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PubMed2005

Spatial registration of multichannel multi-subject fNIRS data to MNI space without MRI.

The registration of functional brain data to the common brain space offers great advantages for inter-modal data integration and sharing. However, this is difficult to achieve in functional near-infrared spectroscopy (fNIRS) because fNIRS data are primary obtained from the head surface and lack structural information of the measured brain. Therefore, in our previous articles, we presented a method for probabilistic registration of fNIRS data to the standard Montreal Neurological Institute (MNI) template through international 10-20 system without using the subject's magnetic resonance image (MRI). In the current study, we demonstrate our method with a new statistical model to facilitate group studies and provide information on different components of variability. We adopt an analysis similar to the single-factor one-way classification analysis of variance based on random effects model to examine the variability involved in our improvised method of probabilistic registration of fNIRS data. We tested this method by registering head surface data of twelve subjects to seventeen reference MRI data sets and found that the standard deviation in probabilistic registration thus performed for given head surface points is approximately within the range of 4.7 to 7.0 mm. This means that, if the spatial registration error is within an acceptable tolerance limit, it is possible to perform multi-subject fNIRS analysis to make inference at the population level and to provide information on positional variability in the population, even when subjects' MRIs are not available. In essence, the current method enables the multi-subject fNIRS data to be presented in the MNI space with clear description of associated positional variability. Such data presentation on a common platform, will not only strengthen the validity of the population analysis of fNIRS studies, but will also facilitate both intra- and inter-modal data sharing among the neuroimaging community.

Adult↗

PubMed1990

Paired individual and mean postsynaptic currents recorded in four-cell networks of Aplysia.

1. Presynaptic neurons B4 and B5 of Aplysia buccal ganglia produce similar inhibitory postsynaptic currents (PSCs) in several postsynaptic follower cells. Two previous papers have characterized the variability of synaptic current amplitude and decay time both for individual PSCs and also for mean values characterizing synapses and have compared PSC amplitude and time course at different synapses sharing a common presynaptic or postsynaptic neuron. 2. To distinguish similarity in synaptic current amplitude or decay introduced by a common pre- or postsynaptic neuron from similarity because of factors common to the particular ganglion or animal, paired synapses were analyzed in four-cell networks in which each of two identified presynaptic neurons produces similar PSCs in each of two postsynaptic cells. Pairing the same synaptic data by common presynaptic or postsynaptic neuron tests if the presynaptic or postsynaptic element partially specifies a parameter; cross-pairing controls for more global factors. Paired values of peak conductance gpeak and decay time constant tau were compared for both individual sequential PSCs and for averages characterizing synapses. Analyses of individual PSCs examine processes affecting synaptic plasticity on a time scale of seconds to minutes, while average values compare more slowly varying factors. 3. Peak amplitudes were compared between individual PSCs in each of 24 paired sets. Correlations of gpeak fluctuations were significantly larger for PSCs produced by the same presynaptic neuron than for postsynaptic or cross pairings (P less than 0.05), consistent with partially correlated fluctuations in transmitter release at different presynaptic terminals. 4. Firing rates of individual presynaptic neurons were modulated to induce variability of test PSCs. These manipulations altered synaptic peak amplitudes in paired postsynaptic neurons, although not to the same degree. Manipulation of a single presynaptic neuron modulated input from that neuron alone to common postsynaptic cells without any effect on input from the paired presynaptic neuron. When fluctuations in the amplitude of gpeak were examined in runs incorporating presynaptic modulation, correlations were strong for sets of PSCs sharing a common presynaptic neuron (R = 0.87), significantly greater (P less than 0.001) than for other pairings. 5. In contrast to the partial presynaptic specification of fluctuations of individual PSCs, values of synaptic amplitude and time course averaged over 21-132 PSCs at a given synapse reflect postsynaptic determinants. Mean values of gpeak characterizing synapses paired by common postsynaptic cell are highly similar (P = 0.0001), in contrast to the lack of similarity seen when the same data are presynaptically (P = 0.11) or cross (P = 0.36) paired.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2001

The development of the skull in Acrochordus granulatus (Schneider) (Reptilia: Serpentes), with special consideration of the otico-occipital complex.

