OBJECTIVE:Gain-of-function (GOF) mutations in RHBDF2 cause tylosis. Patients present with hyperproliferative skin, and keratinocytes from tylosis patients' skin show an enhanced wound-healing phenotype. The curly bare mouse model of tylosis, carrying a GOF mutation in the Rhbdf2 gene (Rhbdf2 cub ), presents with epidermal hyperplasia and shows accelerated cutaneous wound-healing phenotype through enhanced secretion of the epidermal growth factor receptor family ligand amphiregulin. Despite these advances in our understanding of tylosis, key questions remain. For instance, it is not known whether the disease is skin-specific, whether the immune system or the surrounding microenvironment plays a role, and whether mouse genetic background influences the hyperproliferative-skin and wound-healing phenotypes observed in Rhbdf2 cub mice.RESULTS:We performed bone marrow transfers and reciprocal skin transplants and found that bone marrow transfer from C57BL/6 (B6)-Rhbdf2 cub/cub donor mice to B6 wildtype recipient mice failed to transfer the hyperproliferative-skin and wound-healing phenotypes in B6 mice. Furthermore, skin grafts from B6 mice to the dorsal skin of B6-Rhbdf2 cub/cub mice maintained the phenotype of the donor mice. To test the influence of mouse genetic background, we backcrossed Rhbdf2 cub onto the MRL/MpJ strain and found that the hyperproliferative-skin and wound-healing phenotypes caused by the Rhbdf2 cub mutation persisted on the MRL/MpJ strain.

Since the discovery of the "nude" mouse more than 40 years ago, investigators have attempted to model human tumor growth in immunodeficient mice. Here, we summarize how the field has advanced over the ensuing years owing to improvements in the murine recipients of human tumors. These improvements include the discovery of the scid mutation and development of targeted mutations in the recombination-activating genes 1 and 2 (Rag1(null), Rag2(null)) that severely cripple the adaptive immune response of the murine host. More recently, mice deficient in adaptive immunity have been crossed with mice bearing targeted mutations designed to weaken the innate immune system, ultimately leading to the development of immunodeficient mice bearing a targeted mutation in the gene encoding the interleukin 2 (IL2) receptor common γ chain (IL2rg(null), also known in humans as cytokine receptor common subunit γ). The IL2rg(null) mutation has been used to develop several immunodeficient strains of mice, including the NOD-scid IL2rg(null) (NSG) strain. Using NSG mice as human xenograft recipients, it is now possible to grow almost all types of primary human tumors in vivo, including most solid tumors and hematological malignancies that maintain characteristics of the primary tumor in the patient. Programs to optimize patient-specific therapy using patient-derived xenograft tumor growth in NSG mice have been established at several institutions, including The Jackson Laboratory. Moreover, NSG mice can be engrafted with functional human immune systems, permitting for the first time the potential to study primary human tumors in vivo in the presence of a human immune system.

Multiple sites can be used for the engraftment of primary human cells and tissues into murine hosts. For example, leukemias are usually best engrafted intravenously, but they can also be engrafted directly into the bone marrow cavity. Some solid tumors such as colon tumors grow successfully following subcutaneous engraftment, sometimes requiring provision of a Matrigel artificial basement membrane. In certain cases (e.g., human bladder cancer and ductal breast carcinoma), the use of the autochthonous site (bladder and mammary duct, respectively) is often most efficient, whereas the tumors can grow poorly when transplanted subcutaneously or heterochthonously. Here, we present a protocol for the surgical implantation of tissues under the kidney capsule. The kidney is especially suited for the transplantation of normal as well as malignant cells and tissues. It is very accessible, and transplanted tissues are well contained under the renal capsule in a highly vascularized site. Furthermore, the retroperitoneal location of the kidney, together with its separation from other organs, is advantageous both for imaging and biopsy.

