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In the current study, we examined whether delay activity in the avian equivalent of the prefrontal cortex (PFC) represents a neural correlate of a to-be-remembered sample stimulus or an upcoming reward. Birds were trained on a directed forgetting paradigm in which sample stimuli (red and white) were either followed by a cue to remember (high-frequency tone) or a cue to forget (low-frequency tone). The task also incorporated a differential outcomes procedure in which a correct response on the memory test following a red (remember) sample was rewarded with food, but correct responses on the memory test following the white (remember) sample were not. If delay activity represents a sample code, then it should be seen on both red-remember and white-remember trials. On the other hand, if delay activity represents a reward code, then delay activity should be seen only on red-remember trials, but not white-remember trials. Our findings suggest that activity in the avian PFC represents the outcome associated with each sample (reward or no reward) rather than memory for the sample itself. [ABSTRACT FROM AUTHOR]

Abstract: The authors present three patients from a consanguineous family afflicted with novel recessive myoclonic epilepsy characterized by very early onset and a steadily progressive course. The onset is in early infancy, and death occurs in the first decade. In addition to various types of myoclonic seizures, episodic phenomena such as dystonias, postictal enduring hemipareses, autonomic involvements, and periods of obtundation and lethargy were also observed. Developmental and neurological retardation, coupled with systemic infections, leads to a full deterioration. The authors designated the disease progressive myoclonic epilepsy with dystonia (PMED). A genome scan for the family and subsequent fine mapping localized the gene responsible for the disease to the most telomeric 6.73 mega base pairs at the p-terminus of chromosome 16, with a maximum multipoint logarithm-of-odds score of 7.83 and a maximum two-point score of 4.25. A candidate gene was analyzed for mutations in patients, but no mutation was found. [ABSTRACT FROM AUTHOR]

Most time-based declarative languages have limited support for variable definition and manipulation, which causes developers to resort to imperative languages. However, a declarative language should provide a variable handling model sufficiently rich to describe a wide range of interactive applications, avoiding, as much as possible, the help of an imperative scripting language. On the other hand, the declarative simplicity should not be lost, leaving for the imperative objects more complex manipulations, with the necessary care to avoid any impact in the application’s temporal graph. Based on this principle, variables and the presentation state are handled by NCL and Ginga-NCL, as discussed in this paper. NCL is the declarative language of the Brazilian Terrestrial Digital TV System (SBTVD) supported by its middleware called Ginga. NCL and Ginga-NCL are part of ISDB standards and also of ITU-T Recommendations for IPTV services. [ABSTRACT FROM AUTHOR]

NCL, the standard declarative language of the Brazilian Terrestrial Digital TV System and ITU-T Recommendation for IPTV Services, provides a high level of reuse in the design of hypermedia applications. In this paper we detail how its design and conceptual model have succeeded in supporting reuse at a declarative level. NCL supports not only static but also running code reuse. It also allows for reuse inside applications, reuse between applications, and reuse of code spans stored in external libraries. For a specification language to promote reuse, however, it must have a number of usability merits. Aspects of NCL usability are thus analyzed with the Cognitive Dimensions of Notation framework. [ABSTRACT FROM AUTHOR]

The progressive myoclonic epilepsies (PME) are a rare group of inherited neurodegenerative diseases with debilitating evolution, resistance to treatment and poor prognosis. However, advances in molecular genetics have enabled better understanding of the pathogenesis of these diseases, bringing hope for improved treatment options in the future. This manuscript is an overview of the clinical and molecular findings in patients with PME. Furthermore, it describes therapeutic approaches that are currently recommended in the literature. [ABSTRACT FROM AUTHOR]

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Reinhardt K, Grapp M, Schlachter K, Brück W, Gärtner J, Steinfeld R. Novel CLN8 mutations confirm the clinical and ethnic diversity of late infantile neuronal ceroid lipofuscinosis. The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited lysosomal storage diseases and the prototype of childhood onset neurodegenerative disorders. To date, 10 NCL entities (CLN1–CLN10) are known and characterized by accumulation of autofluorescent storage material, age of onset and clinical symptoms. CLN8 was first identified as the causative gene for a late-onset form with progressive epilepsy and mental retardation in Finnish patients. In addition, CLN8 phenotypes were described in Turkish, Israeli and Italian patients with a more rapid progression of visual loss, epilepsy, ataxia and mental decline. Here, we report the first mutations in German (c.611G>T) and Pakistani (c.709G>A) patients. Our findings confirm previous assumptions that the CLN8 variant can occur in many ethnic groups. So far, large CLN gene deletions are only known for the CLN3 gene. Here, we also describe a novel, large CLN8 gene deletion c.544-2566_590del2613 in a Turkish family with a slightly more severe phenotype. Our data indicate that patients with clinical signs of late infantile NCL and characteristic ultrastructural inclusions should also be screened for CLN8 mutations independent of their ethnic origin. [ABSTRACT FROM AUTHOR]

