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Myotonic dystrophy (DM), the most common dystrophy in adults, is an autosomal dominant disease characterized by a variety of multisystemic features. Two genetically distinct forms of DM are identified - type 1 (DM1), the classic form first described by Steinert, and type 2 (DM2), identified by Ricker. DM1 is caused by trinucleotide expansion of CTG in the myotonic dystrophy protein kinase gene, whereas in DM2 the expansion of tetranucleotide repeats (CCTG) in the zinc finger protein 9 gene was identified. Both mutations are dynamic and are located in non-coding parts of the genes. Phenotype variability of DM1 and DM2 is caused by a molecular mechanism due to mutated RNA toxicity. This paper reviews the clinical features of both types of myotonic dystrophies and summarizes current views on pathogenesis of myotonic dystrophy.	Which are the types of myotonic dystrophy?	Two genetically distinct forms of DM are identified - type 1 (DM1), the classic form first described by Steinert, and type 2 (DM2), identified by Ricker.
Numerous clinical studies have shown that anti-EGFR therapies are effective only in a subset of patients with colorectal cancer. Even though mutations in the KRAS gene have been confirmed as negative predictors of the response to EGFR-targeted therapies, not all KRAS wild-type (wt-KRAS) patients will respond to treatment. Recent studies have demonstrated that additionally wild-type BRAF (wt-BRAF) genotype is required for response to panitumumab or cetuximab, suggesting that BRAF genotype criteria should be used together with KRAS genotype for selecting the patients who are about to benefit from the anti-EGFR therapy. In this study, 239 samples obtained from 215 patients with metastatic colorectal cancer were tested for the presence of the seven most common mutations in the KRAS gene and the V600E mutation in the BRAF gene. Among the tested patients, 53.8% of patients had wt-KRAS genotype and 46.2% were KRAS mutants. Around five percent (5.1%) of the tested patients bore the V600E mutation in BRAF gene. All the patients showing to have the V600E mutation in BRAF were wt-KRAS. The concordance of KRAS and BRAF mutational status between primary and metastatic tumor tissue samples was 100%. We have shown that the proportions of mutated and non-mutated KRAS in Slovene patients, as well as the proportion of V600E mutations in BRAF is similar to genotyping results reported by other authors. The tested seven KRAS mutations on codons 12 and 13 were mutually exclusive with the V600E mutation in the BRAF gene. Summing up the results about the KRAS and the BRAF mutation carriers from our study, the portion of potentially non-responsive patients for the anti-EGFR treatment is 51.3%.	Which gene(s) should be genotyped in order to prescribe the drug Cetuximab (anti-EGFR)?	Numerous clinical studies have shown that anti-EGFR therapies are effective only in a subset of patients with colorectal cancer. Even though mutations in the KRAS gene have been confirmed as negative predictors of the response to EGFR-targeted therapies, not all KRAS wild-type (wt-KRAS) patients will respond to treatment. Recent studies have demonstrated that additionally wild-type BRAF (wt-BRAF) genotype is required for response to panitumumab or cetuximab, suggesting that BRAF genotype criteria should be used together with KRAS genotype for selecting the patients who are about to benefit from the anti-EGFR therapy.
Soft tissue sarcomas are rare tumors that represent a major challenge due to varying clinical presentations and often interdisciplinary treatment concepts. Gold standard for the treatment of localized resectable soft tissue sarcomas is complete surgical removal. In metastatic soft tissue sarcoma, systemic therapy is the treatment of choice. The most active drugs are anthracyclines and ifosfamide. Combination chemotherapy has improved both response rate and progression-free survival at the cost of increased toxicity. Imatinib at a dose of 400 mg/day is the gold standard for patients with advanced or metastatic gastrointestinal stromal tumors (GIST). In patients with a mutation in KIT exon 9, 800 mg/day is the recommended dose. In imatinib refractory or intolerant patients, sunitinib is recommended. Regorafenib has been approved for third-line therapy.	Is there a role of regorafenib for sarcoma treatment?	Regorafenib has been approved for third-line therapy.
The Drosophila neuromuscular junction (NMJ) has recently provided new insights into the roles of various proteins in neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), Multiple Sclerosis (MS) Hereditary Spastic Paraplegia (HSP), and Huntington's Disease (HD). Several developmental signaling pathways including WNT, MAPK and BMP/TGF-β signaling play important roles in the formation and growth of the Drosophila NMJ. Studies of the fly homologues of genes that cause neurodegenerative disease at the NMJ have resulted in a better understanding of the roles of these proteins in vivo. These studies may shed light on the pathological mechanisms of these diseases, with implications for reduced BMP/TGF-β signaling in ALS, SMA and HD and increased signaling in HSP and MS.	What links developmental pathways to ALS?	opmental signaling pathways including WNT, MAPK and BMP/TGF-β signaling play important roles in the formation and growth of the Drosophila NMJ. Studies of t
GC level distributions of a species' nuclear genome, or of its compositional fractions, encode key information on structural and functional properties of the genome and on its evolution. They can be calculated either from absorbance profiles of the DNA in CsCl density gradients at sedimentation equilibrium, or by scanning long contigs of largely sequenced genomes. In the present study, we address the quantitative characterization of the compositional heterogeneity of genomes, as measured by the GC distributions of fixed-length fragments. Special attention is given to mammalian genomes, since their compartmentalization into isochores implies two levels of heterogeneity, intra-isochore (local) and inter-isochore (global). This partitioning is a natural one, since large-scale compositional properties vary much more among isochores than within them. Intra-isochore GC distributions become roughly Gaussian for long fragments, and their standard deviations decrease only slowly with increasing fragment length, unlike random sequences. This effect can be explained by 'long-range' correlations, often overlooked, that are present along isochores.	Does GC content vary markedly within a given isochore?	This partitioning is a natural one, since large-scale compositional properties vary much more among isochores than within them.