Dilated cardiomyopathy (DCM) in A/J mice homozygous for the spontaneous thrombocytopenia and cardiomyopathy (trac) mutation results from a single base pair change in the Abcg5 gene. A similar mutation in humans causes sitosterolemia with high plant sterol levels, hypercholesterolemia, and early onset atherosclerosis. Analyses of CD3+ and Mac-3+ cells and stainable collagen in hearts showed inflammation and myocyte degeneration in A/J-trac/trac mice beginning postweaning and progressed to marked dilative and fibrosing cardiomyopathy by 140 days. Transmission electron microscopy (TEM) demonstrated myocyte vacuoles consistent with swollen endoplasmic reticulum (ER). Myocytes with cytoplasmic glycogen and irregular actinomyosin filament bundles formed mature intercalated disks with normal myocytes suggesting myocyte repair. A/J-trac/trac mice fed lifelong phytosterol-free diets did not develop cardiomyopathy. BALB/cByJ-trac/trac mice had lesser inflammatory infiltrates and later onset DCM. BALB/cByJ-trac/trac mice changed from normal to phytosterol-free diets had lesser T cell infiltrates but persistent monocyte infiltrates and equivalent fibrosis to mice on normal diets. B- and T-cell-deficient BALB/cBy-Rag1(null) trac/trac mice fed normal diets did not develop inflammatory infiltrates or DCM. We conclude that the trac/trac mouse has many features of inflammatory DCM and that the reversibility of myocardial T cell infiltration provides a novel model for investigating the progression of myocardial fibrosis.

“Hairpatches” (Hpt) is a naturally occurring, autosomal semi-dominant mouse mutation. Hpt/Hpt homozygotes die in utero, while Hpt/+ heterozygotes exhibit progressive renal failure accompanied by patchy alopecia. This mutation is a model for the rare human disorder “glomerulonephritis with sparse hair and telangiectases" (OMIM 137940). Fine mapping localized the Hpt locus to a 6.7 Mb region of Chromosome 4 containing 62 known genes. Quantitative real time PCR revealed differential expression for only one gene in the interval, T-cell acute lymphocytic leukemia 1 (Tal1), which was highly upregulated in the kidney and skin of Hpt/+ mice. Southern blot analysis of Hpt mutant DNA indicated a new EcoRI site in the Tal1 gene. High throughput sequencing identified an endogenous retroviral class II intracisternal A particle insertion in Tal1 intron 4. Our data suggests that the IAP insertion in Tal1 underlies the histopathological changes in the kidney by three weeks of age, and that glomerulosclerosis is a consequence of an initial developmental defect, progressing in severity over time. The Hairpatches mouse model allows an investigation into the effects of Tal1, a transcription factor characterized by complex regulation patterns, and its effects on renal disease.

Glioma is the one of the most lethal forms of human cancer. The most effective glioma therapy to date-surgery followed by radiation treatment-offers patients only modest benefits, as most patients do not survive more than five years following diagnosis due to glioma relapse 1,2. The discovery of cancer stem cells in human brain tumors holds promise for having an enormous impact on the development of novel therapeutic strategies for glioma 3. Cancer stem cells are defined by their ability both to self-renew and to differentiate, and are thought to be the only cells in a tumor that have the capacity to initiate new tumors 4. Glioma relapse following radiation therapy is thought to arise from resistance of glioma stem cells (GSCs) to therapy 5-10. In vivo, GSCs are shown to reside in a perivascular niche that is important for maintaining their stem cell-like characteristics 11-14. Central to the organization of the GSC niche are vascular endothelial cells 12. Existing evidence suggests that GSCs and their interaction with the vascular endothelial cells are important for tumor development, and identify GSCs and their interaction with endothelial cells as important therapeutic targets for glioma. The presence of GSCs is determined experimentally by their capability to initiate new tumors upon orthotopic transplantation 15. This is typically achieved by injecting a specific number of GBM cells isolated from human tumors into the brains of severely immuno-deficient mice, or of mouse GBM cells into the brains of congenic host mice. Assays for tumor growth are then performed following sufficient time to allow GSCs among the injected GBM cells to give rise to new tumors-typically several weeks or months. Hence, existing assays do not allow examination of the important pathological process of tumor initiation from single GSCs in vivo. Consequently, essential insights into the specific roles of GSCs and their interaction with the vascular endothelial cells in the early stages of tumor initiation are lacking. Such insights are critical for developing novel therapeutic strategies for glioma, and will have great implications for preventing glioma relapse in patients. Here we have adapted the PoRTS cranial window procedure 16and in vivo two-photon microscopy to allow visualization of tumor initiation from injected GBM cells in the brain of a live mouse. Our technique will pave the way for future efforts to elucidate the key signaling mechanisms between GSCs and vascular endothelial cells during glioma initiation.

