bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative expression analysis of blastocyst-derived gene transcripts in preimplantation developmental stages of in vitro-produced bovine embryos using real-time polymerase chain reaction technology
Authors: El-Halawany Nermin , Ponsuksili Siriluck , Wimmers Klaus , Gilles Markus , Tesfaye Dawit , Schellander Karl
Published: January 2005

The main objective of the present study was to analyse the quantitative expression pattern of genes from a subtracted blastocyst transcriptome throughout the preimplantation developmental stages of in vitro-produced bovine oocytes and embryos. For this purpose, Day 5 morula (M) cDNAs were subtracted from Day 7 blastocyst (B) cDNAs (B–M) and used to establish a B–M subtracted cDNA library, as reported previously. From the total generated clones, 19 were analysed quantitatively. The mRNA samples isolated from pools of immature oocytes (n = 150), mature oocytes (n = 150) and two-cell (n = 80), four-cell (n = 40), eight-cell (n = 20), morula (n = 6) and blastocyst (n = 3) embryos were reverse transcribed and subjected to real-time polymerase chain reaction (PCR) using sequence-specific primers and SYBR green as the DNA dye. A relative standard curve method was used to analyse the real-time data taking the morula stage as a calibrator. Applying suppression subtractive hybridisation (SSH), a total of 71 clones, which represent 33 different expressed sequence tags, were generated and available for analysis. Most transcripts were analysed for the first time in bovine embryogenesis. The real-time PCR has validated the results of SSH positively for 84% (16/19) of transcripts, whereas 16% (3/19) showed deviation in the expression pattern from the one seen during SSH. Several transcript-specific expression patterns were observed for genes that play decisive roles in bovine embryogenesis. In addition to identification, accurately quantifying the expression profiles of transcripts during development will pave the way towards understanding the molecular mechanisms of embryogenesis and their potential role in early embryo development. Most importantly, the present study has contributed to the enrichment of bovine embryo gene collection by generating new transcripts involved in bovine embryo development.
Effect of exogenous DMNPE-caged ATP on in vitro-matured bovine oocytes prior to parthenogenetic activation, fertilisation and nuclear transfer
Authors: Xue Jun , Cooney Melissa A. , Hall Vanessa J. , Korfiatis Natasha A. , Tecirlioglu R. Tayfur , French Andrew J. , Ruddock Nancy T.
Published: January 2005

Adenosine triphosphate (ATP) plays an important role during fertilisation of the mammalian oocyte through its ability to alter the frequency and duration of calcium oscillations. It has also been shown that higher ATP levels correlate with increased developmental competence in bovine and human oocytes. During somatic cell nuclear transfer (NT), the incoming nucleus is remodelled extensively, undoubtedly using a variety of ATP-dependent enzymes. The aim of the present study was to determine whether additional exogenous ATP influences activation of parthenogenetic (PA), in vitro-fertilised (IVF) or cloned (NT) in vitro-matured bovine oocytes. Blastocyst development and cell numbers in PA embryos were found to increase in a dose-dependent manner following the photorelease of 0, 50, 100, 500 and 1000 μm DMNPE-caged ATP (adenosine 5′-triphosphate, P3-(1-(4,5-dimethoxy-2-nitrophenyl)ethyl) ester, disodium salt). No cleavage was found following release of 2 and 5 mm DMNPE-caged ATP or with DMNPE-caged ATP (not photoreleased). There were also no differences in blastocyst rates or cell numbers between the control group and groups treated with caged, but not photoreleased, ATP. The addition of exogenous ATP before IVF or to NT couplets did not result in a significant increase in blastocyst development or cell number. Embryo transfer is necessary to determine whether exogenous ATP can positively affect reprogramming, resulting in higher cloned pregnancy rates or live-term births.
Dynamics of the responses in secretion of luteinising hormone, leptin and insulin following an acute increase in nutrition in mature male sheep
Authors: Zhang Song , Blache Dominique , Blackberry Margaret A. , Martin Graeme B.
Published: January 2005

In Merino rams, an increase in the plane of nutrition increases the frequency of luteinising hormone (LH) pulses within a few days and this response is correlated with changes in the circulating concentrations of metabolic hormones. To analyse early dynamic aspects of these responses, we studied mature rams fed with diets that contained either low or high amounts of energy and protein. Jugular blood was sampled every 20 min for 96 h, including a control period of 24 h before the change of diet in the high-diet group. In the high-diet group, a significant increase in LH pulse frequency was first detected 6 h after the increase in nutrition on Day 1 and the frequency remained significantly elevated throughout the 72-h treatment period, except for a 12-h period on Day 2. Following the change of diet, insulin concentrations increased within 3 h and leptin concentrations increased within 7 h, after which time the concentrations of both hormones remained high. Dietary treatment did not affect the concentrations of thyroxine or insulin-like growth factor-I, but the high diet increased the concentrations of tri-iodothyronine. These observations are consistent with insulin and leptin playing a role in the early activation of the gonadotrophin-releasing hormone–LH axis by nutritional inputs.
Sperm transport, size of the seminal plug and the timing of ovulation after natural mating in the female tammar wallaby Macropus eugenii
Authors: Paris Damien B. B. P. , Taggart David A. , Paris Monica C. J. , Temple-Smith Peter D. , Renfree Marilyn B.
Published: January 2005

