ABstrAct: Upon the completion of a three-year evaluation of natural occurrence of storage diseases within a range of cultivars or advanced selections and a simultaneous assessment of their other characteristics, an apple ideotype has been proposed that could be used in breeding of new cultivars resistant to these diseases. The ideotype combines the potential of apples for long-term storage with higher skin thickness and toughness, a lower production of ethylene, a higher natural content of calcium, a higher content of total phenolic compounds and antioxidant capacity, a higher flesh firmness, and a higher acidity of juice expressed in pH values. For some of these characteristics, threshold values have been suggested in the paper. The genotypes preselected according to these criteria should be chosen on the basis of the final screening with Pezicula alba inoculum test. The result of the inoculation test should be equal to or bet- ter than the standard cultivar Gala. Future research is required to determine the feasibility of the ideotype in routine breeding programs.
The hydrolysis of sphingolipids by lysosomal enzymes requires the presence of additional proteins, which have been called activator proteins. The number of activator proteins, their specificity, exact mechanism of action, and response to a storage process all remain to be determined. In this study, antibodies to an activator protein known to bind sphingolipids and activate the enzymatic hydrolysis of GM1 ganglioside and sulfatide were used to estimate the concentration of this activator protein in small samples of liver and brain from patients with lysosomal storage diseases. By using rocket immunoelectrophoresis, the concentration of cross-reacting material (CRM) was determined. Control livers had an average of 0.95 +/- 0.18 (mean +/- 1 SD) microgram CRM/mg protein in the extracts, and control brains had an average of 0.25 +/- 0.14 microgram CRM/mg protein. Extremely high levels of CRM were found in extracts of livers from patients with type 1 GM1 gangliosidosis (15.1 and 16.9), and type A Niemann-Pick disease (10.7). Extracts of brain samples revealed a large amount of CRM in type 1 GM1 gangliosidosis (14.8), Tay-Sachs disease (5.3 and 8.7), and Sandhoff disease (13.5). Significantly elevated CRM was also measured in brain samples from patients with type 2 GM1 gangliosidosis, type A Niemann-Pick disease, metachromatic leukodystrophy, and Krabbe disease. The highest levels are found in those genetic diseases where the lipids stored, […]
The majority of advanced selections that were partially resistant to storage diseases in this study were characterised by a higher content of acids and by taste with a perception of being more acid than sweet. Their taste was slightly inferior to presently grown cultivars, therefore, they could be proposed only as donors of storage disease resistance for the new crosses in apple breeding programmes. A cer- tain exception in this respect was HL 1711, which usually receives the highest scores for taste; but fruit appearance of the selection is inferior because of poor colouring and flat shape of the ribbed fruits. Selections HL 322, HL 212 and HL 514 had better fruit quality but their resistance to storage diseases was not so remarkable.
A defective efflux of free sialic acid from the lysosomal compartment has been found in the clinically heterogeneous group of sialic acid storage disorders. Using radiolabeled sialic acid (NeuAc) as a substrate, we have recently detected and characterized a proton-driven carrier for sialic acid in the lysosomal membrane from rat liver. This carrier also recognizes and transports other acidic monosaccharides, among which are uronic acids. If no
The fruits were infected with the storage disease Penicillium expansum. This fungus is a wound parasite, for infection the fruits need to be wounded in advance. In concrete the apples were punctured at 4 places, divided equally over the fruit, using a sterilized nail, mounted in a cork plug, creating a 1-mm wide by 2-mm deep cylindrical wound. As the fruits were dipped before the artificial infection, the trial was set up to evaluate the preventive efficiency of the test objects.