Although researchers have yet to establish a link between muscular dystrophy (MD) and sarcomas in human patients, literature suggests that the MD genes dystrophin and dysferlin act as tumor suppressor genes in mouse models of MD. For instance, dystrophin-deficient mdx and dysferlin-deficient A/J mice, models of human Duchenne MD and limb-girdle MD type 2B, respectively, develop mixed sarcomas with variable penetrance and latency. To further establish the correlation between MD and sarcoma development, and to test whether a combined deletion of dystrophin and dysferlin exacerbates MD and augments the incidence of sarcomas, we generated dystrophin and dysferlin double mutant mice (STOCK-Dysf(prmd)Dmd(mdx-5Cv)). Not surprisingly, the double mutant mice develop severe MD symptoms and, moreover, develop rhabdomyosarcoma (RMS) at an average age of 12 months, with an incidence of >90%. Histological and immunohistochemical analyses, using a panel of antibodies against skeletal muscle cell proteins, electron microscopy, cytogenetics, and molecular analysis reveal that the double mutant mice develop RMS. The present finding bolsters the correlation between MD and sarcomas, and provides a model not only to examine the cellular origins but also to identify mechanisms and signal transduction pathways triggering development of RMS.

A saddle of duty and a bit of habitdrove me to Hebrew schoolevery Tuesday and Thursday afternoonto learn a new alphabetfor memorizing the ancient tribal ritesand horrible historical wrongs.During years of what seemed forced laborI sat sullen, clock-, cloud-, and crotch-watching.Now when I am even older than those ancientHebrew teachers I studiously ignored,I finally know three Hebrew lessons by heart.Hineni: as a leafless twig patiently awaits spring, listenfor God's voice. Hazaq: carry our heavy sacksof pain shoulder to shoulder and tell stories on the way.Sheheheyanu: at this lavish feast raise the first cupto our shy host.I even see why our sages call lovemakingon Shabbat a mitzvah. Then and thereI am fully present. We reach for each otherwith strong and strengthening arms,and God knowsevery vital organ singsthank you thank youthank you. Years ago, teaching The Waste Land, I began thinking about the three instructions in “What the Thunder Said” about how to escape the wasteland. What could be more ironic than beginning my Jewish spiritual journey with a noted anti-Semite's central poem? I teach the poem because it is important, but it is a poem in which I have little personal interest. Abstruse allusions to literature in Sanskrit, French, German, Italian, Latin, and ancient Greek—it arouses either self-satisfaction (if I catch any of the allusions) or self-criticism (when I don't). Neither response—“I am smart” or “I am dumb”—is what I seek in literature. So nothing could be more ironic than the truth that it was pondering those three edicts translated as give, sympathize, and control that began my own Jewish search.I decided that give in the poem means to give yourself to God, sympathize means to have sympathy for others, and control means to control negative parts of yourself. Then I saw that the three categories themselves—relationship to self, to others, and to God or the sacred—were clarifying and useful. That is: how I relate to myself (Eliot's “control”), how I relate to others (Eliot's “sympathy”), and how I relate to God (Eliot's “give oneself”).Beginning with these categories I began to formulate my own key words. My love of Hebrew scripture led me to think about these three areas in Jewish terms. There are, no doubt, many paths to wisdom, but Judaism is my path. Family holidays, temple music, Hebrew school three days a week as a child, my own parents' devotion to their temple—of course, Judaism is my path.I think I first encountered the word Hineni in Saul Bellow's Herzog. When I finally got around to actually reading the Hebrew scriptures years later, the word leaped out to me. How many of our patriarchs (our scriptures are undeniably patriarchal, but that's another story) answer God's question “where are you?” in that contraction of the Hebrew words for here-I, meaning “here I am.” I love those stories and read them metaphorically. To me Hineni means centeredness, presentness, and the kind of listening Yeats called hearing “in the deep heart's core.” The shema, our primary Jewish sentence, is about hearing, so listening to that voiceless voice we say, Hineni. Achieving such wisdom—no, working toward such wisdom—is my goal for my relationship with myself. So let Hineni replace Eliot's self-control. Arguably this is “only” a matter of word choice, since working toward the ability to say Hineni no doubt involves controlling other impulses, including flight from self, in noise and motion. Sit still and know that I am God.Self and others—Eliot's sympathize? Here my watchword comes from our Jewish tradition but in a roundabout way. I was introduced to it by of all things a reference to Edmund Wilson's gravestone. Wilson was not a Jew, but for his tombstone he nevertheless chose hazak, hazak v'nithazek—be strong, be strong, and let us strengthen one another. These are the words spoken when the reading of the Torah ends for one year and begins again—invoking the mutual strength to go on. I extract the phrase from its context and use it this way: First I tell myself—be strong, then I tell the other or others to be strong, then together we say, let us strengthen one another. As a woman, I know the word strong is usually applied to men and often implies physical power. But I have come to believe that real weakness is internal—and dangerous. Dangerous because out of weakness we fail to do what we know is right and so betray ourselves and others. Arguably, all our sins of omission and commission, from failure to speak out when something needs to be said, to acting out of envy, jealousy, or spite, come from weakness. To nurture others is to help them become stronger. To comfort others is to ease their pain, so that they can regain or develop their strength. Comfort and nurture share the same goal of strengthening. Of course I relate this to Buber's magnificent I/thou relationship with others and maybe ideally with everything that lives. Be strong, oceans of this beautiful planet, be strong. Survive our pollution.I have spent much of my life thinking about God. Big deal, who hasn't? I still find it hard to get beyond the anthropomorphism of the old man in the sky with the long beard. But I have more or less given up the useless speculation and come to accept something simple: gratitude. To God or to the