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Nasopharyngeal carcinoma (NPC) is closely linked to Epstein–Barr virus (EBV) infection. Curcumae Rhizoma, a traditional Chinese herb, has shown antitumor effects, primarily through its component curcumol (Cur), which has been shown to reduce NPC cell invasion and migration by targeting nucleolin (NCL) and Epstein–Barr Virus Nuclear Antigen 1 (EBNA1). We constructed an EBV-positive NPC cell model using C666-1 cells and performed transcriptomics studies after treatment with curcumol, which revealed a significant enrichment of ubiquitin-mediated proteolysis, the PI3K-AKT and mTOR signaling pathways, cell cycle and apoptosis involved in tumor invasion and migration. To investigate the importance of NCL and EBNA1 in curcumol-resistant EBV-positive NPC, we performed a multi-omics study using short hairpin NCL (shNCL) and shEBNA1 EBV-positive NPC cells, and the proteomics results showed enrichment in complement and coagulation cascades and ubiquitin-mediated proteolysis signaling pathways. Here, we focused on ubiquitin-conjugating enzyme E2C (UBE2C), which plays an important role in the ubiquitin-mediated proteolysis signaling pathway. In addition, metabolomics revealed that UBE2C is highly associated with 4-Aminobutanoic acid (GABA). In vitro studies further validated the function of the key targets, suggesting that UBE2C plays an important role in NCL and EBNA1-mediated curcumol resistance to nasopharyngeal carcinoma invasion and metastasis.

Fault detection and continuous condition monitoring in structural and machine elements are very sensitive topics and gaining significant value as a current research area. Due to the continuous loading and unloading of these elements, fatigue occurs. For the above-mentioned reason, crack is initiated and propagated. The initiation of any type of crack changes the physical properties of the structural and machine elements, which directly affects the lifetime of the element. The presence of any discontinuity changes the physical properties of the element, which also changes elastic properties. These alterations in physical properties change the modal properties of the structural elements. These changes in the vibration criteria can be used for the identification and quantification of the damage. In this research work, the vibration parameters are combined with Artificial Intelligence (AI) to predict the damage location. Here the natural evolution-based Genetic Algorithm (GA) has been used for the training of vibration features (frequencies). It has been discovered that the original AI methods are sometimes not able to give the proper prediction of damage location as they may be trapped in the local optimum. So, to counteract this loophole and to make it more flexible so that it can adjust to the constraints of real-life problems, a data mining method using Regression Analysis (RA) has been proposed and the results have been compared.

Abstract Background Breast cancer targeting diagnostic agent with effective imaging ability is important in guiding plan formulation, prediction, and curative effect evaluation of tumors in clinic. A tumor-targeting nanoprobe based on the functional and programmable Liquid–Liquid phase separation of AS1411 promoted by Ru(II) complex RuPEP may develop into a potential phosphorescence probe to detect breast cancer cells, where AS1411 act as a tumor-targeting guidance moiety to distinguish tumor cells from normal cells and RuPEP act as a light-emitting element to highlight breast cancer cells. Methods Here we designed and constructed a nanoprobe AS1411@RuPEP, and the physicochemical and biochemical properties were characterized by TEM, AFM and EDS. The breast cancer targeting diagnostic capacity was evaluated by normal/tumor cell co-culture assay, tumor cells targeting tracking in xenograft model and cancerous area selectively distinguishing in human patient tissue. Results Further studies indicated that the nanoprobe exhibits excellent tumor-targeting imaging ability in vitro and in vivo by effectively recognize the over-expressed nucleolin (NCL) on the breast cancer cells membrane. Intriguingly, we discovered that the selectively enrichment of nanoprobe particles in tumor cells is related to ATP-dependent NCL transport processes that rely on the AS1411 component of nanoprobe to recognize NCL. Furthermore, preferential accumulation of nanoprobe is clearly differentiating the human breast cancer tissue surrounding non-cancerous tissue in histological analysis. Conclusion This study produce a potent nanoprobe can be used as a convenient tool to highlight and distinguish tumor cells in vivo, and indicate the tumorous grading and staging in human breast cancer patient pathological section, which provides an effective way for breast cancer diagnostic imaging by targeting recognize NCL.