The skull of Acrochordus has been characterized by the absence of a crista circumfenestralis (a synapomorphy shared by all snakes), and by the absence of a recessus scalae tympani that in other squamates forms by subdivision of the embryonic metotic fissure. These traits have variably been identified as either plesiomorphic or paedomorphic. The study of the development of the osteocranium in a series of cleared and stained embryos of Acrochordus shows a close correspondence to the development of the skull in other snakes. The exception is the formation of the postorbital from two ossification centers. The significance of this observation, which might suggest the embryonic fusion of a postfrontal with a postorbital, remains enigmatic, as it is based on one side only of the skull of a single specimen. By contrast, a rudimentary and modified crista circumfenestralis can be identified in the skull of Acrochordus. Furthermore, absence of a recessus scalae tympani is not due to an undivided fissura metotica, but results from the obliteration of the anterior part of the metotic fissure instead. With respect to this character, Acrochordus is neither plesiomorphic, nor paedomorphic, but autapomorphic. This interpretation of the skull of Acrochordus is compatible with the sister-group relationships this genus shares with colubroid snakes.

Animals↗

PubMed2006

Mucin profiles in signet-ring cell carcinoma.

CONTEXT: Signet-ring cell carcinoma (SRCC) is a poorly differentiated mucin-producing adenocarcinoma that may arise from many different organs, but all SRCCs share identical morphology. It is not possible to differentiate sites of origin for metastatic SRCC based on morphology alone. Mucins are high-molecular-weight glycoproteins differentially expressed in glandular epithelia and in adenocarcinomas. OBJECTIVE: To identify mucin profiles of primary and metastatic SRCCs using immunohistochemistry to determine whether mucin staining could help distinguish sites of origin. DESIGN: Forty-seven SRCCs, including 38 primary (21 stomach, 11 colorectum, and 6 breast) and 9 metastases from these primary sites were retrieved from archival files. Consecutive tissue sections were immunostained with monoclonal antibodies against MUC1, MUC2, MUC4, MUC5AC (MUC5), and MUC6 on separate slides. Cytoplasmic staining was scored based on proportion of positive tumor cells as follows: 0+ (<5%), 1+ (5%-25%), 2+ (26%-50%), and 3+ (>50%). Mucin profiles were recorded as MUC+, MUCv, and MUC- for consistent, variable, and negative expression, respectively. RESULTS: The mucin profiles for gastric, colorectum, and breast SRCCs are MUC1.2.4.5.6v, MUC2.4+/MUC5v/ MUC1.6-, and MUC1+/MUC2.5.6v/MUC4-, respectively. Mucin profiles of metastatic cases shared profiles with their respective primaries. CONCLUSIONS: Signet-ring cell carcinomas of the stomach, colorectum, and breast have distinct mucin expression patterns that are maintained in metastases. Mucin profiling may be useful to identify the origin of a metastatic SRCC of unknown primary.

Carcinoma, Signet Ring Cell↗

PubMedDate not supplied

A qualitative study of increasing beta-blocker use after myocardial infarction: Why do some hospitals succeed?

CONTEXT: Based on evidence that beta-blockers can reduce mortality in patients with acute myocardial infarction (AMI), many hospitals have initiated performance improvement efforts to increase prescription of beta-blockers at discharge. Determination of the factors associated with such improvements may provide guidance to hospitals that have been less successful in increasing beta-blocker use. OBJECTIVES: To identify factors that may influence the success of improvement efforts to increase beta-blocker use after AMI and to develop a taxonomy for classifying such efforts. DESIGN, SETTING, AND PARTICIPANTS: Qualitative study in which data were gathered from in-depth interviews conducted in March-June 2000 with 45 key physician, nursing, quality management, and administrative participants at 8 US hospitals chosen to represent a range of hospital sizes, geographic regions, and changes in beta-blocker use rates between October 1996 and September 1999. MAIN OUTCOME MEASURES: Initiatives, strategies, and approaches to improve care for patients with AMI. RESULTS: The interviews revealed 6 broad factors that characterized hospital-based improvement efforts: goals of the efforts, administrative support, support among clinicians, design and implementation of improvement initiatives, use of data, and modifying variables. Hospitals with greater improvements in beta-blocker use over time demonstrated 4 characteristics not found in hospitals with less or no improvement: shared goals for improvement, substantial administrative support, strong physician leadership advocating beta-blocker use, and use of credible data feedback. CONCLUSIONS: This study provides a context for understanding efforts to improve care in the hospital setting by describing a taxonomy for classifying and evaluating such efforts. In addition, the study suggests possible elements of successful efforts to increase beta-blocker use for patients with AMI.

