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Intrahepatic cholangiocarcinoma (iCCA) is a fatal malignancy of the biliary system. The lack of a detailed understanding of oncogenic signaling or global gene expression alterations has impeded clinical iCCA diagnosis and therapy. The role of protein lactylation, a newly unraveled post-translational modification that orchestrates gene expression, remains largely elusive in the pathogenesis of iCCA. Proteomics analysis of clinical iCCA specimens and adjacent tissues was performed to screen for proteins aberrantly lactylated in iCCA. Mass spectrometry, macromolecule interaction and cell behavioral studies were employed to identify the specific lactylation sites on the candidate protein(s) and to decipher the downstream mechanisms responsible for iCCA development, which were subsequently validated using a xenograft tumor model and clinical samples. Nucleolin (NCL), the most abundant RNA-binding protein in the nucleolus, was identified as a functional lactylation target that correlates with iCCA occurrence and progression. NCL was lactylated predominantly at lysine 477 by the acyltransferase P300 in response to a hyperactivity of glycolysis, and promoted the proliferation and invasion of iCCA cells. Mechanistically, lactylated NCL bound to the primary transcript of MAP kinase-activating death domain protein (MADD) and led to efficient translation of MADD by circumventing alternative splicing that generates a premature termination codon. NCL lactylation, MADD translation and subsequent ERK activation promoted xenograft tumor growth and were associated with overall survival in patients with iCCA. NCL is lactylated to upregulate MADD through an RNA splicing-dependent mechanism, which potentiates iCCA pathogenesis via the MAPK pathway. Our findings reveal a novel link between metabolic reprogramming and canonical tumor-initiating events, and uncover biomarkers that can potentially be used for prognostic evaluation or targeted treatment of iCCA. Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive liver malignancy with largely uncharacterized pathogenetic mechanisms. Herein, we demonstrated that glycolysis promotes P300-catalyzed lactylation of nucleolin, which upregulates MAP kinase-activating death domain protein (MADD) through precise mRNA splicing and activates ERK signaling to drive iCCA development. These findings unravel a novel link between metabolic rewiring and canonical oncogenic pathways, and reveal new biomarkers for prognostic assessment and targeting of clinical iCCA. [Display omitted] • Nucleolin is a lactylation target that mediates iCCA pathogenesis. • Nucleolin is lactylated predominantly at lysine 477 by P300 in glycolytic iCCA cells. • Lactylated nucleolin upregulates MADD by preventing RNA mis-splicing. • Lactylated nucleolin/MADD/pERK predicts poor prognosis of patients with iCCA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

Background: Lung adenocarcinoma (LUAD), as the most common type of lung cancer, poses a significant threat to public health. Tumor heterogeneity plays a crucial role in carcinogenesis, which could be largely deciphered by next‐generation sequencing (NGS). Methods: We obtained and screened single‐cell RNA sequencing (scRNA‐seq) data from 16 LUAD samples, and endothelial cells (ECs) were grouped into three clusters. The origin of EC differentiation was explored by pseudo‐time analysis. CellChat analysis was used to detect potential communication between ECs and malignant cells, and gene regulatory network analysis was used to identify changes in transcription factor activity. We explored the prognosis of specific ECs clusters and their effects on the tumor microenvironment (TME) at the bulk transcriptome level. 5‐Ethynyl‐2′‐ deoxyuridine (EdU) and Ki‐67 staining were conducted to study the proliferative phenotype of LUAD cell lines. Western blotting targeting the phosphorylation of PI3K–AKT proteins was utilized for determination of the downstream pathway of NCL. Results: COL3A1‐positive ECs showed the highest crosstalk interaction with malignant cells, indicating that they have important effects on driving LUAD carcinogenesis. Vascular endothelial growth factor (VEGF) signaling pathway was identified as the main signaling pathway, mediating signal transduction from malignant cells. The TME‐related genes of COL3A1‐positive ECs were significantly more highly expressed. COL3A1‐positive ECs showed unique metabolic and immune characteristics, as well as highly activated metabolic signaling pathways and inflammatory responses. Importantly, LUAD patients with low COL3A1‐positive ECs scores displayed an inferior prognosis outcome and a higher risk of metastasis. The key target gene NCL, which is involved in the interaction between epithelial cells and cancer cells, has been identified through screening. Flow cytometry showed that knockdown of NCL prompted the apoptosis of A549 and NCI‐H1299. Western blotting showed that knockdown of NCL decreased the phosphorylation of AKT and PI3K, which identified the downstream pathway of NCL. Conclusions: COL3A1‐positive ECs have important effects on the development of LUAD and the formation of an immune microenvironment. Furthermore, we identified a key target gene, NCL, which is involved in the interaction between endothelial cells and cancer cells. NCL also affected the apoptosis and proliferation in LUAD through the PI3K–AKT pathway. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cells (HSC) emerge from hemogenic endothelial cells (HEC) in the aorta-gonad-mesonephros (AGM) region of embryos, which go through the pre-HSC process. Various intrinsic and extrinsic factors are involved in this process. We recently discovered that the existence of distinct macroautophagic/autophagic statuses in hematopoietic precursors is related to the hematopoietic potential of pre-HSCs and the depletion of the Atg5 (autophagy related 5) gene specifically in endothelial cells impaired in the transition of endothelial to pre-HSCs, by hampering the autophagic process, likely via the NCL (nucleolin) pathway.Abbreviation: Atg5: autophagy related 5; EGFP: enhanced green fluorescent protein; EHT: endothelial-to-hematopoietic transition; HEC: hemogenic endothelial cell; HSC: hematopoietic stem cell; NCL: nucleolin; RFP: red fluorescent protein. [ABSTRACT FROM AUTHOR]