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Long non-coding RNA LINC01296 has been shown to predict the invasiveness and poor outcomes of patients with NB. Our study validated its prognostic value and investigated the biological function and potential mechanism of LINC01296 regulating NB. Results illuminated that LINC01296 expression was significantly correlated with unfavorable prognosis and malignant clinical features according to the public NB database. We identified that silencing LINC01296 repressed NB cell proliferation and migration and promoted apoptosis. Moreover, LINC01296 knockdown inhibited tumor growth in vivo. The opposite results were observed through the dCas9 Synergistic Activation Mediator System (dCas9/SAM) activating LINC01296. Mechanistically, we revealed that LINC01296 could directly bind to nucleolin (NCL), forming a complex that activated SRY-box transcription factor 11 (SOX11) gene transcription and accelerated tumor progression. In conclusion, our findings uncover a crucial role of the LINC01296-NCL-SOX11 complex in NB tumorigenesis and may serve as a prognostic biomarker and effective therapeutic target for NB.

Asynchronous circuits is an alternative to design digital systems that is becoming the interest of many researchers in the digital design area mainly due to it’s low-power consumption and robustness. One of the most compelling design paradigms of asynchronous circuits is the NULL Convention Logic (NCL). The pipeline is a very common technique used in digital circuits to achieve high throughput. Although one can implement a pipeline using NCL gates, recent works have shown that register-less pipelines are possible using modified NCL gates. In this paper we propose two new Register-Less NCL (RL-NCL) pipeline architectures and two new methods to design NCL gates, which can be implemented even in Field Programmable Gate Arrays (FPGAs) or using the standard cells method. The new design of the proposed architecture was able to achieve an average area reduction of 27,32%, an average latency reduction of 14,1% and an average throughput increase of 5,54% comparing with the conventional NCL pipeline architecture.

Batten disease is a family of rare, fatal, neuropediatric diseases presenting with memory/learning decline, blindness, and loss of motor function. Recently, we reported the use of an AAV9-mediated gene therapy that prevents disease progression in a mouse model of CLN6-Batten disease (Cln6nclf), restoring lifespans in treated animals. Despite the success of our viral-mediated gene therapy, the dosing strategy was optimized for delivery to the brain parenchyma and may limit the therapeutic potential to other disease-relevant tissues, such as the eye. Here, we examine whether cerebrospinal fluid (CSF) delivery of scAAV9.CB.CLN6 is sufficient to ameliorate visual deficits in Cln6nclf mice. We show that intracerebroventricular (i.c.v.) delivery of scAAV9.CB.CLN6 completely prevents hallmark Batten disease pathology in the visual processing centers of the brain, preserving neurons of the superior colliculus, thalamus, and cerebral cortex. Importantly, i.c.v.-delivered scAAV9.CB.CLN6 also expresses in many cells throughout the central retina, preserving many photoreceptors typically lost in Cln6nclf mice. Lastly, scAAV9.CB.CLN6 treatment partially preserved visual acuity in Cln6nclf mice as measured by optokinetic response. Taken together, we report the first instance of CSF-delivered viral gene reaching and rescuing pathology in both the brain parenchyma and retinal neurons, thereby partially slowing visual deterioration.

The neuronal ceroid lipofuscinoses (NCLs) are a group of childhood-onset neurodegenerative lysosomal storage disorders mainly affecting the brain and the retina. In the NCLs, disease-causing mutations in 13 different ceroid lipofuscinoses genes (CLN) have been identified. The clinical symptoms include seizures, progressive neurological decline, deterioration of motor and language skills, and dementia resulting in premature death. In addition, the deterioration and loss of vision caused by progressive retinal degeneration is another major hallmark of NCLs. To date, there is no curative therapy for the treatment of retinal degeneration and vision loss in patients with NCL. In this review, the key findings of different experimental approaches in NCL animal models aimed at attenuating progressive retinal degeneration and the decline in retinal function are discussed. Different approaches, including experimental enzyme replacement therapy, gene therapy, cell-based therapy, and immunomodulation therapy were evaluated and showed encouraging therapeutic benefits. Recent experimental ocular gene therapies in NCL animal models with soluble lysosomal enzyme deficiencies and transmembrane protein deficiencies have shown the strong potential of gene-based approaches to treat retinal dystrophies in NCLs. In CLN3 and CLN6 mouse models, an adeno-associated virus (AAV) vector-mediated delivery of CLN3 and CLN6 to bipolar cells has been shown to attenuate the retinal dysfunction. Therapeutic benefits of ocular enzyme replacement therapies were evaluated in CLN2 and CLN10 animal models. Since brain-targeted gene or enzyme replacement therapies will most likely not attenuate retinal neurodegeneration, there is an unmet need for treatment options additionally targeting the retina in patients with NCL. The long-term benefits of these therapeutic interventions aimed at attenuating retinal degeneration and vision loss in patients with NCL remain to be investigated in future clinical studies.