Adrenergic beta-Antagonists↗

PubMed1999

Protein loops on structurally similar scaffolds: database and conformational analysis.

A general problem in comparative modeling and protein design is the conformational evaluation of loops with a certain sequence in specific environmental protein frameworks. Loops of different sequences and structures on similar scaffolds are common in the Protein Data Bank (PDB). In order to explore both structural and sequential diversity of them, a data base of loops connecting similar secondary structure fragments is constructed by searching the data base of families of structurally similar proteins and PDB. A total of 84 loop families having 2-13 residues are found among the well-determined structures of resolution better than 2.5 A. Eight alpha-alpha, 20 alpha-beta, 19 beta-alpha, and 37 beta-beta families are identified. Every family contains more than 5 loop motifs. In each family, no loops share same sequence and all the frameworks are well superimposed. Forty-three new loop classes are distinguished in the data base. The structural variability of loops in homologous proteins are examined and shown in 44 families. Motif families are characterized with geometric parameters and sequence patterns. The conformations of loops in each family are clustered into subfamilies using average linkage cluster analysis method. Information such as geometric properties, sequence profile, sequential and structural variability in loop, structural alignment parameters, sequence similarities, and clustering results are provided. Correlations between the conformation of loops and loop sequence, motif sequence, and global sequence of PDB chain are examined in order to find how loop structures depend on their sequences and how they are affected by the local and global environment. Strong correlations (R > 0.75) are only found in 24 families. The best R value is 0.98. The data base is available through the Internet.

Amino Acid Sequence↗

PubMed2004

Dependency issues in survival analyses of 55,782 primary hip replacements from 47,355 patients.

Artificial hip joints are used in only one hip for about 85 per cent of the patients and in both hips (bilateral) for about 15 per cent of the patients. The occurrence of bilateral prostheses and the influence they have in survival analyses of joint arthroplasties are seldom considered. In this study we therefore focus on issues related to bilateral primary hip prostheses, time to revision surgery, and some commonly used statistical methods. We used information from 47,355 patients with 55,782 primary hip prostheses reported to the Norwegian Arthroplasty Register between 1987 and 2000. Due to the large number of diagnoses, fixation techniques for the prostheses, and combination of prostheses brands, we furthermore considered a 'homogeneous' subset of 8703 prostheses from 7930 patients with primary osteoarthritis, and Charnley prosthesis fixed with antibiotic-containing Palacos cement. Kaplan-Meier curves for all prostheses, ignoring that some patients have bilateral prostheses, were compared with Kaplan-Meier curves using only the first inserted prostheses, and with survival curves modified for patients with bilateral prostheses. Cox regression analyses were used to assess explanatory variables and to adjust for confounding factors. The results from the ordinary Cox regression analyses were compared with results from a marginal model, a shared gamma frailty model, and a model using a time dependent covariate to condition on failures in the opposite hip. We found no practical difference between the three calculated survival curves for the hip replacement data. The ordinary Cox-model and the marginal model gave equivalent results. In the shared gamma frailty model estimates for the risk factors were comparable with the former two approaches. The estimated frailty variance was higher when all data were used, even after adjustment for confounding factors. For the 'homogeneous' data the estimated frailty variance was negligible. Using a time dependent covariate to condition on previous revisions in the opposite hip, we found a higher risk of revision for the remaining primary hip prosthesis if the opposite hip had been revised (RR = 3.49, p < 0.0001). There was no difference in risk for revision between right and left hip prostheses. If the time interval between the two primary operations was more than two years, for the full data, the first hip prosthesis had an increased risk of revision compared to prostheses in patients with only one prosthesis (RR = 1.25, p = 0.01). For the 'homogeneous' data no statistically significant difference was found between unilateral and bilateral prostheses. A revision in one hip, for patients with bilateral prostheses, is a risk factor for revision of the other hip. Thus, in analyses of prostheses survival, dependencies between two hip prostheses from one patient should be considered. However, ignoring possible dependencies does not necessarily have an impact on the results on standard risk factors.

