bluuebunny/crossref_metadata_2025 huggingface dataset:
A cycle of Vam7p release from and PtdIns 3-P–dependent rebinding to the yeast vacuole is required for homotypic vacuole fusion
Authors: Boeddinghaus Christine , Merz Alexey J. , Laage Rico , Ungermann Christian
Published: July 2002

Vacuole fusion requires a coordinated cascade of priming, docking, and fusion. SNARE proteins have been implicated in the fusion itself, although their precise role in the cascade remains unclear. We now report that the vacuolar SNAP-23 homologue Vam7p is a mobile element of the SNARE complex, which moves from an initial association with the cis-SNARE complex via a soluble intermediate to the docking site. Soluble Vam7p is specifically recruited to vacuoles and can rescue a fusion reaction poisoned with antibodies to Vam7p. Both the recombinant Vam7p PX domain and a FYVE domain construct of human Hrs block the recruitment of Vam7p and vacuole fusion, demonstrating that phosphatidylinositol 3-phosphate is a primary receptor of Vam7p on vacuoles. We propose that the Vam7p cycle is linked to the availability of a lipid domain on yeast vacuoles, which is essential for coordinating the fusion reaction prior to and beyond docking.
Differential Expression of Chemokine Receptors and Chemotactic Responsiveness of Type 1 T Helper Cells (Th1s) and Th2s
Authors: Bonecchi Raffaella , Bianchi Giancarlo , Bordignon Paola Panina , D'Ambrosio Daniele , Lang Rosmarie , Borsatti Alessandro , Sozzani Silvano , Allavena Paola , Gray Patrick A. , Mantovani Alberto , Sinigaglia Francesco
Published: July 2002

T helper cells type 1 (Th1s) that produce interferon-γ predominantly mediate cellular immune responses and are involved in the development of chronic inflammatory conditions, whereas Th2s which produce large amounts of IL-4 and IL-5 upregulate IgE production and are prominent in the pathogenesis of allergic diseases. The precise factors determining whether Th1- or Th2-mediated immune responses preferentially occur at a peripheral site of antigen exposure are largely unknown. Chemokines, a superfamily of polypeptide mediators, are a key component of the leukocyte recruitment process. Here we report that among four CXC (CXCR1-4) and five CC (CCR1-5) chemokine receptors analyzed, CXCR3 and CCR5 are preferentially expressed in human Th1s. In contrast, Th2s preferentially express CCR4 and, to a lesser extent, CCR3. In agreement with the differential chemokine receptor expression, Th1s and Th2s selectively migrate in response to the corresponding chemokines. The differential expression of chemokine receptors may dictate, to a large extent, the migration and tissue homing of Th1s and Th2s. It may also determine different susceptibility of Th1s and Th2s to human immunodeficiency virus strains using different fusion coreceptors.
Complement-dependent Clearance of Apoptotic Cells by Human Macrophages
Authors: Mevorach Dror , Mascarenhas John O. , Gershov Debra , Elkon Keith B.
Published: July 2002

Apoptotic cells are rapidly engulfed by phagocytes, but the receptors and ligands responsible for this phenomenon are incompletely characterized. Previously described receptors on blood- derived macrophages have been characterized in the absence of serum and show a relatively low uptake of apoptotic cells. Addition of serum to the phagocytosis assays increased the uptake of apoptotic cells by more than threefold. The serum factors responsible for enhanced uptake were identified as complement components that required activation of both the classical pathway and alternative pathway amplification loop. Exposure of phosphatidylserine on the apoptotic cell surface was partially responsible for complement activation and resulted in coating the apoptotic cell surface with C3bi. In the presence of serum, the macrophage receptors for C3bi, CR3 (CD11b/CD18) and CR4 (CD11c/CD18), were significantly more efficient in the uptake of apoptotic cells compared with previously described receptors implicated in clearance. Complement activation is likely to be required for efficient uptake of apoptotic cells within the systemic circulation, and early component deficiencies could predispose to systemic autoimmunity by enhanced exposure to and/or aberrant deposition of apoptotic cells.
Fractalkine and CX3CR1 Mediate a Novel Mechanism of Leukocyte Capture, Firm Adhesion, and Activation under Physiologic Flow
Authors: Fong Alan M. , Robinson Lisa A. , Steeber Douglas A. , Tedder Thomas F. , Yoshie Osamu , Imai Toshio , Patel Dhavalkumar D.
Published: July 2002

Leukocyte migration into sites of inflammation involves multiple molecular interactions between leukocytes and vascular endothelial cells, mediating sequential leukocyte capture, rolling, and firm adhesion. In this study, we tested the role of molecular interactions between fractalkine (FKN), a transmembrane mucin-chemokine hybrid molecule expressed on activated endothelium, and its receptor (CX3CR1) in leukocyte capture, firm adhesion, and activation under physiologic flow conditions. Immobilized FKN fusion proteins captured resting peripheral blood mononuclear cells at physiologic wall shear stresses and induced firm adhesion of resting monocytes, resting and interleukin (IL)-2–activated CD8+ T lymphocytes and IL-2–activated NK cells. FKN also induced cell shape change in firmly adherent monocytes and IL-2–activated lymphocytes. CX3CR1-transfected K562 cells, but not control K562 cells, firmly adhered to FKN-expressing ECV-304 cells (ECV-FKN) and tumor necrosis factor α–activated human umbilical vein endothelial cells. This firm adhesion was not inhibited by pertussis toxin, EDTA/EGTA, or antiintegrin antibodies, indicating that the firm adhesion was integrin independent. In summary, FKN mediated the rapid capture, integrin-independent firm adhesion, and activation of circulating leukocytes under flow. Thus, FKN and CX3CR1 mediate a novel pathway for leukocyte trafficking.
The Cutaneous Lymphocyte Antigen Is an Essential Component of the L-selectin Ligand Induced on Human Vascular Endothelial Cells
Authors: Tu LiLi , Delahunty Martha D. , Ding Han , Luscinskas Francis W. , Tedder Thomas F.
Published: July 2002