The distribution of spermatozoa and seminal plug in the reproductive tract and the timing of ovulation were examined at various times in a naturally mated monovular macropodid marsupial, namely the tammar wallaby (Macropus eugenii). After the first post partum (p.p.) mating, 28 females were isolated and their reproductive tracts dissected at 0.5, 6, 18, 36 and 40 h post coitum (p.c.). Each tract was ligated into 13 major anatomical sections and spermatozoa and eggs were recovered by flushing. Mating was possibly delayed by handling and occurred 21.7 ± 2.5 h p.p. in these animals. Copulation lasted 7.8 ± 0.7 min. Within 0.5 h after a single mating, the tract contained 25.8 ± 10.2 × 106 spermatozoa and 21.6 ± 8.8 g of seminal plug, 96% and 70% of which was lost within 6 h p.c. respectively. Spermatozoa reached the uterus, isthmus and ampulla of the oviduct on the side of the developing follicle within 0.5, 6 and 18 h p.c., respectively, and a uterine population of 26.1 ± 12.103 spermatozoa was maintained for over 40 h. Sperm numbers were reduced at the cervix (up to 57-fold) and uterotubule junction (eight-fold) and only one in approximately 7500 ejaculated spermatozoa (3.4 ± 0.9 × 103) reached the oviduct on the follicle side. Differential transport of spermatozoa was not observed. Although the numbers of spermatozoa were reduced in the parturient uterus, they were highly variable and were not significantly different to those in the non-parturient uterus. Ovulation and recovery of sperm-covered eggs from the isthmus occurred 36–41 h p.c. (49–72 h p.p.). In contrast with the polyovular dasyurid and didelphid marsupials, the tammar wallaby ejaculates large numbers of spermatozoa, but transport is relatively inefficient and sperm storage in the tract before ovulation is limited.
Olig2 and Ngn2 function in opposition to modulate gene expression in motor neuron progenitor cells
Authors: Lee Soo-Kyung , Lee Bora , Ruiz Esmeralda C. , Pfaff Samuel L.
Published: January 2005

Spinal motor neurons and oligodendrocytes are generated sequentially from a common pool of progenitors termed pMN cells. Olig2 is a bHLH-class transcription factor in pMN cells, but it has remained unclear how its transcriptional activity is modulated to first produce motor neurons and then oligodendrocytes. Previous studies have shown that Olig2 primes pMN cells to become motor neurons by triggering the expression of Ngn2 and Lhx3. Here we show that Olig2 also antagonizes the premature expression of post-mitotic motor neuron genes in pMN cells. This blockade is counteracted by Ngn2, which accumulates heterogeneously in pMN cells, thereby releasing a subset of the progenitors to differentiate and activate expression of post-mitotic motor neuron genes. The antagonistic relationship between Ngn2 and Olig2 is mediated by protein interactions that squelch activity as well as competition for shared DNA-binding sites. Our data support a model in which the Olig2/Ngn2 ratio in progenitor cells serves as a gate for timing proper gene expression during the development of pMN cells: Olig2high maintains the pMN state, thereby holding cells in reserve for oligodendrocyte generation, whereas Ngn2high favors the conversion of pMN cells into post-mitotic motor neurons.
Regulation of the Neurospora circadian clock by an RNA helicase
Authors: Cheng Ping , He Qun , He Qiyang , Wang Lixin , Liu Yi
Published: January 2005

The eukaryotic circadian oscillators consist of autoregulatory negative-feedback loops. FRQ, WC-1, and WC-2 are three known components of the negative-feedback loop of the Neurospora circadian oscillator. FRQ represses its own transcription by interacting with the WC-1/WC-2 complex and inhibiting WC's role in transcriptional activation. Here we show that all FRQ associates with FRH, an essential DEAD box-containing RNA helicase in Neurospora. The budding yeast homolog of FRH, Dob1p/Mtr4p, is a cofactor of exosome, an important regulator of RNA metabolism in eukaryotes. Down-regulation of FRH by inducible expression of a hairpin RNA leads to low levels of FRQ but high levels of frq RNA and the abolishment of circadian rhythmicities. FRH is associated with the WC complex and this interaction is maintained in a frq null strain. Disruption of the FRQ–FRH complex by deleting a domain in FRQ eliminates the FRQ–WC interaction, suggesting that FRH mediates the interaction between FRQ and the WC complex. These data demonstrate that FRH is an essential component in the circadian negative-feedback loop and reveal an unexpected role of an RNA helicase in regulating gene transcription.
High incidence of proviral integrations in the Hoxa locus in a new model of E2a–PBX1-induced B-cell leukemia
Authors: Bijl Janet , Sauvageau Martin , Thompson Alexander , Sauvageau Guy
Published: January 2005

Relevant mouse models of E2a–PBX1-induced pre-B cell leukemia are still elusive. We now report the generation of a pre-B leukemia model using E2a–PBX1 transgenic mice, which lack mature and precursor T-cells as a result of engineered loss of CD3ϵ expression (CD3ϵ–/–). Using insertional mutagenesis and inverse-PCR, we show that B-cell leukemia development in the E2a–PBX1 × CD3ϵ–/– compound transgenic animals is significantly accelerated when compared to control littermates, and document several known and novel integrations in these tumors. Of all common integration sites, a small region of 19 kb in the Hoxa gene locus, mostly between Hoxa6 and Hoxa10, represented 18% of all integrations in the E2a–PBX1 B-cell leukemia and was targeted in 86% of these leukemias compared to 17% in control tumors. Q-PCR assessment of expression levels for most Hoxa cluster genes in these tumors revealed an unprecedented impact of the proviral integrations on Hoxa gene expression, with tumors having one to seven different Hoxa genes overexpressed at levels up to 6600-fold above control values. Together our studies set the stage for modeling E2a–PBX1-induced B-cell leukemia and shed new light on the complexity pertaining to Hox gene regulation. In addition, our results show that the Hoxa gene cluster is preferentially targeted in E2a–PBX1-induced tumors, thus suggesting functional collaboration between these oncogenes in pre-B-cell tumors.
Not just another hole in the wall: understanding intercellular protein trafficking
Authors: Gallagher Kimberly L. , Benfey Philip N.
Published: January 2005