Conducting clinical trials in rare diseases is challenging. In trials that aim to use natural history control cohorts for evaluation of efficacy, lack of data on natural history of disease prolongs development of future therapies significantly. Therefore, collection of valid natural history data in clinical settings is needed to advance drug development. These data need to fulfill requirements on type of collection, quantifiable measures on the course of disease, verification and monitoring as well as compliance to strict data protection and sharing policies. Disease registries can be a source for patient data. Late-infantile CLN2 disease is characterized by rapid psychomotor decline and epilepsy. Natural-history data of 140 genotype-confirmed CLN2 patients from two independent, international cohorts were analyzed in a natural history study. Both datasets included quantitative ratings with disease-specific clinical scores. Among 41 patients for whom longitudinal assessments spanning an extended disease course were available within the DEM-CHILD DB (an international NCL disease patient database, NCT04613089), a rapid loss of motor and language abilities was documented in quantitative detail. Data showed that the course of disease in late-infantile CLN2 disease is highly predictable with regard to the loss of language and motor function and that the results were homogeneous across multiple and international sites. These data were accepted by EMA and FDA as valid natural-history controls for the evaluation of efficacy in experimental therapies for CLN2 disease and led to an expedited approval of intracerebroventricular enzyme replacement therapy with cerliponase alpha in May 2017.

Frontotemporal lobar degeneration (FTLD) is a complex disease, characterized by progressive degeneration of frontal and temporal lobes. Mutations in progranulin (GRN) gene have been found in up to 50% of patients with familial FTLD. Abnormal deposits of post-translationally-modified TAR DNA-binding protein of 43 kDa (TDP-43) represent one of the main hallmarks of the brain pathology. To investigate in peripheral cells the presence of the different TDP-43 forms, especially the toxic 25 kDa fragments, we analyzed lymphoblastoid cell lines (LCLs) and the derived extracellular vesicles (EVs) from patients carrying a GRN mutation, together with wild-type (WT) healthy controls. After characterizing EV sizes and concentrations by nanoparticle tracking analysis, we investigated the levels of different forms of the TDP-43 protein in LCLs and respective EVs by Western blot. Our results showed a trend of concentration decreasing in EVs derived from GRN-mutated LCLs, although not reaching statistical significance. A general increase in p-TDP-43 levels in GRN-mutated LCLs and EVs was observed. In particular, the toxic 25 kDa fragments of p-TDP-43 were only present in GRN-mutated LCLs and were absent in the WT controls. Furthermore, these fragments appeared to be more concentrated in EVs than in LCLs, suggesting a relevant role of EVs in spreading pathological molecules between cells.

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders that affect children and adults. They share some similar clinical features and the accumulation of autofluorescent storage material. Since the discovery of the first causative genes, more than 530 mutations have been identified across 13 genes in cases diagnosed with NCL. These genes encode a variety of proteins whose functions have not been fully defined; most are lysosomal enzymes, or transmembrane proteins of the lysosome or other organelles. Many mutations in these genes are associated with a typical NCL disease phenotype. However, increasing numbers of variant disease phenotypes are being described, affecting age of onset, severity or progression, and including some distinct clinical phenotypes. This data is collated by the NCL Mutation Database which allows analysis from many perspectives. This article will summarise and interpret current knowledge and understanding of their genetic basis and phenotypic heterogeneity.

Avian metapneumovirus subgroup C (aMPV/C) is highly pathogenic to various avian species with acute respiratory tract clinicopathology and/or drops in egg production. Nucleolin (NCL), an important nucleolar protein, has been shown to regulate multiple viral replication and serve as a functional receptor for viral entry and internalization. Whether NCL is involved in aMPV/C pathogenesis is not known. In this study, we found that aMPV/C infection altered the subcellular localization of NCL in cultured cells. siRNA-targeted NCL resulted in a remarkable decline in aMPV/C replication in Vero cells. DF-1 cells showed a similar response after CRISPR/Cas9-mediated knock out of NCL during aMPV/C infection. Conversely, NCL overexpression significantly increased aMPV/C replication. Pretreatment with AS1411-a aptamer, a guanine (G)-rich oligonucleotide that forms four-stranded structures and competitively binding to NCL, decreased aMPV/C replication and viral titers in cultured cells. Additionally, we found that the aMPV/C fusion (F) protein specifically interacts with NCL through its central domain and that AS1411 disrupts this interaction, thus inhibiting viral replication. Taken together, these results reveal that the aMPV/C F protein interacts with NCL, which is employed by aMPV/C for efficient replication, thereby highlighting the strategic potential for control and therapy of aMPV/C infection.