Mutations in either C1C-7, a late endosomal/lysosomal member of the CLC family of chloride channels and transporters, or in its β-subunit Ostml cause osteopetrosis and lysosomal storage disease in mice and humans. The severe phenotype of mice globally deleted for C1C-7 or Ostml and the absence of storage material in cultured cells hampered investigations of the mechanism leading to lysosomal pathology in the absence of functional C1C-7/Ostml transporters. Tissue-specific C1C-7-knockout mice now reveal that accumulation of storage material occurs cell-autonomously in neurons or renal proximal tubular cells lacking C1C-7. Almost all C1C-7-deficient neurons die The activation of glia is restricted to brain regions where C2C-7 has been inactivated. The effect of C1C-7 disruption on lysosomal function was investigated in renal proximal tubular cells, which display high endocytotic activity. Pulse-chase endocytosis experiments in vivo with mice carrying chimeric deletion of C1C-7 in proximal tubules allowed a direct comparison of the handling of endocytosed protein between cells expressing or lacking C1C-7. Whereas protein was endocytosed similarly in cells of either genotype, its half-life increased significantly in C1C-7-deficient cells. These experiments demonstrate that lysosomal pathology is a cell-autonomous consequence of C1C-7 disruption and that C1C-7 is important for lysosomal protein degradation. [ABSTRACT FROM AUTHOR]

Autosomal recessively inherited progressive myoclonus epilepsies (PMEs) include Lafora disease, Unverricht-Lundborg disease, the neuronal ceroid lipofuscinoses, type I sialidosis (cherry-red spot myoclonus), action myoclonus–renal failure syndrome, and type III Gaucher disease. Almost all the autosomal recessively inherited PMEs are lysosomal diseases, with the exception of Lafora disease in which neither the accumulating material nor the gene products are in lysosomes. Progress in identifying the causative defects of PME is near-complete. Much work lies ahead to resolve the pathobiology and neurophysiology of this group of devastating disorders. [ABSTRACT FROM AUTHOR]

Abstract: The neuronal ceroid lipofuscinoses (NCL) are severe neurodegenerative lysosomal storage disorders of childhood, characterized by accumulation of autofluorescent ceroid lipopigments in most cells. NCLs are caused by mutations in at least ten recessively inherited human genes, eight of which have been characterized. The NCL genes encode soluble and transmembrane proteins, localized to the endoplasmic reticulum (ER) or the endosomal/lysosomal organelles. The precise function of most of the NCL proteins has remained elusive, although they are anticipated to carry pivotal roles in the central nervous system. Common clinical features in NCL, including retinopathy, motor abnormalities, epilepsia and dementia, also suggest that the proteins may be functionally linked. All subtypes of NCLs present with selective neurodegeneration in the cerebral and cerebellar cortices. Animal models have provided valuable data about the pathological characteristics of NCL and revealed that early glial activation precedes neuron loss in the thalamocortical system. The mouse models have also been efficiently utilized for the evaluation of therapeutic strategies. The tools generated by the accomplishments in genomics have further substantiated global analyses and these have initially provided new insights into the NCL field. This review summarizes the current knowledge of the NCL proteins, basic characteristics of each disease and studies of pathogenetic mechanisms in animal models of these diseases. [Copyright &y& Elsevier]

Abstract: Channelopathies, defined as diseases that are caused by mutations in genes encoding ion channels, are associated with a wide variety of symptoms. Impaired chloride transport can cause diseases as diverse as cystic fibrosis, myotonia, epilepsy, hyperekplexia, lysosomal storage disease, deafness, renal salt loss, kidney stones and osteopetrosis. These disorders are caused by mutations in genes belonging to non-related gene families, i.e. CLC chloride channels and transporters, ABC transporters, and GABA- and glycine receptors. Diseases due to mutations in TMEM16E and bestrophin 1 might be due to a loss of Ca++-activated Cl− channels, although this remains to be shown. [Copyright &y& Elsevier]

