CapProNet: Deep Feature Learning via Orthogonal Projections onto Capsule Subspaces

In this paper, we formalize the idea behind capsule nets of using a capsule vector rather than a neuron activation to predict the label of samples. To this end, we propose to learn a group of capsule subspaces onto which an input feature vector is projected. Then the lengths of resultant capsules are used to score the probability of belonging to different classes. We train such a Capsule Projection Network (CapProNet) by learning an orthogonal projection matrix for each capsule subspace, and show that each capsule subspace is updated until it contains input feature vectors corresponding to the associated class. We will also show that the capsule projection can be viewed as normalizing the multiple columns of the weight matrix simultaneously to form an orthogonal basis, which makes it more effective in incorporating novel components of input features to update capsule representations. In other words, the capsule projection can be viewed as a multi-dimensional weight normalization in capsule subspaces, where the conventional weight normalization is simply a special case of the capsule projection onto 1D lines. Only a small negligible computing overhead is incurred to train the network in low-dimensional capsule subspaces or through an alternative hyper-power iteration to estimate the normalization matrix. Experiment results on image datasets show the presented model can greatly improve the performance of the state-of-the-art ResNet backbones by $10-20\%$ and that of the Densenet by $5-7\%$ respectively at the same level of computing and memory expenses. The CapProNet establishes the competitive state-of-the-art performance for the family of capsule nets by significantly reducing test errors on the benchmark datasets.Comment: Liheng Zhang, Marzieh Edraki, Guo-Jun Qi. CapProNet: Deep Feature Learning via Orthogonal Projections onto Capsule Subspaces, in Proccedings of Thirty-second Conference on Neural Information Processing Systems (NIPS 2018), Palais des Congr\`es de Montr\'eal, Montr\'eal, Canda, December 3-8, 201

Compact Cas9s and Their Natural Inhibitors for Genome Editing

Recent advances with the bacterial CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) defense system as genome editing tools have opened a new avenue for targeting disease-causing mutations. The programmability of the Cas9 endonuclease by RNA makes it a potentially powerful therapeutic tool to correct such mutations. The CRISPR-Cas9 system consists of a Cas9 endonuclease that is guided by RNA (sgRNA) to create double-stranded breaks in a target DNA segment complementary to the guide. This process is dependent on a 2-8 nucleotide sequence (called PAM) that is adjacent to the target and functions as a Cas9 binding signal. Each Cas9 ortholog recognizes a unique PAM. However, factors such as the size of Cas9 or the frequency of its PAM sequence in the genome have hindered its clinical use. The Cas9 from Streptococcus pyogenes (SpyCas9) is commonly used in research because its PAM (NGG, where “N” symbolizes any nucleotide) is present every ~8 bp in the genome, providing robust targeting potential. However, it is too large to fit into typical viral vectors used for in vivo delivery, namely adeno-associated vectors (AAV). While several Cas9 orthologs have been characterized, none satisfied the need for a compact, accurate Cas9 with a short PAM. In this thesis, we use two approaches to identify new compact Cas9 orthologs with small PAMs, one using anti-CRISPR proteins and one by searching through closely related Cas9s. First, we use the presence of anti-CRISPRs (naturally occurring, phage-encoded peptides that inhibit CRISPR-Cas9 described in chapter 2) in a genome as indicators of Cas9s that may be highly active. These orthologs come with the added advantage of having inhibitors that can be used as off-switches. We characterize four Cas9s that are targeted by anti-CRISPR proteins and show that they recognize diverse PAMs in vitro. One of the four Cas9’s, namely HpaCas9 from Haemophilus parainfluenzae, induces efficient genome editing in mammalian cells. However, its long N4GATTT PAM does not satisfy the short PAM criterion. For our second approach, we asked whether closely related Cas9 orthologs with drastically different PAM-interacting domains (PIDs, the domain responsible for PAM recognition) recognize different PAMs, and if so, can be used for genome editing. To this end, we exploited natural variation in the PID of closely related Cas9s to identify a compact ortholog from Neisseria meningitidis (Nme2Cas9). Nme2Cas9 recognizes a simple dinucleotide PAM (N4CC) that provides a high target site density. All-in-one AAV delivery of Nme2Cas9 with a guide RNA into adult mouse liver produces efficient genome editing and reduced serum cholesterol with exceptionally high specificity. We further expand our single-AAV platform to pre-implanted zygotes for streamlined generation of genome-edited mice. Finally, we show preliminary data on how CRISPR-Cas9 can be used for therapeutic genome editing for Amytrophic Lateral Sclerosis. Our new findings promise to accelerate the development of genome editing tools for biomedical and therapeutic applications