Development and differentiation of multicellular organisms requires cell-to-cell communication. In plants direct signaling and exchange of macromolecules between cells is possible through plasmodesmata. Recently direct exchange of membrane-bound vesicles and organelles has been demonstrated between animal cells through formation of cytoplasmic bridges (tunneling nanotubes) in vitro. Here we review recent developments in cell-to-cell trafficking of macromolecules in plants and animals.
The p400 E1A-associated protein is a novel component of the p53 → p21 senescence pathway
Authors: Chan Ho Man , Narita Masako , Lowe Scott W. , Livingston David M.
Published: January 2005

Adenovirus E1A-associated p400 belongs to the SWI2/SNF2 family of chromatin remodeling proteins. Here, we report that p400 is a component of the p53–p21WAF1/CIP1/sid1 pathway, regulating the p21 transcription and senescence induction program. Acute depletion of p400 expression by shRNA (short hairpin RNA) synthesis led to premature senescence of untransformed human fibroblasts, whose features include G1 arrest, p21 induction, senescence-associated heterochromatic foci (SAHF), and β-gal staining. Importantly, p400shRNA-induced premature senescence phenotypes were rescued by coexpression of p53-shRNA or p21-shRNA. Furthermore, p400 complex colocalized with p53 on the p21 promoter. These data suggest that the p400 complex inhibits p53 → p21 transcription and the development of premature senescence.
Distinct functions of junD in cardiac hypertrophy and heart failure
Authors: Ricci Romeo , Eriksson Urs , Oudit Gavin Y. , Eferl Robert , Akhmedov Alexander , Sumara Izabela , Sumara Grzegorz , Kassiri Zamaneh , David Jean-Pierre , Bakiri Latifa , Sasse Bernd , Idarraga Maria-Helena , Rath Martina , Kurz David , Theussl Hans-Christian , Perriard Jean-Claude , Backx Peter , Penninger Josef M. , Wagner Erwin F.
Published: January 2005

Cardiac hypertrophic stimuli induce both adaptive and maladaptive growth response pathways in heart. Here we show that mice lacking junD develop less adaptive hypertrophy in heart after mechanical pressure overload, while cardiomyocyte-specific expression of junD in mice results in spontaneous ventricular dilation and decreased contractility. In contrast, fra-1 conditional knock-out mice have a normal hypertrophic response, whereas hearts from fra-1 transgenic mice decompensate prematurely. Moreover, fra-1 transgenic mice simultaneously lacking junD reveal a spontaneous dilated cardiomyopathy associated with increased cardiomyocyte apoptosis and a primary mitochondrial defect. These data suggest that junD promotes both adaptive-protective and maladaptive hypertrophy in heart, depending on its expression levels.
Mad2 prevents aneuploidy and premature proteolysis of cyclin B and securin during meiosis I in mouse oocytes
Authors: Homer Hayden A. , McDougall Alex , Levasseur Mark , Yallop Katie , Murdoch Alison P. , Herbert Mary
Published: January 2005

In mitosis, the spindle checkpoint protein Mad2 averts aneuploidy by delaying anaphase onset until chromosomes align. Here we show that depletion of Mad2 in meiosis I mouse oocytes induced an increased incidence of aneuploidy. Proteolysis of cyclin B and securin commenced earlier in Mad2-depleted oocytes, resulting in a shortened duration of meiosis I. Furthermore, overexpression of Mad2 inhibited homolog disjunction. We conclude that Mad2 delays the onset of cyclin B and securin degradation and averts aneuploidy during meiosis I in mammalian oocytes. The data suggest a link between trisomies such as Down syndrome and defective oocyte spindle checkpoint function.
Genome-wide regulatory complexity in yeast promoters: Separation of functionally conserved and neutral sequence
Authors: Chin Chen-Shan , Chuang Jeffrey H. , Li Hao
Published: January 2005

To gauge the complexity of gene regulation in yeast, it is essential to know how much promoter sequence is functional. Conservation across species can be a sensitive means of detecting functional sequences, provided that the significance of conservation can be accurately calibrated with the local neutral mutation rate. By analyzing yeast coding and promoter sequences, we find that neutral mutation rates in yeast are uniform genome-wide, in contrast to mammals, where neutral mutation rates vary along chromosomes. We develop an approach that uses this uniform rate to estimate the amount of promoter sequence under purifying selection. This amount is ∼30%, corresponding to roughly 90 bp for a typical promoter. Furthermore, using a hidden Markov model, we are able to separate each promoter into distinct high and low conservation regions. Known regulatory motifs are strongly biased toward high conservation regions, while low conservation regions have mutation rates similar to that of the neutral background. Certain Gene Ontology groupings of genes (e.g., Carbohydrate Metabolism) have large amounts of high conservation sequence, suggesting complexity in their transcriptional regulation. Others (e.g., RNA Processing) have little high conservation sequence and are likely to be simply regulated. The separation of functionally conserved sequence from the neutral background allows us to estimate the complexity of cis-regulation on a genomic scale.
Divergent V1R repertoires in five species: Amplification in rodents, decimation in primates, and a surprisingly small repertoire in dogs
Authors: Young Janet M. , Kambere Marijo , Trask Barbara J. , Lane Robert P.
Published: January 2005

