VpreB serves as an invariant surrogate antigen for selecting immunoglobulin antigen-binding sites

Developmental checkpoints eliminate B cells that synthesize defective immunoglobulin (Ig) heavy (HC) and light (LC) chains. The first checkpoint tests mHCs paired with VpreB/l5 in a pre-B cell receptor (pre-BCR) to determine whether the mHC will be able to bind conventional LCs to form membrane IgM. VpreB and l5 also create a sensing site that interacts with the mHC antigen-binding region complementarity-determining region (CDR)\u2013H3; however, whether this site contributes to Ig repertoire selection and function is unknown. We analyzed the amino acid content of CDR-H3s from HCs cloned from living and apoptotic pre-B cells and from IgG-antigen structures. Using a panel of DH gene\u2013targeted mice, we showed that progressively reducing CDR-H3 tyrosine content increasingly impaired pre-BCR checkpoint passage. Counting from cysteine at framework 3 position 96, we found that VpreB particularly selected for tyrosine at CDR-H3 position 101 and that Y101 also bound antigen in IgG-antigen structures. Therefore, in addition to its stabilization role in the pre-BCR, VpreB also acts as an early invariant antigen by selecting for particular CDR-H3 amino acids. These interactions shape the specificity of the IgG humoral response and may thus impose limitations on development of certain neutralizing antibodies

Sources of stakeholder salience in the responsible investment movement: why do investors sign the Principles for Responsible Investment?

Since its inception in 2006, the United Nations-backed Principles for Responsible Investment (PRI) have grown to over 1300 signatories representing over $45 trillion. This growth is not slowing down. In this paper, we argue that there is a set of attributes which make the PRI salient as a stakeholder and its claim to sign the six PRI important to institutional investors. We use Mitchell et al.’s (Acad Manag Rev 22:853–886, 1997) theoretical framework of stakeholder salience, as extended by Gifford (J Bus Eth 92:79–97, 2010). We use as evidence confidential data from the annual survey of signatories carried out by the PRI in a 5-year period between 2007 and 2011. The findings highlight pragmatic and organizational legitimacy, normative and utilitarian power, and management values as the attributes that contribute most to the salience of the PRI as a stakeholder

Abstracts from the NIHR INVOLVE Conference 2017

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Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial

BackgroundAnterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability.MethodsWe did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score—4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367.FindingsBetween Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5–13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications.InterpretationSurgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management

VpreB serves as an invariant surrogate antigen for selecting immunoglobulin antigen-binding sites

International audienceTransportation networks have become a subject of scientific interest from the second half of the twentieth century. Studies related to growth of the transportation networks after resuming its activity after thirty years have changed focus from the topological complexity of transportation network to their structural properties. In other words, topological complexity has changed into structural complexity. In this paper, this lost scientific direction will be reminded to the present society. Firstly, early studies on the topological complexity will be summarized and compared to each other. Secondly, new studies will be summarized and analyzed in terms of topological complexity. Finally, in conclusion, a means of measuring the topological complexity will be discussed and gaps in current studies will be highlighted

In the Absence of Central pre-B Cell Receptor Selection, Peripheral Selection Attempts to Optimize the Antibody Repertoire by Enriching for CDR-H3 Y101

Sequential developmental checkpoints are used to “optimize” the B cell antigen receptor repertoire by minimizing production of autoreactive or useless immunoglobulins and enriching for potentially protective antibodies. The first and apparently most impactful checkpoint requires μHC to form a functional pre-B cell receptor (preBCR) by associating with surrogate light chain, which is composed of VpreB and λ5. Absence of any of the preBCR components causes a block in B cell development that is characterized by severe immature B cell lymphopenia. Previously, we showed that preBCR controls the amino acid content of the third complementary determining region of the H chain (CDR-H3) by using a VpreB amino acid motif (RDR) to select for tyrosine at CDR-H3 position 101 (Y101). In antibodies bound to antigen, Y101 is commonly in direct contact with the antigen, thus preBCR selection impacts the antigen binding characteristics of the repertoire. In this work, we sought to determine the forces that shape the peripheral B cell repertoire when it is denied preBCR selection. Using bromodeoxyuridine incorporation and evaluation of apoptosis, we found that in the absence of preBCR there is increased turnover of B cells due to increased apoptosis. CDR-H3 sequencing revealed that this is accompanied by adjustments to DH identity, DH reading frame, JH, and CDR-H3 amino acid content. These adjustments in the periphery led to wild-type levels of CDR-H3 Y101 content among transitional (T1), mature recirculating, and marginal zone B cells. However, peripheral selection proved incomplete, with failure to restore Y101 levels in follicular B cells and increased production of dsDNA-binding IgM antibodies

Assessing the importance of individual- and colony-level variation when using seabird foraging ranges as impact assessment and conservation tools

Knowledge of seabird distributions plays a key role in seabird conservation and sustainable marine management, underpinning efforts to designate protected areas or assess the impact of human developments. Technological advances in animal tracking devices increasingly allow researchers to acquire information on the movement of birds from specific colonies. Nevertheless, most seabird colonies have not been subject to such tracking and another means must be found to assess their likely foraging distribution. Consequently, foraging range data collated and summarized across other tracking studies has often been used to estimate species-level foraging distances for use within applied settings. However, generic species-specific foraging ranges must be used with caution due to the amount of variation in seabird foraging behaviour at both the individual and colony level. Specifically, while current reviews of seabird foraging ranges provide summary estimates of maximum foraging range, they typically do not assess the extent of among-colony or among-individual variation around such estimates. To address this, we conducted a variance component analysis of the maximum distance reached from the breeding colony per foraging trip (foraging range) using multi-colony tracking datasets to estimate the degree of between-individual, between-year, and between-colony variation in foraging range in four UK breeding seabirds (Black-legged Kittiwake Rissa tridactyla, Common Guillemot Uria aalge, Razorbill Alca torda & European Shag Gulosus aristotelis). We also provide updated estimates of typical foraging ranges for each species and quantified the influence of breeding stage and colony size. Overall, between-colony variation was typically the largest variance component, explaining 20% - 30% of the observed variation in foraging range across the four species. Individual-level variation was also relatively large among Shags. In Kittiwake, Guillemot, and Shag, but not Razorbill, average foraging ranges were positively associated with colony size. In addition, Kittiwakes and Razorbills travelled further during incubation than chick rearing. More generally, our estimates of mean foraging ranges for each species were subject to a high degree of uncertainty, which should be incorporated into impact assessments carried out using such data