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#38014339 
2023/11/14
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Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer's Disease Model.
Despite strong evidence supporting the involvement of both apolipoprotein E4 (APOE4) and microglia in Alzheimer's Disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-driven AD pathogenesis remain elusive. Here, we examined such effects utilizing microglial depletion in a chimeric model with human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) induced pluripotent stem cell (iPSC)-derived human neurons into the hippocampus of human APOE3 or APOE4 knock-in mice, and depleted microglia in half the chimeric mice. We found that both neuronal APOE and microglial presence were important for the formation of Aβ and tau pathologies in an APOE isoform-dependent manner (APOE4 > APOE3). Single-cell RNA-sequencing analysis identified two pro-inflammatory microglial subtypes with high MHC-II gene expression that are enriched in chimeric mice with human APOE4 neuron transplants. These findings highlight the concerted roles of neuronal APOE, especially APOE4, and microglia in AD pathogenesis.Antara Rao, Nuo Chen, Min Joo Kim, Jessica Blumenfeld, Oscar Yip, Yanxia Hao, Zherui Liang, Maxine R Nelson, Nicole Koutsodendris, Brian Grone, Leo Ding, Seo Yeon Yoon, Patrick Arriola, Yadong Huang
1491 related Products with: Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer's Disease Model.
96 tests96 tests96 tests96 tests4 Membranes/Box16 Arrays/Slide100 μg4 Arrays/Slide50ul100 μg8 Sample Kit
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#38014319 2023/11/14
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The heparin-binding domain of VEGF165 directly binds to integrin αvβ3 and plays a critical role in signaling.
VEGF-A is a key cytokine in tumor angiogenesis and a major therapeutic target for cancer. VEGF165 is the predominant isoform and is the most potent angiogenesis stimulant. VEGFR2/KDR domains 2 and 3 (D2D3) bind to the N-terminal domain (NTD, residues 1-110) of VEGF165. Since removal of the heparin-binding domain (HBD, residues 111-165) markedly reduced the mitogenic activity of VEGF165, it has been proposed that the HBD plays a critical role in the mitogenicity of VEGF165. Integrin αvβ3 has been shown to bind to VEGF165, but the role of integrin αvβ3 in VEGF165 signaling are unclear. Here we describe that αvβ3 specifically bound to the isolated HBD, but not to the NTD. We identified several critical amino acid residues in HBD for integrin binding (Arg-123, Arg-124, Lys-125, Lys-140, Arg-145, and Arg-149) by docking simulation and mutagenesis, and generated full-length VEGF165 that is defective in integrin binding by including mutations in the HBD. The full-length VEGF165 mutant defective in integrin binding (R123A/R124A/K125A/K140A/R145A/R149A) was defective in ERK1/2 phosphorylation, integrin β3 phosphorylation, and KDR phosphorylation, although the mutation did not affect KDR binding to VEGF165. We propose a model in which VEGF165 induces KDR (through NTD)-VEGF165 (through HBD)-integrin αvβ3 ternary complex formation on the cell surface and this process is critically involved in potent mitogenicity of VEGF165.Yoko K Takada, Jessica Yu, Xiaojin Ye, Chun-Yi Wu, Brunie H Felding, Masaaki Fujita, Yoshikazu Takada
1696 related Products with: The heparin-binding domain of VEGF165 directly binds to integrin αvβ3 and plays a critical role in signaling.
100 UG100ug Lyophilized50 ug 100ug Lyophilized100ug1000 TESTS/0.65ml100ug Lyophilized100ug
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#38014225 2023/11/13
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Molecular and Cellular Context Influences SCN8A Variant Function.