Midazolam Efficacy and Side Effects in Generalized and Partial Refractory Status Epilepticus in Children

ObjectiveMidazolam is a significant and effective drug for control of a life-threatening condition, generalized and partial refractory convulsive status epilepticus. The goal of this study was evaluation of midazolam efficacy for management of this serious disease and its two side effects, hypotension and respiratory failure.Materials & MethodsOur study was done using a quasi experimental method; 22 children with generalized refractory convulsive status epilepticus and 13 with partial refractory convulsive status epilepticus were enrolled for the study. All patients received 0.2mg/kg/dose as a bolus intravenous midazolam followed by 1-6 mcg/kg/min continuous intravenous midazolam. Following this, termination of seizures as well as hypotension and respiratory failure were evaluated.ResultsMidazolam ceased stop convulsions in 81.81% (18) patients with generalized seizures, and in 76.92% (10) patients with partial seizures, showing no significant difference between these two types of seizures (p=0.52) Hypotension was induced in 18.18% (4) patients with generalized seizures and in 30.70% (4) patients with partial seizures, again difference not significant (p=0.14). There was respiratory failure in 21.73% (5) patients with generalized seizure and in 7.69% (1) patients with partial seizure, difference not significant.(p=0.09)ConclusionThere was no significant difference in efficacy and creation of hypotension and respiratory failure after continuous intravenous infusion of midazolam between generalized and partial refractory convulsive status epilepticus.

Global versus Localized Generative Adversarial Nets

In this paper, we present a novel localized Generative Adversarial Net (GAN) to learn on the manifold of real data. Compared with the classic GAN that {\em globally} parameterizes a manifold, the Localized GAN (LGAN) uses local coordinate charts to parameterize distinct local geometry of how data points can transform at different locations on the manifold. Specifically, around each point there exists a {\em local} generator that can produce data following diverse patterns of transformations on the manifold. The locality nature of LGAN enables local generators to adapt to and directly access the local geometry without need to invert the generator in a global GAN. Furthermore, it can prevent the manifold from being locally collapsed to a dimensionally deficient tangent subspace by imposing an orthonormality prior between tangents. This provides a geometric approach to alleviating mode collapse at least locally on the manifold by imposing independence between data transformations in different tangent directions. We will also demonstrate the LGAN can be applied to train a robust classifier that prefers locally consistent classification decisions on the manifold, and the resultant regularizer is closely related with the Laplace-Beltrami operator. Our experiments show that the proposed LGANs can not only produce diverse image transformations, but also deliver superior classification performances

Frequency of Meningitis in Children Presenting with Febrile Seizures at Ali- Asghar Children’s Hospital

