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James Robinson

Publications and source records attributed to James Robinson.

At least 19 recordsLinked to original sources
PubMed2026

HLA Diversity of Over 500,000 Individuals on the DATRI Register Across 18 Regions in India.

Registries of unrelated stem cell donors can use HLA haplotype frequencies to aid in registry management. DATRI is India's largest registry with over 550,000 donors, with donors in 35 of India's 36 states and union territories. A geographical based analysis on HLA haplotype frequencies has not previously been carried out with an Indian dataset of this size. To balance granularity and accuracy in estimating 5-locus haplotype frequencies for HLA-A, -C, -B, -DRB1 and -DQB1, we grouped donors into 18 regions with a minimum population size of 2000 donors. We identified the most frequent haplotype as A*33:03-ARD~C*07:01-ARD~B*44:03-ARD~DRB1*07:01-ARD~DQB1*02:01-ARD in Odisha (6.09%), which was also the most frequent haplotype in nine other regions. Assigning the most likely diplotypes to donors, there were a total of 57,959 haplotypes and just 202 (0.3%) of those were present in all 18 regions. HLA-B had the greatest number of alleles across the whole dataset (559) and HLA-DQB1 the least (167). However, HLA-C displayed the most inter-region diversity with only 6.7% of HLA-C alleles present in all regions (average 9.5%). We clustered the regions, using Nei's standard genetic distance, and these correlated with geography; however, three regions (North India, Kerala, and the Gujarat area) did not fit into any cluster. These regions each had one or more distinctive haplotypes that were very frequent (≥ 0.5%) in that region alone. Additionally, the Gujarat area had the lowest diversity metrics. These data can be used to inform the management of registries and contribute to our understanding of HLA diversity globally.

Humans↗
PubMed2025

Proteomic Profiling of the Large-Vessel Vasculitis Spectrum Identifying Shared Signatures of Innate Immune Activation and Stromal Remodeling.

OBJECTIVE: Takayasu arteritis (TAK) and giant cell arteritis (GCA), the most common forms of large-vessel vasculitis (LVV), can result in serious morbidity. Understanding the molecular basis of LVV should aid in developing better biomarkers and treatments. METHODS: Plasma proteomic profiling of 184 proteins was performed in two cohorts. Cohort 1 included patients with established TAK (n = 96) and large-vessel GCA (LV-GCA) (n = 35) in addition to healthy control participants (HCs) (n = 35). Cohort 2 comprised patients presenting acutely with possible cranial GCA (C-GCA) in whom the diagnosis was subsequently confirmed (C-GCA, n = 150) or excluded (Not C-GCA, n = 89). Proteomic findings were compared to published transcriptomic data from LVV-affected arteries. RESULTS: In cohort 1, comparison to HCs revealed 52 differentially abundant proteins (DAPs) in TAK and 72 DAPs in LV-GCA. Within-case analyses identified 16 and 18 disease activity-associated proteins in TAK and LV-GCA, respectively. In cohort 2, comparing C-GCA versus not C-GCA revealed 31 DAPs. Analysis within C-GCA cases suggested the presence of distinct endotypes, with more pronounced proteomic changes in the biopsy-proven subgroup. Cross-comparison of TAK, LV-GCA, and biopsy-proven C-GCA revealed highly similar plasma proteomic profiles, with 26 shared DAPs including interleukin 6 (IL-6), monocyte/macrophage-related proteins (CCL7, CSF1), tissue remodeling proteins (TIMP1, TNC), and novel associations (TNFSF14, IL-7R). Plasma proteomic findings reflected LVV arterial phenotype; for 42% of DAPs, the corresponding gene was differentially expressed in tissue. CONCLUSION: These findings suggest shared pathobiology across the LVV spectrum involving innate immunity, lymphocyte homeostasis, and tissue remodeling. Network-based analyses highlighted immune-stromal cross-talk and identified novel therapeutic targets (eg, TNFSF14).

Humans↗
PubMed2007

Using navigation to measure rotation kinematics during ACL reconstruction.