The V1R gene family comprises one of two types of putative pheromone receptors expressed in the mammalian vomeronasal organ (VNO). We searched the most recent mouse, rat, dog, chimpanzee, and human genome sequence assemblies to compile a near-complete repertoire of V1R genes for each species. Dog, human, and chimpanzee have very few intact V1Rs (8, 2, and 0, respectively) compared to more than a hundred intact V1Rs in each of the rat (106) and mouse (165) genomes. We also provide the first description of the diversity of V1R pseudogenes in these species. We identify at least 165 pseudogenes in mouse, 110 in rat, 102 in chimpanzee, 115 in human, and 54 in dog. Primate and dog pseudogenes are distributed among almost all V1R subfamilies seen in rodents, indicating that the common ancestor of these species had a diverse V1R repertoire. We find that V1R genes were subject to strikingly different fates in different species and in different subfamilies. In rodents, some subfamilies remained relatively stable or underwent roughly equivalent expansion in mouse and rat; other subfamilies expanded in one species but not the other. The small number of intact V1Rs in the dog genome is unexpected given the presumption that dogs, like rodents, have a functional VNO, and a complex system of pheromone-based behaviors. We identify an intact transient receptor potential channel 2β in the dog genome, consistent with a functional VNO in dogs. The diminished V1R repertoire in dogs raises questions about the relative contributions of V1Rs versus other candidate pheromone receptor genes in the establishment of complex pheromone systems in mammals.
Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs
Authors: Pesu Marko , Candotti Fabio , Husa Matthew , Hofmann Sigrun R. , Notarangelo Luigi D. , O'Shea John J.
Published: January 2005

Summary:  The recent elucidation of the multiple molecular mechanisms underlying severe combined immunodeficiency (SCID) is an impressive example of the power of molecular medicine. Analysis of patients and the concomitant generation of animal models mimicking these disorders have quickly provided great insights into the pathophysiology of these potentially devastating illnesses. In this review, we summarize the discoveries that led to the understanding of the role of cytokine receptors and a specific tyrosine kinase, Janus kinase 3 (Jak3), in the pathogenesis of SCID. We discuss how the identification of mutations of Jak3 in autosomal recessive SCID has facilitated the diagnosis of these disorders, offered new insights into the biology of this kinase, permitted new avenues for therapy, and provided the rationale for a generation of a new class of immunosuppressants.
Human disease resulting from gene mutations that interfere with appropriate nuclear factor‐κB activation
Authors: Orange Jordan S. , Levy Ofer , Geha Raif S.
Published: January 2005

Summary:  The nuclear factor (NF)‐κB family of transcription factors serves vital roles in a wide array of cell functions. An increasing number of human genetic lesions that result in defined disease entities are linked to inappropriate activation of NF‐κB. The resulting aberrant NF‐κB function can lead to cellular defects that ultimately impair normal developmental processes, host immune defenses, or both. Molecular defects that lie upstream in cell‐signaling pathways and rely upon NF‐κB activation tend to give a more specific phenotype, whereas those closer to the actual NF‐κB proteins have broader defects. A detailed study of these diseases can provide insight into the biochemistry of NF‐κB activation as well as the role of NF‐κB in human health.
Hyper‐immunoglobulin M syndromes caused by intrinsic B‐lymphocyte defects
Authors: Durandy Anne , Revy Patrick , Imai Kohsuke , Fischer Alain
Published: January 2005

Summary:  Hyper‐immunoglobulin M (IgM) syndromes are primary immunodeficiencies characterized by normal or elevated serum IgM levels with the absence of other isotypes, pinpointing to a defect in the Ig class switch recombination (CSR). The delineation of hyper‐IgM syndromes made it possible to better define the mechanisms underlying the two major events of antibody maturation in humans, CSR and introduction of somatic hypermutation (SHM) in the variable region of immunoglobulins. The description of the activation‐induced cytidine deaminase (AID) deficiency, characterized by a defect in both CSR and SHM, demonstrated for the first time that this molecule acts as a master player in the antigen‐induced Ig gene‐modification events responsible for both CSR and SHM. However, deleterious mutations located in the C‐terminus lead to a CSR defect without affecting SHM, providing evidence for a role of AID in CSR distinct from the cytidine deaminase activity, likely by binding to a specific CSR cofactor. Molecular causes of two other hyper‐IgM conditions have not yet been defined. However, they may be caused by either a defect in AID targeting on S regions or a CSR‐specific DNA‐repair defect. The mechanism of action of AID remains somewhat debated, but the observation that uracil‐DNA‐glycosylase deficiency leads to a severe hyper‐IgM syndrome strongly argues in favor of a DNA‐editing activity of AID.
Severe combined immunodeficiency. A model disease for molecular immunology and therapy
Authors: Fischer Alain , Le Deist Françoise , Hacein‐Bey‐Abina Salima , André‐Schmutz Isabelle , De Saint Basile Geneviève , De Villartay Jean‐Pierre , Cavazzana‐Calvo Marina
Published: January 2005