life source, I don't know to whom or what. Just gratitude for this spectacular world and for my own personal blessings. And that is our wonderful sheheheyanu—once again taken to mean what I believe the words to mean. Gratitude for life itself, gratitude for sustenance, for breath, food, water, all that. Gratitude for bringing me to this moment or time. How wonderful that there are a multiplicity of meanings for zmon. To this stage of life—which, in my case, is approaching old age. To the joy of the seasons and weather (the first cool breeze of autumn in San Antonio). To a particular time of day or night and so, potentially, to every moment.One evening my husband and I sat on plastic chairs in a field outside a cabin in Leakey, Texas, watching fireflies and repeated sheets of lightning blaze the sky, and I thought like Othello, “If it were now to die, 'twere now to be most happy.” And since Hebrew can put adjectives after the nouns they modify, the Hebrew is “time this.” This. Gratitude for this, just this. Mrs. Ramsay, Virginia Woolf's beloved character, exclaims, “It is enough, it is enough.” Dayenu.Marge Piercy's great and very Jewish poem “To Be of Use” explains why I have written these ideas. Rereading these words I realize how hopelessly literary my mind is. Not surprising I suppose for an English professor and poet that literature—whether Hebrew scripture or modernist classics—is central to my path. I say Hineni, Hazak, and Sheheheyanu. What do you say?Side by side on the museum wallSoutine's “Cellist” and Chagall's “Dream Village.”Notes instruct us that both were born in Russiaand lived in France, but not thatboth were Jews.The cellist's mouth is locked tightin controlled hysteriaand his cello's sickening reds and yellows are humantorsos split open, stinking corpses, smolderingflesh.Brilliant red roses and forest greenleaves rise off “The Dream Village” canvas,as if only thick paint can carry the lush fragrance.On the right a cow, standing on her back legs,plays a violin. Top right, lovers talk overa garden fence. Bottom left, they sweetly kiss.Sun and moon, father and mother,watch over the village. I am about to fallinto the swirling blues of Chagall's skywhen the solitary male figure behindthe village suddenly seems ominous.This is Chagall's dream village, not nightmare,I tell myself. Stop thinking Cossack, Nazi,but I, too, am a Jew.He unstraps his sandalsdrops his robe into a heapand stands wonderingif he is ridiculous or posturing.Shaking his curly head to castoff doubt, he begins. Empty-mindedhe lets his body tell his long, tangled story—legendary triumphs, weakness, cunningerrors and sin—Uriah, Uriah!On and on, arms and legs, head and torsoconfess and exult before he collapseson the cold floor, panting.When again breath enters his lungs, he stands.Am I moving, he wonders,or is something moving me?Without answering he begins to dance again.Leaping, crouching, stretching, lungingnow a fetal ball, now a flowering tree,desert wind, frigid Jordan Riverhis body, prayer.Rage darkened my mind when I saw David,God's pet, dance almost nakedbefore the ecstatic crowd.Despite the deafening tumult—shouts, horns, trumpets and cymbals—he heard me say he had dishonored himselfbaring his body to handmaids of his own servants.While the breasts of his other wives swelledand their bellies pushed against their robes,I prayed to God to help me regain his favor,but year after year David disdained me.Every baby's cry called to my dry breasts, andmy body withered long before I was old.Saul's daughter, David's wife, but withoutDavid's love and seed, I was nothing.Every night when I close my eyes I am back in that houseterrified and torn. The cruel men of our townpounded on our door with their fistshowling for me to shove the messengers outfor them to abuse. Instead I offered themBasha and Vered, my virgin daughters.What should I have done?I chose to protect the strangersand honor the sacred laws of hospitality.When they heard my offer,my daughters shrank back into a cornerand clutched each other.They never looked at me without wariness again.After their mother looked back, they clung to each otherfor comfort, only to each other.What did God want me to do?I know the men of our town were monsters, butwhat about me? What about me?“I am with child,” I told David.Is adultery acceptable to The Inscrutable?Despite charms and herbs, Uriah and Iwere childless. I learned the answer when Ephraim diedsoon after birth, and I feared I would never again say“I am with child.” Did our second son provethat God had forgiven me? All my life I watchedover Solomon, maneuvered to make him king.My old age was sweetened by his devotion. Yet in my dreamsEphraim cries,his tiny fingers grasp air.(Judges 19 and 20)Sisters, the official version cut out my nameand my suffering, but even what's left is vile.So no one reads it, no one knows it,no one wants to know it. But I must tell you my story.After days joyfully feasting in my father's homemy husband and I stopped for the night in Gibeah.Only one old man offered us hospitality,and soon other town's men circled the house, demandingthe old man give them my husband to abuse. Insteadmy own husband pushed me out the door.What those men did to my bodyall night long, all night long, is beyond words.Nobody—including God—responded to my screams,nobody pitied my bloody, broken body.At dawn I crawled back to the old man's threshold and died.My husband slung my body over an ass and took it home.Do you think he felt regret and guilt?That he wept and mourned me?He chopped my body into twelve pieces and sent themthroughout the borders of Israel. The official version stresseshow desire for revenge united the tribes who defeatedthe evildoers after days of savage fighting.Hurrah for slaughter, men's true love.Sisters, no story is clearer or more instructive than mine:No matter how they deny it, we women are only bodies to men,created to relieve their lust and give them sons.If it serves their needs, we canbe raped, murdered, even hacked into pieces.No longer useful as wombs, our mutilated bodiescan still serve their purposes—now you understandthe true meaning of woman as man's helper.I curse all men everywhereand God. Yes, God himself,who created usbut loves only them.They could not trust the intangible.So they built themselvesa golden calfsleek, shiny, satisfyingto the hand.Moses melted the calfand forced them to drink the liquid gold.As in a dream we play both parts:worship and consume.The toxic gold lies leadenin our bellies.We are stuffed but never full,voracious but never satisfied.Disbelief, the tapeworm gnawing in our guts.

