scholarly journals An APP ectodomain mutation outside of the Aβ domain promotes Aβ production in vitro and deposition in vivo

2021 ◽  
Vol 218 (6) ◽  
Author(s):  
Xulun Zhang ◽  
Can Martin Zhang ◽  
Dmitry Prokopenko ◽  
Yingxia Liang ◽  
Sherri Y. Zhen ◽  
...  
Keyword(s):  
Coding Region ◽  
Age And Gender ◽  
Single Nucleotide ◽  
Aβ Peptides ◽  
Transfected Cells ◽  
And Gender ◽  
App Gene ◽  
Aβ Production

Familial Alzheimer’s disease (FAD)–linked mutations in the APP gene occur either within the Aβ-coding region or immediately proximal and are located in exons 16 and 17, which encode Aβ peptides. We have identified an extremely rare, partially penetrant, single nucleotide variant (SNV), rs145081708, in APP that corresponds to a Ser198Pro substitution in exon 5. We now report that in stably transfected cells, expression of APP harboring the S198P mutation (APPS198P) leads to elevated production of Aβ peptides by an unconventional mechanism in which the folding and exit of APPS198P from the endoplasmic reticulum is accelerated. More importantly, coexpression of APP S198P and the FAD-linked PS1ΔE9 variant in the brains of male and female transgenic mice leads to elevated steady-state Aβ peptide levels and acceleration of Aβ deposition compared with age- and gender-matched mice expressing APP and PS1ΔE9. This is the first AD-linked mutation in APP present outside of exons 16 and 17 that enhances Aβ production and deposition.

Failure of Demonstrated Clinical Efficacy of Antibiotic-Bonded Continuous Ambulatory Peritoneal Dialysis (CAPD) Catheters

1990 ◽  
Vol 10 (1) ◽  
pp. 57-59 ◽  
Author(s):  
Stanley Z. Trooskin ◽  
Richard A. Harvey ◽  
T. w. J. Lennard ◽  
Ralph S. Greco
Keyword(s):  
Clinical Trial ◽  
Peritoneal Dialysis ◽  
Continuous Ambulatory Peritoneal Dialysis ◽  
Infectious Complications ◽  
Clinical Report ◽  
Age And Gender ◽  
And Gender ◽  
To Receive

Previous in vitro, in vivo, and a preliminary clinical report have demonstrated efficacy of noncovalently bonding antibiotics to the surface of continuous ambulatory peritoneal dialysis (CAPO) catheters in decreasing infectious complications. A larger prospective randomized clinical trial was completed. Eighty-six patients with chronic renal failure were enrolled in the study and randomized to receive either a surfactant treated or untreated control catheter. All catheters were soaked in cefoxitin at the time of insertion. Groups were comparable in terms of pre-existing illnesses, age, and gender. No differences were shown in the incidence of cathetertract infections, peritonitis or mechanical complications. There was also no differences in microbiologic culture results. Therefore, it is concluded that this clinical trial did not demonstrate a reduction in catheter-related infectious complications by antibiotic bonding.

scholarly journals Single nucleotide polymorphisms of the c-MYC gene’s relationship with formation of Burkitt’s lymphoma using bioinformatics analysis

2018 ◽  
Author(s):  
Anfal Osama Mohamed Sati ◽  
Weaam Anwer Osman ◽  
Enas Abdalla Mohammed Ahmedon ◽  
Safa Hamed Elneel Yousif ◽  
Enas Dawoud Khairi ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Homo Sapiens ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Nucleotide Polymorphisms ◽  
Coding Region ◽  
Single Nucleotide ◽  
Myc Gene