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.

Footnotes 1 https://assistant.google.com/platforms/tv/ 2 The Ginga-NCL extension implementation presented in this work can be accessed at https://github.com/marinaivanov/ginga-mulsemedia/tree/multimodal 3 https://github.com/TeleMidia/ginga 4 https://gaming.tobii.com/tobii-eye-tracker-4c/ 5 https://help.tobii.com/hc/en-us/articles/213414285-Specifications-for-the-Tobii-Eye-Tracker-4C 6 Video of the application running at: https://1drv.ms/u/s!AvKXFJ6ipz46hqgcEWo39TPNhFC4JQ?e=xyetJ1 7 NCL applications and the script can be accessed at http://bit.do/fHiw4 8 https://forumsbtvd.org.br/tv3 0/ We experimented with each application to evaluate and compare the NCL extension proposal response time and an NCL 3.0 application with Lua scripts. Keywords: NCL; Ginga-NCL; Multimodal interaction; Multi-user interaction; Digital tv applications EN NCL Ginga-NCL Multimodal interaction Multi-user interaction Digital tv applications 4821 4846 26 01/30/23 20230215 NES 230215 Introduction Multimedia applications allow the synchronization of different media types such as text, image, video, and audio. Batista et al. [[7]] propose a Ginga module that enables NCL applications to use resources from other secondary devices to control content display, interaction, and event capture. Extended Ginga-NCL implementation Ginga-NCL is the DTV Ginga middleware subsystem, which allows the execution of multimedia applications specified in NCL [[1]]. [Extracted from the article]

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.

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. [ABSTRACT FROM AUTHOR]

Purpose: Patients with CLN2 suffer from epileptic seizures, rapid psychomotor decline and vision loss in early childhood. The aim of the study was to provide longitudinal ophthalmic data of patients with confirmed genetic mutation and non-classical disease course, marked by later onset, protracted progression and prolonged life span. Methods: Prospective, observational study to assess visual acuity, retinal features (Weil Cornell Ophthalmic Score), central retinal thickness (CRT) measured by optical coherence tomography and general disease progression (Hamburg CLN2 motor language score) in non-classical CLN2 patients. Results: All patients received intracerebroventricular enzyme replacement therapy with cerliponase alfa. Mean age at last follow-up was 12.4 years; mean follow-up time 2.6 years. All cases demonstrated a stable Hamburg motor language CLN2 Score and Weill Cornell LINCL Ophthalmic Severity Score. Visual function remained stable in 4/6 patients, 2/6 patients showed a decrease, 4/6 cases had a stable CRT and 2/6 showed a reduction of CRT. One patient showed a massive macular thinning and low vision. A correlation with a specific mutation or age could not be verified. Discussion: The presented longitudinal study characterizes the variable ocular involvement in non-classical CLN2 disease and contributes to the natural history description. The functional and morphologic data outline the necessity of regular ophthalmic examination. Summary statement : Ocular phenotyping and description of retinal degeneration in non-classical CLN2 disease. [ABSTRACT FROM AUTHOR]

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.