CLN5 disease (MIM: 256731) represents a rare late-infantile form of neuronal ceroid lipofuscinosis (NCL), caused by mutations in the CLN5 gene that encodes the CLN5 protein (CLN5p), whose physiological roles stay unanswered. No cure is currently available for CLN5 patients and the opportunities for therapies are lagging. The role of lysosomes in the neuro-pathophysiology of CLN5 disease represents an important topic since lysosomal proteins are directly involved in the primary mechanisms of neuronal injury occurring in various NCL forms. We developed and implemented a lysosome-focused, label-free quantitative proteomics approach, followed by functional validations in both CLN5-knockout neuronal-like cell lines and Cln5−/− mice, to unravel affected pathways and modifying factors involved in this disease scenario. Our results revealed a key role of CLN5p in lipid homeostasis and sphingolipid metabolism and highlighted mutual NCL biomarkers scored with high lysosomal confidence. A newly generated cln5 knockdown zebrafish model recapitulated most of the pathological features seen in NCL disease. To translate the findings from in-vitro and preclinical models to patients, we evaluated whether two FDA-approved drugs promoting autophagy via TFEB activation or inhibition of the glucosylceramide synthase could modulate in-vitro ROS and lipid overproduction, as well as alter the locomotor phenotype in zebrafish. In summary, our data advance the general understanding of disease mechanisms and modifying factors in CLN5 disease, which are recurring in other NCL forms, also stimulating new pharmacological treatments.

Neuronal ceroid lipofuscinoses (NCLs) are a group of rare, inherited, neurodegenerative lysosomal storage disorders that affect children and adults. They are traditionally grouped together, based on shared clinical symptoms and pathological ground. To date, 13 autosomal recessive gene variants, as well as one autosomal dominant gene variant, of NCL have been described. These genes encode a variety of proteins, whose functions have not been fully defined; most are lysosomal enzymes, transmembrane proteins of the lysosome, or other organelles. Common symptoms of NCLs include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and, in rare adult-onset cases, dementia. Depending on the mutation, these symptoms can vary, with respect to the severity and onset of symptoms by age. Currently, all forms of NCL are fatal, and no curative treatments are available. Herein, we provide an overview to summarize the current knowledge regarding the pathophysiology, genetics, and clinical manifestation of these conditions, as well as the approach to diagnosis.

The Weather Research and Forecasting model (WRF) is an atmospheric simulation system designed for both research and operational applications. This worldwide used model requires a sophisticated modeling experience and computing skills. In this study, WRF model was used to predict many atmospheric parameters based on the initial conditions extracted from NOMADS data sets. The study area is basically the region surrounded by the longitudes and latitudes: 15o-75o E and 10.5o-45o N which typically includes the Middle East region. The model was installed on Linux platform with a grid size of 10 km in the X and Y directions. A low pressure trough was tracked in its movement from west to east via the Middle East during the period from 1 to 7 January 2010 as a case study of the WRF model. MATLAB and NCAR Command Language (NCL) were used to display the model output. To evaluate the forecasted parameters and patterns, some comparisons were made between the predicted and actual weather charts. Wind speeds and directions in the prognostic and actual charts of 700 hPa were in agreement. However, the predicted values of geopotential heights in WRF are somewhat overestimate the actual ones. This may be attributed to the differences in the data sources and data analysis methods of the two data agencies, NOMADS and ECMWF.

Abstract Background Neuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative disorders characterized by an accumulation of lipofuscin in the body's tissues. NCLs are associated with variable age of onset and progressive symptoms including seizures, psychomotor decline, and loss of vision. Methods We describe the clinical and molecular characteristics of four Russian patients with NCL (one female and three males, with ages ranging from 4 to 5 years). The clinical features of these patients include cognitive and motor deterioration, seizures, stereotypies, and magnetic resonance imaging signs of brain atrophy. Exome sequencing was performed to identify the genetic variants of patients with NCL. Additionally, we tested 6,396 healthy Russians for NCL alleles. Results We identified five distinct mutations in four NCL‐associated genes of which two mutations are novel. These include a novel homozygous frameshift mutation in the CLN6 gene, a compound heterozygous missense mutation in the KCTD7 gene, and previously known mutations in KCTD7, TPP1, and MFSD8 genes. Furthermore, we estimated the Russian population carrier frequency of pathogenic and likely pathogenic variants in 13 genes associated with different types of NCL. Conclusion Our study expands the spectrum of mutations in lipofuscinosis. This is the first study to describe the molecular basis of NCLs in Russia and has profound and numerous clinical implications for diagnosis, genetic counseling, genotype–phenotype correlations, and prognosis.