Juvenile neuronal ceroid lipofuscinosis (JNCL, CLN3) is an inherited lysosomal disease. We used longitudinal MRI, for the first time, to evaluate the rate of brain volume alterations in JNCL. Six patients (mean ages of 12.4 years and 17.3 years) and 12 healthy controls were studied twice with 1.5 T MRI. White matter (WM), gray matter (GM) and CSF volumes were measured from the sets of T1-weighted 3-dimensional MR images using a fully automated image-processing procedure. The brain volume alterations were calculated as percentage change per year. The GM and whole brain volumes decreased and the CSF volume increased significantly more in the patients than in controls (p-values for the null hypothesis of equal means were 0.001, 0.004, and 0.005, respectively). We found no difference in the WM volume change between the populations. In patients, the GM volume decreased 2.4 % (SD 0.5 %, p 0.0001 for the null hypothesis of zero mean change between observations), the whole brain volume decreased 1.1 % (SD 0.5 %, p = 0.003), and the CSF volume increased 2.7 % (SD 1.8 %, p = 0.01) per year. In normal controls, only the mean white matter volume was significantly altered (0.8 % increase, SD 0.7 %, and p = 0.001). We demonstrated by longitudinal MRI that the annual rate of the gray matter loss in adolescent JNCL patients is as high as 2.4 %. [ABSTRACT FROM AUTHOR]

A total of 931 internal and external technical reports were published from BARC during 1990-2006. Internal technical reports are circulated only within the units of the Department of Atomic Energy, India, whereas external technical reports are distributed within the organisation as well as to other organisations in India and abroad. Only external reports are signalled by the INIS database. An author collaboration study has indicated that greatest proportion of reports (209, 22.4%) had three authors. Author collaboration parameters Collaboration Coefficient (CC), Collaboration Index (CI) and Degree of Collaboration (DC) indicated a trend towards collaborative research rather than solo research. Collaboration between the divisions of BARC and between BARC and other institutions has been reduced considerably from 2000 onwards. Of the 810 Technical Reports that were in the purview of nuclear science and technology, 609 (75.2%) were of single discipline, 187 (23.1%) were of two disciplines and 14 (1.7%) were of three disciplines. The highest number of technical reports (231, 28.8%) belonged to the S21 (specific nuclear reactors and associated plants) subject category. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

CLC genes are expressed in species from bacteria to human and encode Cl--channels or Cl-/H+-exchangers. CLC proteins assemble to dimers, with each monomer containing an ion translocation pathway. Some mammalian isoforms need essential β -subunits (barttin and Ostm1). Crystal structures of bacterial CLC Cl-/H+-exchangers, combined with transport analysis of mammalian and bacterial CLCs, yielded surprising insights into their structure and function. The large cytosolic carboxy-termini of eukaryotic CLCs contain CBS domains, which may modulate transport activity. Some of these have been crystallized. Mammals express nine CLC isoforms that differ in tissue distribution and subcellular localization. Some of these are plasma membrane Cl- channels, which play important roles in transepithelial transport and in dampening muscle excitability. Other CLC proteins localize mainly to the endosomal-lysosomal system where they may facilitate luminal acidification or regulate luminal chloride concentration. All vesicular CLCs may be Cl-/H+-exchangers, as shown for the endosomal ClC-4 and -5 proteins. Human diseases and knockout mouse models have yielded important insights into their physiology and pathology. Phenotypes and diseases include myotonia, renal salt wasting, kidney stones, deafness, blindness, male infertility, leukodystrophy, osteopetrosis, lysosomal storage disease and defective endocytosis, demonstrating the broad physiological role of CLC-mediated anion transport. [ABSTRACT FROM AUTHOR]

Juvenile neuronal ceroid lipofuscinosis (CLN3) is characterized by progressive cerebral atrophy. The purpose of this study was to re-evaluate the three-dimensional magnetic resonance (3D-MR) images of patients with CLN3 using voxel-based morphometry (VBM) to achieve a detailed understanding of the affected brain regions. T1-weighted 3D-MR images of 15 patients with CLN3 (age range: 12–25 years, mean age 17.6 years) and 15 age- and sex-matched controls were analyzed using VBM. VBM showed strikingly focal alterations in the brains of CLN3 patients: the gray matter volume was significantly decreased in the dorsomedial part of the thalami of CLN3 patients. In addition, the volume of the white matter was significantly decreased in the corona radiata, containing cortical efferents and afferents in the transition between the internal capsule and the subcortical white matter. These data suggest that the dorsomedial part of the thalamus and the corona radiata may have a central, previously unrecognized role in the pathogenesis of CLN3. [ABSTRACT FROM AUTHOR]