Summary:  Severe combined immunodeficiencies (SCIDs) consist of genetically determined arrest of T‐cell differentiation. Ten different molecular defects have now been identified, which all lead to early death in the absence of therapy. Transplantation of allogeneic hematopoietic stem cells (HSCT) can restore T‐cell development, thus saving the lives of SCID patients. In this review, the different characteristics of HSCT are discussed along with the available data regarding the long‐term outcome. Transient thymopoiesis caused by an exhaustion of donor progenitor cells and possibly a progressive loss of thymus function can lead to a progressive decline in T‐cell functions. The preliminary results of gene therapy show the correction of two SCID conditions. Based on the assumption that long‐lasting pluripotent progenitor cells are transduced, these data suggest that gene therapy could overcome the long‐term recurrence of the T‐cell immunodeficiency. SCID is thus a disease model for experimental therapy in the hematopoietic system.
Bruton's tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profiling
Authors: Lindvall Jessica M. , Blomberg K. Emelie M. , Väliaho Jouni , Vargas Leonardo , Heinonen Juhana E. , Berglöf Anna , Mohamed Abdalla J. , Nore Beston F. , Vihinen Mauno , Smith C. I. Edvard
Published: January 2005

Summary:  Bruton's tyrosine kinase (Btk) is encoded by the gene that when mutated causes the primary immunodeficiency disease X‐linked agammaglobulinemia (XLA) in humans and X‐linked immunodeficiency (Xid) in mice. Btk is a member of the Tec family of protein tyrosine kinases (PTKs) and plays a vital, but diverse, modulatory role in many cellular processes. Mutations affecting Btk block B‐lymphocyte development. Btk is conserved among species, and in this review, we present the sequence of the full‐length rat Btk and find it to be analogous to the mouse Btk sequence. We have also analyzed the wealth of information compiled in the mutation database for XLA (BTKbase), representing 554 unique molecular events in 823 families and demonstrate that only selected amino acids are sensitive to replacement (P < 0.001). Although genotype–phenotype correlations have not been established in XLA, based on these findings, we hypothesize that this relationship indeed exists. Using short interfering‐RNA technology, we have previously generated active constructs downregulating Btk expression. However, application of recently established guidelines to enhance or decrease the activity was not successful, demonstrating the importance of the primary sequence. We also review the outcome of expression profiling, comparing B lymphocytes from XLA‐, Xid‐, and Btk‐knockout (KO) donors to healthy controls. Finally, in spite of a few genes differing in expression between Xid‐ and Btk‐KO mice, in vivo competition between cells expressing either mutation shows that there is no selective survival advantage of cells carrying one genetic defect over the other. We conclusively demonstrate that for the R28C‐missense mutant (Xid), there is no biologically relevant residual activity or any dominant negative effect versus other proteins.
CXCR4 mutations in WHIM syndrome: a misguided immune system?
Authors: Diaz George A.
Published: January 2005

Summary:  Chemokines and their receptors are key molecules in the development and function of immune cell populations and the organization of lymphoid organs. Despite their central role in immunologic function, genetic studies exploring the intersection of chemokines or their receptors and human health have revealed few associations of unambiguous significance. The best‐characterized examples have revealed striking selective advantage conferred by loss of receptors used as portals of entry by pathogens. Recently, mutations in the CXCR4 chemokine receptor gene were identified in a dominantly inherited immunodeficiency disease, WHIM syndrome. Genetic and biochemical evidences suggest that the loss of the receptor cytoplasmic tail domain results in aberrant signaling. Analyses of mutant cell responses to the receptor ligand CXCL12 have revealed enhanced chemotaxis, confirming the gain‐of‐function effect of the truncation mutations. The clinical features and potential mechanism of immunodeficiency in WHIM syndrome patients are discussed in this review.
Defects in the interferon‐γ and interleukin‐12 pathways
Authors: Rosenzweig Sergio D. , Holland Steven M.
Published: January 2005

Summary:  The interferon‐γ (IFN‐γ)/interleukin‐12 (IL‐12) pathway is a pivotal player in the immune system and is central to controlling mycobacterial infections. We highlight the most recent and relevant advances in understanding this pathway and their repercussions on basic and clinical science. Human mutations in IFN‐γ receptor‐1 (IFN‐γR1), IFN‐γR2, IL‐12p40, IL‐12 receptor‐β1, signal transducer and activator of transcription‐1, and nuclear factor‐κB essential modulator are analyzed in the context of genetic susceptibility to mycobacterial diseases. A diagnostic and therapeutic approach is described. The IFN‐γ/IL‐12 pathway is central in immune control of both environmental and autochthonous challenges, as reflected in human mutations and animal models. Besides being crucial for mycobacterial control, the IFN‐γ/IL‐12 pathway is also involved in the pathogenesis of autoimmune disease as well as tumor development and control. Genotype–phenotype correlations have been established for certain genes in this pathway, some of which have therapeutic implications.
Hyper‐IgE syndromes
Authors: Grimbacher Bodo , Holland Steven M. , Puck Jennifer M.
Published: January 2005