With the development of novel targeted therapies, including exon skipping/inclusion and gene replacement therapy, the field of neuromuscular diseases has drastically changed in the last several years. Until 2016, there had been no FDA-approved drugs to treat Duchenne muscular dystrophy (DMD), the most common muscular dystrophy. However, several new personalized therapies, including antisense oligonucleotides eteplirsen for DMD exon 51 skipping and golodirsen and viltolarsen for DMD exon 53 skipping, have been approved in the last 4 years. We are witnessing the start of a therapeutic revolution in neuromuscular diseases. However, the studies also made clear that these therapies are still far from a cure. Personalized genetic medicine for neuromuscular diseases faces several key challenges, including the difficulty of obtaining appropriate cell and animal models and limited its applicability. This Special Issue "Molecular Diagnosis and Novel Therapies for Neuromuscular/Musculoskeletal Diseases" highlights key areas of research progress that improve our understanding and the therapeutic outcomes of neuromuscular diseases in the personalized medicine era.	What type of DMD can viltolarsen be used for?	en for DMD exon 51 skipping and golodirsen and viltolarsen for DMD exon 53 skipping, have been approved in the last 4 years. We are witnessing the sta
Dysregulated microRNA (miRNA) expression contributes to the pathogenesis of hematopoietic malignancies, including chronic lymphocytic leukemia (CLL). However, an understanding of the mechanisms that cause aberrant miRNA transcriptional control is lacking. In this study, we comprehensively investigated the role and extent of miRNA epigenetic regulation in CLL. Genome-wide profiling conducted on 24 CLL and 10 healthy B cell samples revealed global DNA methylation patterns upstream of miRNA sequences that distinguished malignant from healthy cells and identified putative miRNA promoters. Integration of DNA methylation and miRNA promoter data led to the identification of 128 recurrent miRNA targets for aberrant promoter DNA methylation. DNA hypomethylation accounted for more than 60% of all aberrant promoter-associated DNA methylation in CLL, and promoter DNA hypomethylation was restricted to well-defined regions. Individual hyper- and hypomethylated promoters allowed discrimination of CLL samples from healthy controls. Promoter DNA methylation patterns were confirmed in an independent patient cohort, with 11 miRNAs consistently showing an inverse correlation between DNA methylation status and expression level. Together, our findings characterize the role of epigenetic changes in the regulation of miRNA transcription and create a repository of disease-specific promoter regions that may provide additional insights into the pathogenesis of CLL.	Are microRNA (miR) regulated through DNA methylation of their promoters?	Integration of DNA methylation and miRNA promoter data led to the identification of 128 recurrent miRNA targets for aberrant promoter DNA methylation
Cryptochrome 1 and 2 act as essential components of the central and peripheral circadian clocks for generation of circadian rhythms in mammals. Here we show that mouse cryptochrome 2 (mCRY2) is phosphorylated at Ser-557 in the liver, a well characterized peripheral clock tissue. The Ser-557-phosphorylated form accumulates in the liver during the night in parallel with mCRY2 protein, and the phosphorylated form reaches its maximal level at late night, preceding the peak-time of the protein abundance by approximately 4 h in both light-dark cycle and constant dark conditions. The Ser-557-phosphorylated form of mCRY2 is localized in the nucleus, whereas mCRY2 protein is located in both the cytoplasm and nucleus. Importantly, phosphorylation of mCRY2 at Ser-557 allows subsequent phosphorylation at Ser-553 by glycogen synthase kinase-3beta (GSK-3beta), resulting in efficient degradation of mCRY2 by a proteasome pathway. As assessed by phosphorylation of GSK-3beta at Ser-9, which negatively regulates the kinase activity, GSK-3beta exhibits a circadian rhythm in its activity with a peak from late night to early morning when Ser-557 of mCRY2 is highly phosphorylated. Altogether, the present study demonstrates an important role of sequential phosphorylation at Ser-557/Ser-553 for destabilization of mCRY2 and illustrates a model that the circadian regulation of mCRY2 phosphorylation contributes to rhythmic degradation of mCRY2 protein.	What is the function of cryptochrome-1 in mouse?	Cryptochrome 1 and 2 act as essential components of the central and peripheral circadian clocks for generation of circadian rhythms in mammals
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest red cell enzymopathy in humans and has an X-linked inheritance. It has been reported from India more than 30 years ago and the prevalence varies from 0-27% in different caste, ethnic and linguistic groups. The major clinical manifestations are drug induced hemolytic anemia, neonatal jaundice and chronic non-spherocytic hemolytic anemia. Individuals with G6PD deficiency have a selective advantage against falciparum malaria. Thirteen biochemically characterized variants have been reported from India. At the molecular level, G6PD Mediterranean is the most common deficient variant in the caste groups whereas, G6PD Orissa is more prevalent among the tribal of India. The third common variant seen in India is G6PD Kerala-Kalyan.	Has Glucose-6-phosphate dehydrogenase (G6PD) deficiency an X-linked inheritance?	Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest red cell enzymopathy in humans and has an X-linked inheritance
The FaceBase Consortium consists of ten interlinked research and technology projects whose goal is to generate craniofacial research data and technology for use by the research community through a central data management and integrated bioinformatics hub. Funded by the National Institute of Dental and Craniofacial Research (NIDCR) and currently focused on studying the development of the middle region of the face, the Consortium will produce comprehensive datasets of global gene expression patterns, regulatory elements and sequencing; will generate anatomical and molecular atlases; will provide human normative facial data and other phenotypes; conduct follow up studies of a completed genome-wide association study; generate independent data on the genetics of craniofacial development, build repositories of animal models and of human samples and data for community access and analysis; and will develop software tools and animal models for analyzing and functionally testing and integrating these data. The FaceBase website (http://www.facebase.org) will serve as a web home for these efforts, providing interactive tools for exploring these datasets, together with discussion forums and other services to support and foster collaboration within the craniofacial research community.	What is the purpose of the FaceBase consortium?	The FaceBase website (http://www.facebase.org) will serve as a web home for these efforts, providing interactive tools for exploring these datasets, together with discussion forums and other services to support and foster collaboration within the craniofacial research community.
Drug-induced adverse reactions, especially type B reactions, represent a major clinical problem. They also impart a significant degree of uncertainty into drug development because they are often not detected until the drug has been released onto the market. Type B reactions are also termed idiosyncratic drug reactions by many investigators due to their unpredictable nature and our lack of understanding of the mechanisms involved. It is currently believed that the majority of these reactions are immune-mediated and are caused by immunogenic conjugates formed from the reaction of a reactive metabolite of a drug with cellular proteins. It has been shown that most drugs associated with idiosyncratic reactions form reactive metabolites to some degree. Covalent binding of reactive metabolites to cellular proteins has also been shown in many cases. However, studies to reveal the role of reactive metabolites and their protein-adducts in the mechanism of drug-induced idiosyncratic reactions are lacking. This review will focus on our current understanding and speculative views on how a reactive metabolite of a drug might ultimately lead to immune-mediated toxicity.	What are reactive metabolites?	This review will focus on our current understanding and speculative views on how a reactive metabolite of a drug might ultimately lead to immune-mediated toxicity