As in all main terrestrial DTV Systems, the Brazilian middleware, named Ginga, supports both declarative applications (through its presentation, or declarative, environment Ginga-NCL) and procedural applications (through its execution, or procedural, environment Ginga-J). Since hybrid applications are common, either type of Ginga application may make use of facilities of both presentation and execution application environments. This paper focuses on the presentation environment Ginga-NCL. The main Brazilian inovations are then presented, regarding the Ginga architecture, the declarative NCL language specification, the editing commands for live application production, and the transport data structure. [ABSTRACT FROM AUTHOR]

Climbing activity, the gradual increase of neural discharge rate across a delay, has been suggested to play a crucial role in interval timing. However, most previous studies demonstrated climbing activity only in conjunction with tasks that involved a passive tracking of the passage of time, but that did not necessitate to actively time an event, e.g. a motor response. To demonstrate the significance of climbing activity for action timing, we trained pigeons in a self-control task requiring either immediate responding to a key after the onset of a light cue (‘rapid-response’ trials), or waiting for a fixed interval after cue presentation before responding to the key (‘wait’ trials). The cue also indicated whether a correctly timed response would be rewarded with a large or a small reward. Single-cell recordings in the Nidopallium caudolaterale, the avian prefrontal cortex, revealed that some neurons showed climbing activity between cue onset and response. Their increase in firing rate was flatter and reached the peak later in wait compared with rapid-response trials. An error analysis confirmed that, relative to correct responses, premature responses were accompanied by steeper, and tardy responses by flatter ramps. In addition, the climbing discharge pattern was modulated by the amount of the anticipated reward, suggesting that timing is an intrinsic property of neurons encoding other task-related information. These results demonstrate the behavioural and motivational significance of climbing activity in prospective information encoding. Our study supports a recent paradigm shift in our understanding of the vertebrate brain evolution, and it provides further evidence for the similarity between the mammalian cortex and the avian pallium. [ABSTRACT FROM AUTHOR]

Abstract: For the majority of families affected by one of the neuronal ceroid lipofuscinoses (NCLs), a biochemical and/or genetic diagnosis can be achieved. In an individual case this information not only increases understanding of the condition but also may influence treatment choices and options. The presenting clinical features prompt initial investigation and also guide clinical care. The clinical labels “infantile NCL”, “late infantile NCL” and “juvenile NCL”, therefore remain useful in practice. In unusual or atypical cases ultra-structural analysis of white blood cells or other tissue samples enables planning and prioritisation of biochemical and genetic tests.This review describes current methods available to achieve clinical, pathological, biochemical and genetic diagnosis in children presenting with symptoms suggestive of one of the NCLs. [Copyright &y& Elsevier]

Abstract: The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are recessively inherited neurodegenerative disorders that affect humans and other animals, characterised by brain atrophy and the accumulation of lysosome derived fluorescent storage bodies in neurons and most other cells. Common clinical signs include blindness, ataxia, dementia, seizures and premature death. The associated genes for six different human forms have been identified (CLN1, CLN2, CLN3, CLN5, CLN6 and CLN8), and three other human forms suggested (CLNs 4, 7 and 9). A form of NCL in Australian Devon cattle is caused by a single base duplication (c.662dupG) in bovine CLN5. This mutation causes a frame-shift and premature termination (p.Arg221GlyfsX6) which is predicted to result in a severely truncated protein, analogous to disease causing mutations in human Finnish late infantile variant NCL (CLN5), and a simple genetic diagnostic test has been developed. The symptoms and disease course in cattle also matches CLN5. Only one initiation site was found in the bovine gene, equivalent to the third of four possible initiation sites in the human gene. As cattle are anatomically and physiologically similar to humans with a human-like central nervous system and easy to maintain and breed, they provide a valuable alternative model for CLN5 studies. [Copyright &y& Elsevier]