The neuronal ceroid lipofuscinoses (NCL) are a collection of lysosomal storage diseases characterised by the accumulation of characteristic inclusions containing lipofuscin in various tissues of the body and are one of the causes of progressive myoclonic epilepsy. Mutations in at least thirteen genes have been identified as causes of NCL, which can present as infantile, late-infantile, juvenile or adult forms. CLN6 codes for an endoplasmic reticulum transmembrane protein of unknown function. Homozygous and compound heterozygous mutations of the gene are associated with both late-infantile (LINCL) and adult onset (ANCL) forms of NCL, including Kufs disease, comprising ANCL without associated visual loss. Moyamoya, a rare vasculopathy of the circle of Willis, has been reported in conjunction with a number of inflammatory and other diseases, as well as a handful of lysosomal storage diseases. To our knowledge, this is the first reported case of Moyamoya in the context of the neuronal ceroid lipofuscinoses or a CLN6-related disease.

Abstract Background Neuronal ceroid lipofuscinoses (NCLs) are the most common autosomal recessive neurodegenerative disorders in children. Clinical manifestations include progressive cognitive decline, motor impairment, ataxia, visual loss, seizures and early death. To date more than 440 NCL-causing mutations in 13 genes are known. Case presentation We report clinical and genetic characteristics of a 5-year-old girl affected by ceroid lipofuscinosis type 7 (NCL7). She had progressive motor and mental deterioration since the age of 2,5 years. Later she developed progressive vision loss, stereotypies, action myoclonus and epilepsy. By the age of 5 years she stopped walking. Based on symptoms, diagnosis of Rett syndrome was suggested, but no abnormalities were detected in MeCP2. We identified a novel homozygous mutation in MFSD8 gene (c.525 T > A, p.Cys175Ter). To our knowledge, this is the first report of MFSD8 gene mutation in a Russian patient with variant late-infantile NCL. Conclusions Our results enlarge mutational spectrum of ceroid lipofuscinosis type 7 and demonstrate tremendous diagnosis value of exome sequencing for pediatric NCLs. Also we confirmed that NCL should be suspected in patients with Rett-like phenotype at onset and negative MECP2 mutation.

Abstract Background Long non-coding RNAs (lncRNAs) function as key molecules in cancer progression. The lncRNA CYTOR plays oncogenic roles in multiple types of cancer, yet the detailed molecular mechanisms of those roles remain unknown. The aim of this study was to investigate the clinical significance, biological function and interacting partners of CYTOR in colorectal cancer (CRC). Methods A systematic and comprehensive analysis of CYTOR expression was performed in 138 CRC samples and in the TCGA and GEO databases. Biological function was investigated through knockdown and overexpression of CYTOR in vitro and in vivo. In addition, its protein binding partner was identified and validated using ChIRP-MS and RNA immunoprecipitation assays. Their key interaction sites on CYTOR were verified by CRISPR/Cas9 and a series of mutant constructs. Furthermore, the downstream targets of CYTOR were confirmed via immunoblotting and luciferase reporter assays. Results CYTOR was significantly up-regulated in CRC samples and associated with poor prognosis, promoting proliferation and metastasis in vitro and in vivo. NCL and Sam68 could recognize their specific motifs and directly bind to EXON1 of CYTOR. Moreover, EXON1 was the key functional site mediating the interaction of CYTOR with NCL and Sam68. NCL and Sam68 functioned as oncogenes to promote CRC progression. Furthermore, we confirmed that the heterotrimeric complex of CYTOR, NCL and Sam68 activated the NF-κB pathway and EMT to contribute to CRC progression. Conclusion CYTOR plays important roles in CRC progression by interacting with NCL and Sam68 and may serve as a prognostic biomarker and/or an effective target for CRC therapies.

Abstract Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is a group of genetically distinct lysosomal disorders that mainly affect the central nervous system, resulting in progressive motor and cognitive decline primarily in children. Multiple distinct genes involved in the metabolism of lipids have been identified to date with various mutations in this family of diseases. There is no cure for these diseases but some new therapeutic approaches have been tested that offer more hope than the standard palliative care. Many of the therapeutic advances require invasive procedures but some progress in slowing the disease has been found and more options can be expected in the future. We also review the literature on children with disease/conditions other than NCL for the non-invasive use, safety, and tolerability of a lipid-lowering drug, gemfibrozil, as a potential treatment for NCLs. Gemfibrozil has shown efficacy in an animal model of NCL known as CLN2 (late infantile classic juvenile) and has been shown to be safe for lowering lipids in children. Among the 200 non-NCL children found in the published literature who were treated with gemfibrozil for NCL-related problems, only 3 experienced adverse events, including 2 with muscle pain and 1 with localized linear IgA bullous dermatitis. We conclude that gemfibrozil is safe for long-term use in children, causes minimal adverse events, is well tolerated, and may delay the progression of NCLs. Gemfibrozil may potentially be an alternative to more invasive therapeutic approaches currently under investigation and has the potential to be used in combination with other therapeutic approaches.

