134 research outputs found
Heparan Sulfate as a Therapeutic Target in Tauopathies: Insights From Zebrafish
Microtubule-associated protein tau (MAPT) hyperphosphorylation and aggregation, are two hallmarks of a family of neurodegenerative disorders collectively referred to as tauopathies. In many tauopathies, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) and Pick’s disease, tau aggregates are found associated with highly sulfated polysaccharides known as heparan sulfates (HSs). In AD, amyloid beta (Aβ) peptide aggregates associated with HS are also characteristic of disease. Heparin, an HS analog, promotes misfolding, hyperphosphorylation and aggregation of tau protein in vitro. HS also provides cell surface receptors for attachment and uptake of tau seeds, enabling their propagation. These findings point to HS-tau interactions as potential therapeutic targets in tauopathies. The zebrafish genome contains genes paralogous to MAPT, genes orthologous to HS biosynthetic and chain modifier enzymes, and other genes implicated in AD. The nervous system in the zebrafish bears anatomical and chemical similarities to that in humans. These homologies, together with numerous technical advantages, make zebrafish a valuable model for investigating basic mechanisms in tauopathies and identifying therapeutic targets. Here, we comprehensively review current knowledge on the role of HSs in tau pathology and HS-targeting therapeutic approaches. We also discuss novel insights from zebrafish suggesting a role for HS 3-O-sulfated motifs in tau pathology and establishing HS antagonists as potential preventive agents or therapies for tauopathies
Antimicrobial susceptibility and distribution of TEM and CTX-M genes among ESBL-producing Klebsiella pneumoniae and Pseudomonas aeruginosa causing urinary tract infection
Background: Extended spectrum beta lactamases (ESBLs) have been observed in nearly all the species of family Enterobacteriaceae. The enzymes are plasmid mediated and are derived from broad-spectrum beta lactamase TEM and CTX-M by a limited number of mutations. This study was undertaken to characterize ESBL producers among Klebsiella pneumoniae and Pseudomonas aeruginosa by PCR, which were initially screened by phenotypic method. Materials and Methods: A cross-sectional study was performed to evaluate 180 strains (30 K. pneumoniae and 150 P. aeruginosa) isolated from urine culture of hospitalized patients (Amir Al-Momenin Hospital, Zabol, south-eastern Iran) suffered from urinary tract infections during a period of six months. The prevalence of ESBL producing K. pneumoniae and P. aeruginosa was evaluated by disk diffusion test and polymerase chain reaction (PCR) by detecting TEM and CTX-M gene. Results: The results of the study revealed that the prevalence of ESBL producing P. aeruginosa and K. pneumoniae by disk diffusion test was 13.3% for P. aeruginosa and 66.6% for K. pneumoniae. Seventy five percent and 65% of K. pneumoniae harboured the gene TEM and CTX-M, respectively. Forty five percent of P. aeruginosa isolates harboured the gene TEM but none of them demonstrated the gene CTX-M using PCR method. Conclusion: ESBL producing P. aeruginosa and K. pneumoniae isolates showed a high prevalence in this study. Therefore it seems that continuous surveillance is essential to monitor the ESBLs producing microorganisms in hospitals and community
Tau Hyperphosphorylation and Oxidative Stress, a Critical Vicious Circle in Neurodegenerative Tauopathies?
Goblet Cell Tumors of the Appendix: Clinical & Molecular Features
View full abstracthttps://openworks.mdanderson.org/leading-edge/1047/thumbnail.jp
Utility of plasma tumor marker levels in management of patients with appendiceal adenocarcinoma
View full abstracthttps://openworks.mdanderson.org/leading-edge/1049/thumbnail.jp
HS3ST2 expression is critical for the abnormal phosphorylation of tau in Alzheimer's disease-related tau pathology
Heparan sulphate (glucosamine) 3-O-sulphotransferase 2 (HS3ST2, also known as 3OST2) is an enzyme predominantly expressed in neurons wherein it generates rare 3-O-sulphated domains of unknown functions in heparan sulphates. in Alzheimer's disease, heparan sulphates accumulate at the intracellular level in disease neurons where they co-localize with the neurofibrillary pathology, while they persist at the neuronal cell membrane in normal brain. However, it is unknown whether HS3ST2 and its 3-O-sulphated heparan sulphate products are involved in the mechanisms leading to the abnormal phosphorylation of tau in Alzheimer's disease and related tauopathies. Here, we first measured the transcript levels of all human heparan sulphate sulphotransferases in hippocampus of Alzheimer's disease (n = 8; 76.8 +/- 3.5 years old) and found increased expression of HS3ST2 (P < 0.001) compared with control brain (n = 8; 67.8 +/- 2.9 years old). Then, to investigate whether the membrane-associated 3-O-sulphated heparan sulphates translocate to the intracellular level under pathological conditions, we used two cell models of tauopathy in neuro-differentiated SH-SY5Y cells: a tau mutation-dependent model in cells expressing human tau carrying the P-301L mutation hTau P-301L, and a tau mutation-independent model in where tau hyperphosphorylation is induced by oxidative stress. Confocal microscopy, fluorescence resonance energy transfer, and western blot analyses showed that 3-O-sulphated heparan sulphates can be internalized into cells where they interact with tau, promoting its abnormal phosphorylation, but not that of p38 or NF-kappa