Molecular dynamics (MD) simulations were conducted to investigate the impact of hybrid wettability on thermal properties, specifically focusing on the constant volume molar heat capacity and thermal conductivity of Nano-confined liquid (NCL). The simulation domain, maintained at a temperature of 100 K, consisted of a ∼ 3 nm — thin film of liquid argon entrapped between two solid copper surfaces with hybrid wettability. Hybrid wettability surfaces were produced by varying the solid–liquid interaction parameter and applying two different wettability factors (μ) to the same surface. In this study, key findings pertaining to the influence of hybrid wettability on heat capacity and thermal conductivity include: (i) The heat capacity of liquid confined within hybrid wettability surfaces surpasses the heat capacity of the liquid in its bulk form. The heat capacity of bulk argon liquid is 20 J/mol k, but the liquid confined in the Hybrid I surface has a maximum heat capacity of roughly ∼ 53.2 J/mol k, which is 2.3 times higher. (ii) Remarkably, liquid confined in patterned wettability surfaces exhibited higher maximum heat capacity compared to the liquid confined inside uniform (Fully hydrophobic or hydrophilic) surfaces. The maximal heat capacity of liquid confined in Hybrid I surface is approximately ∼ 53.2 J/mol K, while the heat capacity of confined argon in a fully hydrophilic surface is around ∼ 30 J/mol K. (iii) Moreover, the heat capacity exhibits intriguing patterns. As the proportion of hydrophilic regions on the hybrid surfaces rose, there was a corresponding increase in heat capacity up to a specific threshold, beyond which the heat capacity dropped. (iv) Unlike Heat capacity, thermal conductivity exhibits a consistent behavior. A gradual decrease of thermal conductivity in the liquid region is observed as hydrophilic portions of the hybrid surface increase. The incorporation of hybrid wettability surfaces transforms the behavior of nano-confined liquid, inducing both structural and dynamic changes. These structural and dynamic variations result in the division of the entire simulation domain into two distinct zones: (i) Solid-like nanolayer zones located near the walls and (ii) Liquid zones located further away from the wall. The behavior of argon molecules in these two zones is completely different. Argon molecules in the solid-like layer exhibit increased density, higher potential energy, less translational motion and vigorous vibration over a frequency range of ∼ 0 to ∼ 3 THz. Conversely, the argon molecules in the liquid layer mostly exhibit translational motion. However, this translational motion is hindered as the hydrophilic area of the surface increases resulting in a reduction in overall molecular mobility. The observed variations in heat capacity and thermal conductivity of the Nano-confined liquid were elucidated by taking into account the combined influence of structural modifications of argon molecules occurring in solid-like nanolayer regions and the dynamic alterations of argon molecules in liquid regions. The findings of this study will provide valuable insights for improving cooling systems in electronic chips and nanoscale memory devices, advancing energy storage systems with potential applications in various biological domains in the future. [ABSTRACT FROM AUTHOR]

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.

Numerical cognition is ubiquitous in the animal kingdom. Domestic chicks are a widely used developmental model for studying numerical cognition. Soon after hatching, chicks can perform sophisticated numerical tasks. Nevertheless, the neural basis of their numerical abilities has remained unknown. Here, we describe number neurons in the caudal nidopallium (functionally equivalent to the mammalian prefrontal cortex) of young domestic chicks. Number neurons that we found in young chicks showed remarkable similarities to those in the prefrontal cortex and caudal nidopallium of adult animals. Thus, our results suggest that numerosity perception based on number neurons might be an inborn feature of the vertebrate brain. [ABSTRACT FROM AUTHOR]

Shortly after birth, both naïve animals and newborn babies exhibit a spontaneous attraction to faces and face-like stimuli. While neurons selectively responding to faces have been found in the inferotemporal cortex of adult primates, face-selective domains in the brains of young monkeys seem to develop only later in life after exposure to faces. This has fueled a debate on the role of experience in the development of face-detector mechanisms, since face preferences are well documented in naïve animals, such as domestic chicks reared without exposure to faces. Here, we demonstrate that neurons in a higher-order processing brain area of one-week-old face-naïve domestic chicks selectively respond to a face-like configuration. Our single-cell recordings show that these neurons do not respond to alternative configurations or isolated facial features. Moreover, the population activity of face-selective neurons accurately encoded the face-like stimulus as a unique category. Thus, our findings show that face selectivity is present in the brains of very young animals without preexisting experience., Competing Interests: Competing interests statement:The authors declare no competing interest.