Abstract: The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by the accumulation of autofluorescent storage material in many cell types, including neurons. Most NCL subtypes are inherited in an autosomal recessive manner and characterized clinically by epileptic seizures, progressive psychomotor decline, visual failure, variable age of onset, and premature death. To date, seven genes underlying human NCLs have been identified. Most of the mutations in these genes are associated with specific disease subtypes, while some result in variable disease onset, severity and progression. In addition to these, there are still disease subgroups with unknown molecular genetic backgrounds. Although apparent clinical homogeneity exists within some of these subgroups, actual genetic heterogeneity may complicate gene identification. Additional clues to the identification of these unknown genes may come from animal models of NCL and from functional studies of already known genes which may suggest further candidates. [Copyright &y& Elsevier]

Abstract: Neuronal ceroid lipofucinoses (NCLs) are a group of severe neurodegenerative disorders characterized by accumulation of autofluorescent ceroid lipopigment in patients'' cells. The different forms of NCL share many similar pathological features but result from mutations in different genes. The genes affected in NCLs encode both soluble and transmembrane proteins and are localized to ER or to the endosomes/lysosomes. Due to selective vulnerability of the central nervous system in the NCL disorders, the corresponding proteins are proposed to have important, tissue specific roles in the brain. The pathological similarities of the different NCLs have led not only to the grouping of these disorders but also to suggestion that the NCL proteins function in the same biological pathway. Despite extensive research, including the development of several model organisms for NCLs and establishment of high-throughput techniques, the precise biological function of many of the NCL proteins has remained elusive. The aim of this review is to summarize the current knowledge of the functions, or proposed functions, of the different NCL proteins. [Copyright &y& Elsevier]

Abstract: The neuronal ceroid lipofuscinoses (NCLs) are neurodegenerative disorders. Nevertheless, small model organisms, including those lacking a nervous system, have proven invaluable in the study of mechanisms that underlie the disease and in studying the functions of the conserved proteins associated to each disease. From the single-celled yeast, Saccharomyces cerevisiae and Schizosaccharomyces pombe, to the worm, Caenorhabditis elegans and the fruitfly, Drosophila melanogaster, biochemical and, in particular, genetic studies on these organisms have provided insight into the NCLs. [Copyright &y& Elsevier]

Neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive neurodegenerative disorders typically characterized by the accumulation of autofluorescent material in tissues. On the basis of clinical features, age at onset, and molecular genetic defects, it is possible to distinguish at least nine forms. The CLN8 form was first described in Finland, where all the patients are homozygous for a p.Arg24Gly mutation in CLN8. More recently, it has been found that a subset of a Turkish variant of late infantile NCL (v-LINCL) is also associated with CLN8 mutations. To identify the molecular defect in Italian patients with v-LINCL, the CLN8 gene was directly sequenced in 10 patients. Controls were screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Five fluorescent-labeled microsatellite markers covering 1 cM around the gene were used for haplotype analysis. In three Italian v-LINCL patients, identified in a small area in southern Italy, we detected four new mutations in CLN8: c.66delG (p.Gly22fs), c.88G>C (p.Ala30Pro), c.473A>G (p.Tyr158Cys), and c.581A>G (p.Gln194Arg). The single-base deletion was found in two unrelated patients. The novel missense mutations were not identified in ethnically matched control chromosomes. Our findings expand the number of CLN8 variants and corroborate the notion that CLN8 patients are not confined to the Finnish population. [ABSTRACT FROM AUTHOR]

Working memory, the ability to temporarily retain task-relevant information across a delay, is frequently investigated using delayed matching-to-sample (DMTS) or delayed Go/No-Go tasks (DGNG). In DMTS tasks, sample cues instruct the animal which type of response has to be executed at the end of a delay. Typically, performance decreases with increasing delay duration, indicating that working memory fades across a delay. However, no such performance decrease has been found when the sample cues exist of present vs. absent stimuli, suggesting that pigeons do not rely on working memory, but seem to respond by default in those trials. We trained 3 pigeons in a DGNG task and found a similar default response pattern: The diverging slopes of the retention functions on correct Go and No-Go trials suggested that pigeons by default omitted their response following No-Go stimuli, but actively retained task-relevant information across the delay for successful responses on Go trials. We conducted single-cell recordings in the avian nidopallium caudolaterale, a structure comparable to the mammalian prefrontal cortex. On Go trials, many neurons displayed sustained elevated activity during the delay preceding the response, replicating previous findings and suggesting that task-relevant information was neurally represented and maintained across the delay. However, the same units did not show enhanced delay activity preceding correct response suppressions in No-Go trials. This activation-inactivation pattern presumably constitutes a neural correlate of the default response strategy observed in the DGNG task. [ABSTRACT FROM AUTHOR]