The spontaneous mouse mutation "thrombocytopenia and cardiomyopathy" (trac) causes macrothrombocytopenia, prolonged bleeding times, anemia, leukopenia, infertility, cardiomyopathy, and shortened life span. Homozygotes show a 20-fold decrease in platelet numbers and a 3-fold increase in platelet size with structural alterations and functional impairments in activation and aggregation. Megakaryocytes in trac/trac mice are present in increased numbers, have poorly developed demarcation membrane systems, and have decreased polyploidy. The thrombocytopenia is not intrinsic to defects at the level of hematopoietic progenitor cells but is associated with a microenvironmental abnormality. The trac mutation maps to mouse chromosome 17, syntenic with human chromosome 2p21-22. A G to A mutation in exon 10 of the adenosine triphosphate (ATP)-binding cassette subfamily G, member 5 (Abcg5) gene, alters a tryptophan codon (UGG) to a premature stop codon (UAG). Crosses with mice doubly transgenic for the human ABCG5 and ABCG8 genes rescued platelet counts and volumes. ABCG5 and ABCG8 form a functional complex that limits dietary phytosterol accumulation. Phytosterolemia in trac/trac mice confirmed a functional defect in the ABCG5/ABCG8 transport system. The trac mutation provides a new clinically significant animal model for human phytosterolemia and provides a new means for studying the role of phytosterols in hematologic diseases and testing therapeutic interventions.