Pathogenic variants in , which encodes the voltage-gated sodium (Na ) channel Na 1.6, are associated with neurodevelopmental disorders including epileptic encephalopathy. Previous approaches to determine variant function may be confounded by the use of a neonatal-expressed alternatively spliced isoform of Na 1.6 (Na 1.6N), and engineered mutations to render the channel tetrodotoxin (TTX) resistant. In this study, we investigated the impact of alternative splicing on variant function by comparing the functional attributes of 15 variants expressed in two developmentally regulated splice isoforms (Na 1.6N, Na 1.6A). We employed automated patch clamp recording to enhance throughput, and developed a novel neuronal cell line (ND7/LoNav) with low levels of endogenous Na current to obviate the need for TTX-resistance mutations. Expression of Na 1.6N or Na 1.6A in ND7/LoNav cells generated Na currents that differed significantly in voltage-dependence of activation and inactivation. TTX-resistant versions of both isoforms exhibited significant functional differences compared to the corresponding wild-type (WT) channels. We demonstrated that many of the 15 disease-associated variants studied exhibited isoform-dependent functional effects, and that many of the studied variants exhibited functional properties that were not easily classified as either gain- or loss-of-function. Our work illustrates the value of considering molecular and cellular context when investigating variants.Carlos G Vanoye, Tatiana V Abramova, Jean-Marc DeKeyser, Nora F Ghabra, Madeleine J Oudin, Christopher B Burge, Ingo Helbig, Christopher H Thompson, Alfred L George
1703 related Products with: Molecular and Cellular Context Influences SCN8A Variant Function.
10 mg200.00 ug 6 ml Ready-to-use 100 mg100ug 100ul200ul0.1 mg100 mg1 ml
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#38014143 2023/11/15
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The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.
Variants in the gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson's disease (PD). However, neither the specific variants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis. Previous studies have found that catB can cleave monomeric and fibrillar alpha-synuclein, a key protein involved in the pathogenesis of PD that accumulates in the brains of PD patients. However, truncated synuclein isoforms generated by catB cleavage have an increased propensity to aggregate. Thus, catB activity could potentially contribute to lysosomal degradation and clearance of pathogenic alpha synuclein from the cell, but also has the potential of enhancing synuclein pathology by generating aggregation-prone truncations. Therefore, the mechanisms linking catB to PD pathophysiology remain to be clarified. Here, we conducted genetic analyses of the association between common and rare variants and risk of PD. We then used genetic and pharmacological approaches to manipulate catB expression and function in cell lines and induced pluripotent stem cell-derived dopaminergic neurons and assessed lysosomal activity and the handling of aggregated synuclein fibrils. We find that catB inhibition impairs autophagy, reduces glucocerebrosidase (encoded by ) activity, and leads to an accumulation of lysosomal content. In cell lines, reduction of gene expression impairs the degradation of pre-formed alpha-synuclein fibrils, whereas gene activation enhances fibril clearance. In midbrain organoids and dopaminergic neurons treated with alpha-synuclein fibrils, catB inhibition potentiates the formation of inclusions which stain positively for phosphorylated alpha-synuclein. These results indicate that the reduction of catB function negatively impacts lysosomal pathways associated with PD pathogenesis, while conversely catB activation could promote the clearance of pathogenic alpha-synuclein.Jace Jones-Tabah, Kathy He, Konstantin Senkevich, Nathan Karpilovsky, Ghislaine Deyab, Yuting Cousineau, Daria Nikanorova, Taylor Goldsmith, Esther Del Cid Pellitero, Carol X-Q Chen, Wen Luo, Zhipeng You, Narges Abdian, Isabella Pietrantonio, Thomas Goiran, Jamil Ahmad, Jennifer A Ruskey, Farnaz Asayesh, Dan Spiegelman, Cheryl Waters, Oury Monchi, Yves Dauvilliers, Nicolas Dupré, Irina Miliukhina, Alla Timofeeva, Anton Emelyanov, Sofya Pchelina, Lior Greenbaum, Sharon Hassin-Baer, Roy N Alcalay, Austen Milnerwood, Thomas M Durcan, Ziv Gan-Or, Edward A Fon
2349 related Products with: The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.
96 tests96 tests100ug196 tests
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#38014115 2023/11/17
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Protein-lipid interactions drive presynaptic assembly upstream of cell adhesion molecules.