L-selectin mediates leukocyte rolling on vascular endothelium during inflammation. Although vascular endothelium can be activated with inflammatory cytokines to express functional L-selectin ligands, these ligands have not been well characterized. In this study, fucosyltransferase VII cDNA (Fuc-TVII) transfection of the EA.hy926 human vascular endothelial cell line (926-FtVII) induced functional L-selectin ligand expression and expression of sialyl Lewisx (sLex), as defined by HECA-452 (cutaneous lymphocyte antigen; CLA) and CSLEX-1 mAbs. Cytokine activation of human umbilical vein endothelial cells (HUVEC) also induced functional L-selectin ligand expression, with increased CLA expression and Fuc-TVII transcription. The majority of L-selectin–dependent lymphocyte attachment to activated HUVEC and 926-FtVII cells was blocked specifically by treating the endothelial cells with the HECA-452 mAb, but not the CSLEX-1 mAb. CLA-bearing ligands on vascular endothelium also required sulfation and appropriate molecular scaffolds for functional activity, but were distinct from the L-selectin ligands previously identified by the MECA-79 mAb. These findings demonstrate that the HECA-452– defined antigen, CLA, is an essential carbohydrate component of vascular L-selectin ligands.
Fcγ Receptor–mediated Induction of Dendritic Cell Maturation and Major Histocompatibility Complex Class I–restricted Antigen Presentation after Immune Complex Internalization
Authors: Regnault Armelle , Lankar Danielle , Lacabanne Valérie , Rodriguez Ana , Théry Clotilde , Rescigno Maria , Saito Takashi , Verbeek Sjef , Bonnerot Christian , Ricciardi-Castagnoli Paola , Amigorena Sebastian
Published: July 2002

Dendritic cells (DCs) express several receptors for the Fc portion of immunoglobulin (Ig)G (FcγR), which mediate internalization of antigen–IgG complexes (immune complexes, ICs) and promote efficient major histocompatibility complex (MHC) class II–restricted antigen presentation. We now show that FcγRs have two additional specific attributes in murine DCs: the induction of DC maturation and the promotion of efficient MHC class I–restricted presentation of peptides from exogenous, IgG-complexed antigens. Both FcγR functions require the FcγR-associated γ chain. FcγR-mediated MHC class I–restricted antigen presentation is extremely sensitive and specific to immature DCs. It requires proteasomal degradation and is dependent on functional peptide transporter associated with antigen processing, TAP1-TAP2. By promoting DC maturation and presentation on both MHC class I and II molecules, ICs should efficiently sensitize DCs for priming of both CD4+ helper and CD8+ cytotoxic T lymphocytes in vivo.
Expression of Stromelysin-3 in Atherosclerotic Lesions: Regulation via CD40–CD40 Ligand Signaling In Vitro and In Vivo
Authors: Schönbeck Uwe , Mach François , Sukhova Galina K. , Atkinson Elizabeth , Levesque Ethan , Herman Michael , Graber Pierre , Basset Paul , Libby Peter
Published: July 2002

Stromelysin-3 is an unusual matrix metalloproteinase, being released in the active rather than zymogen form and having a distinct substrate specificity, targeting serine proteinase inhibitors (serpins), which regulate cellular functions involved in atherosclerosis. We report here that human atherosclerotic plaques (n = 7) express stromelysin-3 in situ, whereas fatty streaks (n = 5) and normal arterial specimens (n = 5) contain little or no stromelysin-3. Stromelysin-3 mRNA and protein colocalized with endothelial cells, smooth muscle cells, and macrophages within the lesion. In vitro, usual inducers of matrix metalloproteinases such as interleukin-1, interferon-γ, or tumor necrosis factor α did not augment stromelysin-3 in vascular wall cells. However, T cell–derived as well as recombinant CD40 ligand (CD40L, CD154), an inflammatory mediator recently localized in atheroma, induced de novo synthesis of stromelysin-3. In addition, stromelysin-3 mRNA and protein colocalized with CD40L and CD40 within atheroma. In accordance with the in situ and in vitro data obtained with human material, interruption of the CD40–CD40L signaling pathway in low density lipoprotein receptor–deficient hyperlipidemic mice substantially decreased expression of the enzyme within atherosclerotic plaques. These observations establish the expression of the unusual matrix metalloproteinase stromelysin-3 in human atherosclerotic lesions and implicate CD40–CD40L signaling in its regulation, thus providing a possible new pathway that triggers complications within atherosclerotic lesions.
Bone Marrow NK1.1− and NK1.1+ T Cells Reciprocally Regulate Acute Graft versus Host Disease
Authors: Zeng Defu , Lewis David , Dejbakhsh-Jones Sussan , Lan Fengshuo , García-Ojeda Marcos , Sibley Richard , Strober Samuel
Published: July 2002

Sorted CD4+ and CD8+ T cells from the peripheral blood or bone marrow of donor C57BL/6 (H-2b) mice were tested for their capacity to induce graft-versus-host disease (GVHD) by injecting the cells, along with stringently T cell–depleted donor marrow cells, into lethally irradiated BALB/c (H-2d) host mice. The peripheral blood T cells were at least 30 times more potent than the marrow T cells in inducing lethal GVHD. As NK1.1+ T cells represented <1% of all T cells in the blood and ∼30% of T cells in the marrow, the capacity of sorted marrow NK1.1− CD4+ and CD8+ T cells to induce GVHD was tested. The latter cells had markedly increased potency, and adding back marrow NK1.1+ T cells suppressed GVHD. The marrow NK1.1+ T cells secreted high levels of both interferon γ (IFN-γ) and interleukin 4 (IL-4), and the NK1.1− T cells secreted high levels of IFN-γ with little IL-4. Marrow NK1.1+ T cells obtained from IL-4−/− rather than wild-type C57BL/6 donors not only failed to prevent GVHD but actually increased its severity. Together, these results demonstrate that GVHD is reciprocally regulated by the NK1.1− and NK1.1+ T cell subsets via their differential production of cytokines.
Comparative Analysis of Genetically Modified Dendritic Cells and Tumor Cells as Therapeutic Cancer Vaccines
Authors: Klein Christoph , Bueler Hansruedi , Mulligan Richard C.
Published: July 2002