How to Cite This Article: Tavasoli A, Afsharkhas L, Edraki A. Frequency of Meningitis in Children Presenting with Febrile Seizure in Ali-Asghar Children’s Hospital. Iran J Child Neurol. 2014 Autumn; 8(4):51-56.AbstractObjectiveFebrile seizures (FS) are the most common type of childhood seizures, affecting 2–5% of children. As the seizure may be the sole presentation of bacterial meningitis in febrile infants, it is mandatory to exclude underlying meningitis in children presenting with fever and seizure. To determine the frequency of meningitis in children with FS and related risk factors, the present study was conducted at Ali-Asghar Children’s Hospital.Materials & MethodsThe records of children aged from 1-month–6 years of age with fever and seizure admitted to the hospital from October 2000–2010 were studied. The charts of patients who had undergone a lumbar puncture were studied and cases of meningitis were selected. The related data was collected and analyzed with SPSS version 16.ResultsA total of 681 patients with FS were known from which 422 (62%) lumbar punctures (LP) were done. Meningitis (bacterial or aseptic) was identified in 19 cases (4.5%, 95% CI 2.9–6.9 by Wilson- Score internal) and bacterial meningitis in 7 (1.65%, 95% CI 0.8–3.3). None of the patients with bacterial meningitis had meningeal irritation signs. Complex FS, first attack of FS, and impaired consciousness were more common in patients with meningitis when compared to non- meningitis patients.ConclusionMeningitis is more common in patients less than 18 months presenting with FS; however, complex features of seizures, first attack of FS, or impaired consciousness seem significant risk factors for meningitis in these children and an LP should be considered in this situation. ReferencesKimia A, Ben-Joseph EP, Rudleo T, et al. Yield of lumbar puncture among children who present with their first complex febrile seizure. Pediatrics.2010; 126: 62-69.Hom J, Medwid K, The low rate of bacterial meningitis in children, ages 6 to 18 months, with simple febrile seizures. AcadEmerg Med 2011; 18(11):1114-1120.Fetveit A. Assessment of febrile seizures in children. Eur J Pediatr 1998; 167(1); 17-27.Subcommittee on Febrile Seizures. Febrile seizures: Guidelines for the neurodiagnostic evaluation of the child with a simple febrile seizure. Pediatrics 2011; 127(2):389-394.Rosman NP. Evaluation of the child who convulses with fever. Pediatr Drugs 2003; 5(7):457- 461.Dubos F, De la Rocque F, Levy C et al. Sensitivity of the bacterial meningitis score in 889 children with bacterial meningitis. J Pediatr 2008; 152:378-382.Nigrovic LE, Kuppermann N, Macias CG, et al. Clinical prediction rule for identifying children with cerebrospinal fluid pleocytosis at very low risk of bacterial meningitis. JAMA 2007; 297(1):52-60.American Academy of Pediatrics. Provisional Committee on quality improvement, Subcommittee on Febrile Seizures. Practice parameter: the neurodiagnostic evaluation of the child with a first simple febrile seizure. Pediatrics 1997; 769-772.Najaf-Zadeh A, Dubos F, Hue V, et al. Risk of bacterial meningitis in young children with a first seizure in the context of fever: a systematic review and meta- analysis. PLoS One. 2013; 8(1):e55270. Doi: 10. 1371/journal. pone.0055270.Owusu-Ofori A, Agbenyega T, Ansong D, et al. Routine lumbar puncture in children with febrile seizures in Ghana: should it continue? International Journal of Infectious Diseases 2004; 8:353-361.Kimia AA, Capraro AJ, Hummel D, Johnston P, Harper MB. Utility of lumbar puncture for first simple febrile seizure among children 6 to 18 months of age. Pediatrics 2009; 123(1): 6–12.Shaked O, Pena BM, Linares MY, Baker RL. Simple febrile seizures: are the AAP guidelines regarding lumbar puncture being followed? Pediatr Emerg Care 2009; 25(1):8-11.Seltz LB, Cohen E, Weinstein M. Risk of bacterial or herpes simplex virus meningitis/encephalitis in children with complex febrile seizures. Pediatr Emerg Care 2009;25(8): 494–497.Casasoprana A, Hachon Le Camus C, Claudet l, et al. Value of lumbar puncture after a first febrile seizure in children aged less than 18 months. A retrospective study of 157 cases. Arch Pediatr, 2013. Pil: S0929-693X (13)00238-8.Kwang SK. Bacterial meningitis beyond the neonatal period. In: Cherry JD, Harrison GJ, Kaplan Sh L, Steinbach W.J, Hotez PJ, eds. Feigin and Cherry’s textbook of pediatric infectious diseases: Philadelphia, Elsevier, Saunders.2014.P:425-472.Ehsanipour F, Khodapanahandeh F, Aslani Z. The prevalence of meningitis in children with febrile seizure hospitalized at Hazrat Rasoul hospital (1997-2002). Journal of Iran University of Medical Sciences 2004; 44;907-912.Al-Eissa YA. Lumbar puncture in the clinical evaluation of children with seizures associated with fever. PediatrEmerg Care 1995; 11(6):347-350.Ghotbi F, Shiva F. An assessment of the necessity of lumbar puncture in children with seizure and fever. J Pak Med Assoc 2009; 59(5):292-295.Tinsa F, EL GhrbiA, NcibiN, et al. Role of lumbar puncture for febrile seizure among infants under one year old. Tunis Med 2010; 88(3): 178-183.Joshi Bataloo R, Rayamaihi A, Mahaseth C. Children with first episode of fever with seizure: is lumbar puncture necessary? JNMA J Nepal Med Assoc 2008;47(171):109-112.Carrol W, Brookfield D. Lumbar puncture following febrile convulsion. Arch Dis Child 2002; 87:238-240.Laditan AA. Analysis of the results of routine lumbar puncture after a first febrile convulsion in Hofuf, Al-Hassa, Saudi Arabia. East Afr Med J 1995;72:376-Rossi LN, Brunelli G, Duzioni N, et al. Lumbar puncture and febrile convulsion. Helv Pediatr Acta 1986; 41(1-2):19-24.Mikati M A. Febrile seizures. In: Behrman RF, Kliegman RM, Jenson HB. (editors). Nelson Textbook of Pediatrics. 19th ed. Philadelphia: Saunders. 2011. Pp: 2017-19