Polyphenols constitute a distinct group of natural compounds of medicinal importance exhibiting wide range of physiological activities as antioxidant, immunestimulant, antitumor and antiparasitic. Yellow fever and dengue fever are mosquito-borne infectious diseases transmitted by Aedes aegyptii, the presence of yellow fever in Sudan and dengue fever in Saudi Arabia are threats to Egypt with the reemerging of Ae. aegyptii in Southern Egypt, larvae control is feasible than flying adults. This work was conducted targeting estimation of the relative levels of total phenolic content, antioxidant potential and larvicidal activity of 110 selected Egyptian plants. The highest total phenolic contents were estimated in aqueous extracts of Coronilla scorpioides L., Forsskaolea tenacissima L., Crataegus sinaica Boiss., Pistacia khinjuk Boiss. and Loranthus acacia Benth.; they were 916.70 +/- 4.80, 813.70 +/- 4.16, 744.90 +/- 4.93, 549.00 +/- 3.93& 460.80 +/- 4.02 mg% while those of methanol extracts were estimated in Coronilla scorpioides, Forsskaolea tenacissima, Crataegus sinaica, Loranthus acacia and Pistacia khinjuk, they were 915.60-4.86, 664.60 +/- 4.16, 659.30 +/- 4.80, 590.80 +/- 4.49 & 588.00 +/- 3.85 mg% respectively. Investigation of the antioxidant potentials revealed that the most potent plants were Co-ronilla scorpioides, Forsskaolea tenacissima, Crataegus sinaica, Pistacia khinjuk and Loranthus acacia with calculated values of 454.80 +/- 4.83, 418.4 +/- 4.16, 399.10 +/- 4.90, 342.5 +/- 2.72 & 239.7 +/- 2.91% for aqueous extracts and 452.9 +/- 4.94, 389.6 +/- 4.6, 378.48 +/- 3.84, 352.3 +/- 3.06 & 346.5 +/- 2.98% for methanol extracts respectively while screening of larvicidal activity proved that Coronilla scorpioides, Forsskaolea tenacissima, Crataegus sinaica, Pistacia khinjuk and Loranthus acacia exhibited highest potency calculated as 22.53 +/- 2.01, 23.85 +/- 2.07, 28.17 +/- 2.06, 31.60 +/- 2.93 & 39.73 +/- 4.58 mg% aqueous extracts and 18.53 +/- 1.95, 18.8 +/- 1.67, 20.17 +/- 1.85, 23.28 +/- 2.7 & 28.48 +/- 3.9 mg% methanol ones respectively.	How is yellow fever virus transmitted?	fever and dengue fever are mosquito-borne infectious diseases transmitted by Aedes aegyptii, the presence of yellow fever in Sudan and dengue fever in Saudi Arabia are threats to Egypt with the reemerging of Ae. aegyptii in Southern Egypt, larvae control is feasible than flying adults
Multiple regulatory elements distant from their targets on the linear genome can influence the expression of a single gene through chromatin looping. Chromosome conformation capture implemented in Hi-C allows for genome-wide agnostic characterization of chromatin contacts. However, detection of functional enhancer-promoter interactions is precluded by its effective resolution that is determined by both restriction fragmentation and sensitivity of the experiment. Here we develop a capture Hi-C (cHi-C) approach to allow an agnostic characterization of these physical interactions on a genome-wide scale. Single-nucleotide polymorphisms associated with complex diseases often reside within regulatory elements and exert effects through long-range regulation of gene expression. Applying this cHi-C approach to 14 colorectal cancer risk loci allows us to identify key long-range chromatin interactions in cis and trans involving these loci.	What is the basis of the capture Hi-C experimental protocol?	Here we develop a capture Hi-C (cHi-C) approach to allow an agnostic characterization of these physical interactions on a genome-wide scale.
Neutrophil extracellular traps (NETs) represent an important defense mechanism against microorganisms. Clearance of NETs is impaired in a subset of patients with systemic lupus erythematosus, and NETosis is increased in neutrophils and, particularly, in low-density granulocytes derived from lupus patients. NETs are toxic to the endothelium, expose immunostimulatory molecules, activate plasmacytoid dendritic cells, and may participate in organ damage through incompletely characterized pathways. To better understand the role of NETs in fostering dysregulated inflammation, we examined inflammasome activation in response to NETs or to LL-37, an antibacterial protein externalized on NETs. Both NETs and LL-37 activate caspase-1, the central enzyme of the inflammasome, in both human and murine macrophages, resulting in release of active IL-1β and IL-18. LL-37 activation of the NLRP3 inflammasome utilizes P2X7 receptor-mediated potassium efflux. NET and LL-37-mediated activation of the inflammasome is enhanced in macrophages derived from lupus patients. In turn, IL-18 is able to stimulate NETosis in human neutrophils. These results suggest that enhanced formation of NETs in lupus patients can lead to increased inflammasome activation in adjacent macrophages. This leads to release of inflammatory cytokines that further stimulate NETosis, resulting in a feed-forward inflammatory loop that could potentially lead to disease flares and/or organ damage.	What is the role of NETs in systemic lupus erythematosus?	Neutrophil extracellular traps (NETs) represent an important defense mechanism against microorganisms. Clearance of NETs is impaired in a subset of patients with systemic lupus erythematosus, and NETosis is increased in neutrophils and, particularly, in low-density granulocytes derived from lupus patients. NETs are toxic to the endothelium, expose immunostimulatory molecules, activate plasmacytoid dendritic cells, and may participate in organ damage through incompletely characterized pathways.
The Ascomycete pathogen Fusarium graminearum can infect all cereal species and lower grain yield, quality and safety. The fungus can also cause disease on Arabidopsis thaliana. In this study, the disease-causing ability of two F. graminearum mutants was analysed to further explore the parallels between the wheat (Triticum aestivum) and Arabidopsis floral pathosystems. Wild-type F. graminearum (strain PH-1) and two isogenic transformants lacking either the mitogen-activated protein kinase MAP1 gene or the trichodiene synthase TRI5 gene were individually spray- or point-inoculated onto Arabidopsis and wheat floral tissue. Disease development was quantitatively assessed both macroscopically and microscopically and deoxynivalenol (DON) mycotoxin concentrations determined by enzyme-linked immunosorbent assay (ELISA). Wild-type strain inoculations caused high levels of disease in both plant species and significant DON production. The map1 mutant caused minimal disease and DON accumulation in both hosts. The tri5 mutant, which is unable to produce DON, exhibited reduced pathogenicity on wheat ears, causing only discrete eye-shaped lesions on spikelets which failed to infect the rachis. By contrast, the tri5 mutant retained full pathogenicity on Arabidopsis floral tissue. This study reveals that DON mycotoxin production is not required for F. graminearum to colonize Arabidopsis floral tissue.	The pathogen Fusarium graminearum affects what type of plant species?	The Ascomycete pathogen Fusarium graminearum can infect all cereal species and lower grain yield, quality and safety.
Polyadenylation is a process of endonucleolytic cleavage of the mRNA, followed by addition of up to 250 adenosine residues to the 3' end of the mRNA. Polyadenylation is essential for eukaryotic mRNA expression, and CstF-64 is a subunit of the CstF polyadenylation factor that is required for accurate polyadenylation. We discovered that there are two forms of the CstF-64 protein in mammalian male germ cells, one of which (CstF-64) is expressed in all tissues, the other of which (tauCstF-64) is expressed only in male germ cells and in brain (albeit at significantly lower levels in the brain). Therefore, we were surprised to find that, using reverse transcription-PCR, cDNA cloning, and RNA blot analyses, tauCstF-64 mRNA was expressed at higher levels in brain than in testis. Also, tauCstF-64 mRNA was expressed at lower but detectable levels in all tissues tested, including epididymis, heart, kidney, liver, lung, muscle, ovary, spleen, thymus, and uterus. These results suggest the hypothesis that tauCstF-64 mRNA is regulated at the translational or post-translational level.	Is polyadenylation a process that stabilizes a protein by adding a string of Adenosine residues to the end of the molecule?	Polyadenylation is a process of endonucleolytic cleavage of the mRNA, followed by addition of up to 250 adenosine residues to the 3' end of the mRNA.