AbstractBurkitt’s lymphoma (BL) is an aggressive form of non-Hodgkin lymphoma, originates from germinal center B cells, MYC gene (MIM ID 190080) is an important proto-oncogene transcriptional factor encoding a nuclear phosphoprotein for central cellular processes. Dysregulated expression or function of c-MYC is one of the most common abnormalities in BL. This study focused on the investigation of the possible role of single nucleotide polymorphisms (SNPs) in MYC gene associated with formation of BL.MYC SNPs were obtained from NCBI database. SNPs in the coding region that are non-synonymous (nsSNPs) were analysed by multiple programs such as SIFT, Polyphen2, SNPs&GO, PHD-SNP and I-mutant. In this study, a total of 286 Homo sapiens SNPs were found. Roughly, forty-eight of them were deleterious and were furtherly investigated.Eight SNPs were considered most disease causing [rs4645959 (N26S), rs4645959 (N25S), rs141095253 (P396L), rs141095253 (P397L), rs150308400 (C233Y), rs150308400 (C147Y), rs150308400 (C147Y), rs150308400 (C148Y)] according to the four softwares used. Two of which have not been reported previously [rs4645959 (N25S), rs141095253 (P396L)]. SNPs analysis helps is a diagnostic marker which helps in diagnosing and consequently, finding therapeutics for clinical diseases. This is through SNPs genotyping arrays and other techniques. Thus, it is highly recommended to confirm the findings in this study in vivo and in vitro.

scholarly journals A novel hypoxic long noncoding RNA KB-1980E6.3 maintains breast cancer stem cell stemness via interacting with IGF2BP1 to facilitate c-Myc mRNA stability

Oncogene ◽  
2021 ◽  
Author(s):  
Pengpeng Zhu ◽  
Fang He ◽  
Yixuan Hou ◽  
Gang Tu ◽  
Qiao Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Underlying Mechanism ◽  
Rapid Expansion ◽  
Breast Cancer Patients ◽  
Coding Region ◽  
Signaling Axis

AbstractThe hostile hypoxic microenvironment takes primary responsibility for the rapid expansion of breast cancer tumors. However, the underlying mechanism is not fully understood. Here, using RNA sequencing (RNA-seq) analysis, we identified a hypoxia-induced long noncoding RNA (lncRNA) KB-1980E6.3, which is aberrantly upregulated in clinical breast cancer tissues and closely correlated with poor prognosis of breast cancer patients. The enhanced lncRNA KB-1980E6.3 facilitates breast cancer stem cells (BCSCs) self-renewal and tumorigenesis under hypoxic microenvironment both in vitro and in vivo. Mechanistically, lncRNA KB-1980E6.3 recruited insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) to form a lncRNA KB-1980E6.3/IGF2BP1/c-Myc signaling axis that retained the stability of c-Myc mRNA through increasing binding of IGF2BP1 with m6A-modified c-Myc coding region instability determinant (CRD) mRNA. In conclusion, we confirm that lncRNA KB-1980E6.3 maintains the stemness of BCSCs through lncRNA KB-1980E6.3/IGF2BP1/c-Myc axis and suggest that disrupting this axis might provide a new therapeutic target for refractory hypoxic tumors.

Influence of Age and Gender on the In Vitro Serum Protein Binding of Flecainide

1993 ◽  
Vol 28 (3) ◽  
pp. 259-264 ◽  
Author(s):  
R. Zordan ◽  
R. Padrini ◽  
V. Bernini ◽  
D. Piovan ◽  
M. Ferrari
Keyword(s):  
Protein Binding ◽  
Serum Protein ◽  
Serum Protein Binding ◽  
Age And Gender ◽  
And Gender

scholarly journals Impact of Body Site, Age, and Gender on the Collagen/Elastin Index by Noninvasive in vivo Vertical Two-Photon Microscopy

2017 ◽  
Vol 30 (5) ◽  
pp. 260-267 ◽  
Author(s):  
Carolin Czekalla ◽  
Karl-Heinz Schönborn ◽  
Nadine Döge ◽  
Sora Jung ◽  
Maxim E. Darvin ◽  
...  
Keyword(s):  
Body Site ◽  
Age And Gender ◽  
Two Photon Microscopy ◽  
Two Photon ◽  
And Gender

scholarly journals The closely related Drosophila sry beta and sry delta zinc finger proteins show differential embryonic expression and distinct patterns of binding sites on polytene chromosomes