Aged↗

PubMed2000

Spatial and temporal aspects of eye-hand coordination across different tasks.

The way in which saccadic eye movements are elicited influences their latency and accuracy. Accordingly, different tasks elicit different types of saccades. Using the tasks steps, gap, memory, scanning and antisaccade, we analyzed combined eye and hand movements to determine whether both motor systems share control strategies. Errors and latencies were measured to examine whether changes in eye motor behavior are reflected in hand motor behavior. Directional and variable errors of eye and hand changed differently according to the tasks. Moreover, errors of the two systems did not correlate for any of the tasks investigated. Contrary to errors, mean latencies of eye movements were organized in the same pattern as hand movements. A correlation of latencies indicates that both motor systems rely on common information to initiate movement. Temporal coupling was stronger for intentional tasks than for reflexive tasks.

Adult↗

PubMed1996

Structural characterization of recombinant domain II of the basement membrane proteoglycan perlecan.

Mouse perlecan domain II (325 residues), consisting of four cysteine-rich LA modules, one IG module and a link region, was obtained in purified form from a stably transfected mammalian cell clone. Rotary shadowing electron microscopy demonstrated a globular domain connected to a short rod-like segment of variable length. This suggested that tandem arrays of LA modules form rod-like elements. Folding into a native structure was indicated by the sharing of immunological epitopes with tissue perlecan, a CD spectrum demonstrating 37% beta structure and a limited susceptibility to proteolysis. The domain also showed N-glycosylation of a single acceptor site and 7-8 O-linked oligosaccharides. The latter were located mainly in the link region within proline-rich sequences.

Amino Acid Sequence↗

PubMed2005

Identification of functional promoters in the msp2 expression loci of Anaplasma marginale and Anaplasma phagocytophilum.

Organisms in the family Anaplasmataceae are important tick-borne pathogens of livestock worldwide and cause recently emergent infections in humans. Despite their medical importance, very little is known about how these organisms regulate gene expression in the mammalian host, the tick vector, or during transition between the host and vector. However, it is clear that gene regulation, in addition to recombinatorial mechanisms, is essential for these small genome pathogens to adapt to distinctly different environments. In this study, we identify and establish the function of three promoter elements in the locus encoding major outer membrane protein expression sites in both Anaplasma marginale and Anaplasma phagocytophilum. Gene expression from this locus involves both classical and atypical polycistronic transcripts. The identified promoter elements have a structure similar to that defined in Escherichia coli and are functional in driving protein expression in a prokaryotic cell-free transcription and translation system and in recombinant E. coli. The two strongest promoters identified in vitro and with recombinant E. coli were also shown to be functional in A. marginale infected cells, as determined by quantification of downstream transcripts. The promoters in both A. marginale and A. phagocytophilum have similar structure and activity, supporting the conclusion that the two loci are syntenic with conservation of function. In addition, they share structural elements within the promoters that appear to be likely sites for regulation. These data enhance our understanding of how expression of these variable outer membrane proteins may be controlled in the key stages of tick-borne transmission and infection.

Animals↗

PubMed1998

Nitric oxide and its role in apoptosis.