Rotational kinematics of the knee is not fully restored after single-bundle anterior cruciate ligament (ACL) reconstruction. Cadaveric experiments using knee testing machines have suggested anatomical reconstruction replacing the anteromedial and posterolateral bundles could restore knee kinematics more effectively than single-bundle reconstruction. However, practical tools to objectively assess knee rotational laxities clinically have not been available. We used an optically based computer-assisted navigation system to measure the tibiofemoral motion kinematics in four fresh whole cadavers. Standard clinical knee laxity tests (anterior drawer, Lachman, and pivot shift) were performed and the kinematics described in terms of tibial axial rotation and anteroposterior translation. Data were obtained for intact knees after excision of the ACL and sequential reconstruction of the anteromedial and posterolateral bundles. In the ACL-deficient knee, the mean maximum tibial rotation during the pivot shift test was 27 degrees and mean maximum translation 11 mm. Reconstruction of the anteromedial bundle reduced the rotational component to 18 degrees and translation to 7 mm. Reconstruction of the posterolateral bundle reduced rotation to 14 degrees . This pilot study suggests computer assisted navigation could provide a practical method to objectively measure the pivot shift and may be used clinically to demonstrate differences in the control of tibiofemoral rotation kinematics afforded by single and two-bundle ACL reconstructions.

Aged↗
PubMed2006

Mutations within Wnt pathway genes in sporadic colorectal cancers and cell lines.

Wnt signaling pathway activation via mutation of genetic components, commonly adenomatous polyposis coli (APC), has a major role in colorectal cancer (CRC). Most components have not been assessed for mutation in sporadic CRC. We have analyzed AXIN2, CK1alpha, DKK1, GSK-3beta, SOX17, LRP6 and PPP2R1B, beta-catenin and APC in a collection of sporadic CRCs (n = 47) and CRC cell lines (CLs; n = 26). The CRC set was enriched for microsatellite unstable cancers (MSI+, 30%, 14/47). Somatic mutation was not found in CK1alpha, DKK1, LRP6, beta-catenin or GSK-3beta; but heterozygous frame-shift mutations, and an in-frame deletion mutation were detected in exon 7 of AXIN2 (CRCs, 11%, 5/47; CLs, 8%, 2/26). Our data refute a previous suggestion that a CRC-related mutational hot-spot occurred in the Huntington elongation A subunit TOR (HEAT) repeat 2 of PPP2R1B; this "hotspot" is, more likely, a rare germline polymorphism. An early investigation proposing a high mutational frequency in HEAT repeat 13 was not substantiated. A heterozygous SOX17 mutation (L194P) was also found in a cell line. APC gene mutations were identified in 64% (30/47) of cancers and 7% of these (2/30) had an additional mutation in another Wnt gene. Overall, 70% (33/47) of CRCs had a somatic mutation in a Wnt pathway gene. The number of tumors containing such a mutation was not significantly higher in MSI+ (57%, 8/14) compared to MSI- (76%, 25/33) cancers (p = 0.3, Fisher's exact test); APC mutation was significantly increased in the MSI- subgroup (p = 0.02, Fisher's exact test). Further, mutational screening of other Wnt pathway genes is warranted.

Base Sequence↗
PubMed2006

ISAG/IUIS-VIC Comparative MHC Nomenclature Committee report, 2005.

Nomenclature for Major Histocompatibility Complex (MHC) genes and alleles in species other than humans and mice has historically been overseen either informally by groups generating sequences, or by formal nomenclature committees set up by the International Society for Animal Genetics (ISAG). The suggestion for a Comparative MHC Nomenclature Committee was made at the ISAG meeting held in Göttingen, Germany (2002), and the committee met for the first time at the Institute for Animal Health, Compton, UK in January 2003. To publicize its activity and extend its scope, the committee organized a workshop at the International Veterinary Immunology Symposium (IVIS) in Quebec (2004) where it was decided to affiliate with the Veterinary Immunology Committee (VIC) of the International Union of Immunological Societies (IUIS). The goals of the committee are to establish a common framework and guidelines for MHC nomenclature in any species; to demonstrate this in the form of a database that will ensure that in the future, researchers can easily access a source of validated MHC sequences for any species; to facilitate discussion on this area between existing groups and nomenclature committees. A further meeting of the committee was held in September 2005 in Glasgow, UK. This was attended by most of the existing committee members with some additional invited participants (Table 1). The aims of this meeting were to facilitate the inclusion of new species onto the database, to discuss extension, improvement and funding of the database, and to address a number of nomenclature issues raised at the previous workshop.

