855 research outputs found
Matrix Metalloproteinases, New Insights into the Understanding of Neurodegenerative Disorders
Matrix metalloproteinases (MMPs) are a subfamily of zinc-dependent proteases that are re-sponsible for degradation and remodeling of extracellular matrix proteins. The activity of MMPs is tightly regulated at several levels including cleavage of prodomain, allosteric activation, com-partmentalization and complex formation with tissue inhibitor of metalloproteinases (TIMPs). In the central nervous system (CNS), MMPs play a wide variety of roles ranging from brain devel-opment, synaptic plasticity and repair after injury to the pathogenesis of various brain disorders. Following general discussion on the domain structure and the regulation of activity of MMPs, we emphasize their implication in various brain disorder conditions such as Alzheimer\u27s disease, multiple sclerosis, ischemia/reperfusion and Parkinson\u27s disease. We further highlight accumu-lating evidence that MMPs might be the culprit in Parkinson\u27s disease (PD). Among them, MMP-3 appears to be involved in a range of pathogenesis processes in PD including neuroinflamma-tion, apoptosis and degradation of cc-synuclein and DJ-1. MMP inhibitors could represent poten-tial novel therapeutic strategies for treatments of neurodegenerative diseases
Role of Matrix Metalloproteinase 3-mediated alpha-Synuclein Cleavage in Dopaminergic Cell Death
Evidence suggests that the C-terminal truncation of alpha-synuclein is equally important as aggregation of alpha-synuclein in Parkinson disease (PD). Our previous results showed that an endopeptidase, matrix metalloproteinase-3 (MMP3), was induced and activated in dopaminergic (DA) cells upon stress conditions. Here, we report that MMP3 cleaved alpha-synuclein in vitro and in vivo and that alpha-synuclein and MMP3 were co-localized in Lewy bodies (LB) in the postmortem brains of PD patients. Incubation of alpha-synuclein with the catalytic domain of MMP3 (cMMP3) resulted in generation of several peptides, and the peptide profiles of WT alpha-synuclein (WTsyn) and A53T mutant (A53Tsyn) were different. Combined analysis using mass spectrometry and N-terminal determination revealed that MMP3 generated C-terminally truncated peptides of amino acids 1-78, 1-91, and 1-93 and that A53Tsyn produced significantly higher quantities of these peptides. Similar sizes of peptides were detected in N27 DA cells under oxidative stress and RNA interference to knock down MMP3-attenuated peptide generation. Co-overexpression of cMMP3 with either WTsyn or A53Tsyn led to a reduction in Triton X-100-insoluble aggregates and an increase in protofibril-like small aggregates. In addition, overexpression of the 1-93-amino acid peptide in the substantia nigra led to DA neuronal loss without LB-like aggregate formation. The results strongly indicate that MMP3 digestion of alpha-synuclein in DA neurons plays a pivotal role in the progression of PD through modulation of alpha-synuclein in aggregation, LB formation, and neurotoxicity
Challenges in overcoming advanced-stage or relapsed refractory extranodal NK/T-cell lymphoma: meta-analysis of individual patient data
IntroductionExtranodal NK/T-cell lymphoma (ENKTCL), a non-Hodgkin lymphoma, is known for its destructive local impact on nasal structures and systemic induction of inflammatory cytokines. Concurrent treatment with radiation and nonanthracycline- based chemotherapy has improved survival rates in patients with localized disease stages. However, survival outcomes vary significantly in advanced-stage and relapsed or refractory (R/R) cases.MethodsTherefore, we conducted a meta-analysis using random effects models to assess prognostic factors in advanced or R/R ENKTCL, employing a digital extractor on Kaplan–Meier graphs owing to the scarcity of published prospective trials for these patients.ResultsWe observed that patients with advanced ENKTCL treated with Lasparaginase had a median progression-free survival (PFS) of 14.3 months and an overall survival (OS) of 19 months. In R/R ENKTCL, PFS and OS were 11.7 and 15.6 months, respectively. Additionally, OS outcomes in advanced-stage ENKTCL were better in the asparaginase group than that in the non-asparaginase group, with PEG-asparaginase showing superior results compared with that using Lasparaginase. Epstein–Barr Virus (EBV)-DNA positivity in the bloodstream prior to treatment was associated with poor outcomes in advanced-stage ENKTCL, and similar trends were observed in patients with R/R ENKTCL and post-treatment EBV viremia.DiscussionCollectively, these findings suggest that chemotherapy with Lasparaginase or PEG-asparaginase can enhance survival in advanced or R/R ENKTCL. However, future strategies must be developed to effectively suppress EBV viremia and achieve a deep response toward tumor eradication