Streptococcus suis (S. suis) causes serious diseases in pigs, and certain serotypes also pose a risk to humans. The expression of capsular polysaccharides (CPS) is considered an important virulence property of the pathogen. Recently, some serotypes have been reclassified as other organisms, while novel S. suis serotypes are being described. Although the CPS can be typed by serological methods using antisera, the presence of unique sequences for each capsular polysaccharide synthesis locus (cps locus) enables convenient PCR-based serotyping. In this study, we characterized 33 non-serotypeable S. suis strains obtained from diseased pigs in the Czech Republic by sequencing and analyzing the cps locus. Phylogenetic analysis of cpn60 confirmed that all isolates belong to the S. suis species. Four isolates had cps loci similar to the previously described reference S. suis serotypes. Eleven isolates were classified as recently described novel cps loci (NCLs). Nine isolates had substitutions, insertions and/or deletions in their cps loci and showed only partial similarity to the already described NCLs. Another eight isolates had previously undescribed cps locus structures and were proposed as novel NCLs. One isolate had lost the genes encoding capsule biosynthesis. Only four sequence types (ST) had two isolates each; the rest had unique STs. Two isolates harbored the classical virulence associated genes (VAGs) mrp and sly. Another isolate had only the mrp gene, while a different isolate harbored only the sly gene. This study provides insight into untypeable isolates in the Czech Republic, highlighting the genetic diversity and potential for novel serotype identification., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This research paper explores the value of cybersecurity competitions in cyber defense education and its impact on the cybersecurity industry and workforce development. Competitions are considered active and challenge based learning that can be used as effective pedagogies to improve student interest, motivation, and problem solving in education. For cyber defense education quality assurance, student participation in cyber competitions is required for the National Centers of Academic Excellence in Cyber Defense Education (NCAE-CDE) designation by the US National Security Agency and Department of Homeland Security (NSA/DHS). This research is based on the Challenge Based Learning (CBL) framework and explores the pedagogical benefits of cybersecurity competitions through the case study of the National Cyber League (NCL) competition. The case study in this research focuses on mapping the features and knowledge and skill domains of the NCL competition to relevant NCAE-CDE program criteria and knowledge units and presents sample data on students' participation and performance from a NCAE-CDE designated institution. This study also analyzes the quantitative data and qualitative observations and reflections on student participation in the NCL competition and their performance in cyber defense educational programs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Oligodendrocytes, the myelinating cells of the central nervous system (CNS), perform vital functions in neural protection and communication, as well as cognition. Enhanced production of oligodendrocytes has been identified as a therapeutic approach for neurodegenerative and neurodevelopmental disorders. In the postnatal brain, oligodendrocytes are generated from the neural stem and precursor cells (NPCs) in the subventricular zone (SVZ) and parenchymal oligodendrocyte precursor cells (OPCs). Here, we demonstrate exogenous Hepatoma Derived Growth Factor (HDGF) enhances oligodendrocyte genesis from murine postnatal SVZ NPCs in vitro without affecting neurogenesis or astrogliogenesis. We further show that this is achieved by increasing proliferation of both NPCs and OPCs, as well as OPC differentiation into oligodendrocytes. In vivo results demonstrate that intracerebroventricular infusion of HDGF leads to increased oligodendrocyte genesis from SVZ NPCs, as well as OPC proliferation. Our results demonstrate a novel role for HDGF in regulating SVZ precursor cell proliferation and oligodendrocyte differentiation. Summary Statement: Hepatoma derived growth factor (HDGF) is produced by neurons. However, its role in the central nervous system is largely unknown. We demonstrate HDGF enhances i) oligodendrocyte formation from subventricular zone neural stem cells, and ii) oligodendrocyte precursor proliferation in vitro and in vivo. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

Oligodendrocytes, the myelinating cells of the central nervous system (CNS), perform vital functions in neural protection and communication, as well as cognition. Enhanced production of oligodendrocytes has been identified as a therapeutic approach for neurodegenerative and neurodevelopmental disorders. In the postnatal brain, oligodendrocytes are generated from the neural stem and precursor cells (NPCs) in the subventricular zone (SVZ) and parenchymal oligodendrocyte precursor cells (OPCs). Here, we demonstrate exogenous Hepatoma Derived Growth Factor (HDGF) enhances oligodendrocyte genesis from murine postnatal SVZ NPCs in vitro without affecting neurogenesis or astrogliogenesis. We further show that this is achieved by increasing proliferation of both NPCs and OPCs, as well as OPC differentiation into oligodendrocytes. In vivo results demonstrate that intracerebroventricular infusion of HDGF leads to increased oligodendrocyte genesis from SVZ NPCs, as well as OPC proliferation. Our results demonstrate a novel role for HDGF in regulating SVZ precursor cell proliferation and oligodendrocyte differentiation. [ABSTRACT FROM AUTHOR]

