B Cell Receptor–independent Stimuli Trigger Immunoglobulin (Ig) Class Switch Recombination and Production of IgG Autoantibodies by Anergic Self-Reactive B Cells

In both humans and animals, immunoglobulin (Ig)G autoantibodies are less frequent but more pathogenic than IgM autoantibodies, suggesting that controls over Ig isotype switching are required to reinforce B cell self-tolerance. We have used gene targeting to produce mice in which hen egg lysozyme (HEL)-specific B cells can switch to all Ig isotypes (SWHEL mice). When crossed with soluble HEL transgenic (Tg) mice, self-reactive SWHEL B cells became anergic. However, in contrast to anergic B cells from the original nonswitching anti-HEL × soluble HEL double Tg model, self-reactive SWHEL B cells also displayed an immature phenotype, reduced lifespan, and exclusion from the splenic follicle. These differences were not related to their ability to Ig class switch, but instead to competition with non-HEL–binding B cells generated by VH gene replacement in SWHEL mice. When activated in vitro with B cell receptor (BCR)-independent stimuli such as anti-CD40 monoclonal antibody plus interleukin 4 or lipopolysaccharide (LPS), anergic SWHEL double Tg B cells proliferated and produced IgG anti-HEL antibodies as efficiently as naive HEL-binding B cells from SWHEL Ig Tg mice. These results demonstrate that no intrinsic constraints to isotype switching exist in anergic self-reactive B cells. Instead, production of IgG autoantibodies is prevented by separate controls that reduce the likelihood of anergic B cells encountering BCR-independent stimuli. That bacteria-derived LPS could circumvent these controls may explain the well-known association between autoantibody-mediated diseases and episodes of systemic infection

Tree scattering amplitudes of the spin-4/3 fractional superstring I: the untwisted sectors

Scattering amplitudes of the spin-4/3 fractional superstring are shown to satisfy spurious state decoupling and cyclic symmetry (duality) at tree-level in the string perturbation expansion. This fractional superstring is characterized by the spin-4/3 fractional superconformal algebra---a parafermionic algebra studied by Zamolodchikov and Fateev involving chiral spin-4/3 currents on the world-sheet in addition to the stress-energy tensor. Examples of tree scattering amplitudes are calculated in an explicit c=5 representation of this fractional superconformal algebra realized in terms of free bosons on the string world-sheet. The target space of this model is three-dimensional flat Minkowski space-time with a level-2 Kac-Moody so(2,1) internal symmetry, and has bosons and fermions in its spectrum. Its closed string version contains a graviton in its spectrum. Tree-level unitarity (i.e., the no-ghost theorem for space-time bosonic physical states) can be shown for this model. Since the critical central charge of the spin-4/3 fractional superstring theory is 10, this c=5 representation cannot be consistent at the string loop level. The existence of a critical fractional superstring containing a four-dimensional space-time remains an open question.Comment: 42 pages, 4 figures, latex, IASSNS-HEP-93/57, CLNS-92/117

An alternative approach to produce versatile retinal organoids with accelerated ganglion cell development

Genetically complex ocular neuropathies, such as glaucoma, are a major cause of visual impairment worldwide. There is a growing need to generate suitable human representative in vitro and in vivo models, as there is no effective treatment available once damage has occured. Retinal organoids are increasingly being used for experimental gene therapy, stem cell replacement therapy and small molecule therapy. There are multiple protocols for the development of retinal organoids available, however, one potential drawback of the current methods is that the organoids can take between 6 weeks and 12 months on average to develop and mature, depending on the specific cell type wanted. Here, we describe and characterise a protocol focused on the generation of retinal ganglion cells within an accelerated four week timeframe without any external small molecules or growth factors. Subsequent long term cultures yield fully differentiated organoids displaying all major retinal cell types. RPE, Horizontal, Amacrine and Photoreceptors cells were generated using external factors to maintain lamination.</p

‘Een kakafonie van woeste woede’: reflecties op de opkomst van de ‘boze burger’

Brexit en het Oekraïne-referendum; de vaak luidruchtige en soms gewelddadige opstand tegen de komst van asielzoekerscentra; de verkiezing van Donald Trump in de VS en de electorale opmars van populistische partijen als PVV, FvD en Denk in eigen land; de (vooral op sociale media hevig gevoerde) Zwarte Pieten-discussie en woedende Groningers die Mark Rutte op tv de les lezen: de afgelopen paar jaren leken het tijdperk van ‘de boze burger’. Veel politici en bestuurders vinden het moei‐ lijk om om te gaan met diens opgekropte woede. Anderen werpen zich op als de bondgenoten van de ‘gewone burger’ of ‘kleine man’ tegen ‘dé elite’ en ‘hét systeem’. Beleid ‘emotioneert’ en de verh