Nitric oxide (NO.), a potentially toxic molecule, has been implicated in a wide range of diverse (patho)physiological processes. It is appreciated that the production of NO. from L-arginine is important for nonspecific host defense, helping to kill tumors and intracellular pathogens. Cytotoxicity as a result of a massive NO.-formation is now established to initiate apoptosis. Apoptotic cell death in RAW 264.7 macrophages and several other systems as a result of inducible NO-synthase activation comprises upregulation of the tumor suppressor p53, activation of caspases, chromatin condensation, and DNA fragmentation. The involvement of NO was established by blocking adverse effects by NO-synthase inhibition. Overexpression of the antiapoptotic protein Bcl-2 rescued cells from apoptosis by blocking signal propagation downstream of p53 and upstream of caspase activation. As the wide variety of NO.-effects is achieved through its interactions with targets via redox and additive chemistry, the biological milieu, as a result of internal and external stimuli, may modulate toxicity. Therefore, transducing pathways of NO. are not only adopted to cytotoxicity but also refer to cell protection. NO.-signaling during protection from apoptosis is in part understood by the requirement of gene transcription and protein synthesis. NO.-formation causes upregulation of protective proteins such as heat shock proteins, cyclooxygenase-2, or heme oxygenase-1 which in a cell specific way may attenuate apoptotic cell death. Alternatively, protection may result as a consequence of a diffusion controlled NO./O2- (superoxide) interaction. The NO./O2--interaction redirects the apoptotic initiating activity of either NO. or O2- towards protection as long as reduced glutathione compensates the resultant oxidative stress. Protective principles may further arise from cyclic GMP formation or thiol modification. NO shares with other toxic molecules such as tumor necrosis factor-alpha the unique ability to initiate and to block apoptosis, depending on multiple variables that are being elucidated. The crosstalk between cell destructive and protective signaling pathways, their activation or inhibition under the modulatory influence of NO. will determine the role of NO in apoptotic cell death.

Animals↗

PubMed2003

Cloning and characterization of five cDNAs encoding peritrophin-A domains from the cat flea, Ctenocephalides felis.

Five cDNAs encoding peritrophin-A domains were identified as expressed sequence tags (ESTs) from flea hindgut and Malpighian tubule (HMT) cDNA libraries. The full-length cDNAs for each were subsequently isolated and sequenced. Three of the encoded proteins were similar to published peritrophin sequences, and thus were called "peritrophin-like", or PL1, PL2, and PL3. The other two sequences had similarity to both mucin and peritrophin proteins, and were called "mucin/peritrophin-like", or MPL1 and MPL2. The predicted protein sequences encoded by these cDNAs all contained a signal sequence and one or more peritrophin-A domains, which have been shown in other proteins to bind chitin. Aside from the peritrophin-A domains, the sequences shared little or no similarity to each other or to other proteins in the GenBank non-redundant database. The predicted protein sequences were variable in size, ranging in length from 81 to 453 amino acids. The two MPL proteins contained putative N-linked and O-linked glycosylation sites, including a region of seven nearly perfect tandem repeats in the MPL1 protein sequence. Northern blot analysis of different flea lifestages and fed adult timepoints showed distinct mRNA expression patterns for each gene, although all five transcripts were primarily or exclusively detected in the HMT tissues in adults. The PL1 protein was detected by immuno-blot in soluble and insoluble protein extracts from unfed and fed adult fleas. The PL1 protein from the insoluble fractions appeared to be approximately 1 kDa larger than the PL1 protein from the soluble protein fractions. Immunohistochemistry performed on flea thin sections revealed that the PL1 protein was detected in the Malpighian tubules, hindgut, rectum, and trachea. Unpurified native PL1 protein from both soluble and insoluble protein fractions was tested for chitin-binding activity but did not bind to chitin under the conditions tested. These results show that the flea peritrophin-like proteins may have biological functions that are distinct from the peritrophic matrix and from the binding of chitin.

Amino Acid Sequence↗

PubMed1983

Behavioral responses to amphetamines in identical twins.