Advisory Committees↗
PubMed2006

The IMGT/HLA and IPD databases.

The IMGT/HLA database (www.ebi.ac.uk/imgt/hla) has provided a centralized repository for the sequences of the alleles named by the WHO Nomenclature Committee for Factors of the HLA System since 1998. Since its initial release, the database has rapidly grown in size and is recognized as the primary source of information for the study of sequences of the human major histocompatibility complex. The Immuno Polymorphism Database (IPD; www.ebi.ac.uk/ipd) is a set of specialist databases related to the study of polymorphic genes in the immune system. The IPD currently consists of four databases: IPD-KIR contains the allelic sequences of killer-cell immunoglobulin-like receptors; IPD-MHC is a database of sequences of the major histocompatibility complex of different species; IPD-HPA contains alloantigens expressed only on platelets (human platelet antigens or HPA); and IPD-ESTDAB provides access to the European Searchable Tumour Cell-Line Database, a cell bank of immunologically characterized melanoma cell lines.

Alleles↗
PubMed2006

Morphology of anterior cruciate ligament attachments for anatomic reconstruction: a cadaveric dissection and radiographic study.

PURPOSE: To define the positions of the attachments of the anteromedial (AM) and posterolateral (PL) bundles of the anterior cruciate ligament (ACL). METHODS: The shape and positions of the femoral and tibial attachments of the 2 bundles relative to bony landmarks were measured in 7 fresh-frozen, unpaired cadaveric knees by 6 independent observers. Metallic marker beads were then inserted into the defined anatomic points, and plain radiographs of the specimens were taken. We used the line described by Amis and Jakob on the tibia and the grid prepared by Bernard et al. for the femur to define AM and PL bundle attachment positions. RESULTS: In the cadaveric specimens, referencing the position of the AM bundle tibial attachment from the retro-eminence ridge (RER) resulted in the least interobserver error. On tibial radiographs, the distance between the posterior tibial cortex and the perpendicular projection of the center of the AM bundle attachment onto Amis and Jakob's line was 35.6 +/- 5.1 mm. The ratio of this distance to the length of Amis and Jakob's line (from the anterior cortex) was 36% +/- 3.8% (and 52% +/- 3.4% for the center of the PL bundle). On the femur, the center of the AM bundle was situated at 26.4% +/- 2.6%, and the center of the PL bundle at 32.3% +/- 3.9%, along the length of Blumensaat's line. CONCLUSIONS: The RER provides an easily identifiable and accurate reference point that can be used clinically. On a lateral radiograph, the positions of the tibial attachments can be referenced to Amis and Jakob's line. This method, different from Blumensaat's line, is independent of knee flexion. CLINICAL RELEVANCE: This study details anatomically and radiologically the positions of the attachments of the AM and PL bundles of the ACL. This could assist with accurate tunnel placement in reconstruction surgery and provide reference data for postoperative radiographic evaluation.

Aged↗
PubMed2006

Envelope conformational changes induced by human immunodeficiency virus type 1 attachment inhibitors prevent CD4 binding and downstream entry events.

BMS-488043 is a small-molecule human immunodeficiency virus type 1 (HIV-1) CD4 attachment inhibitor with demonstrated clinical efficacy. The compound inhibits soluble CD4 (sCD4) binding to the 11 distinct HIV envelope gp120 proteins surveyed. Binding of BMS-488043 and that of sCD4 to gp120 are mutually exclusive, since increased concentrations of one can completely block the binding of the other without affecting the maximal gp120 binding capacity. Similarly, BMS-488043 inhibited virion envelope trimers from binding to sCD4-immunoglobulin G (IgG), with decreasing inhibition as the sCD4-IgG concentration increased, and BMS-488043 blocked the sCD4-induced exposure of the gp41 groove in virions. In both virion binding assays, BMS-488043 was active only when added prior to sCD4. Collectively, these results indicate that obstruction of gp120-sCD4 interactions is the primary inhibition mechanism of this compound and that compound interaction with envelope must precede CD4 binding. By three independent approaches, BMS-488043 was further shown to induce conformational changes within gp120 in both the CD4 and CCR5 binding regions. These changes likely prevent gp120-CD4 interactions and downstream entry events. However, BMS-488043 could only partially inhibit CD4 binding to an HIV variant containing a specific envelope truncation and altered gp120 conformation, despite effectively inhibiting the pseudotyped virus infection. Taken together, BMS-488043 inhibits viral entry primarily through altering the envelope conformation and preventing CD4 binding, and other downstream entry events could also be inhibited as a result of these induced conformational changes.