El presente artículo muestra una solución al desarrollo automático de aplicaciones interactivas Ginga-NCL para la Televisión Digital Terrestre, a partir de plantillas prediseñadas. Productores de televisión y gente relacionada con este medio de comunicación masivo, no conocen o simplemente no tienen las herramientas necesarias para la creación de aplicaciones interactivas, en muchos casos ni siquiera se conoce la existencia de una plataforma para el desarrollo de las mismas. Es por esta razón que se propone una metodología totalmente nueva y amigable para el usuario, la cual permita generar aplicaciones interactivas sin tener el conocimiento técnico ni las habilidades de programación que implica su creación. La reducción del tiempo en la generación de aplicaciones, disminución de capital de inversión en la preparación y adiestramiento del personal, cambios on-air en la programación interactiva del canal de televisión, son algunos de los resultados que trae consigo este sistema.

The electric spring (ES) is a kind of electric device used for energy buffering, based on voltage and power management. ES transfers the voltage (or energy) fluctuation in the main bus to the non-critical load (NCL), stabilises the main voltage for critical load, and actively adjusts the power consumption of the NCL to achieve regulation goals of distribution network with wide voltage operational range of NCL. With lots of intermittent and fluctuating renewable energy resources into the energy Internet, the smart load integrated with the ES will play a greater role in the optimal operation of the distribution network. Here, the power flow optimal model of distribution network with the ES is proposed. Under different load levels, the flexible regulation of ES can reduce the overall voltage drop and optimise the operation of distribution network. The benefits of ES for the optimisation of distribution network are verified based on an improved IEEE 33-node case. Numerical results show that the ES relieves the voltage drop of the distribution network and improves the reliability of distribution network based on the interaction between the ES and NCL. The overall energy efficiency and reliability of the distribution network system are improved.

Yeasts provide an excellent genetically tractable eukaryotic system for investigating the function of genes in their biological context, and are especially relevant for those conserved genes that cause disease. We study the role of btn1, the orthologue of a human gene that underlies an early onset neurodegenerative disease (juvenile CLN3 disease, neuronal ceroid lipofuscinosis (NCLs) or Batten disease) in the fission yeast Schizosaccharomyces pombe. A global screen for genetic interactions with btn1 highlighted a conserved key signalling hub in which multiple components functionally relate to this conserved disease gene. This signalling hub includes two major mitogen-activated protein kinase (MAPK) cascades, and centers on the Tor kinase complexes TORC1 and TORC2. We confirmed that yeast cells modelling CLN3 disease exhibit features consistent with dysfunction in the TORC pathways, and showed that modulating TORC function leads to a comprehensive rescue of defects in this yeast disease model. The same pathways may be novel targets in the development of therapies for the NCLs and related diseases.

Goal-directed navigation is a crucial behavior for the survival of animals, especially for the birds having extraordinary spatial navigation ability. In the studies of the neural mechanism of the goal-directed behavior, especially involving the information encoding mechanism of the route, the hippocampus (Hp) and nidopallium caudalle (NCL) of the avian brain are the famous regions that play important roles. Therefore, they have been widely concerned and a series of studies surrounding them have increased our understandings of the navigation mechanism of birds in recent years. In this paper, we focus on the studies of the information encoding mechanism of the route in the avian goal-directed behavior. We first summarize and introduce the related studies on the role of the Hp and NCL for goal-directed behavior comprehensively. Furthermore, we review the related cooperative interaction studies about the Hp-NCL local network and other relevant brain regions supporting the goal-directed routing information encoding. Finally, we summarize the current situation and prospect the existing important questions in this field. We hope this paper can spark fresh thinking for the following research on routing information encoding mechanism of birds.

About two thirds of the patients affected with lysosomal storage diseases (LSD) experience neurological manifestations, such as developmental delay, seizures, or psychiatric problems. In order to develop efficient therapies, it is crucial to understand the neuropathophysiology underlying these symptoms. How exactly lysosomal storage affects biogenesis and function of neurons is still under investigation however recent research highlights a substantial role played by synaptic defects, such as alterations in synaptic spines, synaptic proteins, postsynaptic densities, and synaptic vesicles that might lead to functional impairments in synaptic transmission and neurodegeneration, finally culminating in massive neuronal death and manifestation of cognitive symptoms. Unveiling how the synaptic components are affected in neurological LSD will thus enable a better understanding of the complexity of disease progression as well as identify crucial targets of therapeutic relevance and optimal time windows for targeted intervention.

