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The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan1–3. Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients4, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm)5–7, and is established to increase healthy lifespan in multiple species8,9. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr (ref. 10). We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health11–13. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies14–16 and contrasting with reports that biological aging may not be modifiable17. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality18–20.

To investigate the role of B cells as APCs in acquired tolerance induced by low dose soluble protein Ags, normal and B cell-deficient adult mice were injected i.v. with repeated low doses (10 microgram) of deaggregated OVA, then challenged with OVA in CFA. In animals treated with deaggregated OVA, the in vitro proliferative responses of lymph node T cells to OVA were significantly reduced, and production of the Th1 cytokine, IFN-gamma, in response to OVA was reduced to undetectable levels. This occurred in both normal and B cell-deficient treated animals. B cells were also unnecessary for self tolerance of T cells to the transgenic self Ag, hen egg lysozyme, in a strain with a very low serum lysozyme concentration. Partial low zone tolerance induced by deaggregated, low dose OVA was selective for T cell responses as measured by in vitro proliferation and IL-2 and IFN-gamma production, because Ab responses of B cell-sufficient mice to this T cell-dependent Ag were largely unaffected. Both treated and untreated animals produced equivalent titers of anti-OVA Abs, predominantly of the IgG1 and IgG2b isotypes, following challenge with OVA in CFA.

We have shown that a foreign protein Ag (the F(ab) fragment of rabbit IgG) becomes a particularly effective tolerogen when it is targeted to B lymphocytes in vivo. This is done by injecting the Ag intravenously into mice in the form of the F(ab) fragment of rabbit anti-mouse IgD antibody (F(ab)) rabbit anti-delta). Our hypothesis is that resting B cells are tolerogenic APC for CD4+ T cells in unprimed animals, and induce Ag-specific nonresponsiveness in the Th cell compartment by presenting Ag without appropriate costimulatory signals. In this report, we find that Ag-activated T cells appear to be resistant to tolerance induction, because F(ab) rabbit anti-delta given 5 days after challenge with rabbit F(ab) in alum adjuvant has little or no effect of the subsequent antibody response. Tolerance also fails in this model when B cells are activated independently of Ag by simultaneous injection of activating concentrations of divalent, IgG mouse anti-delta at the same time as F(ab) rabbit anti-delta. Finally, nonresponsiveness in the T cell compartment is not limited to a lesion in T cell help for the antibody response, because T cells from mice treated with F(ab) rabbit anti-delta and then primed with rabbit F(ab) fragments in CFA show reduced T cell proliferation and IL-2 production when restimulated with Ag in vitro.

B cells get help in the antibody response by presenting processed Ag to Th cells. We asked whether the Ag-presenting B cell must induce Th functions before receiving help, or whether B cell activation is a direct consequence of T cell recognition of Ag on the B cell surface. To obtain a prompt and sensitive indication of the receipt of growth signals, we measured mRNA levels of the immediate early genes, c-myc and egr-1, in T and B cells separated from Ag-specific B-T conjugates of normal, resting murine B cells and a Th line. Although Ag-dependent increases in B cell c-myc expression occur as early as 2 h after conjugation, early c-myc expression in the B cell was also seen when the Th cells were activated with immobilized anti-CD3 in the absence of Ag recognition. Therefore, T cell activation rather than Ag recognition per se appears to be responsible for the early c-myc signal in the B cells. The c-myc response in the B cell depends on induction of a contact-dependent helper function in the T cell, which is inhibitable by cyclosporin A acting on the T cell. Delivery of contact help is not blocked by anti-class II MHC antibody. Contact with activated Th cells induces a different pattern of immediate early gene expression from that induced by cross-linking the B cell Ag receptor.

Selectively doped semiconducting metal oxide (SMO) films have been shown to have applications as the sensing element in gas microsensors. Critical to the design and operation of these sensors is the SMO film. In the present work, the electrical properties of both intrinsic and extrinsic (doped with gold) tungsten trioxide (WO3) films, which selectively sorb hydrogen sulfide (H2S), are investigated. Hall effect measurements are performed as a function of film thickness, temperature, gold‐doping concentration, and H2S gas concentration. The conductivity was found to be n type and strongly dependent on temperature, gold doping concentration, and H2S gas concentration and less dependent on film thickness. The mobility was relatively high while the intrinsic carrier concentration was low when compared to typical semiconductor materials. The conductivity was shown to exhibit anomalous behavior at certain temperatures and H2S gas concentrations.