Male, monozygotic twins (six pairs) were repeatedly tested before and after d-amphetamine, l-amphetamine, or placebo administration. Drug effects on cognitive, psychomotor, personality, mood, and pain variables were assessed. Members of a twin pair tended to respond similarly on several tests under placebo conditions, indicating genetic determination of the behavioral variables. In addition, cotwins tended to show similar responses to amphetamine as measured by one test of cognitive function, by several mood and personality variables (hostility, autonomic arousal, friendliness, feelings of tension and loss of control), and tended to have similar plasma levels of both amphetamine isomers. Although shared environmental effects cannot be ruled out, the results are consistent with genetic mediation of a variety of behavioral effects of amphetamines.

Adult↗

PubMed2002

Sequence conservation and distribution of the fusobacterial immunosuppressive protein gene, fipA.

Fusobacterium nucleatum is a gram-negative anaerobe involved in various diseases, including periodontitis. Recently, other investigators isolated the F. nucleatum FDC 364 fusobacterial immunosuppressive protein (FIP). One subunit, FipA, impairs T-cell activation in vitro and shows homology with beta-ketothiolases. However, its distribution and variability among fusobacteria was not reported. Cloned fipA gene sequences from F. nucleatum ssp. polymorphum (ATCC 10953) and F. nucleatum ssp. nucleatum (ATCC 23726) shared 89 and 92% identity, respectively, with FDC 364 fipA, and 90 and 94% identity, respectively, with the FDC 364 FipA predicted amino acid sequence. Southern blot analyses of chromosomal DNA from fusobacterial strains, including F. nucleatum and other Fusobacterium species, were performed using partial fipA sequences as probes. The results indicate that fipA is highly conserved among the F. nucleatum strains examined and that fipA homologues are widely distributed among fusobacteria. A clear relationship between immune suppression, metabolism and the FipA protein remains to be determined.

Acetyl-CoA C-Acetyltransferase↗

PubMed2003

Validation and refinement of survival models for liver retransplantation.

Orthotopic liver retransplantation (re-OLT) is highly controversial. The objectives of this study were to determine the validity of a recently developed United Network for Organ Sharing (UNOS) multivariate model using an independent cohort of patients undergoing re-OLT outside the United States, to determine whether incorporation of other variables that were incomplete in the UNOS registry would provide additional prognostic information, to develop new models combining data sets from both cohorts, and to evaluate the validity of the model for end-stage liver disease (MELD) in patients undergoing re-OLT. Two hundred eighty-one adult patients undergoing re-OLT (between 1986 and 1999) at 6 foreign transplant centers comprised the validation cohort. We found good agreement between actual survival and predicted survival in the validation cohort; 1-year patient survival rates in the low-, intermediate-, and high-risk groups (as assigned by the original UNOS model) were 72%, 68%, and 36%, respectively (P <.0001). In the patients for whom the international normalized ratio (INR) of prothrombin time was available, MELD correlated with outcome following re-OLT; the median MELD scores for patients surviving at least 90 days compared with those dying within 90 days were 20.75 versus 25.9, respectively (P =.004). Utilizing both patient cohorts (n = 979), a new model, based on recipient age, total serum bilirubin, creatinine, and interval to re-OLT, was constructed (whole model chi(2) = 105, P <.0001). Using the c-statistic with 30-day, 90-day, 1-year, and 3-year mortality as the end points, the area under the receiver operating characteristic (ROC) curves for 4 different models were compared. In conclusion, prospective validation and use of these models as adjuncts to clinical decision making in the management of patients being considered for re-OLT are warranted.

Adult↗

PubMed1988

T-cell receptor alpha-chain variable-region haplotypes of normal and autoimmune laboratory mouse strains.