Textbook models of synaptogenesis position cell adhesion molecules such as neurexin as initiators of synapse assembly. Here we discover a mechanism for presynaptic assembly that occurs prior to neurexin recruitment, while supporting a role for neurexin in synapse maintenance. We find that the cytosolic active zone scaffold SYD-1 interacts with membrane phospholipids to promote active zone protein clustering at the plasma membrane, and subsequently recruits neurexin to stabilize those clusters. Employing molecular dynamics simulations to model intrinsic interactions between SYD-1 and lipid bilayers followed by tests of these predictions, we find that PIP -interacting residues in SYD-1's C2 and PDZ domains are redundantly necessary for proper active zone assembly. Finally, we propose that the uncharacterized yet evolutionarily conserved short γ isoform of neurexin represents a minimal neurexin sequence that can stabilize previously assembled presynaptic clusters, potentially a core function of this critical protein.Elisa B Frankel, Araven Tiroumalechetty, Parise S Henry, Zhaoqian Su, Yinghao Wu, Peri T Kurshan
1703 related Products with: Protein-lipid interactions drive presynaptic assembly upstream of cell adhesion molecules.
96tests100ug Lyophilized100 100ug Lyophilized0.1 mg 100ul100ug Lyophilized100ug100ug Lyophilized100ug Lyophilized100ul
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#38014069 2023/11/14
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Aberrant splicing exonizes repeat expansion in ALS/FTD.
A nucleotide repeat expansion (NRE) in the first annotated intron of the gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While C9 NRE-containing RNAs can be translated into several toxic dipeptide repeat proteins, how an intronic NRE can assess the translation machinery in the cytoplasm remains unclear. By capturing and sequencing NRE-containing RNAs from patient-derived cells, we found that C9 NRE was exonized by the usage of downstream 5' splice sites and exported from the nucleus in a variety of spliced mRNA isoforms. aberrant splicing was substantially elevated in both C9 NRE motor neurons and human brain tissues. Furthermore, NREs above the pathological threshold were sufficient to activate cryptic splice sites in reporter mRNAs. In summary, our results revealed a crucial and potentially widespread role of repeat-induced aberrant splicing in the biogenesis, localization, and translation of NRE-containing RNAs.Suzhou Yang, Denethi Wijegunawardana, Udit Sheth, Austin M Veire, Juliana M S Salgado, Manasi Agrawal, Jeffrey Zhou, João D Pereira, Tania F Gendron, Junjie U Guo
1448 related Products with: Aberrant splicing exonizes repeat expansion in ALS/FTD.
100 μg100 μg0.1ml100ug Lyophilized100 μg96T100 μg1mg100ug
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#38012539 2023/11/27
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Tumour 63 protein (p63) in breast pathology: biology, immunohistochemistry, diagnostic applications, and pitfalls.
Tumour protein 63 (p63) is a transcription factor of the p53 gene family, encoded by the TP63 gene located at chromosome 3q28, which regulates the activity of genes involved in growth and development of the ectoderm and derived tissues. p63 protein is normally expressed in the nuclei of the basal cell layer of glandular organs, including breast, in squamous epithelium and in urothelium. p63 immunohistochemical (IHC) staining has several applications in diagnostic breast pathology. It is commonly used to demonstrate myoepithelial cells at the epithelial stromal interface to differentiate benign and in situ lesions from invasive carcinoma and to characterize and classify papillary lesions including the distinction of breast intraduct papilloma from skin hidradenoma. p63 IHC is also used to identify and profile lesions showing myoepithelial cell and/or squamous differentiation, e.g. adenomyoepithelioma, salivary gland-like tumours including adenoid cystic carcinoma, and metaplastic breast carcinoma including low-grade adenosquamous carcinoma. This article reviews the applications of p63 IHC in diagnostic breast pathology and outlines a practical approach to the diagnosis and characterization of breast lesions through the identification of normal and abnormal p63 protein expression. The biology of p63, the range of available antibodies with emphasis on staining specificity and sensitivity, and pitfalls in interpretation are also discussed. The TP63 gene in humans, which shows a specific genomic structure, resulting in either TAp63 (p63) isoform or ΔNp63 (p40) isoform. As illustrated in the figure, both isoforms contain a DNA-binding domain (Orange box) and an oligomerization domain (Grey box). TAp63 contains an N-terminal transactivation (TA) domain (Green box), while ΔNp63 has an alternative terminus (Yellow box). Antibodies against conventional pan-p63 (TP63) bind to the DNA binding domain common to both isoforms (TAp63 and p40) and does not distinguish between them. Antibodies against TAp63 bind to the N-terminal TA domain, while antibodies specific to ΔNp63 (p40) bind to the alternative terminus. Each isoform has variant isotypes (α, β, γ, δ, and ε).Rabab Alkhayyat, Areeg Abbas, Cecily M Quinn, Emad A Rakha
1810 related Products with: Tumour 63 protein (p63) in breast pathology: biology, immunohistochemistry, diagnostic applications, and pitfalls.