spirometry and, when possible, the six-minute walking test, skin, endocrine and cardiac involvement, laboratory data such as blood tests (CK, serum lipids, glycaemia), EMG, ECG and Holter ECG, echocardiography, internal organ ultrasound, respiratory performance and cause of death. The inclusion criteria were: 1) lipid storage myop- athy in patients or family members, 2) Jordans’ anomaly, 3) presence of mutations in the PNAPLA2 or CGI58 genes. Genetic analyses were performed in three Italian centers (Milan, Rome and Pisa). Genomic DNA was extracted from peripheral blood using a Puregene DNA Isolation kit (Gentra Systems, Minneapolis). The coding region of the PNPLA2 gene (GeneBank NM02376) was amplified using the oligonucleotides and PCR amplifica- tion conditions previously reported by Tavian et al. . All CGI58/ABHD5 coding exons (GeneBank NG007090.3) and the candidate promoter region were PCR amplified. The conditions for the genomic amplification followed those described by Redaelli et al. . All PCR products were gel purified (NucleoSpin Extract II, M-Medical) and sequenced on 3730 DNA Analyzers by means of the BigDye® Terminator V1.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, CA).
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Most of present studies on the effect of the last pre- harvest treatment on the infection pressure of apple post-harvest diseases evaluated the effectiveness of fungicidal preparations and substances of the older type, i.e. benzimidazoles, imidazoles, dialkyldithio- carbamates and ftalimides. Possibilities of use against post-harvest diseases of apples of environmentally and toxicologically more prospective active ingredi- ents from the chemical group of strobilurines have not
anti-IDUA antibodies reduced the uptake of IDUA by MPS I fibroblasts to less than 10% of that seen with serum from animals with low or negative titers of antibodies. Fur- thermore, anti-IDUA antibodies reduced delivery of enzyme to organs with low lev- els of macrophages and reduced the ability of ERT to lower GAG levels. For example, IDUA enzyme activity was 2.4- and 5.1-fold higher, respectively, in heart valves and the renal medulla in tolerant dogs than in dogs with high-titer antibodies after administra- tion of the standard dose of 0.58 mg/kg/wk of recombinant human IDUA, while the pathological abnormalities in heart valves and renal medulla, respectively, were only 24% and 60% as severe in tolerized dogs compared with dogs with high-titer anti- bodies. Furthermore, although a 3.4-fold- higher dose of 2 mg/kg/wk further reduced pathological evidence of lysosomal storage in tolerized MPS I dogs, this higher dose was not as effective in animals with high- titer antibodies. These data provide com- pelling evidence that anti-IDUA antibodies adversely affect the efficacy of ERT. The anti-IDUA antibody probably binds to an epitope at or near the M6P modification and sterically inhibits the protein from binding to the M6P receptor and being taken up by the cell, as diagrammed in Fig- ure 1. This study also suggests that the dose of enzyme that is currently used for ERT is too low to be effective at some sites. Early studies to identify the appropriate dose relied upon reduction in lysosomal stor- age in easy-to-treat organs such as liver and spleen (6), and these doses may need to be revised based on these data.
Reports of cranial CT findings in patients with fucosidosis are sparse. Diffuse, severe cerebral and cerebellar atrophy has been reported in the few published cases (1, 2). Although cerebral and cerebellar atrophy was not demonstrated in our patients, this may reflect the young ages of our patients (significantly younger than those for which CT findings have been reported). Fo- cal low-attenuation regions within the corona radiata extending up to the subcortical white matter, in the same distribution as the hyperin- tense periventricular abnormalities seen on T2- weighted images in our first patient, have been described (1). These findings may represent white matter regions of demyelination and glio- sis in areas where the neuronal loss is most severe (4, 7). Similar white matter findings have been reported in a number of other lysosomal storage diseases, including the sphingolipido- ses (eg, metachromatic leukodystrophy, GM 1 gangliosidosis, and Krabbe disease) and muco- polysaccharidoses (9 –12), as well as man- nosidosis, another form of glycoproteinosis (13). The white matter signal abnormalities in these disorders have been presumed to result from the effects of intracellular storage products (ie, demyelination, gliosis, and possibly edema) rather than from prolonged T2 relaxation prop- erties of the storage products themselves (10, 11, 13).