Abstract: The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are fatal inherited neurodegenerative diseases characterized by gross brain atrophy, blindness, and intracellular accumulation of lysosome-derived storage bodies. A CLN6 form in sheep is studied as a large animal model of the human diseases. This study describes neuropathological changes in brains from presymptomatic affected sheep. Activated astrocytes and focal clusters of activated microglia were present in outer layers of occipital and somatosensory cortical regions as early as 12 days of age, together with activated perivascular macrophages. Astrocytic activation and progressive transformation of microglia to brain macrophages preceded neurodegeneration and spread to different cortical areas, most prominently in regions associated with clinical symptoms. In contrast, storage body accumulation was much more evenly spread across regions. These data support suggestions that neurodegeneration and storage body accumulation may be independent manifestations of CLN6 mutation and indicate that glial cell activation may be an important mediator in pathogenesis. [Copyright &y& Elsevier]

Abstract: Three different arrangements of heat exchange from a hot fluid stream to a cold fluid stream such as, direct heat exchanger and fluid coupled indirect heat exchanger both with forced circulation loop as well as thermally driven natural circulation loop have been considered in the present work. Dynamic performance of these three arrangements has been studied for four different excitations namely, step, ramp, exponential and sinusoidal. These excitations are imposed at the hot fluid inlet temperature. Finite element technique is used to solve the transient one-dimensional conservation equations. A thorough comparison of the dynamic performance of these three arrangements is made. It is found that the direct heat exchanger does not have any time delay between the response and the excitation function. Moreover, the phase difference between the sinusoidal excitation and response is the lowest in this case. [Copyright &y& Elsevier]

Kufs disease, the late-onset form of a group of neurodegenerative disorders, known as the neuronal ceroid-lipofuscinoses, is characterized by intraneuronal/extraneuronal accumulation of proteins that are visible as fingerprint inclusions and granular osmiophilic deposits (GRODs) at the ultrastructural level. A problematic case of Kufs disease in a 53-year-old female affected by progressive gait disturbances, myoclonus, epilepsy, and profound dementia is presented. Laboratory, biochemical, and molecular genetic tests were unremarkable. A magnetic resonance imaging of the brain revealed a moderate atrophy over both hemispheres with no white matter changes. Ultrastructural examination of rectal mucosa biopsies showed fingerprint inclusions in perivascular smooth muscle cells. Pathological examination of autoptic tissues showed numerous intraneuronal PAS-positive, diastase-resistant inclusions corresponding to GRODs at the ultrastructural examination, but no fingerprint inclusions. Cerebellum, skeletal, and cardiac muscles, skin, and liver were unaffected. The present case illustrates the diagnostic difficulties encountered while examining Kufs disease pathological samples. Main problematic issues include (1) specificity and diagnostic value of fingerprint inclusions when found exclusively in perivascular smooth muscle cells; (2) safe distinction of GRODs from lipofuscin inclusions in cerebral tissue; and (3) reliability in using extraneural tissues and, in particular, rectal mucosa biopsies for diagnostic purposes. [ABSTRACT FROM AUTHOR]

We report here the intracellular (pHi) and lysosomal pH in fibroblasts of six forms of neuronal ceroid lipofuscinoses (NCLs). Acid extrusion rate and pHi values were measured by the membrane-permeant acetoxymethyl ester of the indicator dye, 2′,7′-bis(carboxyethyl)-5-(and-6)-carboxy-fluorescein (BCECF) and lysosomal pH by a spectrofluorometric assay utilizing a novel acidotropic probe, Lysosensor yellow/blue. Intracellular pH was normal in all NCLs. Elevated lysosomal pH was detected in all NCL forms except CLN2 and CLN8. Elevated pH most probably disturbs the catalytic activity of lysosomes and is one important factor in explaining accumulation of ceroid and lipofuscin-like autofluorescent lipopigments characteristic of NCLs. Using the novel spectrofluorometric assay introduced in this study provides a fast and repeatable technique to measure intralysosomal pH from cell suspensions. [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., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)