Eph receptor tyrosine kinases and their ligands, ephrins, mediate neurodevelopmental processes such as boundary formation, axon guidance, vasculogenesis, and cell migration. We determined the expression profiles of the Eph family members in five glioma cell lines under migrating and nonmigrating conditions. EphB2 mRNA was overexpressed in all five during migration (1.2-2.8-fold). We found abundant EphB2 protein as well as strong phosphorylation of EphB2 in migrating U87 cells. Confocal imaging showed EphB2 localized in lamellipodia of motile U87 cells. Treatment with ephrin-B1/Fc chimera stimulated migration and invasion of U87, whereas treatment with a blocking EphB2 antibody significantly inhibited migration and invasion. Forced expression of EphB2 in U251 cells stimulated cell migration and invasion and diminished adhesion concomitant with the tyrosine phosphorylation of EphB2. U251 stably transfected with EphB2 showed more scattered and more pronounced invasive growth in an ex vivo rat brain slice. In human brain tumor specimens, EphB2 expression was higher in glioblastomas than in low-grade astrocytomas or normal brain; patterns of phosphorylated EphB2 matched the expression levels. Laser capture microdissection of invading glioblastoma cells revealed elevated EphB2 mRNA (1.5-3.5-fold) in 7 of 7 biopsy specimens. Immunohistochemistry demonstrated EphB2 localization primarily in glioblastoma cells (56 of 62 cases) and not in normal brain. This is the first demonstration that migrating glioblastoma cells overexpress EphB2 in vitro and in vivo; glioma migration and invasion are promoted by activation of EphB2 or inhibited by blocking EphB2. Dysregulation of EphB2 expression or function may underlie glioma invasion.	Do ephrins play a role in brain cancer?	migrating glioblastoma cells overexpress EphB2 in vitro and in vivo; glioma migration and invasion are promoted by activation of EphB2 or inhibited by blocking EphB2. Dysregulation of EphB2 expression or function may underlie glioma invasion
Sudden cardiac death (SCD) in young athletes is generally caused by inherited cardiac disorders. While these events are relatively few compared to other cardiac deaths, they are tragic in that death occurs in a young, otherwise healthy person. The genetic abnormalities most associated with SCD are hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. As a result of growing awareness that these deaths can be prevented, guidelines have been issued in both Europe and the United States to help screen and determine qualification for young persons who want to participate in competitive athletics. There remains debate on the how extensive screening should be, in particular over the use of the 12-lead electrocardiogram (ECG), with European guidelines mandating ECG and United States guidelines not recommending routine use of the ECG.	Is long QT syndrome a cause for sudden cardiac death in athletes?	The genetic abnormalities most associated with SCD are hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia.
Hirschsprung's disease (HSCR) is a fairly frequent cause of intestinal obstruction in children. It is characterized as a sex-linked heterogonous disorder with variable severity and incomplete penetrance giving rise to a variable pattern of inheritance. Although Hirschsprung's disease occurs as an isolated phenotype in at least 70% of cases, it is not infrequently associated with a number of congenital abnormalities and associated syndromes, demonstrating a spectrum of congenital anomalies. Certain of these syndromic phenotypes have been linked to distinct genetic sites, indicating underlying genetic associations of the disease and probable gene-gene interaction, in its pathogenesis. These associations with HSCR include Down's syndrome and other chromosomal anomalies, Waardenburg syndrome and other Dominant sensorineural deafness, the Congenital Central Hypoventilation and Mowat-Wilson and other brain-related syndromes, as well as the MEN2 and other tumour associations. A number of other autosomal recessive syndromes include the Shah-Waardenburg, the Bardet-Biedl and Cartilage-hair hypoplasia, Goldberg-Shprintzen syndromes and other syndromes related to cholesterol and fat metabolism among others. The genetics of Hirschsprung's disease are highly complex with the majority of known genetic sites relating to the main susceptibility pathways (RET an EDNRB). Non-syndromic non-familial, short-segment HSCR appears to represent a non-Mendelian condition with variable expression and sex-dependent penetrance. Syndromic and familial forms, on the other hand, have complex patterns of inheritance and being reported as autosomal dominant, recessive and polygenic patterns of inheritance. The phenotypic variability and incomplete penetrance observed in Hirschsprung's disease could also be explained by the involvement of modifier genes, especially in its syndromic forms. In this review, we look at the chromosomal and Mendelian associations and their underlying signalling pathways, to obtain a better understanding of the pathogenetic mechanisms involved in developing aganglionosis of the distal bowel.	What is the common feature in congenital central hypoventilation and Mowat-Wilson syndromes?	These associations with HSCR include Down's syndrome and other chromosomal anomalies, Waardenburg syndrome and other Dominant sensorineural deafness, the Congenital Central Hypoventilation and Mowat-Wilson and other brain-related syndromes, as well as the MEN2 and other tumour associations.
The different XK mutations may have different effects upon the XK gene product and thus may account for the variable phenotype.	Mutation of which gene is associated with McLeod syndrome?	The different XK mutations may have different effects upon the XK gene product and thus may account for the variable phenotype.
Netrin-1 is a secreted protein that directs long-range axon guidance during early stages of neural circuit formation and continues to be expressed in the mammalian forebrain during the postnatal period of peak synapse formation. Here we demonstrate a synaptogenic function of netrin-1 in rat and mouse cortical neurons and investigate the underlying mechanism. We report that netrin-1 and its receptor DCC are widely expressed by neurons in the developing mammalian cortex during synapse formation and are enriched at synapses in vivo. We detect DCC protein distributed along the axons and dendrites of cultured cortical neurons and provide evidence that newly translated netrin-1 is selectively transported to dendrites. Using gain and loss of function manipulations, we demonstrate that netrin-1 increases the number and strength of excitatory synapses made between developing cortical neurons. We show that netrin-1 increases the complexity of axon and dendrite arbors, thereby increasing the probability of contact. At sites of contact, netrin-1 promotes adhesion, while locally enriching and reorganizing the underlying actin cytoskeleton through Src family kinase signaling and m-Tor-dependent protein translation to locally cluster presynaptic and postsynaptic proteins. Finally, we demonstrate using whole-cell patch-clamp electrophysiology that netrin-1 increases the frequency and amplitude of mEPSCs recorded from cortical pyramidal neurons. These findings identify netrin-1 as a synapse-enriched protein that promotes synaptogenesis between mammalian cortical neurons.	Is Netrin-1 a secreted protein?	Netrin-1 is a secreted protein that directs long-range axon guidance during early stages of neural circuit formation and continues to be expressed in the mammalian forebrain during the postnatal period of peak synapse formation.
