Non-human primates are valuable for modelling human disorders and for developing therapeutic strategies; however, little work has been reported in establishing transgenic non-human primate models of human diseases. Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor impairment, cognitive deterioration and psychiatric disturbances followed by death within 10-15 years of the onset of the symptoms 1-4 . HD is caused by the expansion of cytosineadenine-guanine (CAG, translated into glutamine) trinucleotide repeats in the first exon of the human huntingtin (HTT) gene 5 . Mutant HTT with expanded polyglutamine (polyQ) is widely expressed in the brain and peripheral tissues 2,6 , but causes selective neurodegeneration that is most prominent in the striatum and cortex of the brain. Although rodent models of HD have been developed, these models do not satisfactorily parallel the brain changes and behavioural features observed in HD patients. Because of the close physiological 7 , neurological and genetic similarities 8,9 between humans and higher primates, monkeys can serve as very useful models for understanding human physiology and diseases 10,11 . Here we report our progress in developing a transgenic model of HD in a rhesus macaque that expresses polyglutamine-expanded HTT. Hallmark features of HD, including nuclear inclusions and neuropil aggregates, were observed in the brains of the HD transgenic monkeys. Additionally, the transgenic monkeys showed important clinical features Correspondence to: Anthony W. S. Chan.Author Information Reprints and permissions information is available at www.nature.com/reprints. Correspondence and requests for materials should be addressed to A.W.S.C. (achan@genetics.emory.edu).. * These authors contributed equally to this work. Author Contributions S.-H.Y. carried out assisted reproductive technique (ART) in monkeys, viral gene transfer, construct design and molecular analysis; P.-H.C., construct design and evaluation; K.P.-N., ART in monkeys; H.B., animal management; behavioural testing and all animal procedures; K.L., animal care and behavioural testing; E.C.H.C., molecular analysis; J.-J.Y., preparation of high titre lentiviruses; B.S., J.L. and Z.H.F., neuropathological analysis; J.O., surgical procedures and animal care; Y.S., neuropathological analysis; J.B., design of behavioural and cognitive testing; S.M.Z., experimental design and manuscript preparation; S.H.L. and X.J.-L., construct design, analysis and manuscript preparation; A.W.S.C., ART in monkey, viral gene transfer, experimental design, construct design, molecular analysis and manuscript preparation. We injected 130 mature rhesus oocytes with high titre lentiviruses expressing exon 1 of the human HTT gene with 84 CAG repeats (HTT-84Q; Fig. 1c) and lentiviruses expressing the green fluorescent protein (GFP) gene (Fig. 1c), under the control of the human polyubiquitin-C promoter, into the perivitelline space. After fertilization by intracytoplasmic sperm injecti...
Cumulative evidence indicates that breast cancer-associated gene 1 (BRCA1) participates in DNA damage repair and cell-cycle checkpoint control, serving as a tumor susceptibility gene to maintain the global genomic stability. However, whether BRCA1 has a direct role in cell proliferation and differentiation, two key biological functions in tumorigenesis, remains unclear. Here we demonstrate BRCA1 mediates differentiation of mammary epithelial cell (MEC) for acinus formation by using the in vitro 3D culture system. Reduction of BRCA1 in MEC by RNA interference impairs the acinus formation but enhances proliferation. Such aberrations can be rescued by expression of wild-type BRCA1 as well as a mutant at the RAD50-binding domain but not at the C-terminal BRCT domain, suggesting that the C-terminal BRCT domain has a critical role in these processes. Consistently, depletion of BRCA1 up-regulates the gene expression for proliferation but down-regulates that for differentiation. Moreover, application of the medium conditioned by differentiating normal MEC can reverse the phenotypes of differentiation-defective breast cancer cells bearing reduced BRCA1 functions. Our observation implies BRCA1 is involved in secretion of certain paracrine͞autocrine factors that induce MEC differentiation in response to extracellular matrix signals, providing, in part, an explanation for the etiological basis of either sporadic or familial breast