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#38012535 2023/11/27
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1,2,3-Triazole-based esters and carboxylic acids as nonclassical carbonic anhydrase inhibitors capable of cathepsin B inhibition.
Herein, we report the design and synthesis of a library of 28 new 1,2,3-triazole derivatives bearing carboxylic acid and ester moieties as dual inhibitors of carbonic anhydrase (CA) and cathepsin B enzymes. The synthesised compounds were assayed in vitro for their inhibition potential against four human CA (hCA) isoforms, I, II, IX and XII. The carboxylic acid derivatives displayed low micromolar inhibition against hCA II, IX and XII in contrast to the ester derivatives. Most of the target compounds showed poor inhibition against the hCA I isoform. 4-Fluorophenyl appended carboxylic acid derivative 6c was found to be the most potent inhibitor of hCA IX and hCA XII with a K value of 0.7 μM for both the isoforms. The newly synthesised compounds showed dual inhibition towards CA as well as cathepsin B. The ester derivatives exhibited higher % inhibition at 10 M concentration as compared with the corresponding carboxylic acid derivatives against cathepsin B. The results from in silico studies of the target compounds with the active site of cathepsin B were found in good correlation with the in vitro results. Moreover, two compounds, 5i and 6c, showed cytotoxic activity against A549 lung cancer cells, with IC values lower than 100 μM.Kiran Siwach, Manishita Rani, Lalit Vats, Simone Giovannuzzi, Avijit Kumar Paul, Mettle Brahma, Neetu Kumari, Mulaka Maruthi, Neera Raghav, Claudiu T Supuran, Pawan K Sharma
1095 related Products with: 1,2,3-Triazole-based esters and carboxylic acids as nonclassical carbonic anhydrase inhibitors capable of cathepsin B inhibition.
500 tests50 mg430 tests48 assays100tests100μl1 kit
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#38012420 2023/11/27
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Transcription start site choice diversifies mRNA isoforms and defines cancer cell behavior.
2249 related Products with: Transcription start site choice diversifies mRNA isoforms and defines cancer cell behavior.
-24 wells96TTwo 96-Well Microplate Ki
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#38012158 2023/11/27
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Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcripts by excessive ethanol drinking.
The underlying genetic and epigenetic mechanisms driving functional adaptations in neuronal excitability and excessive alcohol intake are poorly understood. Small-conductance Ca-activated K (K2 or SK) channels encoded by the KCNN family of genes have emerged from preclinical studies as a key contributor to alcohol-induced functional neuroadaptations in alcohol-drinking monkeys and alcohol-dependent mice. Here, this cross-species analysis focused on KCNN3 DNA methylation, gene expression, and single nucleotide polymorphisms, including alternative promoters in KCNN3, that could influence surface trafficking and function of K2 channels. Bisulfite sequencing analysis of the nucleus accumbens tissue from alcohol-drinking monkeys and alcohol-dependent mice revealed a differentially methylated region in exon 1A of KCNN3 that overlaps with a predicted promoter sequence. The hypermethylation of KCNN3 in the accumbens paralleled an increase in the expression of alternative transcripts that encode apamin-insensitive and dominant-negative K2 channel isoforms. A polymorphic repeat in macaque KCNN3 encoded by exon 1 did not correlate with alcohol drinking. At the protein level, K2.3 channel expression in the accumbens was significantly reduced in very heavy-drinking monkeys. Together, our cross-species findings on epigenetic dysregulation of KCNN3 represent a complex mechanism that utilizes alternative promoters to potentially impact the firing of accumbens neurons. Thus, these results provide support for hypermethylation of KCNN3 as a possible key molecular mechanism underlying harmful alcohol intake and alcohol use disorder.Patrick J Mulholland, Audrey E Padula, Larry J Wilhelm, Byung Park, Kathleen A Grant, Betsy M Ferguson, Rita Cervera-Juanes