Low-intensity blood flow restricted (LI-BFR) resistance training has been shown to produce comparable increases in muscle hypertrophy to traditional high-intensity (HI) resistance training. However, a comparison of the acute vascular responses between the two types of exercise has not been made. The purpose of this study is to compare the acute vascular responses of HI, low-intensity (LI), and LI-BFR resistance exercise. Using a randomized, cross-over design, 11 young (28 ± 5 years) males completed three acute resistance exercise bouts (HI, LI and LI-BFR). Before (Pre), and starting at 15- and 45-min after each exercise bout, large (LAEI) and small (SAEI) artery compliance and calf blood flow were assessed. Calf blood flow was normalized per unit pressure as calf vascular conductance (CVC). Repeated measures (condition × time) ANOVA revealed a main time effect for LAEI and a main condition effect for SAEI. LAEI increased following exercise but returned to baseline at 45-min post. SAEI was greater during the HI condition compared to the LI or LI-BFR conditions. There was a significant condition × time interaction for CVC. CVC was elevated at 15- and 45-min post during the HI condition and at 15-min following the LI condition. CVC was not altered following the LI-BFR condition. These results suggest that HI, LI, and LI-BFR resistance exercise cause similar acute increases in large artery compliance but HI causes greater increases in small artery compliance and calf vascular conductance than LI or LI-BFR resistance exercise.	Is resistance training usually associated with increasing muscle hypertrophy?	Low-intensity blood flow restricted (LI-BFR) resistance training has been shown to produce comparable increases in muscle hypertrophy to traditional high-intensity (HI) resistance training. Ho
Preeclampsia is a pregnancy-specific disorder, of which one of its major subtypes, the placental subtype is considered a response to an ischemic placental environment, impacting fetal growth and pregnancy outcome. Inflammatory immune responses have been linked to metabolic and inflammatory disorders as well as reproductive failures. In healthy pregnancy, immune regulatory mechanisms prevent excessive systemic inflammation. However, in preeclampsia, the regulation of immune responses is disrupted as a result of aberrant activation of innate immune cells and imbalanced differentiation of T-helper cell subsets creating a cytotoxic environment . Recognition events that facilitate immune interaction between maternal decidual T cells, NK cells, and cytotrophoblasts are considered an indirect cause of the incomplete remodeling of spiral arteries in preeclampsia. The mechanisms involved include the activation of immune cells and the subsequent secretion of cytokines and placental growth factors affecting trophoblast invasion, angiogenesis, and eventually placentation. In this review, we focus on the role of excessive systemic inflammation as the result of a dysregulated immune system in the development of preeclampsia. These include insufficient control of inflammation, failure of tolerance toward paternal antigens at the fetal-maternal interface, and subsequent over- or insufficient activation of immune mediators. It is also possible that external stimuli, such as bacterial endotoxin, may contribute to the excessive systemic inflammation in preeclampsia by stimulating the release of pro-inflammatory cytokines. In conclusion, a disrupted immune system might be a predisposing factor or result of placental oxidative stress or excessive inflammation in preeclampsia. Preeclampsia can thus be considered a hyperinflammatory state associated with defective regulation of the immune system proposed as a key element in the pathological events of the placental subtype of this disorder.	Is disruption of immune regulation mechanisms associated with adverse pregnancy outcomes, including preeclampsia (PE)?	s review, we focus on the role of excessive systemic inflammation as the result of a dysregulated immune system in the development of preeclampsia. These
Ryanodine receptor (RyR) is a Ca(2+) channel that mediates Ca(2+) release from intracellular stores. Altered Ca(2+) homeostasis in skeletal muscle which usually occurs as a result of point mutations in type 1 RyR1 (RyR1) is a key molecular event triggering malignant hyperthermia (MH). There are three RyR isoforms, and we herein show, for the first time, that human dendritic cells (DCs) preferentially express RyR1 mRNA among them. The RyR activator, 4-chloro-m-cresol (4CmC), induced Ca(2+) release in DCs, and this response was eliminated by dantrolene, an inhibitor of the RyR1, and was unaffected by xestospongin C, a selective inhibitor of IP(3) receptor. Activation of RyR1 reduced LPS-induced IL-10 production, promoted the expression of HLA-DR and CD86, and thereby exhibited an improved capacity to stimulate allogeneic T cells. These findings demonstrate that RyR1-mediated calcium signaling modifies diverse DC responses and suggest the feasibility of using DC preparations for the diagnosis of MH.	How many and which are the different isoforms for the ryanodine receptor?	There are three RyR isoforms,
IDH1/2 mutation is the most frequent genomic alteration found in gliomas, affecting 40% of these tumors and is one of the earliest alterations occurring in gliomagenesis. We investigated a series of 1305 gliomas and showed that IDH mutation is almost constant in 1p19q codeleted tumors. We found that the distribution of IDH1(R132H) , IDH1(nonR132H) , and IDH2 mutations differed between astrocytic, mixed, and oligodendroglial tumors, with an overrepresentation of IDH2 mutations in oligodendroglial phenotype and an overrepresentation of IDH1(nonR132H) in astrocytic tumors. We stratified grade II and grade III gliomas according to the codeletion of 1p19q and IDH mutation to define three distinct prognostic subgroups: 1p19q and IDH mutated, IDH mutated--which contains mostly TP53 mutated tumors, and none of these alterations. We confirmed that IDH mutation with a hazard ratio = 0.358 is an independent prognostic factor of good outcome. These data refine current knowledge on IDH mutation prognostic impact and genotype-phenotype associations.	The 1p19q co-deletion is associated with what types of tumors?	We investigated a series of 1305 gliomas and showed that IDH mutation is almost constant in 1p19q codeleted tumors.
The interaction of DNA with proteins in the context of chromatin has to be tightly regulated to achieve so different tasks as packaging, transcription, replication and repair. The very rapid and transient post-translational modification of proteins by poly(ADP-ribose) has been shown to take part in all four. Originally identified as immediate cellular answer to a variety of genotoxic stresses, already early data indicated the ability of this highly charged nucleic acid-like polymer to modulate nucleosome structure, the basic unit of chromatin. At the same time the enzyme responsible for synthesizing poly(ADP-ribose), the zinc-finger protein poly(ADP-ribose) polymerase-1 (PARP1), was shown to control transcription initiation as basic factor TFIIC within the RNA-polymerase II machinery. Later research focused more on PARP-mediated regulation of DNA repair and cell death, but in the last few years, transcription as well as chromatin modulation has re-appeared on the scene. This review will discuss the impact of PARP1 on transcription and transcription factors, its implication in chromatin remodeling for DNA repair and probably also replication, and its role in controlling epigenetic events such as DNA methylation and the functionality of the insulator protein CCCTC-binding factor.	How is CTCF activated post-translationally?	The very rapid and transient post-translational modification of proteins by poly(ADP-ribose) has been shown to take part in all four.
Huntington's disease (HD) is caused by a genetic mutation that results in polyglutamine expansion in the N-terminal regions of huntingtin. As a result, this polyQ expansion leads to the misfolding and aggregation of mutant huntingtin as well as age-dependent neurodegeneration. The genetic mutation in HD allows for generating a variety of animal models that express different forms of mutant huntingtin and show differential pathology. Studies of these animal models have provided an important insight into the pathogenesis of HD. Mouse models of HD include transgenic mice, which express N-terminal or full-length mutant huntingtin ubiquitously or selectively in different cell types, and knock-in mice that express full-length mutant Htt at the endogenous level. Large animals, such as pig, sheep, and monkeys, have also been used to generate animal HD models. This review focuses on the different features of commonly used transgenic HD mouse models as well as transgenic large animal models of HD, and also discusses how to use them to identify potential therapeutics. Since HD shares many pathological features with other neurodegenerative diseases, identification of therapies for HD would also help to develop effective treatment for different neurodegenerative diseases that are also caused by protein misfolding and occur in an age-dependent manner.	What gene is mutated in Huntington's disease?	Huntington's disease (HD) is caused by a genetic mutation that results in polyglutamine expansion in the N-terminal regions of huntingtin.