Comparison of the antibody responses to Plasmodium vivax and Plasmodium falciparum antigens in residents of Mandalay, Myanmar
<p>Abstract</p> <p>Background</p> <p>The aim of this study was to investigate the profile of antibodies against several antigens of <it>Plasmodium vivax </it>and <it>Plasmodium falciparum </it>in Mandalay, Myanmar.</p> <p>Methods</p> <p>Malaria parasites were identified by microscopic examination. To test the antibodies against <it>P. vivax </it>and <it>P. falciparum </it>in sera, an indirect immunofluorescence antibody test (IFAT) was performed using asexual blood parasite antigens. An enzyme-linked immunosorbent assay (ELISA) was performed with circumsporozoite protein (CSP), Pvs25 and Pvs28 recombinant proteins of transmission-blocking vaccine candidates for <it>P. vivax</it>, and liver stage specific antigen-1 and -3 (PfLSA-1, PfLSA-3) for <it>P. falciparum</it>.</p> <p>Results</p> <p>Fourteen patients among 112 were found to be infected with <it>P. vivax </it>and 26 with <it>P. falciparum </it>by thick smear examination. Twenty-three patients were found to be infected with <it>P. vivax</it>, 19 with <it>P. falciparum </it>and five with both by thin smear examination. Blood samples were divided into two groups: Group I consisted of patients who were positive for infection by microscopic examination, and Group II consisted of those who showed symptoms, but were negative in microscopic examination. In <it>P. falciparum</it>, IgG against the blood stage antigen in Group I (80.8%) was higher than in Group II (70.0%). In <it>P. vivax</it>, IgG against the blood stage antigen in Group I (53.8%) was higher than in Group II (41.7%). However, the positivity rate of the PvCSP VK210 subtype in Group II (40.0%) was higher than in Group I (23.1%). Similarly for the PvCSP VK247 subtype, Group II (21.7%) was higher than that for Group I (9.6%). A similar pattern was observed in the ELISA using Pvs25 and Pvs28: positive rates of Group II were higher than those for Group I. However, those differences were not shown significant in statistics.</p> <p>Conclusions</p> <p>The positive rates for blood stage antigens of <it>P. falciparum </it>were higher in Group I than in Group II, but the positive rates for antigens of other stages (PfLSA-1 and -3) showed opposite results. Similar to <it>P. falciparum</it>, the positive rate of pre-blood stage (CSP VK210 and 247 subtype) and post-blood stage (Pvs25 and 28) antigens of <it>P. vivax </it>were higher in Group II than in Group I. Therefore, sero-diagnosis is not helpful to discriminate between malaria patients and symptomatic individuals during the epidemic season in Myanmar.</p
Application of immortalized mouse dental papilla cells for tooth bioengineering
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Loss of Autophagy Diminishes Pancreatic β Cell Mass and Function with Resultant Hyperglycemia
SummaryAutophagy is a cellular degradation-recycling system for aggregated proteins and damaged organelles. Although dysregulated autophagy is implicated in various diseases including neurodegeneration, its role in pancreatic β cells and glucose homeostasis has not been described. We produced mice with β cell-specific deletion of Atg7 (autophagy-related 7). Atg7 mutant mice showed impaired glucose tolerance and decreased serum insulin level. β cell mass and pancreatic insulin content were reduced because of increased apoptosis and decreased proliferation of β cells. Physiological studies showed reduced basal and glucose-stimulated insulin secretion and impaired glucose-induced cytosolic Ca2+ transients in autophagy-deficient β cells. Morphologic analysis revealed accumulation of ubiquitinated protein aggregates colocalized with p62, which was accompanied by mitochondrial swelling, endoplasmic reticulum distension, and vacuolar changes in β cells. These results suggest that autophagy is necessary to maintain structure, mass and function of pancreatic β cells, and its impairment causes insulin deficiency and hyperglycemia because of abnormal turnover and function of cellular organelles
Prognostic value of European LeukemiaNet 2022 criteria and genomic clusters using machine learning in older adults with acute myeloid leukemia