We have directly compared the efficacy of two immunotherapeutic strategies for the treatment of cancer: “vaccination” of tumor-bearing mice with genetically modified dendritic cells (DCs), and vaccination with genetically modified tumor cells. Using several different preexisting tumor models that make use of B16F10 melanoma cells expressing a target tumor antigen (human melanoma-associated gene [MAGE]-1), we found that vaccination with bone marrow–derived DCs engineered to express MAGE-1 via adenoviral-mediated gene transfer led to a dramatic decrease in the number of metastases in a lung metastasis model, and led to prolonged survival and some long-term cures in a subcutaneous preexisting tumor model. In contrast, vaccination with granulocyte/macrophage colony-stimulating factor (GM-CSF)–transduced tumor cells, previously shown to induce potent antitumor immunity in standard tumor challenge assays, led to a decreased therapeutic effect in the metastasis model and no effect in the subcutaneous tumor model. Further engineering of DCs to express either GM-CSF, tumor necrosis factor α, or CD40 ligand via retroviral-mediated gene transfer, led to a significantly increased therapeutic effect in the subcutaneous tumor model. The immunological mechanism, as shown for GM-CSF–transduced DCs, involves MAGE-1–specific CD4+ and CD8+ T cells. Expression of GM-CSF by DCs led to enhanced cytotoxic T lymphocyte activity, potentially mediated by increased numbers of DCs in draining lymph nodes. Our results suggest that clinical studies involving the vaccination with genetically modified DCs may be warranted.
Tumor Necrosis Factor α Stimulates Osteoclast Differentiation by a Mechanism Independent of the Odf/Rankl–Rank Interaction
Authors: Kobayashi Kanichiro , Takahashi Naoyuki , Jimi Eijiro , Udagawa Nobuyuki , Takami Masamichi , Kotake Shigeru , Nakagawa Nobuaki , Kinosaki Masahiko , Yamaguchi Kyoji , Shima Nobuyuki , Yasuda Hisataka , Morinaga Tomonori , Higashio Kanji , Martin T. John , Suda Tatsuo
Published: July 2002

Osteoclast differentiation factor (ODF, also called RANKL/TRANCE/OPGL) stimulates the differentiation of osteoclast progenitors of the monocyte/macrophage lineage into osteoclasts in the presence of macrophage colony-stimulating factor (M-CSF, also called CSF-1). When mouse bone marrow cells were cultured with M-CSF, M-CSF–dependent bone marrow macrophages (M-BMMφ) appeared within 3 d. Tartrate-resistant acid phosphatase–positive osteoclasts were also formed when M-BMMφ were further cultured for 3 d with mouse tumor necrosis factor α (TNF-α) in the presence of M-CSF. Osteoclast formation induced by TNF-α was inhibited by the addition of respective antibodies against TNF receptor 1 (TNFR1) or TNFR2, but not by osteoclastogenesis inhibitory factor (OCIF, also called OPG, a decoy receptor of ODF/RANKL), nor the Fab fragment of anti–RANK (ODF/RANKL receptor) antibody. Experiments using M-BMMφ prepared from TNFR1- or TNFR2-deficient mice showed that both TNFR1- and TNFR2-induced signals were important for osteoclast formation induced by TNF-α. Osteoclasts induced by TNF-α formed resorption pits on dentine slices only in the presence of IL-1α. These results demonstrate that TNF-α stimulates osteoclast differentiation in the presence of M-CSF through a mechanism independent of the ODF/RANKL–RANK system. TNF-α together with IL-1α may play an important role in bone resorption of inflammatory bone diseases.
Clonal Expansions of Cd8+ T Cells Dominate the T Cell Infiltrate in Active Multiple Sclerosis Lesions as Shown by Micromanipulation and Single Cell Polymerase Chain Reaction
Authors: Babbe Holger , Roers Axel , Waisman Ari , Lassmann Hans , Goebels Norbert , Hohlfeld Reinhard , Friese Michael , Schröder Roland , Deckert Martina , Schmidt Stephan , Ravid Rivka , Rajewsky Klaus
Published: July 2002

Clonal composition and T cell receptor (TCR) repertoire of CD4+ and CD8+ T cells infiltrating actively demyelinating multiple sclerosis (MS) lesions were determined with unprecedented resolution at the level of single cells. Individual CD4+ or CD8+ T cells were isolated from frozen sections of lesional tissue by micromanipulation and subjected to single target amplification of TCR-β gene rearrangements. This strategy allows the assignment of a TCR variable region (V region) sequence to the particular T cell from which it was amplified. Sequence analysis revealed that in both cases investigated, the majority of CD8+ T cells belonged to few clones. One of these clones accounted for 35% of CD8+ T cells in case 1. V region sequence comparison revealed signs of selection for common peptide specificities for some of the CD8+ T cells in case 1. In both cases, the CD4+ T cell population was more heterogeneous. Most CD4+ and CD8+ clones were represented in perivascular infiltrates as well as among parenchymal T cells. In case 2, two of the CD8+ clones identified in brain tissue were also detected in peripheral blood. Investigation of the antigenic specificities of expanded clones may help to elucidate their functional properties.
Novel Functional Sets of Lipid-Derived Mediators with Antiinflammatory Actions Generated from Omega-3 Fatty Acids via Cyclooxygenase 2–Nonsteroidal Antiinflammatory Drugs and Transcellular Processing
Authors: Serhan Charles N. , Clish Clary B. , Brannon Jessica , Colgan Sean P. , Chiang Nan , Gronert Karsten
Published: July 2002

Aspirin therapy inhibits prostaglandin biosynthesis without directly acting on lipoxygenases, yet via acetylation of cyclooxygenase 2 (COX-2) it leads to bioactive lipoxins (LXs) epimeric at carbon 15 (15-epi-LX, also termed aspirin-triggered LX [ATL]). Here, we report that inflammatory exudates from mice treated with ω-3 polyunsaturated fatty acid and aspirin (ASA) generate a novel array of bioactive lipid signals. Human endothelial cells with upregulated COX-2 treated with ASA converted C20:5 ω-3 to 18R-hydroxyeicosapentaenoic acid (HEPE) and 15R-HEPE. Each was used by polymorphonuclear leukocytes to generate separate classes of novel trihydroxy-containing mediators, including 5-series 15R-LX5 and 5,12,18R-triHEPE. These new compounds proved to be potent inhibitors of human polymorphonuclear leukocyte transendothelial migration and infiltration in vivo (ATL analogue > 5,12,18R-triHEPE > 18R-HEPE). Acetaminophen and indomethacin also permitted 18R-HEPE and 15R-HEPE generation with recombinant COX-2 as well as ω-5 and ω-9 oxygenations of other fatty acids that act on hematologic cells. These findings establish new transcellular routes for producing arrays of bioactive lipid mediators via COX-2–nonsteroidal antiinflammatory drug–dependent oxygenations and cell–cell interactions that impact microinflammation. The generation of these and related compounds provides a novel mechanism(s) for the therapeutic benefits of ω-3 dietary supplementation, which may be important in inflammation, neoplasia, and vascular diseases.
P62dok, a Negative Regulator of Ras and Mitogen-Activated Protein Kinase (Mapk) Activity, Opposes Leukemogenesis by P210bcr-abl
Authors: Di Cristofano Antonio , Niki Masaru , Zhao Mingming , Karnell Fredrick G. , Clarkson Bayard , Pear Warren S. , Van Aelst Linda , Pandolfi Pier Paolo
Published: July 2002