cancer due to the loss or reduction of BRCA1.breast cancer ͉ tumor suppressor ͉ 3D culture ͉ matrix gel M utations in the breast cancer susceptibility gene breast cancer-associated gene 1 (BRCA1) account for up to half of hereditary breast cancer cases (1, 2) and almost all hereditary breast and ovarian cancer cases (3). Also, decreased BRCA1 expression is often found during sporadic breast cancer progression (4). Despite that a tissue-specific role of BRCA1 in breast and ovary is speculated (3), the cumulated evidence primarily converges on its universal functions, DNA damage repair, cell-cycle checkpoint control, and transcriptional regulation, to maintain genomic stability (3).The BRCA1 protein encompasses distinctive modules to interact with various proteins of diverse functions (5, 6). The N terminus possesses a RING finger domain, which dimerizes with BARD1 to exhibit ubiquitin ligase activity (5). The central region possesses two nuclear localization signals (5) and interacts with the DNA damage repair complex RAD50͞MRE11͞NBS1, transcription repressor ZBRK1, and BRCA2 (3, 6, 7). The C terminus possesses two tandem repeats of the BRCT motif, which is commonly found in DNA repair proteins (5) and interacts with CtIP, HDAC, and BACH1 (6,8,9). Loss of BRCA1 function leads to genomic instability, which diverges into two consequences (10). One is to trigger cell cycle arrest and apoptosis through activation of p53 (10). Alternatively, BRCA1 deficiency perturbs the chromosomal integrity (11) and increases the mutation rate of other genes (10). Breast tumors from the BRCA1 germ-line mutation carrie...
The current study retro specti vely review ed the cases of 68 patient s who had undergone total laryn gectomy and tracheoesophageal pun cture (TEP) ove r a lo-year period. Fifty-one patients under went p rimary TEP and i 7 underw ent seconda ry TEP. Nearly 80% of pati ents who received TEP at the time of laryngectomy achieved excellent voice quality perceptu ally. in contrast, only 50% of secondary TEP patients achieved excellent voice ratings. This diff erence was statistically robust (p = 0.03). A lthough both surgical and prosthesis-related comp lications occurred more fre quently fo llo wing prim ary TEp, statistically significant differences were not achieved. Neith er pre-nor p ostoperati ve radi oth erapy had any effe ct on voice restoration or complication rates. Based on thes e data, p rimary TEP may be pref erable fo r several reasons, ineluding a greater likelihood ofsuccessful voice restorati on, a sho rter duration ofpostoperat ive aphonia, and the elimination ofthe needf or a second opera tion and interim tube f eedin gs.
Despite the importance of intestinal stem cells (ISCs) for epithelial maintenance, there is limited understanding of how immune-mediated damage affects ISCs and their niche. We found that stem cell compartment injury is a shared feature of both alloreactive and autoreactive intestinal immunopathology, reducing ISCs and impairing their recovery in T cell–mediated injury models. Although imaging revealed few T cells near the stem cell compartment in healthy mice, donor T cells infiltrating the intestinal mucosa after allogeneic bone marrow transplantation (BMT) primarily localized to the crypt region lamina propria. Further modeling with ex vivo epithelial cultures indicated ISC depletion and impaired human as well as murine organoid survival upon coculture with activated T cells, and screening of effector pathways identified interferon-γ (IFNγ) as a principal mediator of ISC compartment damage. IFNγ induced JAK1- and STAT1-dependent toxicity, initiating a proapoptotic gene expression program and stem cell death. BMT with IFNγ–deficient donor T cells, with recipients lacking the IFNγ receptor (IFNγR) specifically in the intestinal epithelium, and with pharmacologic inhibition of JAK signaling all resulted in protection of the stem cell compartment. In addition, epithelial cultures with Paneth cell–deficient organoids, IFNγR-deficient Paneth cells, IFNγR–deficient ISCs, and purified stem cell colonies all indicated direct targeting of the ISCs that was not dependent on injury to the Paneth cell niche. Dysregulated T cell activation and IFNγ production are thus potent mediators of ISC injury, and blockade of JAK/STAT signaling within target tissue stem cells can prevent this T cell–mediated pathology.
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