Anti-HIV Agents↗
PubMed2005

Neutralization and infectivity characteristics of envelope glycoproteins from human immunodeficiency virus type 1 infected donors whose sera exhibit broadly cross-reactive neutralizing activity.

In this study, we tested the hypothesis that donors with broadly cross-reactive HIV-1 neutralizing (BCN) sera are infected with viruses encoding envelope glycoproteins (Envs) with unusual immunogenic properties. Cloned env genes were from samples of donors previously identified as having BCN antibodies (BCN donors) and from other donors not known to have such antibodies (non-BCN donors). Neutralization properties of viruses pseudotyped with BCN and non-BCN Envs were determined using BCN, non-BCN sera and broadly cross-neutralizing monoclonal antibodies (Mabs). BCN sera neutralized with higher frequency and geometric mean titers than non-BCN sera. Viruses pseudotyped with BCN Envs were mostly resistant to neutralization by anti-gp120 Mabs but tended to be more sensitive to the anti-gp41 Mabs, 2F5 and 4E10 than non-BCN Env-pseudotyped viruses. Sequence analysis of clones obtained from sequential samples of two BCN donors revealed respective 2F5 epitope mutations T662A and K665T. The K665T mutation evolved as the predominant genotype in the respective donor, consistent with an escape mutation event. The A662T mutation reduced sensitivity to 4E10, as well as 2F5 and homologous sera, consistent with neutralization escape mutation and targeting of the 2F5 epitope region by the serum. Our study suggests that viruses infecting these BCN donors encoded Envs that may have been unusually competent for induction of antibodies against the membrane proximal epitope region (MPER) of gp41, and these Envs may be useful vaccine components.

Amino Acid Sequence↗
PubMed2005

Reduced bone tunnel enlargement post hamstring ACL reconstruction with poly-L-lactic acid/hydroxyapatite bioabsorbable screws.

Bone tunnel enlargement following anterior cruciate ligament (ACL) reconstruction can complicate revision surgery. This study compared postoperative tibial tunnel widening in patients who underwent arthroscopically assisted, single-incision, four-strand hamstring ACL reconstruction using a poly-L-lactic acid/hydroxyapatite blend (PLLA+HA) bioabsorbable interference screw for tibial fixation, with those in whom a plain poly-L-lactic acid (PLLA) screw was used. Thirty-four patients (13 with PLLA+HA tibial interference screw fixation and 21 with plain PLLA tibial interference screws) underwent a spiral CT scan to assess maximum tibial tunnel cross-sectional area at an average of 28.7 months follow-up. An assessment of tunnel wall sclerosis adjacent to the screw (cortication) was also made. The two groups were well matched for age, sex and graft diameters. Mean tibial tunnel enlargement in patients with PLLA+HA screws was 29.9% at average 30.9 months follow-up compared with 46% in patients with plain PLLA screw at an average 26.5 months follow-up (p=0.03). The tunnel wall adjacent to the screw appeared corticated in only 21% of patients with PLLA+HA screws (p=0.02) compared with 73% of patients with PLLA screws. The blending of HA with PLLA appears to reduce postoperative tunnel widening, and the reduced tunnel wall sclerosis seen postoperatively may indicate improved screw incorporation.

Absorbable Implants↗
PubMed2005

Two-bundle, four-tunnel anterior cruciate ligament reconstruction.