Vol. 27, No. 4 ♦ 2009 writes to her father in her journal when her decision to stay with her sons is challenged. The war ends and she returns to her husband and to their apartment with its view of the Seine. But it is no longer home. The plans for the peace monument are filed away in the drawers of various offices and agencies, and Ilana holds two secrets: she has extended the lease on the small Jerusalem apartment and she is pregnant, paternity unknown. The plot ends with Ilana’s death on the Autobahn. She is driving to a conference, thinking about the ‘open holy forms’ of the Sabbath, the Sabbatical, and the huts, and how landscape and architecture teach the ways of peace. Like John Lennon, Ilana Tsuriel imagines a world without possessions, without countries, or religion; nothing to kill or die for, though the wars, both present and past, hover darkly over this optimism. When Ilana, happy to be on the road but exhausted from it all, falls asleep at the wheel, it is clear that the territorial conflicts—for land and heart—have exacted another sacrificial offering. This provocative and intelligent novel, poignantly reflecting the complex texture of life in Israel today, begins with Ilana’s year of mourning for her father and ends with her sons beginning their year of mourning for her. The spiral of hope and loss—so familiar to Jews and not just, to Israel and not just—is one more open and holy form which will accompany them like a “whispering . . . on the road.” Miriam Sivan University of Haifa

Bonnie Lyons for Isaac Bashevis Singer God, also known as Bashevis, rewards the loving old couple by having their old stove leak gas so they can die together on Shabbas. I first fantasized my aged parents going down together in a plane crash. But what about the other passengers and crew? I revised: while the plane lands safely my parents are ejected from their seats, fly off into space holding hands as in a Chagall painting. These days it’s not death and the maiden. It’s disease and decline and decrepitude. My father died first, mind intact, perfectly able to see her wasting body and vacant face. What happened inside her those last four years? Vivid earthy memories like the best home movies, says God, also known as Bonnie.