Fractional Superstrings with Space-Time Critical Dimensions Four and Six

We propose possible new string theories based on local world-sheet symmetries corresponding to extensions of the Virasoro algebra by fractional spin currents. They have critical central charges $c=6(K+8)/(K+2)$ and Minkowski space-time dimensions $D=2+16/K$ for $K\geq2$ an integer. We present evidence for their existence by constructing modular invariant partition functions and the massless particle spectra. The dimension $4$ and $6$ strings have space-time supersymmetry.Comment: 9 page

BAFF selectively enhances the survival of plasmablasts generated from human memory B cells

The generation of Ig-secreting cells (ISCs) from memory B cells requires interactions between antigen-specific (Ag-specific) B cells, T cells, and dendritic cells. This process must be strictly regulated to ensure sufficient humoral immunity while avoiding production of pathogenic autoantibodies. BAFF, a member of the TNF family, is a key regulator of B cell homeostasis. BAFF exerts its effect by binding to three receptors — transmembrane activator of and CAML interactor (TACI), B cell maturation antigen (BCMA), and BAFF receptor (BAFF-R). To elucidate the contribution of BAFF to the differentiation of B cells into ISCs, we tracked the fate of human memory B cells stimulated with BAFF or CD40L. BAFF and CD40L significantly increased the overall number of surviving B cells. This was achieved via distinct mechanisms. CD40L induced proliferation of nondifferentiated blasts, while BAFF prevented apoptosis of ISCs without enhancing proliferation. The altered responsiveness of activated memory B cells to CD40L and BAFF correlated with changes in surface phenotype such that expression of CD40 and BAFF-R were reduced on ISCs while BCMA was induced. These results suggest BAFF may enhance humoral immunity in vivo by promoting survival of ISCs via a BCMA-dependent mechanism. These findings have wide-ranging implications for the treatment of human immunodeficiencies as well as autoimmune diseases.This work was supported by the National Health and Medical Research Council of Australia. S.G. Tangye was supported by a U2000 Postdoctoral Fellowship awarded by the University of Sydney. P.D. Hodgkin is a Senior Research Fellow of the National Health and Medical Research Council of Australia. F. Mackay is a Wellcome Trust Senior Research Fellow

Low-Lying States of the Six-Dimensional Fractional Superstring

The $K=4$ fractional superstring Fock space is constructed in terms of \bZ_4 parafermions and free bosons. The bosonization of the \bZ_4 parafermion theory and the generalized commutation relations satisfied by the modes of various parafermion fields are reviewed. In this preliminary analysis, we describe a Fock space which is simply a tensor product of \bZ_4 parafermion and free boson Fock spaces. It is larger than the Lorentz-covariant Fock space indicated by the fractional superstring partition function. We derive the form of the fractional superconformal algebra that may be used as the constraint algebra for the physical states of the FSS. Issues concerning the associativity, modings and braiding properties of the fractional superconformal algebra are also discussed. The use of the constraint algebra to obtain physical state conditions on the spectrum is illustrated by an application to the massless fermions and bosons of the $K=4$ fractional superstring. However, we fail to generalize these considerations to the massive states. This means that the appropriate constraint algebra on the fractional superstring Fock space remains to be found. Some possible ways of doing this are discussed.Comment: 69 pages, LaTeX, CLNS 91/112

Discovery of Middle Pleistocene fossil and stone tool-bearing deposits at Groot Kloof, Ghaap escarpment, Northern Cape province

We report the discovery of a major fossil-bearing and archaeological complex of karstic deposits at Groot Kloof in the escarpment of the Ghaap Plateau, around 100 km southwest of Taung. The region is known for open fluvial and lacustrine sites sampling Lower and Middle Pleistocene tool types and the long, but discontinuous sequence ofWonderwerk Cave. Research at Groot Kloof has concentrated on two of four localities. One locality has yielded fossils from the Florisian Land Mammal Age and lithics that may sample a late Early Stone Age/early Middle Stone Age type industry. The second locality has been dated using U-Th to 248 &lt;U&gt;+&lt;/U&gt; 37 kyr ago for fossil-bearing tufa, and normal magnetic polarity for various tufa and breccia. The occurrence of fossils embedded within tufa rather than infilling a cavity is unusual. Small pockets of Later Stone Age artefact-bearing breccia and rock art also occur. The significance of Groot Kloof is underscored by current debate about the emergence of modern humans in which the appearance of modern behaviour is posited to have occurred inthis and other regions during this part of the Middle Pleistocene