Novel 5-oxo-hexahydroquinoline derivatives: design, synthesis, in vitro P-glycoprotein-mediated multidrug resistance reversal profile and molecular dynamics simulation study

Overexpression of the efflux pump P-glycoprotein (P-gp) is one of the important mechanisms of multidrug resistance (MDR) in many tumor cells. In this study, 26 novel 5-oxo-hexahydroquinoline derivatives containing different nitrophenyl moieties at C-4 and various carboxamide substituents at C-3 were designed, synthesized and evaluated for their ability to inhibit P-gp by measuring the amount of rhodamine 123 (Rh123) accumulation in uterine sarcoma cells that overexpress P-gp (MES-SA/Dx5) using flow cytometry. The effect of compounds with highest MDR reversal activities was further evaluated by measuring the alterations of MES-SA/Dx5 cells' sensitivity to doxorubicin (DXR) using MTT assay. The results of both biological assays indicated that compounds bearing 2-nitrophenyl at C-4 position and compounds with 4-chlorophenyl carboxamide at C-3 demonstrated the highest activities in resistant cells, while they were devoid of any effect in parental nonresistant MES-SA cells. One of the active derivatives, 5c, significantly increased intracellular Rh123 at 100 mu M, and it also significantly reduced the IC50 of DXR by 70.1% and 88.7% at 10 and 25 mu M, respectively, in MES-SA/Dx5 cells. The toxicity of synthesized compounds against HEK293 as a noncancer cell line was also investigated. All tested derivatives except for 2c compound showed no cytotoxicity. A molecular dynamics simulation study was also performed to investigate the possible binding site of 5c in complex with human P-gp, which showed that this compound formed 11 average H-bonds with Ser909, Thr911, Arg547, Arg543 and Ser474 residues of P-gp. A good agreement was found between the results of the computational and experimental studies. The findings of this study show that some 5-oxo-hexahydroquinoline derivatives could serve as promising candidates for the discovery of new agents for P-gp-mediated MDR reversal

A hydrogeochemical review of riverine mine tailings deposition at Freeport Indonesia