p62dok has been identified as a substrate of many oncogenic tyrosine kinases such as the chronic myelogenous leukemia (CML) chimeric p210bcr-abl oncoprotein. It is also phosphorylated upon activation of many receptors and cytoplamic tyrosine kinases. However, the biological functions of p62dok in normal cell signaling as well as in p210bcr-abl leukemogenesis are as yet not fully understood. Here we show, in hemopoietic and nonhemopoietic cells derived from p62dok−/− mice, that the loss of p62dok results in increased cell proliferation upon growth factor treatment. Moreover, Ras and mitogen-activated protein kinase (MAPK) activation is markedly sustained in p62dok−/− cells after the removal of growth factor. However, p62dok inactivation does not affect DNA damage and growth factor deprivation–induced apoptosis. Furthermore, p62dok inactivation causes a significant shortening in the latency of the fatal myeloproliferative disease induced by retroviral-mediated transduction of p210bcr-abl in bone marrow cells. These data indicate that p62dok acts as a negative regulator of growth factor–induced cell proliferation, at least in part through downregulating Ras/MAPK signaling pathway, and that p62dok can oppose leukemogenesis by p210bcr-abl.
Mechanism of Transforming Growth Factor β–induced Inhibition of T Helper Type 1 Differentiation
Authors: Gorelik Leonid , Constant Stephanie , Flavell Richard A.
Published: July 2002

Regulation by transforming growth factor (TGF)-β plays an important role in immune homeostasis. TGF-β inhibits T cell functions by blocking both proliferation and differentiation. Here we show that TGF-β blocks Th1 differentiation by inhibiting the expression of T-bet, the apparent masterregulator of T helper (Th)1 differentiation. Restoration of T-bet expression through retroviral transduction of T-bet into developing Th1 cells abrogated the inhibitory effect of TGF-β. In addition, we show that, contrary to prior suggestions, downregulation of interleukin 12 receptor β2 chain is not key to the TGF-β–mediated effect. Furthermore, we show that the direct inhibitory effect of TGF-β on T cells is responsible, at least in part, for the inability of BALB/c mice to mount a Leishmania-specific Th1 response and to clear Leishmanial infection.
Functional Impact of the Ryanodine Receptor on the Skeletal Muscle L-Type Ca2+ Channel
Authors: Avila Guillermo , Dirksen Robert T.
Published: July 2002

L-type Ca2+ channel (L-channel) activity of the skeletal muscle dihydropyridine receptor is markedly enhanced by the skeletal muscle isoform of the ryanodine receptor (RyR1) (Nakai, J., R.T. Dirksen, H.T. Nguyen, I.N. Pessah, K.G. Beam, and P.D. Allen. 1996. Nature. 380:72–75.). However, the dependence of the biophysical and pharmacological properties of skeletal L-current on RyR1 has yet to be fully elucidated. Thus, we have evaluated the influence of RyR1 on the properties of macroscopic L-currents and intracellular charge movements in cultured skeletal myotubes derived from normal and “RyR1-knockout” (dyspedic) mice. Compared with normal myotubes, dyspedic myotubes exhibited a 40% reduction in the amount of maximal immobilization-resistant charge movement (Qmax, 7.5 ± 0.8 and 4.5 ± 0.4 nC/μF for normal and dyspedic myotubes, respectively) and an approximately fivefold reduction in the ratio of maximal L-channel conductance to charge movement (Gmax/Qmax). Thus, RyR1 enhances both the expression level and Ca2+ conducting activity of the skeletal L-channel. For both normal and dyspedic myotubes, the sum of two exponentials was required to fit L-current activation and resulted in extraction of the amplitudes (Afast and Aslow) and time constants (τslow and τfast) for each component of the macroscopic current. In spite of a >10-fold in difference current density, L-currents in normal and dyspedic myotubes exhibited similar relative contributions of fast and slow components (at +40 mV; Afast/[Afast + Aslow] ∼ 0.25). However, both τfast and τslow were significantly (P < 0.02) faster for myotubes lacking the RyR1 protein (τfast, 8.5 ± 1.2 and 4.4 ± 0.5 ms; τslow, 79.5 ± 10.5 and 34.6 ± 3.7 ms at +40 mV for normal and dyspedic myotubes, respectively). In both normal and dyspedic myotubes, (−) Bay K 8644 (5 μM) caused a hyperpolarizing shift (∼10 mV) in the voltage dependence of channel activation and an 80% increase in peak L-current. However, the increase in peak L-current correlated with moderate increases in both Aslow and Afast in normal myotubes, but a large increase in only Afast in dyspedic myotubes. Equimolar substitution of Ba2+ for extracellular Ca2+ increased both Afast and Aslow in normal myotubes. The identical substitution in dyspedic myotubes failed to significantly alter the magnitude of either Afast or Aslow. These results demonstrate that RyR1 influences essential properties of skeletal L-channels (expression level, activation kinetics, modulation by dihydropyridine agonist, and divalent conductance) and supports the notion that RyR1 acts as an important allosteric modulator of the skeletal L-channel, analogous to that of a Ca2+ channel accessory subunit.
Functional Effects of Central Core Disease Mutations in the Cytoplasmic Region of the Skeletal Muscle Ryanodine Receptor
Authors: Avila Guillermo , Dirksen Robert T.
Published: July 2002