Summary:  The hyper‐immunoglobulin E (IgE) syndromes (HIES) are primary immunodeficiencies characterized by the clinical triad of recurrent staphylococcal abscesses, recurrent cyst‐forming pneumonia, and an elevated serum IgE level of >2000 IU/ml. Most cases are sporadic; however, multiplex families displaying autosomal dominant (AD) and autosomal recessive (AR) inheritance have been described. In most sporadic and AD cases, the HIES clinical triad is part of a multisystem disorder including abnormalities of the soft tissue, skeletal, and dental systems. In contrast, those with AR‐HIES have severe molluscum contagiosum and other viral infections and may develop severe neurological complications. Unlike patients with sporadic HIES and AD‐HIES, those with AR‐HIES lack skeletal or dental involvement and do not develop lung cysts. Additional variants of HIES are discussed in this review. The etiology of HIES is still unresolved. Recent research points toward a skewed T helper 1 (Th1) cell/Th2 cell ratio and the involvement of chemokines. Therapy for HIES is directed at prevention and management of infections by using sustained systemic antibiotics and antifungals along with topical therapy for eczema and drainage of abscesses. Anti‐staphylococcal antibiotic prophylaxis is useful. Interferons, immunoglobulin supplementation, or low‐dose cyclosporine A have been reported to benefit selected patients, but they are not generally indicated.
Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular, and immunological features
Authors: Lougaris Vassilios , Badolato Raffaele , Ferrari Simona , Plebani Alessandro
Published: January 2005

Summary:  CD40 is a member of the tumor necrosis factor receptor family, which is expressed by a variety of cells including B cells, macrophages, dendritic cells, and other nonimmune cell types. CD40 activation is critical for B‐cell proliferation, immunoglobulin (Ig)‐isotype switching, and germinal center formation. In physiological conditions, the activation of CD40 occurs by binding to its natural ligand, CD154, which is expressed on activated T cells. The in vivo critical role of CD40–CD154 interaction on B‐cell differentiation and isotype switching is provided by the discovery that mutations in either CD40 or CD154 gene cause the hyper IgM syndrome, termed HIGM3 or HIGM1, respectively, characterized by very low levels of serum IgG, IgA, and IgE, with normal or elevated IgM, associated with a defective germinal center formation. Originally considered humoral primary immunodeficiencies, the clinical features and the defect of T‐cell priming, resulting from a defective T–B cell or dendritic cell interaction, is now considered as combined immunodeficiencies. In this article, we present a comprehensive overview of the clinical, genetic, and immunological features of patients with hyper IgM syndrome due to CD40 mutations.
Molecular and cellular pathogenesis of X‐linked lymphoproliferative disease
Authors: Nichols Kim E. , Ma Cindy S. , Cannons Jennifer L. , Schwartzberg Pamela L. , Tangye Stuart G.
Published: January 2005

Summary:  X‐linked lymphoproliferative disease (XLP) is an inherited immune defect caused by mutations in the Src homology 2 domain‐containing gene 1A, which encodes the adapter protein, signaling lymphocytic activation molecule (SLAM)‐associated protein (SAP). SAP is expressed in T cells, natural killer (NK) cells, and NKT cells, where it binds to the cytoplasmic domain of the surface receptor SLAM (CD150) and the related receptors, 2B4 (CD244), CD84, Ly9 (CD229), NK‐T‐B‐antigen, and CD2‐like receptor‐activating cytotoxic T cells. SAP also binds to the Src family tyrosine kinase Fyn and recruits it to SLAM, which leads to the generation of downstream phosphotyrosine signals. While the roles of the SLAM family receptors are only beginning to be understood, experiments suggest that these molecules regulate important aspects of lymphocyte function, such as proliferation, cytokine secretion, cytotoxicity, and antibody production. Thus, in XLP patients who lack functional SAP, the SLAM family receptors may not signal properly. This property likely contributes to the phenotypes of XLP, including fulminant infectious mononucleosis, lymphoma, and hypogammaglobulinemia. Further studies of SAP and the SLAM family receptors will provide insights into XLP and elucidate the signaling events regulating lymphocyte ontogeny and function.
DNA deamination in immunity
Authors: Petersen‐Mahrt Svend
Published: January 2005

Summary:  A functional immune system is one of the prerequisites for the survival of a species. Humans have one of the most complicated immune systems, with the ability to learn from and adapt to pathogens. At first, a primary repertoire of antibodies is generated, which, upon antigen encounter, will diversify and adapt to produce a highly specific and potent secondary response, part of which is kept in memory to fight off future infections. In this review, the mechanism as well as the specificities of the key protein in the secondary immune response, activation‐induced cytidine deaminase (AID), are highlighted, as well as its role in the DNA deamination model of immunoglobulin diversification. The review also highlights aspects of AID's regulation on both the transcriptional as well as post‐translational level and its potential molecular mechanism and specificity. Furthermore, it expands outside the involvement of AID in somatic hypermutation, class switching, and gene conversion to discuss the implications of DNA deamination in epigenetic modifications of DNA (as a potential demethylase), the induction of mutations during oncogenesis, and includes an evolutionary comparison to the DNA deaminase family member APOBEC3G, a key protein in human immunodeficiency virus pathogenesis.
Genetic analysis of patients with defects in early B‐cell development
Authors: Conley Mary Ellen , Broides Arnon , Hernandez‐Trujillo Vivian , Howard Vanessa , Kanegane Hirokazu , Miyawaki Toshio , Shurtleff Sheila A.
Published: January 2005

