toluene by the acidic hydronium ion