Central core disease (CCD) is a human myopathy that involves a dysregulation in muscle Ca2+ homeostasis caused by mutations in the gene encoding the skeletal muscle ryanodine receptor (RyR1), the protein that comprises the calcium release channel of the SR. Although genetic studies have clearly demonstrated linkage between mutations in RyR1 and CCD, the impact of these mutations on release channel function and excitation-contraction coupling in skeletal muscle is unknown. Toward this goal, we have engineered the different CCD mutations found in the NH2-terminal region of RyR1 into a rabbit RyR1 cDNA (R164C, I404M, Y523S, R2163H, and R2435H) and characterized the functional effects of these mutations after expression in myotubes derived from RyR1-knockout (dyspedic) mice. Resting Ca2+ levels were elevated in dyspedic myotubes expressing four of these mutants (Y523S > R2163H > R2435H R164C > I404M RyR1). A similar rank order was also found for the degree of SR Ca2+ depletion assessed using maximal concentrations of caffeine (10 mM) or cyclopiazonic acid (CPA, 30 μM). Although all of the CCD mutants fully restored L-current density, voltage-gated SR Ca2+ release was smaller and activated at more negative potentials for myotubes expressing the NH2-terminal CCD mutations. The shift in the voltage dependence of SR Ca2+ release correlated strongly with changes in resting Ca2+, SR Ca2+ store depletion, and peak voltage–gated release, indicating that increased release channel activity at negative membrane potentials promotes SR Ca2+ leak. Coexpression of wild-type and Y523S RyR1 proteins in dyspedic myotubes resulted in release channels that exhibited an intermediate degree of SR Ca2+ leak. These results demonstrate that the NH2-terminal CCD mutants enhance release channel sensitivity to activation by voltage in a manner that leads to increased SR Ca2+ leak, store depletion, and a reduction in voltage-gated Ca2+ release. Two fundamentally distinct cellular mechanisms (leaky channels and EC uncoupling) are proposed to explain how altered release channel function caused by different mutations in RyR1 could result in muscle weakness in CCD.
A note on regular isotopy of singular links
Authors: Tsau Chichen
Published: July 2002

We show that two isotopic oriented 4-valent singular link diagrams with transverse intersections are regularly isotopic if and only if they have the same writhe and the same rotation number.
Asymptotic behavior of nonexpansive sequences and mean points
Authors: Jung Jong , Park Jong
Published: July 2002

Let

E
E

be a real Banach space with norm

‖
⋅
‖

\Vert \cdot \Vert

and let

{

x
n

}

n
≥
0

\{x_n\}_{n \ge 0}

be a nonexpansive sequence in

E
E

(i.e.,

‖

x

i
+
1

−

x

j
+
1

‖
≤
‖

x
i

−

x
j

‖

\Vert x_{i + 1} - x_{j + 1}\Vert \le \Vert x_i - x_j\Vert

for all

i
,
j
≥
0

i, j \ge 0

). Let
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="upper K equals intersection Underscript n equals 1 Overscript normal infinity Endscripts ModifyingAbove c o With bar left-brace left-brace x Subscript i Baseline minus x Subscript i minus 1 Baseline right-brace Subscript i greater-than-or-equal-to n Baseline right-brace">

K
=

⋂

n
=
1

∞

c
o

¯

{
{

x
i

−

x

i
−
1

}

i
≥
n

}

K = \bigcap _{n = 1}^{\infty }\overline {co}\{\{x_i - x_{i - 1}\}_{i \ge n}\}

. We deal with the mean point of

{

x
n

n

}

\{\frac {x_n}{n}\}

concerning a Banach limit. We show that if

E
E

is reflexive and

d
=
d
(
0
,
K
)

d = d(0,K)

, then

d
=
d
(
0
,

c
o

¯

{

x
n

−

x
0

n

}
)

d = d(0,\overline {co}\{\frac {x_n - x_0}{n}\})

and there exists a unique point

z
0

z_0

with

‖

z
0

‖
=
d

\Vert z_0\Vert = d

such that

z
0

∈

c
o

¯

{

x
n

−

x
0

n

}

z_0 \in \overline {co}\{\frac {x_n - x_0}{n}\}

. This result is applied to obtain the weak and strong convergence of

{

x
n

n

}

\{\frac {x_n}{n}\}

.
Bounds for the operator norms of some Nörlund matrices
Authors: Johnson P. , Mohapatra R. , Ross David
Published: July 2002

Suppose

(

p
n

)

n
≥
0

(p_n)_{n \geq 0}

is a non-increasing sequence of non-negative numbers with

p
0

=
1

p_0 = 1

,

P
n

=

∑

j
=
0

n

p
j

P_n = \sum _{j=0}^n p_j

,

n
=
0
,
1
…

n = 0, 1 \dots

, and

A
=
A
(

p
n

)
=
(

a

n
k

)

A = A(p_n) = (a_{nk})

is the lower triangular matrix defined by

a

n
k

=

p

n
−
k

/

P
n

a_{nk} = p_{n-k} / P_n

,

0
≤
k
≤
n

0 \leq k \leq n

, and

a

n
k

=
0

a_{nk} = 0

,

n
>
k

n > k

. We show that the operator norm of

A
A

as a linear operator on

ℓ
p

\ell _p

is no greater than

p

/

(
p
−
1
)

p / (p-1)

, for

1
>
p
>
∞

1 > p > \infty

; this generalizes, yet again, Hardy’s inequality for sequences, and simplifies and improves, in this special case, more generally applicable results of D. Borwein, Cass, and Kratz. When the

p
n

p_n

tend to a positive limit, the operator norm of

A
A

on

ℓ
p

\ell _p

is exactly

p

/

(
p
−
1
)

p/(p-1)

. We also give some cases when the operator norm of

A
A

on

ℓ
p

\ell _p

is less than

p

/

(
p
−
1
)

p/(p-1)

.
The convergence of the Bochner-Riesz means at the critical index
Authors: Chen Lung-Kee , Fan Dashan
Published: July 2002

In this paper, we study the pointwise convergence of the Bochner-Riesz means at the critical index on the space

L

log
+

⁡
L
(

Q
n

)
.

L\log ^+ L (Q_n).