This study is carried out at PT Freeport Indonesia (PTFI), one of the world’s largest copper‐gold mines. Due to steep terrain, high intensity rainfall and seismic activity, and after exhaustive studies, years of planning and engagement with government and other stakeholders, a controlled river tailings management system has been adopted to transport the tailings as the only feasible system. The tailings are transported to an engineered deposition area in the lowlands and coastal zones called the Modified Deposition Area (ModADA). Understanding the long‐term geochemical stability of the deposited tailings is critical for tailings management. As such, the study aims to evaluate the performance of a geochemically managed discharge approach under tropical climatic conditions by studying the relationships between geomorphic setting, geochemical processes and fate of carbonate‐rich sulphidic mine tailings transported via the river. The result of this study indicates that the ore‐feed blending strategy applied by PTFI has achieved the objective of ensuring that there will be no or minimal acid generation resulted from tailings deposition in ModADA.\ua0\ua

Implication of Manifold Assumption in Deep Learning Models for Computer Vision Applications

The Deep Neural Networks (DNN) have become the main contributor in the field of machine learning (ML). Specifically in the computer vision (CV), there are applications like image and video classification, object detection and tracking, instance segmentation and visual question answering, image and video generation are some of the applications from many that DNNs have demonstrated magnificent progress. To achieve the best performance, the DNNs usually require a large number of labeled samples, and finding the optimal solution for such complex models with millions of parameters is a challenging task. It is known that, the data are not uniformly distributed on the sample space, rather they are residing on a low-dimensional manifold embedded in the ambient space. In this dissertation, we specifically investigate the effect of manifold assumption on various applications in computer vision. First we propose a novel loss sensitive adversarial learning (LSAL) paradigm in training GAN framework that is built upon the assumption that natural images are lying on a smooth manifold. It benefits from the geodesic of samples in addition to the distance of samples in the ambient space to differentiate between real and generated samples. It is also shown that the discriminator of a GAN model trained based on LSAL paradigm is also successful in semi-supervised classification of images when the number of labeled images are limited. Then we propose a novel Capsule projection Network (CapProNet) that models the manifold of data through the union of subspace capsules in the last layer of a CNN image classifier. The CapProNet idea has been further extended to the general framework of Subspace Capsule Network that not only does model the deformation of objects but also parts of objects through the hierarchy of sub- space capsules layers. We apply the subspace capsule network on the tasks of (semi-) supervised image classification and also high resolution image generation. Finally, we verify the reliability of DNN models by investigating the intrinsic properties of the models around the manifold of data to detect maliciously trained Trojan models

Investigation of the attenuation and release of Cu2+ Ions by polymer-treated tailings

This study investigated the attenuation and release behaviour of copper ions using a standard kaolin-silt slurry as the synthetic tailings in a high solids/high salinity application before and after inline flocculation. A homogenous, synthetic tailings slurry was prepared in a 0.6 M NaCl solution and treated in a low-shear mixer by adding Magnafloc® 336 flocculant. Following the evaluation of morphological properties of both the untreated (UT) and polymer-treated tailings (PT), identical equilibrium tests were performed via the bottle-point method constant concentration technique. The maximum copper ions uptake capacity of polymer-treated tailings was 25% more than the untreated slurry at the equilibrium state in a chemisorption process in which the ions had the capability of binding onto one location on the sorbent, which could be influencing other binding sites on the same sorbent. Polymer treatment resulted in a highly porous structure that exhibited an increased capacity to adsorb and retain copper ions compared to the UT materials. This behaviour indicates the strong binding between the copper ions and active site of the treated tailings particles with greater capability of this material for preserving heavy metal ions within their structure across a wide pH range (2–10) compared to the UT materials. The results advance the fundamental understanding of how inline flocculation can considerably improve the sorption capacity of high solids/high salinity tailings favouring potential long-term rehabilitation purposes at mine closure and the role of sorption and desorption of heavy metal ions’ behaviour play to achieve this goal. © 2022 by the authors. Licensee MDPI, Basel, Switzerland