Lesion studies suggest a role of the avian hippocampus in spatial and episodic memory. However, whether the avian hippocampus is also involved in processing categorical information and non-spatial working memory contents remains unknown. To address this question, we trained two crows in a delayed-match-to-sample test to assess and briefly memorize the number of items in dot displays, i.e., their numerosity. We recorded neuronal activity in hippocampus while crows solved this task. Hardly any hippocampal neurons responded to the category ‘numerosity,’ during neither sample presentation, nor during the memory delay. This was in striking contrast to previous recordings in the telencephalic association area ‘nidopallium caudolaterale’ (NCL) of the same crows, in which we previously reported an abundance of numerosity-selective and working memory-selective neurons. Our data suggest that categorical information is not processed in the avian hippocampus.

As digital circuit design continues to evolve due to progress of semiconductor processes well into the sub 100 nm range, clocked architectures face limitations in a number of cases where clockless asynchronous architectures generate less noise and produce less electro-magnetic interference (EMI). This paper develops the Delay-Insensitive Ternary Logic (DITL) asynchronous design paradigm that combines design aspects of similar dual-rail asynchronous paradigms and Boolean logic to create a single wire per bit, three voltage signaling and logic scheme. DITL is compared with other delay insensitive paradigms, such as Pre-Charge Half-Buffers (PCHB) and NULL Convention Logic (NCL) on which it is based. An application of DITL is discussed in designing secure digital circuits resistant to side channel attacks based on measurement of timing, power, and EMI signatures. A Secure DITL Adder circuit is designed at the transistor level, and several variance parameters are measured to validate the efficiency of DITL in resisting side channel attacks. The DITL design methodology is then applied to design a secure 8051 ALU.

La TV Digital es una tecnología, que va a transformar la experiencia de ver televisión. Imagen y sonido en alta definición junto con la interactividad son posibles gracias al pasaje de la transmisión analógica a la digital, la cual permite enviar datos, video, audio, aplicaciones, etc. a través de los canales de transmisión. Estas señales digitales son más eficientes que las analógicas y tienen como principal ventaja la posibilidad de enviar servicios a través del mismo canal, permitiendo un uso eficiente del espectro de transmisiones. Emergen nuevas posibilidades para el desarrollo de software, puesto que una aplicación interactiva de TV Digital es un software, específicamente una aplicación multimedia a través de la cual el televidente puede interactuar vía control remoto. Esto significa que el televidente también puede recibir video/audio, software que posibilitan que interactúe con el contenido vinculado. En estos nuevos escenarios resulta necesario llevar adelante experiencias de desarrollo de aplicaciones interactivas para TV Digital. Poner en práctica procesos, estrategias y herramientas, y su consecuente análisis promete arribar a propuestas razonables. En este sentido, este trabajo condensa las experiencias en el desarrollo de prototipos realizados en el Laboratorio de TV Digital de la UNPA que se iniciaron en el año 2011.

Mutations in the major facilitator superfamily domain containing 8 (MFSD8) gene coding for the lysosomal CLN7 membrane protein result in CLN7 disease, a lysosomal storage disease of childhood. CLN7 disease belongs to a group of inherited disorders, called neuronal ceroid lipofuscinoses (NCL), which are characterized by the accumulation of autofluorescent ceroid lipopigments, neuroinflammation, photoreceptor- and neurodegeneration. We have disrupted the Mfsd8 gene by insertion of a lacZ gene-trap cassette between exons 1 and 2 in mice and have analyzed the impact of Cln7 depletion on neuronal and visceral tissues. Analysis of lacZ reporter gene activity in heterozygous Mfsd8(wt/tm1a) mice showed strong Mfsd8 mRNA expression in the cerebral cortex, in the hippocampus and in the kidney. Homozygous Mfsd8(tm1a/tm1a) mice were viable and fertile and resembled biochemically the NCL-phenotype of human CLN7 patients including the accumulation of autofluorescent material in the brain and peripheral tissues and of subunit c of mitochondrial ATP synthase in the cerebellum and nuclei of distinct brain regions, and the degeneration of photoreceptor cells in the retina. Lysosomal storage was found in large neurons of the medulla, the hippocampus and in Purkinje cells of the cerebellum in mutant mice. The ultrastructure of the storage material revealed dense lamellar bodies with irregular forms within cerebellar and hippocampal neurons. In the brain loss of Cln7 was accompanied by mild reactive microgliosis and subtle astrogliosis by 10 months of age, respectively. In summary we have generated a mouse model which is partly valuable as some but not all neuropathological features of human CLN7 disease are recapitulated thus representing an animal model to study CLN7-specific disease mechanisms.