Once diagnosed, treatment of Morquio syndrome requires a system-specific and multidisciplinary approach, often involv- ing primary care physicians, orthopedists, pulmonologist, cardiologists, and anesthesiologists. Other MPS and lyso- somal storage diseases – Hurler syndrome (MPS I), Hunter syndrome (MPS II), Maroteaux-Lamy syndrome (MPS VI), Gaucher disease, Fabry disease, and Pompe disease – are currently being treated with enzyme replacement therapy (ERT). Hematopoietic stem cell therapy (HSCT) has played an important role in the treatment of Hurler syndrome and is currently under intensive study for the treatment of other MPSs. The role of ERT and HSCT for the treatment of MPS IV-A is also under investigation.
The glycogen storage diseases remain poorly understood. Although they are in- frequent conditions, they remain serious and deserve to be recognized. The types I and III are the most common. The diagnosis should be considered in a large smooth hepatomegaly and hypoglycemia constant height and weight delay. Diet plays a major role in treatment. However, despite treatment, growth may remain weak, requiring a long-term monitoring because it is an incurable disease.
Abstract: Accumulating evidence supports that gut dysbiosis may relate to various liver diseases. Alcoholics with high intestinal permeability had a decrease in the abundance of Ruminnococcus. Intestinal dysmotility, increased gastric pH, and altered immune responses in addition to environmental and genetic factors are likely to cause alcohol-associated gut microbial changes. Alcohol-induced dysbiosis may be associated with gut barrier dysfunction, as microbiota and their products modulate barrier function by affecting epithelial pro-inflammatory responses and mucosal repair functions. High levels of plasma endotoxin are detected in alcoholics, in moderate fatty liver to advanced cirrhosis. Decreased abundance of Faecalibacterium prausnitzii, an anti-inflammatory commensal, stimulating IL-10 secretion and inhibiting IL-12 and interferon-γ expression. Proteobacteria, Enterobacteriaceae, and Escherichia were reported to be increased in NAFLD (nonalcoholic fatty liver disease) patients. Increased abundance of fecal Escherichia to elevated blood alcohol levels in these patients and gut microbiota enriched in alcohol-producing bacteria produce more alcohol (alcohol hypothesis). Some undetermined pathological sequences related to gut dysbiosis may facilitate energy-producing and proinflammatory conditions for the progression of NAFLD. A shortage of autochthonous non-pathogenic bacteria and an overgrowth of potentially pathogenic bacteria are common findings in cirrhotic patients. The ratio of the amounts of beneficial autochthonous taxa (Lachnospiraceae + Ruminococaceae + Veillonellaceae + Clostridiales Incertae Sedis XIV) to those of potentially pathogenic taxa (Enterobacteriaceae + Bacteroidaceae) was low in those with early death and organ failure. Cirrhotic patients with decreased microbial diversity before liver transplantation were more likely to develop post-transplant infections and cognitive impairment related to residual dysbiosis. Patients with PSC had marked reduction of bacterial diversity. Enterococcus and Lactobacillus were increased in PSC patients (without liver cirrhosis.) Treatment-naive PBC patients were associated with altered composition and function of gut microbiota, as well as a lower level of diversity. As serum anti-gp210 antibody has been considered as an index of disease progression, relatively lower species richness and lower abundance of Faecalibacterium spp. in gp210-positive patients are interesting. The dysbiosis-induced altered bacterial metabolites such as a hepatocarcinogenesis promotor DCA, together with a leaky gut and bacterial translocation. Gut protective Akkermansia and butyrate-producing genera were decreased, while genera producing-lipopolysaccharide were increased in early hepatocellular carcinoma (HCC) patients.