The transition from a specified germ cell to a population of pluripotent cells occurs rapidly following fertilization. During this developmental transition, the zygotic genome is largely transcriptionally quiescent and undergoes significant chromatin remodeling. In Drosophila, the DNA-binding protein Zelda (also known as Vielfaltig) is required for this transition and for transcriptional activation of the zygotic genome. Open chromatin is associated with Zelda-bound loci, as well as more generally with regions of active transcription. Nonetheless, the extent to which Zelda influences chromatin accessibility across the genome is largely unknown. Here we used formaldehyde-assisted isolation of regulatory elements to determine the role of Zelda in regulating regions of open chromatin in the early embryo. We demonstrate that Zelda is essential for hundreds of regions of open chromatin. This Zelda-mediated chromatin accessibility facilitates transcription-factor recruitment and early gene expression. Thus, Zelda possesses some key characteristics of a pioneer factor. Unexpectedly, chromatin at a large subset of Zelda-bound regions remains open even in the absence of Zelda. The GAGA factor-binding motif and embryonic GAGA factor binding are specifically enriched in these regions. We propose that both Zelda and GAGA factor function to specify sites of open chromatin and together facilitate the remodeling of the early embryonic genome.	Is the zelda transcription factor a chromatin remodeller?	Open chromatin is associated with Zelda-bound loci, as well as more generally with regions of active transcriptio
The generalized exocrinopathy cystic fibrosis (CF) is the most common severe genetic disease in Caucasian populations. A panel of more than 700 chromosomes from German and Turkish CF patients was screened for disease-causing mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene by chemical cleavage of mismatch, single strand conformation polymorphism, restriction analysis and direct sequencing of genomic DNA amplified by polymerase chain reaction. Besides the major 3-bp deletion, delta F508 that was found on 73% of German CF chromosomes, more than 50 other missense, nonsense, frame-shift, and splice-site mutations have already been identified. In general, a CFTR mutation is linked with a single 10-marker haplotype which indicates that in most cases a particular mutation spread from a common ancestor. The comparison of mutation genotypes with the disease phenotype emphasized the causative role of the type and localization of the CFTR mutation for clinical course and prognosis. Pancreatic status and the risk of colonization of airways with opportunistic pathogens are genetically determined. Most patients who are harbouring mutations in the nucleotide binding folds were suffering from severe CF disease. Mild or even aberrant forms of CF were observed for many missense mutations located in the putative transmembrane domains or for mutations that are expected to result in a truncated protein of half of wild-type CFTR.	Which is the most common CFTR mutation in Caucasians?	Besides the major 3-bp deletion, delta F508 that was found on 73% of German CF chromosomes, more than 50 other missense, nonsense, frame-shift, and splice-site mutations have already been identified.
Multiple myeloma (MM) is a plasma cell neoplasm that results in over 11,000 deaths in the United States annually. The backbone therapy for the treatment of MM patients almost always includes combinations with corticosteroids such as dexamethasone (DEX). We found that DEX in combination with selinexor, an inhibitor of exportin-1 (XPO1) activity, synergistically inhibits the mTOR pathway and subsequently promotes cell death in MM cells. Specifically, we show that selinexor induces the expression of the glucocorticoid receptor (GR) and when combined with dexamethasone increases GR transcriptional activity. Moreover, we found that key downstream targets of the mTOR pathway are deregulated by the combination and identified a mechanism in which GR enhances the expression of REDD1 in GR positive cells while suppressing mTOR activity and cell viability. While the single agent activity of selinexor in MM cells appears to be GR-independent, synergy with DEX depends on GR expression. These data suggest that patients with tumor cells that are GR positive will benefit substantially from the combination. The current findings are consistent with the beneficial therapeutic outcome in patients with MM when treated with the combination of selinexor and DEX. In addition, they provide a rationale for testing GR and REDD1 as predictive and prognostic markers of response, respectively, for patients treated with this beneficial combination.	Is Selinexor effective for multiple myeloma?	We found that DEX in combination with selinexor, an inhibitor of exportin-1 (XPO1) activity, synergistically inhibits the mTOR pathway and subsequently promotes cell death in MM cells.
DOOR syndrome (deafness, onychodystrophy, osteodystrophy, and mental retardation) is a rarely described disorder with less than 35 reports in the literature. The hallmarks of the syndrome, represented in the DOOR acronym, include sensorineural hearing loss, hypoplastic or absent nails on the hands and feet, small or absent distal phalanges of the hands and feet, and mental retardation. The purpose of our communication is to report on an additional patient with DOOR syndrome, delineate common as well as less frequent manifestations of DOOR syndrome, bring attention to the under appreciated facial features in DOOR syndrome, document the natural history of this disorder, and propose a suggested workup of those suspected of DOOR syndrome. DOOR syndrome is associated with characteristic, coarse facial features with large nose with wide nasal bridge, bulbous tip and anteverted nares, a long prominent philtrum and downturned corners of the mouth. The natural history is one of a deteriorative course, with progressive neurological manifestations including sensorineural deafness, seizures from infancy, optic atrophy, and a peripheral polyneuropathy. The majority of patients with DOOR syndrome have elevated levels of 2-oxoglutarate in the urine and plasma. In this report, we present a newborn with manifestations consistent with DOOR syndrome and a progressive clinical course. A comprehensive literature review reveals 32 patients with DOOR syndrome. In conclusion, DOOR syndrome is a neurometabolic disorder with recognizable facial features and a progressive natural history.	List features of the DOOR syndrome.	The hallmarks of the syndrome, represented in the DOOR acronym, include sensorineural hearing loss, hypoplastic or absent nails on the hands and feet, small or absent distal phalanges of the hands and feet, and mental retardation.
Oncogenic activation of the mitogen-activated protein (MAP) kinase cascade in murine fibroblasts initiates a senescence-like cell cycle arrest that depends on the ARF/p53 tumor suppressor pathway. To investigate whether p53 is sufficient to induce senescence, we introduced a conditional murine p53 allele (p53(val135)) into p53-null mouse embryonic fibroblasts and examined cell proliferation and senescence in cells expressing p53, oncogenic Ras, or both gene products. Conditional p53 activation efficiently induced a reversible cell cycle arrest but was unable to induce features of senescence. In contrast, coexpression of oncogenic ras or activated mek1 with p53 enhanced both p53 levels and activity relative to that observed for p53 alone and produced an irreversible cell cycle arrest that displayed features of cellular senescence. p19(ARF) was required for this effect, since p53(-/-) ARF(-/-) double-null cells were unable to undergo senescence following coexpression of oncogenic Ras and p53. Although the levels of exogenous p53 achieved in ARF-null cells were relatively low, the stabilizing effects of p19(ARF) on p53 could not explain the cooperation between oncogenic Ras and p53 in promoting senescence. Hence, enforced p53 expression without oncogenic ras in p53(-/-) mdm2(-/-) double-null cells produced extremely high p53 levels but did not induce senescence. Taken together, our results indicate that oncogenic activation of the MAP kinase pathway in murine fibroblasts converts p53 into a senescence inducer through both quantitative and qualitative mechanisms.	Which oncogenes are able to induce cellular senescence?	In contrast, coexpression of oncogenic ras or activated mek1 with p53 enhanced both p53 levels and activity relative to that observed for p53 alone and produced an irreversible cell cycle arrest that displayed features of cellular senescence.
