The Fab conformations in the solution structure of human IgG4 restricts access to its Fc region: implications for functional activity.

Human IgG4 antibody shows therapeutically-useful properties compared to the IgG1, IgG2 and IgG3 subclasses. Thus IgG4 does not activate complement, and shows conformational variability. These properties are attributable to its hinge region, which is the shortest of the four IgG subclasses. Using high throughput scattering methods, we have studied the solution structure of wild-type IgG4(Ser222) and a hinge mutant IgG4(Pro222) in different buffers and temperatures, where the proline substitution suppresses the formation of half-antibody. Analytical ultracentrifugation showed that both IgG4 forms were principally monomeric with sedimentation coefficients s020,w of 6.6-6.8 S. A monomer-dimer equilibrium was observed in heavy water buffer at low temperature. Scattering showed that the X-ray radius of gyration RG was unchanged with concentration in 50-250 mM NaCl buffers, while the neutron RG values showed a concentration-dependent increase as the temperature decreased in heavy water buffers. The distance distribution curves P(r) revealed two peaks, M1 and M2 that shifted below 2 mg/ml to indicate concentration-dependent IgG4 structures, in addition to IgG4 dimer formation at high concentration in heavy water. Constrained X-ray and neutron scattering modelling revealed asymmetric solution structures for IgG4(Ser222) with extended hinge structures. The IgG4(Pro222) structure was similar. Both IgG4 structures showed that their Fab regions were positioned close enough to the Fc region to restrict C1q binding. Our new molecular models for IgG4 explain its inability to activate complement, and clarifies aspects of its stability and function for therapeutic applications

The Mass Function of Dark Halos in Superclusters and Voids

A modification of the Press-Schechter theory allowing for presence of a background large-scale structure (LSS) - a supercluster or a void, is proposed. The LSS is accounted as the statistical constraints in form of linear functionals of the random overdensity field. The deviation of the background density within the LSS is interpreted in a pseudo-cosmological sense. Using the constraints formalism may help us to probe non-trivial spatial statistics of haloes, e.g. edge and shape effects on boundaries of the superclusters and voids. Parameters of the constraints are connected to features of the LSS: its mean overdensity, a spatial scale and a shape, and spatial momenta of higher orders. It is shown that presence of a non-virialized LSS can lead to an observable deviation of the mass function. This effect is exploited to build a procedure to recover parameters of the background perturbation from the observationally estimated mass function.Comment: 23 pages, 6 figures; to be appeared in Astronomy Reports, 2014, Vol. 58, No. 6, pp. 386-39

Cybersecurity Readiness of E-tail Organisations:A Technical Perspective

Cybersecurity readiness is a challenging issue for online retail businesses which are losing billions of dollars due to cyber-crimes and a lack of readiness to manage these. Therefore, research into cybersecurity readiness in the online retail industry is needed. Technical tools are the foremost measures of defence against these attacks. This study investigates cybersecurity readiness from the technical perspective in some UK online retailers. This research adopted a qualitative case study approach with semi-structured interviews for collecting data. A total of 15 interviews were conducted with an online retail company’s staff and management who had responsibility for managing cybersecurity. A thematic analysis method was used to analyse the qualitative data. The research findings show that the company is facing internal and external threats to their information systems and their technical defences are not very effective at present. The company should consider investing more resources in the technical controls to prevent these attacks

Clues from nearby galaxies to a better theory of cosmic evolution

The great advances in the network of cosmological tests show that the relativistic Big Bang theory is a good description of our expanding universe. But the properties of nearby galaxies that can be observed in greatest detail suggest a still better theory would more rapidly gather matter into galaxies and groups of galaxies. This happens in theoretical ideas now under discussion.Comment: published in Natur

Mentorship needs at academic institutions in resource-limited settings: a survey at makerere university college of health sciences