We reviewed 33 patients who underwent anterior cruciate ligament (ACL) reconstruction using a two-bundle, four-tunnel technique. The posterolateral bundle (PLB) and anteromedial bundle (AMB) were individually reconstructed with gracilis and semitendinosus tendon auto-grafts, respectively, using separate tibial and femoral tunnels. At final follow-up (24 months post surgery, range 18-31) the International Knee Documentation Committee's (IKDC) objective final evaluation scores were 69 A, 19 B, 12% C. The mean global subjective IKDC score was 86+/-12 points. Ninety-four percent of the patients had returned to sport after an average of 9 months following surgery and 75% returned to their preinjury sporting level. One patient had suffered a graft rupture as a result of a further sports injury. Eighty-four percent of the patients had a negative pivot shift (IKDC A), 9% a glide (IKDC B), and 6% a "clunk" (IKDC C). The mean postoperative side-to-side laxity, measured with KT1000 arthrometry at manual maximum, was 0.9 mm (SD 1.9). Eighty-one percent of the patients had less than 3 mm difference, with only one patient having greater than 5 mm. Our early experience with this new technique appears to demonstrate satisfactory results that are at least equivalent to other techniques and show an apparent trend towards improved control of anterior laxity.

Adolescent↗
PubMed2005

Highly conserved beta16/beta17 beta-hairpin structure in human immunodeficiency virus type 1 YU2 gp120 is critical for CCR5 binding.

Whereas gp120 CD4-induced structures have been largely documented and at least in part elucidated by crystallization, information about gp120 coreceptor-induced structures remains incomplete despite numerous studies. In this work, mutations were carried out in a selected internal region of HIV-1/YU2 gp120, proximal to the CD4-binding site, because of its highly conserved nature among retroviruses and its high structural stability. The targeted residues, belonging to the beta16/beta17 beta-hairpin, modulate gp120 binding to CD4 and gp120-CD4 complex binding to CCR5. Thus, it appears that this gp120 structure acts as a hinge between the CD4-binding site and the putative coreceptor binding structure. Substitution of amino acid residues like E381A did not affect gp120 binding to CD4 and did not induce significant structural changes in gp120, as demonstrated by epitope analysis, BIACORE analysis, and circular dichroism. Nevertheless, E381 has a critical influence on the maintenance of CCR5 coreceptor binding by forming a salt bridge with K207. Another important element of the beta-hairpin in this interaction is the probable hydrophobic link between F383 and I420. Altogether, these results suggest that the beta-hairpin structure likely governs interactions between the surface of gp120 with native CCR5 or the CCR5 amino-terminal domain (CCR5-Nt). The mutations within the beta-hairpin had a direct effect on the proximal surface of the bridging sheet, the putative CCR5 surface, and the gp120 YU2 HIV-1-CD4 binding site. These results on the gp120-CCR5-Nt binding mechanism contribute to our understanding of CCR5 and HIV-1 gp120 association and HIV-1 entry; they may also contribute to designing novel inhibitors.

Amino Acid Sequence↗
PubMed2005

Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies.

The design of a human immunodeficiency virus-1 (HIV-1) immunogen that can induce broadly reactive neutralizing antibodies is a major goal of HIV-1 vaccine development. Although rare human monoclonal antibodies (mAbs) exist that broadly neutralize HIV-1, HIV-1 envelope immunogens do not induce these antibody specificities. Here we demonstrate that the two most broadly reactive HIV-1 envelope gp41 human mAbs, 2F5 and 4E10, are polyspecific autoantibodies reactive with the phospholipid cardiolipin. Thus, current HIV-1 vaccines may not induce these types of antibodies because of autoantigen mimicry of the conserved membrane-proximal epitopes of the virus. These results may have important implications for generating effective neutralizing antibody responses by using HIV-1 vaccines.

AIDS Vaccines↗
PubMed2005

IPD--the Immuno Polymorphism Database.

The Immuno Polymorphism Database (IPD) (http://www.ebi.ac.uk/ipd/) is a set of specialist databases related to the study of polymorphic genes in the immune system. IPD currently consists of four databases: IPD-KIR, contains the allelic sequences of Killer-cell Immunoglobulin-like Receptors; IPD-MHC, a database of sequences of the Major Histocompatibility Complex of different species; IPD-HPA, alloantigens expressed only on platelets; and IPD-ESTAB, which provides access to the European Searchable Tumour Cell-Line Database, a cell bank of immunologically characterized melanoma cell lines. The IPD project works with specialist groups or nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The IPD project stores all the data in a set of related databases. Those sections with similar data, such as IPD-KIR and IPD-MHC share the same database structure. The sharing of a common database structure makes it easier to implement common tools for data submission and retrieval. The data are currently available online from the website and ftp directory; files will also be made available in different formats to download from the website and ftp server. The data will also be included in SRS, BLAST and FASTA search engines at the European Bioinformatics Institute.