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Figure 13: Backblaze Average Cost per Drive Size. Reprinted from "Hard Drive Cost Per Gigabyte", Backblaze Inc., July 2017. Looking back into January 2018, a storage upgrade project was initiated for the NAS system and the total capacity was doubled in April 2018. In conjunction with Backblaze’s observation shown in Figure 13, we know that making the system upgrade decision was reasonably at the right time in order to avoid business interruptions while maximizing cost saving at the same time.
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Many factors need to be taken into account to ensure trustworthiness and validity of qualitative research. Compared to using a questionnaire, in-depth interviews make it possible to acquire a deeper understanding of the participants’ experiences of a chronic disease. Everyone has experiences in his or her life that may influence the particular questions that are asked and the interpretation of what is said. To ensure credibility, the participants in this study were patients with a chronic disease and, despite differences in the diseases, the results revealed many similarities between them, for example how they felt and thought about their disease as well as how they found similar strategies to cope with their new life situation. Data saturation (when the phenomenon became stronger and similarities between the participants more evident, cohesive and consistent; ) was found, which strengthens the trustworthiness of the results and the transferability to others in the same context, i.e., other patients who are affected by a chronic disease. Trustworthiness was maintained by developing clear coding procedures/coding definitions and peer debriefing with participating interviewers.
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the safety or efficacy of ustekinumab. Ustekinumab is not approved for use in pregnancy or breastfeeding; it may pass through the placenta or milk. Possible side effects are including, an increased risk of infections from a reduced ability to mount an immune response, as well as reactivation of latent infections which involves an increased risk of infections. Serious microbial infections include TB, viral, and fungal diseases. Crohn’s disease patients can develop anal abscesses, gastroenteritis, ophthalmic herpes, pneumonia, and meningitis caused by Listeria monocytogenes. Symptoms are chills, cough, fever, shortness of breath, weight loss, and pain.Patients are required to be tested for possible infectious agents before starting the regimen.Those patients who are predisposed to genetic variation in the proteins IL12 and IL-23 are at a higher risk for disseminated (systemic) infectious diseases such as Salmonella, Mycobacteria, and Bacillus Calmette-Guerin (BCG). Other possible infectious and inflammatory diseases are appendicitis, cholecystitis, cellulitis, diverticulitis, pneumonia, sepsis, osteomyelitis, and viral complications such as gastroenteritis and infectious complications such as gastroenteritis and urinary tract infections. Hypersensitivity: In case of serious allergic response, it is required to stop the medicine as follows; angioedema and anaphylaxis symptoms, episodes of fainting sensation, weakness, swelling of face, eyelids, tongue, throat, chest tightness, or skin rash.
Studies comparing DNA methylation status in newborns with aortic valve stenosis (AVS), TOF, and VSDs have identified several aberrant patterns in diseased patients [75–77]. A total of 52 genes with significantly altered DNA methylation were identified in the blood of newborn AVS patients compared to newborn healthy infants. Of particular interest are APOA5 (a determinant of plasma triglyceride levels) and PCSK9 (an activator of low-density lipoprotein receptors), which were both hypermethylated and are both considered major risk factors for coronary artery disease in adults . In myocardial biopsies from patients with TOF and VSD, hypermethylation was observed in the promoter region of SCO2, which is a cytochrome c oxidase protein. The authors hypothesized that the resultant SCO2 downregulation drives the metabolic state of cardiac cells toward glycolysis, delaying terminal differentiation and promoting cardiomyopathy and heart failure . In another study assessing the DNA methylation of key cardiac transcription factors, Nkx2.5 and chamber-specific Hand1 were found to be hypermethylated in patients with TOF . As expected, the expression of these two transcription factors was found to be downregulated. In a revealing study, monozygotic twins discordant for DORV were analyzed for genomic and epigenomic differences . Not surprisingly, very few genetic differences were identified. However, 121 transcription factor binding sites were differentially methylated, including the hypermethylation of ZIC3 (a zinc finger protein involved in Wnt signaling) and NR2F2 (a protein important in heart development), in the diseased twin. This finding highlights the importance of epigenetics in diseases with complex etiologies, such as CHD.