Development ◽  
1990 ◽  
Vol 110 (1) ◽  
pp. 141-149 ◽  
Author(s):  
F. Payre ◽  
S. Noselli ◽  
V. Lefrere ◽  
A. Vincent
Keyword(s):  
Dna Binding ◽  
Binding Sites ◽  
Polytene Chromosomes ◽  
Duplication Event ◽  
Amino Acid Sequences ◽  
Evolutionary Divergence ◽  
Coding Region ◽  
Protein Coding

Serendipity (sry) beta (beta) and delta (delta) are two finger protein genes resulting from a duplication event. Comparison of their respective protein products shows interspersed blocks of conserved and divergent amino-acid sequences. The most extensively conserved region corresponds to the predicted DNA-binding domain which includes 6 contiguous fingers; no significant sequence conservation is found upstream and downstream of the protein-coding region. We have analysed the evolutionary divergence of the sry beta and delta proteins on two separate levels, their embryonic pattern of expression and their DNA-binding properties in vitro and in vivo. By using specific antibodies and transformant lines containing beta-galactosidase fusion genes, we show that the sry beta and sry delta proteins are maternally inherited and present in embryonic nuclei at the onset of zygotic transcription, suggesting that they are transcription factors involved in this process. Zygotic synthesis of the sry beta protein starts during nuclear division cycles 12–13, prior to cellularisation of the blastoderm, while the zygotic sry delta protein is not detectable before germ band extension (stage 10 embryos). Contrary to sry delta, the zygotic sry beta protein constitutes only a minor fraction of the total embryonic protein. The sry beta and delta proteins made in E. coli bind to DNA, with partly overlapping specificities. Their in vivo patterns of binding to DNA, visualised by immunostaining polytene chromosomes, differ both in the number and position of their binding sites. Thus changes in expression pattern and DNA-binding specificity have contributed to the evolution of the sry beta and delta genes.

scholarly journals STAT3 inhibitor mitigates cerebral amyloid angiopathy and parenchymal amyloid plaques while improving cognitive functions and brain networks

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Jogender Mehla ◽  
Itender Singh ◽  
Deepti Diwan ◽  
James W. Nelson ◽  
Molly Lawrence ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Human Brain ◽  
Cognitive Functions ◽  
Specific Inhibitor ◽  
Amyloid Angiopathy ◽  
In Vitro Experiments ◽  
Aβ Peptides ◽  
Cerebral Amyloid

AbstractPrevious reports indicate a potential role for signal transducer and activator of transcription 3 (STAT3) in amyloid-β (Aβ) processing and neuritic plaque pathogenesis. In the present study, the impact of STAT3 inhibition on cognition, cerebrovascular function, amyloid pathology, oxidative stress, and neuroinflammation was studied using in vitro and in vivo models of Alzheimer’s disease (AD)-related pathology. For in vitro experiments, human brain vascular smooth muscle cells (HBVSMC) and human brain microvascular endothelial cells (HBMEC) were used, and these cultured cells were exposed to Aβ peptides followed by measurement of activated forms of STAT3 expression and reactive oxygen species (ROS) generation. Further, 6 months old 5XFAD/APOE4 (5XE4) mice and age-matched negative littermates were used for in vivo experiments. These mice were treated with STAT3 specific inhibitor, LLL-12 for 2 months followed by neurobehavioral and histopathological assessment. In vitro experiments showed exposure of cerebrovascular cells to Aβ peptides upregulated activated forms of STAT3 and produced STAT3-mediated vascular oxidative stress. 5XE4 mice treated with the STAT3-specific inhibitor (LLL-12) improved cognitive functions and functional connectivity and augmented cerebral blood flow. These functional improvements were associated with a reduction in neuritic plaques, cerebral amyloid angiopathy (CAA), oxidative stress, and neuroinflammation. Reduction in amyloid precursor protein (APP) processing and attenuation of oxidative modification of lipoprotein receptor related protein-1 (LRP-1) were identified as potential underlying mechanisms. These results demonstrate the broad impact of STAT3 on cognitive functions, parenchymal and vascular amyloid pathology and highlight the therapeutic potential of STAT3 specific inhibition for treatment of AD and CAA.