Nucleoli are large nuclear sub-compartments where vital processes, such as ribosome assembly, take place. Technical obstacles still limit our understanding of the biological functions of nucleolar proteins in cell homeostasis and cancer pathogenesis. Since most nucleolar proteins are essential, their abrogation cannot be achieved through conventional approaches. Additionally, the biological activities of many nucleolar proteins are connected to their physiological concentration. Thus, artificial overexpression might not fully recapitulate their endogenous functions. Proteolysis-based approaches, such as the Auxin Inducible Degron (AID) system paired with CRISPR/Cas9 knock-in gene-editing, have the potential to overcome these limitations, providing unprecedented characterization of the biological activities of endogenous nucleolar proteins. We applied this system to endogenous nucleolin (NCL), one of the most abundant nucleolar proteins, and characterized the impact of its acute depletion on Triple-Negative Breast Cancer (TNBC) cell behavior. Abrogation of endogenous NCL reduced proliferation and caused defective cytokinesis, resulting in bi-nucleated tetraploid cells. Bioinformatic analysis of patient data, and quantitative proteomics using our experimental NCL-depleted model, indicated that NCL levels are correlated with the abundance of proteins involved in chromosomal segregation. In conjunction with its effects on sister chromatid dynamics, NCL abrogation enhanced the anti-proliferative effects of chemical inhibitors of mitotic modulators such as the Anaphase Promoting Complex. In summary, using the AID system in combination with CRISPR/Cas9 for endogenous gene editing, our findings indicate a novel role for NCL in supporting the completion of the cell division in TNBC models, and that its abrogation could enhance the therapeutic activity of mitotic-progression inhibitors., Competing Interests: Conflict of Interest Statement DP and CMC are inventors of the patent application WO2017011411A1 (methods and compositions relating to anti-NCL recombinant immunoagents). DP and TJM are consultants and own equity Koru Biopharma, which is developing anti-NCL agents.

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. [ABSTRACT FROM AUTHOR]

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.

Natural Circulation Loop (NCL) which is also called as a thermosyphon system is the heat transfer loop which uses no pump or external device to drive the loop fluid. In the present paper, a comparative study on thermal characteristics of two loop fluids viz. water and Al2O3/water nanofluid is made. Experiments are conducted on in-house designed test rig. Thermo-hydraulic behaviour of loop fluid is presented. Two parameters such as heat input, nanofluid concentration are varied in order to study their individual and combined effects. It is concluded that Al2O3/water nanofluid as loop fluid results in higher mass flow rates as compared to the water. Different derived quantities such as Nusselt number and Grashof number are calculated. Quantitative comparison is made between water and Al2O3/water nanofluid. Time to reach steady state is reduced by 22 % using Al2O3/water nanofluid as loop fluid when compared with water. Mass flow rate and Grashof number of the Al2O3/water nanofluid based NCL are enhanced by 6.75% and 26% respectively, when compared with water-based NCL at 1000W heat input. At the heater, the temperature gradient is reduced by 30.2% due to the improved thermal and transport properties of Al2O3/water nanofluid when compared with water at 1000 W heat input. As particle concentration increases from 1% to 5%, Nusselt number increases from 10.1 to 20.1, for the heat input of 1000W. [ABSTRACT FROM AUTHOR]

The planning and execution of head-beak movements are vital components of bird behavior. They require integration of sensory input and internal processes with goal-directed motor output. Despite its relevance, the neurophysiological mechanisms underlying action planning and execution outside of the song system are largely unknown. We recorded single-neuron activity from the associative endbrain area nidopallium caudolaterale (NCL) of two male carrion crows (Corvus corone) trained to plan and execute head-beak movements in a spatial delayed response task. The crows were instructed to plan an impending movement toward one of eight possible targets on the left or right side of a touchscreen. In a fraction of trials, the crows were prompted to plan a movement toward a self-chosen target. NCL neurons signaled the impending motion direction in instructed trials. Tuned neuronal activity during motor planning categorically represented the target side, but also specific target locations. As a marker of intentional movement preparation, neuronal activity reliably predicted both target side and specific target location when the crows were free to select a target. In addition, NCL neurons were tuned to specific target locations during movement execution. A subset of neurons was tuned during both planning and execution period; these neurons experienced a sharpening of spatial tuning with the transition from planning to execution. These results show that the avian NCL not only represents high-level sensory and cognitive task components, but also transforms behaviorally-relevant information into dynamic action plans and motor execution during the volitional perception-action cycle of birds. [ABSTRACT FROM AUTHOR]

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.