The unsaturated soils are difficult to consider within the framework of classical (saturated) soil mechanics. In general, the unsaturated soil is stiffer than the saturated one (hardening), so the location and slope of normal consolidated line (NCL) or the volumetric yielding behavior of unsaturated soil is different from the saturated behavior. This work investigates the volumetric yielding behavior of unsaturated soil; by determine the One-dimensional normal consolidated lines (NCL’s) under different suctions. Two materials namely pure Calcigel bentonite (100B) and a mixture of 30% Calcigel bentonite and 70 % Haider sand (30B) were prepared at two initial conditions (i.e. slurry and loose states). In this type of test, after reaching to the designed suction, the net stress is increased through the test while the suction is kept constant. Thirteen 30B specimens and two 100B specimens were tested under constant suction condition. The constant applied suction in this study was varied from 0 kPa till 39000 kPa because of the possibility to increase the preconsolidation pressure (yield stress) more than 24000 kPa (the maximum limit of the used one-dimensional high stress consolidation equipments). Two techniques (i.e. axis translation technique and vapor equilibrium technique) were used to apply and control suction on tests. The controlled-suction one-dimensional high stress consolidation tests results show that the position and the slope of NCL’s depend on both net stress and suction. The NCL’s either, for low suction value, has void ratio lower than the saturated NCL (associated with slope lower than the saturated NCL), or the NCL has void ratio higher than the saturated NCL (associated with slope higher than the saturated NCL) for higher suction value.

CLN5 disease, late infantile variant phenotype neuronal ceroid lipofuscinosis, is a severe neurodegenerative disease caused by mutations in the CLN5 gene, which encodes a lysosomal protein of unknown function. Cln5-deficiency in mice leads to loss of thalamocortical neurons, and glial activation, but the underlying mechanisms are poorly understood. We have now studied the gene expression of Cln5 in the mouse brain and show that it increases gradually with age and differs between neurons and glia, with the highest expression in microglia. In Cln5−/− mice, we documented early and significant microglial activation that was already evident at 3 months of age. Loss of Cln5 also leads to defective myelination in vitro and in the developing mouse brain. This was accompanied by early alterations in serum lipid profiles, dysfunctional cellular metabolism and lipid transport in Cln5−/− mice. Taken together, these data provide significant new information about events associated with Cln5-deficiency, revealing altered myelination and disturbances in lipid metabolism, together with an early neuroimmune response.

Batten disease (neuronal ceroid lipofuscinoses, NCLs) are a group of inherited childhood diseases that result in severe brain atrophy, blindness and seizures, leading to premature death. To date, eight different genes have been identified, each associated with a different form. Linkage analysis indicated a CLN5 form in a colony of affected New Zealand Borderdale sheep. Sequencing studies established the disease-causing mutation to be a substitution at a consensus splice site (c.571+1G>A), leading to the excision of exon 3 and a truncated putative protein. A molecular diagnostic test has been developed based on the excision of exon 3. Sequence alignments support the gene product being a soluble lysosomal protein. Western blotting of isolated storage bodies indicates the specific storage of subunit c of mitochondrial ATP synthase. This flock is being expanded as a large animal model for mechanistic studies and trial therapies.

Neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive progressive encephalopathies caused by mutations in at least 14 different genes. Despite extensive studies performed in different NCL animal models, the molecular mechanisms underlying neurodegeneration in NCLs remain poorly understood. To model NCL in human cells, we generated induced pluripotent stem cells (iPSCs) by reprogramming skin fibroblasts from a patient with CLN5 (ceroid lipofuscinosis, neuronal, 5) disease, the late infantile variant form of NCL. These CLN5 patient-derived iPSCs (CLN5Y392X iPSCs) harbouring the most common CLN5 mutation, c.1175_1176delAT (p.Tyr392X), were further differentiated into neural lineage cells, the most affected cell type in NCLs. The CLN5Y392X iPSC-derived neural lineage cells showed accumulation of autofluorescent storage material and subunit C of the mitochondrial ATP synthase, both representing the hallmarks of many forms of NCLs, including CLN5 disease. In addition, we detected abnormalities in the intracellular organelles and aberrations in neuronal sphingolipid transportation, verifying the previous findings obtained from Cln5-deficient mouse macrophages. Therefore, patient-derived iPSCs provide a suitable model to study the mechanisms of NCL diseases.