We weaken the hypothesis,

“
x

“ x

is a Lebesgue point", which is required on some research results by instead considering the convergence of averages of the function over balls when the radials of the balls approach to 0.
Weak compactness in 𝐿¹(𝜇,𝑋)
Authors: Díaz Santiago
Published: July 2002

We characterize weak compactness and weak conditional compactness of subsets of

L

1

(
μ
,
X
)

L^{1}(\mu ,X)

in terms of regular methods of summability. We also study when these results still hold using only convergence in the sense of Cesàro.
The zeros of the first two derivatives of a meromorphic function
Authors: Langley J.
Published: July 2002

We prove a theorem which implies the following: if

f
f

is meromorphic of finite order in the plane and

f
′

f’

and

f
f

have only finitely many zeros, then

f
f

has only finitely many poles.
Real instantons, Dirac operators and quaternionic classifying spaces
Authors: Norbury Paul , Sanders Marc
Published: July 2002

Let

M
(
k
,
S
O
(
n
)
)

M(k,SO(n))

be the moduli space of based gauge equivalence classes of

S
O
(
n
)

SO(n)

instantons on principal

S
O
(
n
)

SO(n)

bundles over

S
4

S^4

with first Pontryagin class

p
1

=
2
k

p_1=2k

. In this paper, we use a monad description (Y. Tian, The Atiyah-Jones conjecture for classical groups, preprint, S. K. Donaldson, Comm. Math. Phys. 93 (1984), 453–460) of these moduli spaces to show that in the limit over

n
n

, the moduli space is homotopy equivalent to the classifying space

B
S
p
(
k
)

BSp(k)

. Finally, we use Dirac operators coupled to such connections to exhibit a particular and quite natural homotopy equivalence.
Bidimensional linear systems with singular dynamics
Authors: Novo Sylvia , Obaya Rafael
Published: July 2002

We analyze a class of bidimensional linear systems for which the following characteristics are generic: the system is recurrent and there exists a unique ergodic measure which is concentrated in one ergodic sheet. The trajectories exhibit an oscillatory behaviour from one to the other side of the ergodic sheet which assures the proximal character of the flow.
A class of complete second order linear differential equations
Authors: Oka Hirokazu
Published: July 2002

This paper is concerned with a class of complete second order linear differential equations in a Banach space. We show the existence and uniqueness of classical solutions of
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="StartLayout 1st Row with Label left-parenthesis SE right-parenthesis EndLabel StartLayout Enlarged left-brace 1st Row u left-parenthesis t right-parenthesis equals upper A left-parenthesis t right-parenthesis u prime left-parenthesis t right-parenthesis plus upper B left-parenthesis t right-parenthesis u left-parenthesis t right-parenthesis plus f left-parenthesis t right-parenthesis for t element-of left-bracket 0 comma upper T right-bracket u left-parenthesis 0 right-parenthesis equals x and u prime left-parenthesis 0 right-parenthesis equals y period EndLayout EndLayout">

(SE)

{

u
(
t
)
=
A
(
t
)

u
′

(
t
)
+
B
(
t
)
u
(
t
)
+
f
(
t
)

for 

t
∈
[
0
,
T
]

 
u
(
0
)
=
x
and

u
′

(
0
)
=
y
.

\begin{equation}\tag {SE} \begin {cases} u(t) = A(t)u’(t) + B(t)u(t) + f(t) \text {for $t \in [0,T]$} \ u(0) = x \text {and} u’(0) = y. \end{cases} \end{equation}
Oscillatory singular integrals on 𝐿^{𝑝} and Hardy spaces
Authors: Pan Yibiao
Published: July 2002

We consider boundedness properties of oscillatory singular integrals on

L

p

L^{p}

and Hardy spaces. By constructing a phase function, we prove that

H

1

H^{1}

boundedness may fail while

L

p

L^{p}

boundedness holds for all

p
∈
(
1
,
∞
)

p \in (1, \infty )

. This shows that the

L

p

L^{p}

theory and

H

1

H^{1}

theory for such operators are fundamentally different.
Tychonoff’s Theorem in a category
Authors: Clementino Maria , Tholen Walter
Published: July 2002

A categorical proof of Tychonoff’s Theorem on the productivity of compact topological spaces is provided.
On the set of topologically invariant means on an algebra of convolution operators on 𝐿^{𝑝}(𝐺)
Authors: Granirer Edmond
Published: July 2002

Let

G
G

be a locally compact group,

A

p

=

A

p

(
G
)

A_{p}=A_{p}(G)

the Banach algebra defined by Herz; thus

A

2

(
G
)
=
A
(
G
)

A_{2}(G)=A(G)

is the Fourier algebra of

G
G

. Let

P

M

p

=

A

p

∗

PM_{p}=A^{*}_{p}

the dual,

J
⊂

A

p

J \subset A_{p}

a closed ideal, with zero set

F
=
Z
(
J
)

F=Z(J)

, and

P

=
(

A

p

/

J

)

∗

\mathbb {P} = (A_{p}/J)^{*}

. We consider the set

T
I

M

P

(
x
)
⊂

P

∗

TIM_{\mathbb {P}}(x) \subset {\mathbb {P}}^{*}

of topologically invariant means on

P

\mathbb {P}

at

x
∈
F

x\in F

, where

F
F

is “thin.” We show that in certain cases card 

T
I

M

P

(
x
)
≥

2

c

TIM_{\mathbb {P}}(x) \geq 2^{c}

and

T
I

M

P

(
x
)

TIM_{\mathbb {P}}(x)

does not have the WRNP, i.e. is far from being weakly compact in

P

∗

\mathbb {P}^{*}

. This implies the non-Arens regularity of the algebra

A

p

/

J

A_{p}/J

.
Correspondences of closed submodules
Authors: Zelmanowitz Julius
Published: July 2002

If

N
N

is an

M
M

-faithful

R
R

-module, then there is an order-preserving correspondence between the closed

R
R

-submodules of

N
N

and the closed

S
S

-submodules of

H
o

m
R

(
M
,
N
)

Hom_R(M,N)

, where

S
=
E
n

d
R

M

S=End_RM

.
Generic vanishing for harmonic spinors of twisted Dirac operators
Authors: Anghel Nicolae
Published: July 2002

In this paper we address the problem of generic vanishing for (negative) harmonic spinors of Dirac operators coupled with variable metric connections.
Elementary operators and invariant subalgebras
Authors: Coates Keith
Published: July 2002

We provide an example of an elementary operator which leaves invariant a nest algebra but which cannot be written as a finite sum of multiplications each of which leaves the nest algebra invariant. We also prove that the given operator lies in the completely bounded norm closure of the linear span of the multiplications which leave the nest algebra invariant.
Geometric indices and the Alexander polynomial of a knot
Authors: Fujii Hirozumi
Published: July 2002

It is well-known that any Laurent polynomial

Δ
(
t
)

\Delta (t)

satisfying

Δ
(
t
)
≐
Δ
(

t

−
1

)