Animals↗
PubMed2005

Characterization of antibodies that inhibit HIV gp120 antigen processing and presentation.

Antibodies to the CD4-binding site (CD4bs) of HIV-1 envelope gp120 have been shown to inhibit MHC class II presentation of this antigen, but the mechanism is not fully understood. To define the key determinants contributing to the inhibitory activity of these antibodies, a panel of anti-CD4bs monoclonal antibodies with different affinities was studied and compared to antibodies specific for the chemokine receptor-binding site or other gp120 regions. Anti-CD4bs antibodies that completely obstruct gp120 presentation exhibit three common properties: relatively high affinity for gp120, acid-stable interaction with gp120, and the capacity to slow the kinetics of gp120 proteolytic processing. None of these antibodies prevents gp120 internalization into APC. Notably, the broadly virus-neutralizing anti-CD4bs IgG1b12 does not block gp120 presentation as strongly, because although IgG1b12 has a relatively high affinity, it dissociates from gp120 more readily at acidic pH and only moderately retards gp120 proteolysis. Other anti-gp120 antibodies, regardless of their affinities, do not affect gp120 presentation. Hence, high-affinity anti-CD4bs antibodies that do not dissociate from gp120 at endolysosomal pH obstruct gp120 processing and prevent MHC class II presentation of this antigen. The presence of such antibodies could contribute to the dearth of anti-gp120 T helper responses in chronically HIV-1-infected patients.

Antibodies, Monoclonal↗
PubMed2005

Scorpion-toxin mimics of CD4 in complex with human immunodeficiency virus gp120 crystal structures, molecular mimicry, and neutralization breadth.

The binding surface on CD4 for the HIV-1 gp120 envelope glycoprotein has been transplanted previously onto a scorpion-toxin scaffold. Here, we use X-ray crystallography to characterize atomic-level details of gp120 with this transplant, CD4M33. Despite known envelope flexibility, the conformation of gp120 induced by CD4M33 was so similar to that induced by CD4 that localized measures were required to distinguish ligand-induced differences from lattice variation. To investigate relationships between structure, function, and mimicry, an F23 analog of CD4M33 was devised. Structural and thermodynamic analyses showed F23 to be a better molecular mimic of CD4 than CD4M33. F23 also showed increased neutralization breadth, against diverse isolates of HIV-1, HIV-2, and SIVcpz. Our results lend insight into the stability of the CD4 bound conformation of gp120, define measures that quantify molecular mimicry as a function of evolutionary distance, and suggest how such evaluations might be useful in developing mimetic antagonists with increased neutralization breadth.

Animals↗
PubMed2005

An exploration of self-reported negative affect by adolescents as a reason for smoking: implications for tobacco prevention and intervention programs.

BACKGROUND: Negative affect is related to initiation and maintenance of smoking among youth and understanding its role is important when developing effective prevention and cessation programs. This study investigates the relationship between adolescent negative affect and smoking dependence, behaviors, attitudes, and self-efficacy in order to shed light on differences in adolescent smoking maintenance and cessation. METHODS: 721 smoking youth participated in a cognitive-behavioral smoking cessation program. Reasons for smoking were categorized (alpha = 0.87) and youth were placed into one of two groups based on presence or absence of negative affect. One-way repeated measures ANOVA determined if differences existed between the groups on smoking behaviors, attitudes, and self-efficacy. One-way ANOVA determined if differences existed on Fagerström Nicotine Tolerance Dependence (FTND) scores. RESULTS: Adolescents indicating negative affect for smoking were significantly more likely to have future smoking intentions and had significantly less self-efficacy to quit smoking than adolescent reporting other reasons. CONCLUSIONS: This study supports the need to address negative affect among adolescents participating in prevention and cessation programs. An examination of negative affect will provide program developers and facilitators with information to improve their interventions, assist with cessation, and provide an avenue to access other needed health services.

Adolescent↗