Metastatic urothelial carcinoma (UC) remains an aggressive disease associated with limited treatment options and a reduced survival. In spite of this, the first-line treatment based on platinum-based combinations has remained virtually unchanged for the last 20-30 years. Similarly, before the advent of the immune checkpoint inhibitors, there were no FDA-approved drugs for second-line therapy. In the last few years, impressive signs of anti-tumor activity have been reported with several immunotherapy agents targeting the programmed cell death-1 (PD-1) pathway. Avelumab, a PD-1 ligand (PD-L1) inhibitor, is currently being investigated for the treatment of UC. Areas covered: This article will review the pharmacological characteristics of avelumab, the efficacy studies which led to its approval, its safety profile, as well as its place within the management of urothelial carcinoma with immunotherapy. For that matter, we undertook a literature review of all the studies assessing the pharmacology of avelumab and its efficacy within clinical trials. Expert commentary: Avelumab has shown promising antitumor activity and a manageable safety profile in patients with UC. Its dual mechanism of action, blocking the interaction between PD-L1 and PD-1 and promoting antibody-dependent cell-mediated cytotoxicity could potentially be of great interest since it could produce synergistic clinical efficacy.	Is avelumab effective for bladder cancer?	Avelumab, a PD-1 ligand (PD-L1) inhibitor, is currently being investigated for the treatment of UC. Areas covered: This article will review the pharmacological characteristics of avelumab, the efficacy studies which led to its approval, its safety profile, as well as its place within the management of urothelial carcinoma with immunotherapy.
Weight-restored patients with anorexia nervosa (AN) respond favorably to the selective serotonin reuptake inhibitor fluoxetine, which justifies association studies of the serotonin transporter gene (SLC6A4, alias SERT) and AN. Case-control studies suggest that the least transcriptionally active allele of the SERT gene promoter polymorphism (5-HTTLPR) has an increased frequency in AN patients. However, this finding was not replicated with 55 trios (AN child+parents) and the transmission disequilibrium test (TDT). To clarify the role of the 5-HTTLPR in susceptibility to AN, we used the TDT and 106 Australian trios to provide 93% power to detect a genotypic relative risk (GRR) of 2.0. Our results were negative for this GRR (McNemar's chi(2)=0.01, df=1, p=0.921, odds ratio 1.0, 95% CI 0.7-1.5). Additionally, we found no association with AN females, AN subtype, age at onset, or minimum BMI. We then performed the first reported investigation of epistasis between the SERT gene and norepinephrine transporter gene (SLC6A2, alias NET) in AN, as an earlier study suggested that atypical AN responds to the dual serotonin-norepinephrine reuptake inhibitor venlafaxine. We observed no epistasis between the 5-HTTLPR and a polymorphism within the NET gene promoter polymorphic region (NETpPR) (chi(2)=0.48, df=1, p=0.490). Although 5-HTTLPR modulates serotonin reuptake by the serotonin transporter, our analyses provide no evidence that susceptibility to AN is modified by 5-HTTLPR alone, nor in concert with as yet undetermined functional effects of the NETpPR polymorphism.	Can venlafaxine block NET and SERT?	We then performed the first reported investigation of epistasis between the SERT gene and norepinephrine transporter gene (SLC6A2, alias NET) in AN, as an earlier study suggested that atypical AN responds to the dual serotonin-norepinephrine reuptake inhibitor venlafaxine
The animal gastrointestinal tract contains a complex community of microbes, whose composition ultimately reflects the co-evolution of microorganisms with their animal host. An analysis of 78,619 pyrosequencing reads generated from pygmy loris fecal DNA extracts was performed to help better understand the microbial diversity and functional capacity of the pygmy loris gut microbiome. The taxonomic analysis of the metagenomic reads indicated that pygmy loris fecal microbiomes were dominated by Bacteroidetes and Proteobacteria phyla. The hierarchical clustering of several gastrointestinal metagenomes demonstrated the similarities of the microbial community structures of pygmy loris and mouse gut systems despite their differences in functional capacity. The comparative analysis of function classification revealed that the metagenome of the pygmy loris was characterized by an overrepresentation of those sequences involved in aromatic compound metabolism compared with humans and other animals. The key enzymes related to the benzoate degradation pathway were identified based on the Kyoto Encyclopedia of Genes and Genomes pathway assignment. These results would contribute to the limited body of primate metagenome studies and provide a framework for comparative metagenomic analysis between human and non-human primates, as well as a comparative understanding of the evolution of humans and their microbiome. However, future studies on the metagenome sequencing of pygmy loris and other prosimians regarding the effects of age, genetics, and environment on the composition and activity of the metagenomes are required.	List the three most abundant bacterial phyla present in mouse feces.	The taxonomic analysis of the metagenomic reads indicated that pygmy loris fecal microbiomes were dominated by Bacteroidetes and Proteobacteria phyla.
Liraglutide is a glucagon-like peptide-1 (GLP-1) analog marketed for the treatment of type 2 diabetes. Besides lowering blood glucose, liraglutide also reduces body weight. It is not fully understood how liraglutide induces weight loss or to what degree liraglutide acts directly in the brain. Here, we determined that liraglutide does not activate GLP-1-producing neurons in the hindbrain, and liraglutide-dependent body weight reduction in rats was independent of GLP-1 receptors (GLP-1Rs) in the vagus nerve, area postrema, and paraventricular nucleus. Peripheral injection of fluorescently labeled liraglutide in mice revealed the presence of the drug in the circumventricular organs. Moreover, labeled liraglutide bound neurons within the arcuate nucleus (ARC) and other discrete sites in the hypothalamus. GLP-1R was necessary for liraglutide uptake in the brain, as liraglutide binding was not seen in Glp1r(-/-) mice. In the ARC, liraglutide was internalized in neurons expressing proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). Electrophysiological measurements of murine brain slices revealed that GLP-1 directly stimulates POMC/CART neurons and indirectly inhibits neurotransmission in neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP) via GABA-dependent signaling. Collectively, our findings indicate that the GLP-1R on POMC/CART-expressing ARC neurons likely mediates liraglutide-induced weight loss.	Is liraglutide effective for weight reduction?	Here, we determined that liraglutide does not activate GLP-1-producing neurons in the hindbrain, and liraglutide-dependent body weight reduction in rats was independent of GLP-1 receptors (GLP-1Rs) in the vagus nerve, area postrema, and paraventricular nucleus.