B p65. We showed, in vitro, that the 3-O-sulphated heparan sulphates bind to tau, but not to GSK3B, protein kinase A or protein phosphatase 2, inducing its abnormal phosphorylation. Finally, we demonstrated in a zebrafish model of tauopathy expressing the hTau P-301L, that inhibiting hs3st2 (also known as 3ost2) expression results in a strong inhibition of the abnormally phosphorylated tau epitopes in brain and in spinal cord, leading to a complete recovery of motor neuronal axons length (n = 25; P < 0.005) and of the animal motor response to touching stimuli (n = 150; P < 0.005). Our findings indicate that HS3ST2 centrally participates to the molecular mechanisms leading the abnormal phosphorylation of tau. By interacting with tau at the intracellular level, the 3-O-sulphated heparan sulphates produced by HS3ST2 might act as molecular chaperones allowing the abnormal phosphorylation of tau. We propose HS3ST2 as a novel therapeutic target for Alzheimer's disease.Association France Alzheimer & Maladies ApparenteesSATT Idf InnovCONACyT, MexicoFrench Ministry of Higher Education and ResearchInstitute de Recherche ServierUniv Paris Est, CNRS, Lab Cell Growth Tissue Repair & Regenerat CRRET, UPEC,EA 4397,ERL 9215, F-94000 Creteil, FranceUPMC, Univ Paris 04, Inst Cerveau & Moelle Epiniere, CNRS,UMR 7225,INSERM,U1127,UM75, Paris, FranceHop Robert Debre, INSERM, UMR 1141, F-75019 Paris, FranceSorbonne Paris Cite, Univ Paris Diderot, Paris, FranceUniversidade Federal de São Paulo, Aging & Neurodegenerat Dis Brain Bank Invest Lab, BR-04023062 São Paulo, BrazilGrp Hosp Pitie Salpetriere, Biochim Malad Neurometab, F-75013 Paris, FranceRadboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, NL-6525 ED Nijmegen, NetherlandsUniv Strasbourg, INSERM, U1119, FMTS, F-67000 Strasbourg, FranceUniversidade Federal de São Paulo, Aging & Neurodegenerat Dis Brain Bank Invest Lab, BR-04023062 São Paulo, BrazilCONACyT, Mexico: 308978Web of Scienc
Distinct phenotypes of three-repeat and four-repeat human tau in a transgenic model of tauopathy.
Tau exists as six closely related protein isoforms in the adult human brain. These are generated from alternative splicing of a single mRNA transcript and they differ in the absence or presence of two N-terminal and three or four microtubule binding domains. Typically all six isoforms have been considered functionally similar. However, their differential involvement in particular tauopathies raises the possibility that there may be isoform-specific differences in physiological function and pathological role. To explore this, we have compared the phenotypes induced by the 0N3R and 0N4R isoforms in Drosophila. Expression of the 3R isoform causes more profound axonal transport defects and locomotor impairments, culminating in a shorter lifespan than the 4R isoform. In contrast, the 4R isoform leads to greater neurodegeneration and impairments in learning and memory. Furthermore, the phosphorylation patterns of the two isoforms are distinct, as is their ability to induce oxidative stress. These differences are not consequent to different expression levels and are suggestive of bona fide physiological differences in isoform biology and pathological potential. They may therefore explain isoform-specific mechanisms of tau-toxicity and the differential susceptibility of brain regions to different tauopathies
The Bandim TBscore – reliability, further development, and evaluation of potential uses
Background: The tuberculosis (TB) case detection rate has stagnated at 60% due to disorganized case finding and insensitivity of sputum smear microscopy. Of the identified TB cases, 4% die while being treated, monitored with tools that insufficiently predict failure/mortality. Objective: To explore the TBscore, a recently proposed clinical severity measure for pulmonary TB (PTB) patients, and to refine, validate, and investigate its place in case finding. Design: The TBscore's inter-observer agreement was assessed and compared to the Karnofsky Performance Score (KPS) (paper I). The TBscore's variables underlying constructs were assessed, sorting out unrelated items, proposing a more easily assessable TBscoreII, which was validated internally and externally (paper II). Finally, TBscore and TBscoreII's place in PTB-screening was examined in paper III. Results: The inter-observer variability when grading PTB patients into severity classes was moderate for both TBscore (κ
W=0.52, 95% CI 0.46–0.56) and KPS (κ
W=0.49, 95% CI 0.33–0.65). KPS was influenced by HIV status, whereas TBscore was unaffected by it. In paper II, proposed TBscoreII was validated internally, in Guinea-Bissau, and externally, in Ethiopia. In both settings, a failure to bring down the score by ≥25% from baseline to 2 months of treatment predicted subsequent failure (p=0.007). Finally, in paper III, TBscore and TBscoreII were assessed in health-care-seeking adults and found to be higher in PTB-diagnosed patients, 4.9 (95% CI 4.6–5.2) and 3.9 (95% CI 3.8–4.0), respectively, versus patients not diagnosed with PTB, 3.0 (95% CI 2.7–3.2) and 2.4 (95% CI 2.3–2.5), respectively. Had we referred only patients with cough >2 weeks to sputum smear, we would have missed 32.1% of the smear confirmed cases in our cohort. A TBscoreII>=2 missed 8.6%. Conclusions: TBscore and TBscoreII are useful monitoring tools for PTB patients on treatment, as they could fill the void which currently exists in risk grading of patients. They may also have a role in PTB screening; however, this requires our findings to be repeated elsewhere
- …