\Delta (t) \doteq \Delta (t^{-1})

and

Δ
(
1
)
=
±
1

\Delta (1) = \pm 1

is the Alexander polynomial of a knot in

S
3

S^3

. We show that

Δ
(
t
)

\Delta (t)

can be realized by a knot which has the following properties simultaneously: (i) tunnel number 1; (ii) bridge index 3; and (iii) unknotting number 1.
On rational invariants of the group 𝐸₆
Authors: Iltyakov A.
Published: July 2002

We prove rationality of the field of invariants in several variables of a minimal irreducible representation of a simple algebraic group of type

E
6

E_6

over an algebraically closed field of characteristic zero.
On completely hyperexpansive operators
Authors: Athavale Ameer
Published: July 2002

We introduce and discuss a class of operators, to be referred to as the class of completely hyperexpansive operators, which is in some sense antithetical to the class of contractive subnormals. The new class is intimately related to the theory of negative definite functions on abelian semigroups. The known interplay between positive and negative definite functions from the theory of harmonic analysis on semigroups can be exploited to reveal some interesting connections between subnormals and completely hyperexpansive operators.
The second iterate of a map with dense orbit
Authors: Bourdon Paul
Published: July 2002

Suppose that

X
X

is a Hausdorff topological space having no isolated points and that

f
:
X
→
X

f:X\rightarrow X

is continuous. We show that if the orbit of a point

x
∈
X

x\in X

under

f
f

is dense in

X
X

while the orbit of

x
x

under

f
∘
f

f\circ f

is not, then the space

X
X

decomposes into three sets relative to which the dynamics of

f
f

are easy to describe. This decomposition has the following consequence: suppose that

x
x

has dense orbit under

f
f

and that the closure of the set of points of

X
X

having odd period under

f
f

has nonempty interior; then

x
x

has dense orbit under

f
∘
f

f\circ f

.
Multiple geometrically distinct closed noncollision orbits of fixed energy for N-body type problems with strong force potentials
Authors: Shiqing Zhang
Published: July 2002

Using the equivariant Ljusternik-Schnirelmann theory, we prove that there are at least2(N−1)2N−22(N-1)2^{N-2}geometrically distinct noncollision orbits with prescribed energy for a class of planar N-body type problems with strong force potentials.
An algebraic 𝑆𝐿₂-vector bundle over 𝑅₂ as a variety
Authors: Nagase Teruko
Published: July 2002

We show the stable triviality of all the elements in

VEC
⁡
(

R

2

,

R

n

)

\operatorname {VEC}(R_{2},R_{n})

concretely, and describe

VEC
⁡
(

R

2

,

R

n

)

\operatorname {VEC}(R_{2},R_{n})

as surjection classes from a trivial bundle to another. The results also contain the explicit description of non-linearizable

S

L

2

SL_{2}

actions on

C

n

\mathbb {C}^{n}

.
Point-spectrum-preserving elementary operators on 𝐵(𝐻)
Authors: Wang Qin , Hou Jinchuan
Published: July 2002

Let

H
H

be an infinite dimensional separable Hilbert space over the complex field. Structure characterizations are given for some elementary operators on

B
(
H
)

B(H)

which preserve point spectrum.
Enumerations, countable structures and Turing degrees
Authors: Wehner Stephan
Published: July 2002

It is proven that there is a family of sets of natural numbers which has enumerations in every Turing degree except for the recursive degree. This implies that there is a countable structure which has representations in all but the recursive degree. Moreover, it is shown that there is such a structure which has a recursively represented elementary extension.
The Chern character for classical matrix groups
Authors: Wood Jay
Published: July 2002

We give explicit formulas for representations of classical matrix groups whose Chern characters have lowest order terms equal to standard characteristic classes. For

SO
⁡
(
2
r
)

\operatorname {SO}(2r)

, the Euler class

e
e

does not arise in this way, but

2

r
−
1

e

2^{r-1} e

does arise in this way.
Number of rational points of a singular curve
Authors: Galindo W.
Published: July 2002

In this paper, we give a bound for the number of rational points of a complete, geometrically irreducible, algebraic curve defined over a finite field. We compare it with other known bounds and discuss its sharpness. We also show that the asymptotic Drinfeld-Vladut bound can be generalized to the case of singular curves.
Cauchy-Schwarz and means inequalities for elementary operators into norm ideals
Authors: Jocić Danko
Published: July 2002

The Cauchy-Schwarz norm inequality for normal elementary operators
\[
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="triple-vertical-bar-delimiter sigma-summation Underscript n equals 1 Overscript normal infinity Endscripts upper A Subscript n Baseline upper X upper B Subscript n Baseline triple-vertical-bar-delimiter less-than-or-equal-to triple-vertical-bar-delimiter left-parenthesis sigma-summation Underscript n equals 1 Overscript normal infinity Endscripts upper A Subscript n Superscript asterisk Baseline upper A Subscript n Baseline right-parenthesis Superscript 1 slash 2 Baseline upper X left-parenthesis sigma-summation Underscript n equals 1 Overscript normal infinity Endscripts upper B Subscript n Superscript asterisk Baseline upper B Subscript n Baseline right-parenthesis Superscript 1 slash 2 Baseline triple-vertical-bar-delimiter comma">

⦀

∑

n
=
1

∞

A
n

X

B
n

⦀

≤

⦀
(

∑

n
=
1

∞

A
n
∗

A
n

)

1

/

2

X
(

∑

n
=
1

∞

B
n
∗

B
n

)

1

/

2

⦀

,

\left \Vvert \sum _{n=1}^\infty A_nXB_n \right \Vvert \leq \left \Vvert (\sum _{n=1}^\infty A_n^*A_n)^{1/2}X (\sum _{n=1}^\infty B_n^*B_n)^{1/2} \right \Vvert ,

\]
implies a means inequality for generalized normal derivations
\[
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="triple-vertical-bar-delimiter StartFraction upper A upper X plus upper X upper B Over 2 EndFraction triple-vertical-bar-delimiter less-than-or-equal-to triple-vertical-bar-delimiter upper X triple-vertical-bar-delimiter Superscript 1 minus StartFraction 1 Over r EndFraction Baseline triple-vertical-bar-delimiter StartFraction StartAbsoluteValue upper A EndAbsoluteValue Superscript r Baseline upper X plus upper X StartAbsoluteValue upper B EndAbsoluteValue Superscript r Baseline Over 2 EndFraction triple-vertical-bar-delimiter Superscript StartFraction 1 Over r EndFraction Baseline comma">