This study aimed to validate the new European Leukemia Net (ELN) 2022 criteria for genetic risk stratification in older adults with acute myeloid leukemia (AML) and to determine the most likely set of clusters of similar cytogenetic and mutation properties correlated with survival outcomes in three treatment groups: intensive chemotherapy (IC), hypomethylating agents (HMA) alone, and HMA plus venetoclax (HMA/VEN). The study included 279 patients (aged ≥60 years) who received IC (N=131), HMA (N=76), and HMA/VEN (N=72) between July 2017 and October 2021. No significant differences were observed in survival among the groups according to ELN 2022 risk stratification. Unsupervised hierarchical clustering analysis identified nine genomic clusters (C1-9) with varying survival outcomes depending on treatment type. For example, C4 (predominant for core binding factor-AML) displayed a favorable prognosis in the IC group, but not in the HMA or HMA/VEN groups. The HMA/VEN group had better outcomes than the HMA group in many clusters (C1, 2, 3, and 5); however, the addition of VEN to HMA or IC did not improve the survival outcomes compared with those of HMA alone in C7 and C9 (predominant for -5, del(5q), -7, -17/abn(17p), complex karyotypes, and mutated TP53). The study highlights the limitations of ELN genetic risk stratification in older adults with AML. It emphasizes the need for a more comprehensive approach that considers co-occurring somatic mutations to guide treatment selection in older adults with AML
Prevalence of Clonorchis sinensis Metacercariae in Freshwater Fish from Three Latitudinal Regions of the Korean Peninsula
A large-scale survey was conducted to investigate the infection status of fresh water fishes with Clonorchis sinensis metacercariae (CsMc) in 3 wide regions, which were tentatively divided by latitudinal levels of the Korean peninsula. A total of 4,071 freshwater fishes were collected from 3 regions, i.e., northern (Gangwon-do: 1,543 fish), middle (Chungcheongbuk-do and Gyeongsangbuk-do: 1,167 fish), and southern areas (Jeollanam-do, Ulsan-si, and Gyeongsangnam-do: 1,361 fish). Each fish was examined by the artificial digestion method from 2003 to 2010. In northern areas, only 11 (0.7%) fish of 2 species, Pungtungia herzi and Squalidus japonicus coreanus from Hantan-gang, Cheolwon-gun, Gangwon-do were infected with av. 2.6 CsMc. In middle areas, 149 (12.8%) fish were infected with av. 164 CsMc. In southern areas, 538 (39.5%) fish were infected with av. 159 CsMc. In the analysis of endemicity in 3 regions with an index fish, P. herzi, 9 (6.2%) of 146 P. herzi from northern areas were infected with av. 2.8 CsMc. In middle areas, 34 (31.8%) of 107 P. herzi were infected with av. 215 CsMc, and in southern areas, 158 (92.9%) of 170 P. herzi were infected with av. 409 CsMc. From these results, it has been confirmed that the infection status of fish with CsMc is obviously different among the 3 latitudinal regions of the Korean peninsula with higher prevalence and burden in southern regions
Hierarchical Leak Detection and Localization Method in Natural Gas Pipeline Monitoring Sensor Networks
In light of the problems of low recognition efficiency, high false rates and poor localization accuracy in traditional pipeline security detection technology, this paper proposes a type of hierarchical leak detection and localization method for use in natural gas pipeline monitoring sensor networks. In the signal preprocessing phase, original monitoring signals are dealt with by wavelet transform technology to extract the single mode signals as well as characteristic parameters. In the initial recognition phase, a multi-classifier model based on SVM is constructed and characteristic parameters are sent as input vectors to the multi-classifier for initial recognition. In the final decision phase, an improved evidence combination rule is designed to integrate initial recognition results for final decisions. Furthermore, a weighted average localization algorithm based on time difference of arrival is introduced for determining the leak point’s position. Experimental results illustrate that this hierarchical pipeline leak detection and localization method could effectively improve the accuracy of the leak point localization and reduce the undetected rate as well as false alarm rate
Lumbar Plexopathy Caused by Metastatic Tumor, Which Was Mistaken for Postoperative Femoral Neuropathy
Surgical excision was performed on a 30-years old woman with a painful mass on her left thigh. The pathologic findings on the mass indicated fibromatosis. After the operation, she complained of allodynia and spontaneous pain at the operation site and ipsilateral lower leg. We treated her based on postoperative femoral neuropathy, but symptom was aggravated. We found a large liposarcoma in her left iliopsoas muscle which compressed the lumbar plexus. In conclusion, the cause of pain was lumbar plexopathy related to a mass in the left iliopsoas muscle. Prompt diagnosis of acute neuropathic pain after an operation is important and management must be based on exact causes
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