Summary:  Approximately 85% of patients with defects in early B‐cell development have X‐linked agammaglobulinemia (XLA), a disorder caused by mutations in the cytoplasmic Bruton's tyrosine kinase (Btk). Although Btk is activated by cross‐linking of a variety of cell‐surface receptors, the most critical signal transduction pathway is the one initiated by the pre‐B cell and B‐cell antigen receptor complex. Mutations in Btk are highly diverse, and no single mutation accounts for more than 3% of patients. Although there is no strong genotype/phenotype correlation in XLA, the specific mutation in Btk is one of the factors that influences the severity of disease. Mutations in the components of the pre‐B cell and B‐cell antigen receptor complex account for an additional 5–7% of patients with defects in early B‐cell development. Patients with defects in these proteins are clinically indistinguishable from those with XLA. However, they tend to be younger at the time of diagnosis, and whereas most patients with XLA have a small number of B cells in the peripheral circulation, these cells are not found in patients with defects in µ heavy chain or Igα. Polymorphic variants in the components of the pre‐B cell and B‐cell receptor complex, particularly µ heavy chain and λ5, may contribute to the severity of XLA.
Inherited disorders of human Toll‐like receptor signaling: immunological implications
Authors: Ku Cheng‐Lung , Yang Kun , Bustamante Jacinta , Puel Anne , Von Bernuth Horst , Santos Orchidée Filipe , Lawrence Tatiana , Chang Huey‐Hsuan , Al‐Mousa Hamoud , Picard Capucine , Casanova Jean‐Laurent
Published: January 2005

Summary:  In vitro nine of 10 known human Toll‐like receptors (TLRs) are engaged by well‐defined chemical agonists that mimic microbial compounds, raising the possibility that human TLRs play a critical role in protective immunity in vivo. We thus review here the recently described human primary immunodeficiencies caused by germline mutations in genes encoding molecules involved in cell signaling downstream from TLRs. Subjects with anhidrotic ectodermal dysplasia with immunodeficiency (EDA‐ID) carry either X‐linked recessive hypomorphic mutations in NEMO or autosomal dominant hypermorphic mutations in IKBA. Their cells show a broad defect in nuclear factor‐κB (NF‐κB) activation, with an impaired, but not abolished response to a large variety of stimuli including TLR agonists. EDA‐ID patients show developmental anomalies of skin appendages and a broad spectrum of infectious diseases. Patients with autosomal recessive amorphic mutations in IRAK4 present a purely immunological syndrome and more restricted defects, with specific impairment of the Toll and interleukin‐1 receptor (TIR)–interleukin‐1 receptor‐associated kinase (IRAK) signaling pathway. In these subjects, the NF‐κB‐ and mitogen‐activated protein kinase‐mediated induction of inflammatory cytokines in response to TIR agonists is impaired. The patients present a narrow range of pyogenic bacterial infections that become increasingly rare with age. Altogether, these data suggest that human TLRs play a critical role in host defense. However, they do not provide compelling evidence, as even the infectious phenotype of patients with mutations in IRAK4 may result from impaired signaling via receptors other than TLRs. Paradoxically, these experiments of nature raise the possibility that the entire set of human TLRs is largely redundant in protective immunity in vivo.
Studies of patients' thymi aid in the discovery and characterization of immunodeficiency in humans
Authors: Roifman Chaim M
Published: January 2005

Summary:  Studying the molecular and genetic bases of primary immunodeficiency is valuable at several levels. First, such information directly benefits patients in both short‐ and long‐term management. Sophisticated diagnostic tools based on these studies can be used early and lead to appropriate treatment before potentially fatal infections and complications arise. Genotyping is also critical for future development and implementation of gene therapy. Secondly, investigating primary immunodeficiency helps understand the normal immune system in humans. As described in this report, the roles of ζ‐associated protein of 70 kDa (Zap‐70), CD25, and CD3δ are substantially different in humans when compared with the roles of homologous molecules in other species. Last, information obtained from these studies can be applied to other fields of investigation. Prominent examples for such applications include the intensive effort to design and produce specific inhibitors of Zap‐70 and Janus kinase 3 as specific immunosuppressive agents. Most types of primary immunodeficiency in general and severe combined immunodeficiency in particular are rare and therefore cannot be easily studied by using traditional genetic methodology. Instead, biochemical methods were used to explore for candidate genes as was the case in the discovery of Zap‐70 deficiency. Critical to the success of these discoveries was the careful analysis of patients' thymus glands. Detection of abnormalities in the thymus in these patients, which preceded identification of the genetic defect, aided in the assessment of the severity and nature of the immune disorder (primary versus secondary). Such assessment is critical before high‐risk bone marrow transplantation. Equally important was the contribution of studies of the thymus to the description of novel phenotype of immunodeficiency as clearly demonstrated in defining CD8 lymphocytopenia, Zap‐70 deficiency, and CD25 deficiency. Indeed, analysis of the thymus directly pointed to CD25 as candidate gene. Recently, the study of thymocyte‐derived transcripts using DNA microarrays was key to discovering CD3δ deficiency. Finally, immunohistochemical analysis of the thymus was critical in pinpointing the roles of Zap‐70, CD25, and CD3δ in the development of human T cells.
ROBERT HOOKE, MONUMENTS AND MEMORY
Authors: Stevenson Christine
Published: January 2005