Research Article| January 01 2008 Marge Piercy, Jewish Poet Bonnie Lyons Bonnie Lyons Search for other works by this author on: This Site Google Studies in American Jewish Literature (1981-) (2008) 27: 34–39. https://doi.org/10.2307/41206093 Cite Icon Cite Share Icon Share Twitter Permissions Search Site Citation Bonnie Lyons; Marge Piercy, Jewish Poet. Studies in American Jewish Literature (1981-) 1 January 2008; 27 34–39. doi: https://doi.org/10.2307/41206093 Download citation file: Zotero Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All Scholarly Publishing CollectivePenn State University PressStudies in American Jewish Literature (1981-) Search Advanced Search The text of this article is only available as a PDF. Copyright © 2009 Purdue University2009Purdue University Article PDF first page preview Close Modal You do not currently have access to this content.

Immunodeficient hosts engrafted with human lymphohaematopoietic cells hold great promise as a preclinical bridge for understanding human haematopoiesis and immunity. We now describe a new immunodeficient radioresistant non-obese diabetic mice (NOD) stock based on targeted mutations in the recombination activating gene-1 (Rag1(null)) and interleukin (IL)-2 receptor common gamma chain (IL2r gamma(null)), and compare its ability to support lymphohaematopoietic cell engraftment with that achieved in radiosensitive NOD.CB17-Prkdc(scid) (NOD-Prkdc(scid)) IL2r gamma(null) mice. We observed that immunodeficient NOD-Rag1(null) IL2r gamma(null) mice tolerated much higher levels of irradiation conditioning than did NOD-Prkdc(scid) IL2r gamma(null) mice. High levels of human cord blood stem cell engraftment were observed in both stocks of irradiation-conditioned adult mice, leading to multi-lineage haematopoietic cell populations and a complete repertoire of human immune cells, including human T cells. Human peripheral blood mononuclear cells also engrafted at high levels in unconditioned adult mice of each stock. These data document that Rag1(null) and scid stocks of immunodeficient NOD mice harbouring the IL2r gamma(null) mutation support similar levels of human lymphohaematopoietic cell engraftment. NOD-Rag1(null) IL2r gamma(null) mice will be an important new model for human lymphohaematopoietic cell engraftment studies that require radioresistant hosts.

There are many rodent models of autoimmune diabetes that have been used to study the pathogenesis of human type 1 diabetes (T1D), including the non-obese diabetic (NOD) mouse, the biobreeding (BB) rat, and the transgenic mouse models. However, mice and rats are not humans, and these rodent models do not completely recapitulate the autoimmune pathogenesis of the human disease. In addition, many of the reagents, tools, and therapeutics proposed for use in humans may be species specific and cannot be investigated in rodents. Researchers have used nonhuman primates to more closely mimic the human immune system and, to study species-specific therapeutics, but these studies are associated with additional ethical and economic constraints and, to date, no model of autoimmune diabetes in this species has been described. New animal models are needed that will permit the in vivo investigation of human immune systems and analyses of the pathogenesis of human T1D without putting individuals at risk. To fill this need, we are developing humanized mouse models for the in vivo study of T1D. These models are based on our newly generated stock of NOD-scid IL2rgamma(null) mice, which engraft at higher levels with human hematolymphoid cells and exhibit enhanced function of the engrafted human immune systems compared with previous humanized mouse models. Overall, development of these new generations of humanized mice should facilitate in vivo studies of the human immune system as well as permit the investigation of the pathogenesis and effector phases of human T1D.