Previously, we proposed a new model for understanding the Warburg effect in tumorigenesis and metastasis. In this model, the stromal fibroblasts would undergo aerobic glycolysis (a.k.a., the Warburg effect)--producing and secreting increased pyruvate/lactate that could then be used by adjacent epithelial cancer cells as "fuel" for the mitochondrial TCA cycle, oxidative phosphorylation, and ATP production. To test this model more directly, here we used a matched set of metabolically well-characterized immortalized fibroblasts that differ in a single gene. CL3 fibroblasts show a shift towards oxidative metabolism, and have an increased mitochondrial mass. In contrast, CL4 fibroblasts show a shift towards aerobic glycolysis, and have a reduced mitochondrial mass. We validated these differences in CL3 and CL4 fibroblasts by performing an unbiased proteomics analysis, showing the functional upregulation of 4 glycolytic enzymes, namely ENO1, ALDOA, LDHA and TPI1, in CL4 fibroblasts. Many of the proteins that were upregulated in CL4 fibroblasts, as seen by unbiased proteomics, were also transcriptionally upregulated in the stroma of human breast cancers, especially in the patients that were prone to metastasis. Importantly, when CL4 fibroblasts were co-injected with human breast cancer cells (MDA-MB-231) in a xenograft model, tumor growth was dramatically enhanced. CL4 fibroblasts induced a > 4-fold increase in tumor mass, and a near 8-fold increase in tumor volume, without any measurable increases in tumor angiogenesis. In parallel, CL3 and CL4 fibroblasts both failed to form tumors when they were injected alone, without epithelial cancer cells. Mechanistically, under co-culture conditions, CL4 glycolytic fibroblasts increased mitochondrial activity in adjacent breast cancer cells (relative to CL3 cells), consistent with the "Reverse Warburg Effect". Notably, Western blot analysis of CL4 fibroblasts revealed a significant reduction in caveolin-1 (Cav-1) protein levels. In human breast cancer patients, a loss of stromal Cav-1 is associated with an increased risk of early tumor recurrence, metastasis, tamoxifen-resistance, and poor clinical outcome. Thus, loss of stromal Cav-1 may be an effective marker for predicting the "Reverse Warburg Effect" in the stroma of human breast cancer patients. As such, CL4 fibroblasts are a new attractive model for mimicking the "glycolytic phenotype" of cancer-associated fibroblasts. Nutrients derived from glycolytic cancer associated fibroblasts could provide an escape mechanism to confer drug-resistance during anti-angiogenic therapy, by effectively reducing the dependence of cancer cells on a vascular blood supply.	Which is the primary distinction between the Reverse Warburg effect and the conventional Warburg effect?	Previously, we proposed a new model for understanding the Warburg effect in tumorigenesis and metastasis. In this model, the stromal fibroblasts would undergo aerobic glycolysis (a.k.a., the Warburg effect)--producing and secreting increased pyruvate/lactate that could then be used by adjacent epithelial cancer cells as "fuel" for the mitochondrial TCA cycle, oxidative phosphorylation, and ATP production.
Frontotemporal dementia (FTD) is the second most frequent dementia, after Alzheimer's, in patients under the age of 65. It encompasses clinical entities characterized by behavioral, language, and executive control dysfunction. Neurofilament light chain (NfL) is a new, non-disease specific, widely studied biomarker indicative of axonal injury and degeneration. Various studies have previously explored the role of NfL in the diagnostic process, monitoring, and prognosis of dementia. The current systematic review and meta-analysis include all the available data concerning the role of NfL in frontotemporal dementia and its use as a potential biomarker in differentiating patients with FTD from (a) healthy individuals, (b) Alzheimer's dementia, (c) Dementia with Lewy bodies, (d) Motor Neuron disease, (e) Parkinsonian syndromes, and (f) psychiatric disorders. We also analyze the utility of NfL in distinguishing specific FTD subgroups. Neurofilament light chain has a potential role in differentiating patients with frontotemporal dementia from healthy controls, patients with Alzheimer's dementia, and psychiatric disorders. Higher NfL levels were also noted in patients with semantic primary progressive aphasia (PPA) when compared with behavioral FTD and non-fluent PPA patients. Further studies exploring the use of NfL in frontotemporal dementia are needed.	Is neurofilament light marker for disease?	Neurofilament light chain has a potential role in differentiating patients with frontotemporal dementia from healthy controls, patients with Alzheimer's dementia, and psychiatric disorders.
Complex carbohydrates in the human cervix were studied histochemically using lectins conjugated to horseradish peroxidase and correlated procedures. Stratified squamous epithelium of the exocervix and columnar epithelium of the endocervix in some, but not all specimens showed staining for terminal alpha-N-acetyl-D-galactosamine, alpha-D-galactose, beta-D-galactose and alpha-L-fucose. The staining for alpha-N-acetylgalactosamine and alpha-galactose, the terminal sugars in blood group A and B antigens respectively, corresponded to a large extent with ABO blood type. One exception was the lack of staining for terminal alpha-N-acetylgalactosamine in endocervical secretions in three of nine blood type A patients. A second exception was the staining for terminal alpha-galactose in endocervical secretions in about half of blood type O and A specimens. The type and amount of glycoprotein formed by endocervical columnar cells differed according to location in superficial compared with deep portions of the glands and according to location at the junction with exocervix compared with the more internal regions. Staining of endothelial cells for blood group A and B antigens was confined to subjects of blood type A and B respectively, although three of nine type A specimens showed no lectin reactivity for group A antigen. Endothelial cells evidenced affinity for Ulex europeus I agglutinin demonstrative of fucose in all specimens. Mast cells disclosed lectin affinity consistent with the presence of terminal or internal mannose or N-acetylglucosamine residues. Two blood type O specimens were examined with conjugated lectins at the ultrastructural level. Secretory granules stained for content of terminal alpha-galactose, beta-galactose and fucose. These results support and concur with biochemical studies of complex carbohydrates in human cervical tissues. They reveal, in addition, the location of the blood group antigens in the human exocervix and endocervix and the marked heterogeneity among endocervical columnar cells in glycoprotein production.	List the blood group antigens, associated with blood type	staining for alpha-N-acetylgalactosamine and alpha-galactose, the terminal sugars in blood group A and B antigens respectively, corresponded to a large extent with ABO blood type. One
Gaucher disease is an autosomal recessive disorder resulting from deficient activity of the lysosomal enzyme glucocerebrosidase (GBA, E.C.3.2.1.45). Three clinical forms of Gaucher disease have been described: type 1, nonneuronopathic; type 2, acute neuronopathic; and type 3, subacute neuronopathic (OMIM 230800, 230900, 231000). Over the past decade, recognition of a distinct, perinatal lethal form of Gaucher disease (PLGD) has led researchers and clinicians to evaluate Gaucher disease in the differential diagnosis of congenital ichthyosis and nonimmune hydrops fetalis. To date, more than 30 cases of PLGD have been genotyped and reported. It has been observed that homozygosity for recombinant GBA alleles, which are fundamentally null alleles, leads to early lethality, usually in utero or during the 1st few days of life, whereas genotypes involving a recombinant allele and a missense mutation may be less detrimental. Here, we report a case of Gaucher disease with prenatal onset and death within hours of birth, likely due to compound heterozygosity for the GBA Rec Nci I null allele and a R131C missense mutation. In view of the patient's severe clinical course, and based on reviews of other PLGD cases, we postulate that a missense mutation that abruptly disrupts the structure/function of GBA, in combination with a null allele, may result in early lethality in patients with PLGD. We also speculate that R131C is an extremely severe mutation that has occurred more than once in different populations and, in either the homozygous form or heterozygous with another severe mutation, will result in a poor prognosis.	Which enzyme is deficient in Gaucher's disease?	Gaucher disease is an autosomal recessive disorder resulting from deficient activity of the lysosomal enzyme glucocerebrosidase (GBA, E.C.3.2.1.45)