Lack of association between delayed tooth emergence and single nucleotide polymorphisms in estrogen receptors

2021 ◽  
Vol 32 (6) ◽  
pp. 107-114
Author(s):  
Isabela Ribeiro Madalena ◽  
Caio Luiz Bitencourt Reis ◽  
Daniela Silva Barroso de Oliveira ◽  
Giovana Daniela Pecharki ◽  
Paula Cristina Trevilatto ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Oral Cavity ◽  
Estrogen Receptors ◽  
Permanent Tooth ◽  
Genotype Distribution ◽  
Nucleotide Polymorphisms ◽  
Age And Gender ◽  
Single Nucleotide ◽  
And Gender ◽  
Tooth Emergence

Abstract The purpose of the study was to investigate the association between single nucleotide polymorphisms (SNPs) in genes encoding estrogen receptors (ESR1 and ESR2, respectively) and delayed tooth emergence (DTE). This cross-sectional study was composed of biological unrelated children of both sexes, age ranging from 11 to 13 years old. DTE was defined when the successor primary tooth was still present in the oral cavity after its exfoliation time or the absence of the permanent tooth emergence into the oral cavity. Children were diagnosed with DTE when they had at least one delayed permanent tooth, according to age of exfoliation of each tooth proposed by The American Dental Association. Genomic DNA from saliva was used to evaluate the SNPs in ESR1 (rs9340799 and rs2234693) and ESR2 (rs1256049 and rs4986938) using Real-Time PCR. Chi-square or Fisher exact tests and Logistic Regression adjusted by age and gender were performed. SNP-SNP interaction was accessed by multifactor dimensionality reduction (MDR) analysis also adjusted by gender and age. The established alpha of this study was 5%. Among 537 included children, 296 (55%) were in the “DTE” group and the 241 (45%) were in the “Control” group. Age and gender were not statistically different among the groups (p>0.05). Genotype distribution of the SNPs rs9340799, rs2234693, rs1256049 and rs4986938 were not associated with DTE (p> 0.05). The models elected by MDR were not statistically significant either. Conclusions: The studied SNPs in ESR1 and ESR2 were not associated with permanent DTE.

scholarly journals Human C5-specific single-chain variable fragment ameliorates brain injury in a model of NMOSD

2019 ◽  
Vol 6 (3) ◽  
pp. e561 ◽  
Author(s):  
Wenli Zhu ◽  
Zhen Wang ◽  
Suying Hu ◽  
Ye Gong ◽  
Yuanchu Liu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Phage Display ◽  
Membrane Attack Complex ◽  
Single Chain ◽  
Inflammatory Infiltration ◽  
Transfected Cells ◽  
Complement Dependent Cytotoxicity ◽  
Test Specificity

ObjectiveUsing phage display, we sought to screen single-chain variable fragments (scFvs) against complement C5 to treat neuromyelitis optica spectrum disorder (NMOSD).MethodsAfter 5 rounds of phage display, we isolated individual clones and identified phage clones specifically binding to C5 using ELISA. Using aquaporin-4 (AQP4)-transfected cells in vitro, we confirmed whether these scFvs prevented complement-dependent cytotoxicity (CDC) caused by the serum of patients with NMOSD and human complement (hC). We selected an NMOSD mouse model, in which intracerebral NMOSD immunoglobulin G (IgG) and hC injections induce NMOSD-like lesions in vivo.ResultsWe obtained scFvs to test specificity and blocking efficiency. The scFv C5B3 neutralized C5 in the complement activation pathway, which prevented AQP4-IgG–mediated CDC in AQP4-transfected cells. In an NMOSD mouse model, C5B3 prevented AQP4 and astrocyte loss, decreased demyelination, and reduced inflammatory infiltration and membrane attack complex formation in lesions.ConclusionsWe used phage display to screen C5B3 against C5, which was effective in inhibiting cytotoxicity in vitro and preventing CNS pathology in vivo.

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