Homozygosity for a new spontaneous mouse mutation named “thrombocytopenia and cardiomyopathy” (trac) results in thrombocytopenia, dilated cardiomyopathy, and infertility. A/J-trac/trac mice show a precipitous drop in platelet numbers and increases in platelet volume by 4 weeks of age. By 2–3 months of age, trac/trac mice have a 20-fold decrease in platelet number, a 3-fold increase in platelet volume, and a greatly increased bleeding time. Blood smears showed abnormally large platelets and megakaryocytoid cells. Homozygotes (trac/trac) also developed mild microcytic anemia accompanied by the presence of stomatocytes, a doubling of reticulocyte numbers, and a two-fold decrease in WBC counts. Increased numbers of megakaryocytes were present in bone marrow, spleen, and lungs. Ultrastructural studies of trac/trac megakaryocytes showed a poorly developed demarcation system and a failure to form platelet territories. The trac/trac platelets were enlarged, spherical, and contained numerous small alpha granules. The thrombocytopenia was not associated with defects intrinsic to bone marrow progenitor cells. Although thrombopoietin (TPO) levels were decreased, TPO treatment failed to reverse the thrombocytopenia. To identify the responsible gene, we produced a fine structure genetic map of a 5 megabase interval containing the trac locus on mouse chromosome 17. The human syntenic region is Chr 2p21–p22. Analyses of 1100 F2 progeny from intercross matings of (A/J x C57BL/6) F1 +/trac mice narrowed the interval to 0.3 Mb containing 4 genes. Sequencing of these genes revealed a G to A mutation at base 1435 (refseq nm031884) of Abcg5 (ATP-binding cassette sub-family G, member 5). This G>A base change results in a tryptophan codon (UGG) at amino acid position 463(uniprot) being changed to a premature stop codon (UAG). The transmembrane helices prediction program, TMHMM, predicts that the premature stop codon would truncate the last four of the six transmembrane domains of the ABCG5 protein. No DNA alterations were found in any of the other candidate genes. Genetic crosses of +/trac mice with mice doubly transgenic for the closely linked human ABCG5 and ABCG8 genes (stock B6SJL-Tg(ABCG5/ABCG8)14-2Hobb/J) showed that the transgenes normalized platelet counts and volumes in trac/trac mice. ABCG5 (sterolin-1) functions as part of a heterodimer, with ABCG8, that regulates plant sterol uptake. The trac/trac mutant mice have greatly elevated plasma levels of plant sterols. When placed on a phytosterol-free diet, the thrombocytopenia is reversed. Recent studies have shown that Mediterranean Macrothrombocytopenia is caused by mutations in ABCG5 or ABCG8. Identification of the molecular basis of the mouse Abcg5trac mutation provides a new model for studying the role of phytosterols in pathogenic changes in the hematopoietic, cardiovascular, and reproductive systems.

Research Article| January 01 2007 Nathan Englander and Jewish Fiction from and on the Edge Bonnie Lyons Bonnie Lyons Search for other works by this author on: This Site Google Studies in American Jewish Literature (1981-) (2007) 26: 65–72. https://doi.org/10.2307/41206071 Cite Icon Cite Share Icon Share Twitter Permissions Search Site Citation Bonnie Lyons; Nathan Englander and Jewish Fiction from and on the Edge. Studies in American Jewish Literature (1981-) 1 January 2007; 26 65–72. doi: https://doi.org/10.2307/41206071 Download citation file: Zotero Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All Scholarly Publishing CollectivePenn State University PressStudies in American Jewish Literature (1981-) Search Advanced Search The text of this article is only available as a PDF. Copyright © 2007 Purdue University2007Purdue University Article PDF first page preview Close Modal You do not currently have access to this content.

Acute myelogenous leukemia (AML) is the most common adult leukemia, characterized by the clonal expansion of immature myeloblasts initiating from rare leukemic stem (LS) cells1,2,3. To understand the functional properties of human LS cells, we developed a primary human AML xenotransplantation model using newborn nonobese diabetic/severe combined immunodeficient/interleukin (NOD/SCID/IL)2rγnull mice carrying a complete null mutation of the cytokine γc upon the SCID background4. Using this model, we demonstrated that LS cells exclusively recapitulate AML and retain self-renewal capacity in vivo. They home to and engraft within the osteoblast-rich area of the bone marrow, where AML cells are protected from chemotherapy-induced apoptosis. Quiescence of human LS cells may be a mechanism underlying resistance to cell cycle–dependent cytotoxic therapy. Global transcriptional profiling identified LS cell–specific transcripts that are stable through serial transplantation. These results indicate the potential utility of this AML xenograft model in the development of novel therapeutic strategies targeted at LS cells.