In June 1682, when Robert Hooke (1635–1703) delivered a lecture to the Royal Society on memory – his first and only excursion into human psychology – he had just witnessed a spectacularly public failure of memory when new texts were added to the Monument (1671–76), which he had designed with Christopher Wren. In a direct civic challenge to royal authority, these explained that the ‘Papists’ had set London's Great Fire of September 1666. This paper examines the tensions and accommodations between the City of London and Charles II that accompanied the Monument's erection; the column serves to dramatize the difficulties besetting would‐be memorializers in Restoration England. It is suggested that Hooke's memory lecture must be read, not only in the light of specific political anxieties then attached to memory, but against the other ways in which he grappled with forms of signification, here treated as forms of historical witness.
PRIVILEGING THE OBJECT OF SCULPTURE: ACTUALITY AND HARRY BATES'S PANDORA OF 1890
Authors: Getsy David J.
Published: January 2005

Sculptural representation negotiates between being an image (for instance, a female nude) and an object (a thing made of marble, bronze, etc.). Questions of literality and objecthood are often reserved for assessments of later modernist sculpture, but I demonstrate that this same fundamental set of concerns preoccupied the late‐Victorian sculptor Harry Bates in his Pandora of 1890. In this work, Bates staged sculptural actuality — that is, the equivalence in a sculpture between the thing represented and the sculptural object itself. He did so in order to position himself within late‐Victorian debates about the future of sculpture and to make a polemical case for the potency of the decorative object as a new avenue for sculptors' efforts. Beyond allowing a reconsideration of the art‐theoretical sophistication of so‐called ‘academic’ nineteenth‐century sculpture, Bates's Pandora illuminates on a more general level the parameters of sculptural representation.
PERFORMING THE OTHER: YOKO ONO'S CUT PIECE
Authors: Rhee Jieun
Published: January 2005

Staged five times by Yoko Ono between 1964 and 1966, Cut Piece has been interpreted in a variety of ways, including an exploration of sadism/masochism and violence/victimization. It has also been discussed in terms of feminist discourses on the female body and the male gaze. By contrast, this famous event has rarely been examined in terms of audiences' responses to Ono's performances and in particular the relationship between such responses and the social, cultural, national and ethnic contexts. From sacred prostitution cults of Kumano bikuni to the sexual component of the Western avant garde, this essay examines the emblematic roles that Ono's Cut Piece played during the crucial years of performance art.
Quantitative tests of interaction between pollinating and non‐pollinating fig wasps on dioeciousFicus hispida
Authors: Peng Yan Q. , Yang Da R. , Wang Qiu Y.
Published: January 2005

Abstract. 1. The interaction betweenFicusspecies and their pollinating wasps (Agaonidae) represents a striking example of a mutualism. Figs also shelter numerous non‐pollinating chalcids that exploit the fig–pollinator mutualism.

2. Previous studies showed a weak negative correlation between numbers of pollinating and non‐pollinating adults emerging from the same fruit. Little is known about the patterns and intensities of interactions between fig wasps. In the Xishuangbanna tropical rainforests of China, the dioeciousFicus hispidaL. is pollinated byCeratosolen solmsi marchaliMayr and is also exploited by the non‐pollinatorsPhilotrypesis pilosaMayr,Philotrypesissp., andApocrypta bakeriJoseph. Here, the interaction of pollinator and non‐pollinators onF. hispidais studied quantitatively.

3. The exact time of oviposition was determined for each species of fig wasp. Based on observational and experimental work it is suggested that (i) the relationship between pollinator and non‐pollinators is a positive one, and that the genusPhilotrypesisappears to have no significant impact on the pollinator population, whereasApocryptahas a significant effect on bothPhilotrypesisandCeratosolen; (ii) gall numbers do not always increase with increasing number of foundresses, but developmental mortality of larvae correlates positively with the number of foundresses; and (iii) there is a positive correlation between non‐pollinator numbers and their rates of parasitism, but the three species of non‐pollinators differed in their rates of parasitism and show different effects on pollinator production.

4. The rates of parasitism when combined with the coexistent percentage and developmental mortality, underpin the way non‐pollinating fig wasps successfully exploit and coexist stably in a fig–pollinator mutualism.
Dispersal ability and host‐plant characteristics influence spatial population structure of monophagous beetles
Authors: St Pierre Matthew J. , Hendrix Stephen D. , Lewis Cassandra K.
Published: January 2005

Abstract. 1. Dispersal plays an integral role in determining spatial population structure and, consequently, the long‐term survival of many species. Theoretical studies indicate that dispersal increases with population density and decreasing habitat stability. In the case of monophagous insect herbivores, the stability of host‐plant populations may influence their spatial population structure.

2. The tallgrass prairie in Iowa, U.S.A. is highly fragmented and most prairie insects face a landscape with fewer habitat patches and smaller host‐plant populations than 150 years ago, potentially making dispersal between patches difficult. Some herbivores, however, use native plant species with weedy characteristics that have increased in abundance because of disturbances.

3. Mark–recapture data and presence–absence surveys were used to examine dispersal and spatial population structure of two monophagous beetles with host plants that exhibit different population stability and have responded differently to fragmentation of tallgrass prairie.

4.Chrysochus auratusFabricius exhibits a patchy population structure and has relatively large dispersal distances and frequencies. Its host plant is variable locally in time and space, but is more abundant than 150 years ago. The other species,Anomoea laticlaviaForster, exhibits a metapopulation or non‐equilibrium population structure and has relatively small dispersal distances and frequencies. Its host‐plant populations are stable in time and space.

5. The results indicate that dispersal ability of monophagous beetles reflects the life‐history dynamics of their host plants, but the spatial population structure exhibited today is strongly influenced by how the host plants have responded to the fragmentation process over both time and space.