We used Southern blotting and mRNA analysis to characterize allelic polymorphisms among genes of the T-cell antigen receptor (TCR) alpha-chain variable-region (V alpha) locus in a large panel of normal and autoimmune-susceptible or autoimmune-contributing strains of laboratory mice. Four major V alpha haplotypes were defined on the basis of multiple restriction fragment length polymorphisms for each of nine V alpha subfamily probes used. Southern blotting also revealed haplotype-specific loss of bands within some V alpha subfamilies, consistent with the deletion of particular V alpha genes or sets of genes from haplotype to haplotype. In contrast to the situation in the V beta locus, however, deletion of entire V alpha subfamilies was not observed. The nature of V alpha allelic variability was further explored by using an RNase protection assay to analyze expressed V alpha mRNA sequences in thymocyte RNA. Such analysis revealed both shared and unique patterns of V alpha mRNA expression among the different haplotypes and supported the conclusion that haplotype differences sometimes involve V alpha gene deletions. Interestingly, a disproportionate number of, but not all, autoimmune-susceptible strains, including NZB, SJL, SWR, PL/J, and NOD, share a common V alpha haplotype. The identification of murine TCR V alpha haplotypes should provide a basis for understanding the role of TCR diversity in normal immunoregulatory and immune-response phenomena, as well as autoimmune-disease predisposition.

Alleles↗

PubMed1997

Molecular characterization of TUB, TULP1, and TULP2, members of the novel tubby gene family and their possible relation to ocular diseases.

Tubby, an autosomal recessive mutation, mapping to mouse chromosome 7, was recently found to be the result of a splicing defect in a novel gene with unknown function. Database searches revealed that sequences corresponding to the C terminus of the tub protein were highly conserved across a number of species including humans, mice, Caenorhabditis elegans, Arabidopsis, rice, and maize, and that tub was a member of a gene family. We describe here, TUB, the human homolog of mouse tub, and two newly characterized family members, TULP1 for tubby like protein 1 and TULP2. These three family members, which differ in the N-terminal half of the protein, share 60-90% amino acid identity across their conserved C-terminal region and have distinct tissue expression patterns. Alternatively spliced transcripts with 5' variable sequences, three of which have been identified for the tubby gene, may mediate tissue specific expression. We also report that TUB, TULP1, and TULP2 map to human chromosomes 11p15.4, 6p21.3, and 19q13.1, respectively. TULP1 and TULP2 map within the minimal intervals identified for retinitis pigmentosa 14 on chromosome 6p21.3 and cone-rod dystrophy on chromosome 19q13.1. TULP1 and TULP2, which are expressed in the retina, make excellent candidates for these ocular diseases as a mutation within the tub gene is known to lead to early progressive retinal degeneration.

Adaptor Proteins, Signal Transducing↗

PubMed1995

Both extracellular immunoglobin-like domains of CD80 contain residues critical for binding T cell surface receptors CTLA-4 and CD28.

The B7-related molecules CD80 and CD86 are expressed on antigen-presenting cells, bind the homologous T cell receptors CD28 and CTLA-4, and trigger costimulatory signals important for optimal T cell activation. All four molecules are immunoglobulin superfamily members, each comprising an extracellular Ig variable-like (IgV) domain, with CD80 and CD86 containing an additional Ig constant-like (IgC) domain. Despite limited sequence identity, CD80 and CD86 share similar overall receptor binding properties and effector functions. We have identified, by site-directed mutagenesis of soluble forms of CD80 and CD86, residues in both the IgV and IgC domains that are important for CTLA4Ig and CD28Ig binding. Mutagenesis in the IgV domain of CD80 identified 11 amino acids that support receptor binding. Many of these residues are conserved in the B7 family, are hydrophobic, and approximately map to the GFCC'C" beta-sheet face of an IgV fold. Mutagenesis of corresponding residues in CD86 established that some, but not all, of these residues also played a role in CD86 receptor binding. In general, mutations had a similar effect on CTLA4Ig and CD28Ig binding, thereby indicating that both receptors bind to overlapping sites on CD80 and CD86. Further, mutagenesis of several conserved residues in the ABED beta-sheet face of the IgC domain of CD80 completely ablated receptor binding. Point mutagenesis had a more pronounced effect than complete truncation of the IgC domain. Thus, full CTLA4Ig and CD28Ig binding to B7 molecules is dependent upon residues in the GFC'C" face of the IgV domain and the ABED face of the IgC domain.

Abatacept↗