<p>Abstract</p> <p>Background</p> <p>Mentoring is a core component of medical education and career success. There is increasing global emphasis on mentorship of young scientists in order to train and develop the next leaders in global health. However, mentoring efforts are challenged by the high clinical, research and administrative demands. We evaluated the status and nature of mentoring practices at Makerere University College of Health Sciences (MAKCHS).</p> <p>Methods</p> <p>Pre-tested, self-administered questionnaires were sent by email to all Fogarty alumni at the MAKCHS (mentors) and each of them was requested to complete and email back the questionnaire. In addition to training level and number of mentors, the questionnaires had open-ended questions covering themes such as; status of mentorship, challenges faced by mentors and strategies to improve and sustain mentorship within MAKCHS. Similarly, open-ended questionnaires were sent and received by email from all graduate students (mentees) registered with the Uganda Society for Health Scientists (USHS). Qualitative data from mentors and mentees was analyzed manually according to the pre-determined themes.</p> <p>Results</p> <p>Twenty- two out of 100 mentors responded (14 email and 8 hard copy responses). Up to 77% (17/22) of mentors had Master's-level training and only 18% (4/22) had doctorate-level training. About 40% of the mentors had ≥ two mentees while 27% had none. Qualitative results showed that mentors needed support in terms of training in mentoring skills and logistical/financial support to carry out successful mentorship. Junior scientists and students reported that mentorship is not yet institutionalized and it is currently occurring in an adhoc manner. There was lack of awareness of roles of mentors and mentees. The mentors mentioned the limited number of practicing mentors at the college and thus the need for training courses and guidelines for faculty members in regard to mentorship at academic institutions.</p> <p>Conclusions</p> <p>Both mentors and mentees were willing to improve mentorship practices at MAKCHS. There is need for institutional commitment to uphold and sustain the mentorship best practices. We recommend a collaborative approach by the stakeholders in global health promotion to build local capacity in mentoring African health professionals.</p

Functional magnetic resonance imaging (fMRI) changes and saliva production associated with acupuncture at LI-2 acupuncture point: a randomized controlled study

<p>Abstract</p> <p>Background</p> <p>Clinical studies suggest that acupuncture can stimulate saliva production and reduce xerostomia (dry mouth). We were interested in exploring the neuronal substrates involved in such responses.</p> <p>Methods</p> <p>In a randomized, sham acupuncture controlled, subject blinded trial, twenty healthy volunteers received true and sham acupuncture in random order. Cortical regions that were activated or deactivated during the interventions were evaluated by functional magnetic resonance imaging (fMRI). Saliva production was also measured.</p> <p>Results</p> <p>Unilateral manual acupuncture stimulation at LI-2, a point commonly used in clinical practice to treat xerostomia, was associated with bilateral activation of the insula and adjacent operculum. Sham acupuncture at an adjacent site induced neither activation nor deactivation. True acupuncture induced more saliva production than sham acupuncture.</p> <p>Conclusion</p> <p>Acupuncture at LI-2 was associated with neuronal activations absent during sham acupuncture stimulation. Neuroimaging signal changes appear correlated to saliva production.</p

The Formation and Evolution of the First Massive Black Holes

The first massive astrophysical black holes likely formed at high redshifts (z>10) at the centers of low mass (~10^6 Msun) dark matter concentrations. These black holes grow by mergers and gas accretion, evolve into the population of bright quasars observed at lower redshifts, and eventually leave the supermassive black hole remnants that are ubiquitous at the centers of galaxies in the nearby universe. The astrophysical processes responsible for the formation of the earliest seed black holes are poorly understood. The purpose of this review is threefold: (1) to describe theoretical expectations for the formation and growth of the earliest black holes within the general paradigm of hierarchical cold dark matter cosmologies, (2) to summarize several relevant recent observations that have implications for the formation of the earliest black holes, and (3) to look into the future and assess the power of forthcoming observations to probe the physics of the first active galactic nuclei.Comment: 39 pages, review for "Supermassive Black Holes in the Distant Universe", Ed. A. J. Barger, Kluwer Academic Publisher