⦀

A
X
+
X
B

2

⦀

≤
⦀
X

⦀

1
−

1
r

⦀

|

A

|

r

X
+
X

|

B

|

r

2

⦀

1
r

,

\left \Vvert \frac {AX+XB}2 \right \Vvert \leq \Vvert X \Vvert ^{1-\frac 1r} \left \Vvert \frac {|A|^rX+X|B|^r}2 \right \Vvert ^\frac 1r,

\]
for all

r
≥
2

r\ge 2

, as well as an inequality for normal contractions

A
A

and

B
B

\[
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="triple-vertical-bar-delimiter left-parenthesis upper I minus upper A Superscript asterisk Baseline upper A right-parenthesis Superscript one half Baseline upper X left-parenthesis upper I minus upper B Superscript asterisk Baseline upper B right-parenthesis Superscript one half Baseline triple-vertical-bar-delimiter less-than-or-equal-to triple-vertical-bar-delimiter upper X minus upper A upper X upper B triple-vertical-bar-delimiter comma">

⦀
(
I
−

A
∗

A

)

1
2

X
(
I
−

B
∗

B

)

1
2

⦀

≤
⦀
X
−
A
X
B
⦀
,

\left \Vvert (I-A^*A) ^\frac 12X(I-B^*B)^\frac 12\right \Vvert \leq \Vvert X-AXB\Vvert ,

\]
for all

X
X

in

B
(
H
)

B(H)

and for all unitarily invariant norms

⦀
⋅
⦀
.

\Vvert \cdot \Vvert .
On the relative commutants of subfactors
Authors: Khoshkam M. , Mashood B.
Published: July 2002

Let

A
⊂
B

A\subset B

be factors generated by a periodic tower

A

n

⊂

B

n

A_{n}\subset B_{n}

of finite dimensional

C

∗

C^{*}

-algebras. We prove that for sufficiently large

n
n

,

A

′

∩
B

A^{\prime }\cap B

is

∗
*

-isomorphic to a subalgebra of

A

n

′

∩

B

n

A^{\prime }_{n}\cap B_{n}

.
The convergence of the Fourier integral of a unimodal distribution
Authors: Georgakis Constantine
Published: July 2002

We show that the characteristic function of a unimodal probability distribution function can be inverted by the Fourier transform a.e. if and only if the distribution is absolutely continuous. The result complements Khintchine’s criterion for unimodal distributions.
On the class equation for Hopf algebras
Authors: Lorenz Martin
Published: July 2002

We give a simple proof of the Kac-Zhu class equation for semisimple Hopf algebras over an algebraically closed field of characteristic 0.
𝑝-integral bases of a cubic field
Authors: Alaca Şaban
Published: July 2002

A

p
p

-integral basis of a cubic field

K
K

is determined for each rational prime

p
p

, and then an integral basis of

K
K

and its discriminant

d
(
K
)

d(K)

are obtained from its

p
p

-integral bases.
Note on the topological degree of the subdifferential of a lower semi-continuous convex function
Authors: Aizicovici Sergiu , Chen Yuqing
Published: July 2002

The purpose of the present paper is to prove that the topological degree of the subdifferential of a coercive lower semi-continuous function on a sufficiently large ball in a reflexive Banach space is equal to one.
Integral means and Pólya factorizations
Authors: Elias Uri
Published: July 2002

Integral means of functions and their derivatives are studied. We find a relation between integral means and the Pólya factorization of ordinary linear differential operators.
Contractive mappings, Kannan mappings and metric completeness
Authors: Shioji Naoki , Suzuki Tomonari , Takahashi Wataru
Published: July 2002

In this paper, we first study the relationship between weakly contractive mappings and weakly Kannan mappings. Further, we discuss characterizations of metric completeness which are connected with the existence of fixed points for mappings. Especially, we show that a metric space is complete if it has the fixed point property for Kannan mappings.
Nonsymmetric Osserman pseudo-Riemannian manifolds
Authors: García-Río E. , Vázquez-Abal M. , Vázquez-Lorenzo R.
Published: July 2002

Examples of Osserman pseudo–Riemannian manifolds with metric of any signature

(
p
,
q
)

(p,q)

,

p
p

,

q
q

>
1

>1

which are not locally symmetric are exhibited.
Lie algebras of cohomological codimension one
Authors: Armstrong Grant , Cairns Grant , Kim Gunky
Published: July 2002

We show that if

g

\mathfrak {g}

is a finite dimensional real Lie algebra, then

g

\mathfrak {g}

has cohomological dimension

c
d
(

g

)
=
dim
⁡
(

g

)
−
1

cd(\mathfrak {g})=\dim (\mathfrak {g})-1

if and only if

g

\mathfrak {g}

is a unimodular extension of the two-dimensional non-Abelian Lie algebra

a
f
f

\mathfrak {aff}

.
Equilibrium problems associated with fast decreasing polynomials
Authors: Kuijlaars A. , Dragnev P.
Published: July 2002

The determination of the support of the equilibrium measure in the presence of an external field is important in the theory of weighted polynomials on the real line. Here we present a general condition guaranteeing that the support consists of at most two intervals. Applying this to the external fields associated with fast decreasing polynomials, we extend previous results of Totik and Kuijlaars-Van Assche. In the proof we use the iterated balayage algorithm which was first studied by Dragnev.
On the reduction number of some graded algebras
Authors: Bresinsky Henrik , Hoa Lê
Published: July 2002

The main result of the paper confirms, for generic coordinates, a conjecture which states that

r
(
R

/

I
)
≤
r
(
R

/

i
n
(
I
)
)

r(R/I) \le r(R/in(I))

. Here

I
I

is a homogeneous polynomial ideal in

R
R

and

r
(
R

/

I
)

r(R/I)

and

r
(
R

/

i
n
(
I
)
)

r(R/in(I))

are the reduction numbers.
Modular varieties with the Fraser-Horn property
Authors: Vaggione Diego
Published: July 2002

The notion of central idempotent elements in a ring can be easily generalized to the setting of any variety with the property that proper subalgebras are always nontrivial. We will prove that if such a variety is also congruence modular, then it has factorable congruences, i.e., it has the Fraser-Horn property. (This property is well known to have major implications for the structure theory of the algebras in the variety.)