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Among other dystrophic calcifications that occur in the head and neck region are pulp stones, which present radiographically in the coronal pulp of teeth and sometimes in the radicular pulp as a compact degenerative radiopaque mass of calcified tissues. Pulp stones are usually asymptomatic, and their pathogenies are still unknown. They are more prevalent in patients with systemic or genetic diseases such as dentine dysplasia, dentinogenesis imperfecta, and certain syndromes such as Van der Woude syndrome . Idiopathic pulp stones can be detected mainly by bitewing and periapical radiographs and also by high-resolution PRs . Norman and Johnstone suggested that the pathogenesis of pulp stones is the same as calcification in arteriosclerosis and that pulp stones are the local manifestation of a constitutional metabolic disturbance or dysfunction associated with the presence of a high level of blood calcium (hypercalcemia) [17–19]. A previous study suggested a strong correlation between the detection of pulp stones in PRs and the presence of CAC lesions; if multiple pulp stones are detected in a patient, further evaluation for CACs is required .
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It was recently determined that non-cancer cell lines fail to incorporate edits at an appreciable rate due to p53-induced apoptosis post-DNA damage (i.e., DSB introduction) . Therefore, cells that have an inactivated p53 pathway are preferentially selected for HDR in genome editing experiments, thus leaving a large proportion of gene modified cells as p53 mutants . Although this finding is troublesome for downstream cell therapies due to the possibility of tumorigenesis post-transplantation, the reversible suppression of the p53 pathway using small molecule inhibitors during genome editing may offer a possible solution [54,70]. These findings may partly explain why cancer cell lines, such as HeLa and HEK293T, show much higher genome editing efficiencies than primary cells and iPS cell lines [48,71,72]. Some genetic diseases may impact genome editing success in vivo by hampering repair pathways, such as an impaired Fanconi anemia (FA) repair pathway in FA patients that has been shown to be an integral pathway in Cas9-induced single-stranded template repair . A number of additional variables that debilitate editing success include: (i) low incidence (0.5–20%) of HDR, even in the presence of a correction template [74,75], (ii) manipulated cells are restricted to late S or G2 phase of the cell cycle [47,76–78], and (iii) generated DSBs trigger cellular apoptosis . These factors taken together make HDR a highly inefficient method for mutation correction. A novel genome editing technique, base editing, has been proposed to overcome these issues [11,80,81]. Throughout this review, we will discuss the mechanism of base editing and its application for MPS, as well as putative delivery mechanisms for genome editing systems in vivo.
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Table 1 also reports the emerging classification of diseases based on the recent understanding of the molecular basis LSDs. This subset includes groups of disorders due to: (i) non-enzymatic lysosomal protein defects; (ii) transmembrane protein defects (transporters and structural proteins); (iii) lysosomal enzyme protection defects; (iv) post-translational processing defects of lysosomal enzymes; (v) traf- ficking defects in lysosomal enzymes; and (vi) poly- peptide degradation defects. Finally, another group includes the neuronal ceroid lipofuscinoses (NCLs), which are considered to be lysosomal disorders, even though distinct characteristics exist. While, in the classic LSDs, the deficiency or dysfunction of an enzyme or transporter leads to lysosomal accumulation of specific undegraded substrates or metabolites, accumulating material in NCLs is not a disease-specific substrate but the subunit c of mitochondrial ATP synthase or sphingolipid activa- tor proteins A and D. 27
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Objective: Late-onset Pompe disease (LOPD) is a lysosomal storage disease resulted from deficiency of the enzyme acid α-glucosidase. Patients usually develop a limb-girdle pattern of myopathy and respiratory impairment, and enzyme replacement therapy (ERT) is the only specific treatment available. Recently, LOPD has been associated with low bone mineral density (BMD), but the effect of ERT on BMD is inconclusive. In this report we described our early observations on the change of BMD after ERT in Chinese LOPD patients.