Coupling of membrane Ig (mIg) and CD40 to the extracellularly regulated kinase (ERK) signal transduction pathway was examined in the WEHI-231 B lymphoma and normal mouse B cells. Cross-linking mIg induces ERK activation in both WEHI-231 and normal B cells. In contrast, CD40 cross-linking failed to induce ERK activation in WEHI-231, but signals through CD40 were more effective than mIg as a stimulus for ERK activation in normal B cells. However, several lines of evidence suggest that CD40 and the B cell Ag regulate ERK through distinct pathways that converge at the level of MEK-1, mitogen-activated protein kinase kinase. Abs to mIg or CD40 induced MEK-1 activation with different kinetics. Cross-linking of mIg, but not CD40, induced tyrosine phosphorylation of the SHC adapter molecule that couples receptors to Ras-dependent signaling pathways. Finally, agents that elevate cAMP, causing protein kinase A-mediated inhibition of Raf-1, inhibited activation of ERK in response to mIg cross-linking, but had no affect on ERK activation in response to anti-CD40 or Jun N-terminal kinase activation by signals through either receptor. Thus, CD40 uses an unidentified protein kinase A-insensitive MEK kinase, rather than Raf-1, to regulate ERK activity.

Jesus said ‘I am the way, the truth and the life’, not ‘I am the way, the social convention and the life.’ Gregory the Great It has sometimes been claimed that words of Jesus were reproduced particularly carefully and reverently by scribes. This claim is based on the belief that his words were regarded as so sacred that, while errors of all kinds might be found in less important passages, sentences and phrases, they were handled as reverently as the Massoretic tradition preserved the oracles received by Moses. The claim owes everything to piety, and nothing to the study of the manuscript evidence. Examine any edition of the Gospels that extensively details the manuscript evidence, and you will find that the number of variant readings in a narrative is small. Come to a block of sayings, and the number rises dramatically. The complexity of interpreting Jesus' sayings led to an increase in variant readings. We have encountered this already in the Lord's Prayer, which one might expect to exist in a single form if anything did. But we come now to a problem more thorny and to a situation more tangled than those we have studied so far. The basic reason for the complexity in the passages we are to study and in many others of Jesus' sayings is precisely the importance accorded them. A recent major study (whose title neatly makes the point) has illustrated how much copyists might change the text in order to bring out the meaning which they believed to be correct.

This book represents an important departure in Gospel studies and textual criticism. David Parker offers a different way of reading the Gospels which treats seriously the fact that they first existed as manuscripts. Through an analysis of the different forms of a number of key passages, he demonstrates that the Gospels cannot be properly understood as texts without taking into consideration their physical existence as manuscripts, printed books and electronic text. In conclusion, he argues that the search for an original text of the Gospels overlooks the way in which the early church passed down its traditions. This book challenges many of the assumptions of New Testament scholarship. But, at the same time, it does not assume any prior knowledge of the discipline, and can therefore be used as a unique alternative to traditional primers of New Testament textual criticism.

Treat each according to his deserts, and who shall 'scape a whipping? Hamlet The passages covered so far have all been teaching firmly embedded in the canonical Gospels. That to which we now turn has had a different history. It poses a particular problem for those who believe that there is a single authoritative text, a problem that they generally ignore. For this passage is demonstrably spurious to that text. Read in the lectionaries of most denominations, it attests a tradition about Jesus received into several places in the Gospels at a later date. It is not part of the supposed authoritative and original text. The story of the woman taken in adultery is one of the best-known examples of expansion to the Gospel text. It is generally known as the passage John 7.53–8.11, although it is found elsewhere in some witnesses. Present in the Authorised Version, it has been excised from most modern versions. But it has not gone out of use, nor has attachment to it diminished. It continues a part of the lectionary. This allows us to expand a point made at the end of Chapter 4. There we saw that our reading of one form of the text will be influenced by other forms. Here we learn that passages do not lose their influence once they have been declared and acknowledged to be spurious.

To investigate the role of CD40 ligand in the delivery of help to B cells, we examined the Ag-specific interaction of B cells from CD40-deficient mice with a Th2 cell line in vitro. Small resting B cells from normal mice are stimulated to synthesize DNA when they present monovalent Ag (rabbit Fab anti-Ig) to a rabbit Ig-specific Th cell line. This response, which is independent of a signal through the B cell Ag receptor (sIg), is nearly absent in B cells from CD40-deficient mice. The CD40-deficient B cells are not defective in Ag presentation because they induce T cell IL-4 synthesis as well as normal B cells. Also, CD40-deficient B cells respond to T cell help with DNA synthesis almost as well as normal B cells if an additional signal is provided through sIg. In conjunction with a sIg signal, cell contact with helper T cells induces DNA synthesis more effectively than soluble cytokines. CD40-independent T cell help can also be measured as an early increase in c-myc mRNA levels in CD40-deficient B cells presenting Ag to helper T cells, although the levels of c-myc RNA expression are lower than those in normal B cells. However, c-myc RNA induced by noncognate interaction with anti-CD3-activated T cells is completely CD40 dependent. We conclude that early growth signals from activated Th cells are received by CD40-/- B cells, but that CD40 and/or sIg signals are required for efficient induction of DNA synthesis.

To investigate the role of B cells as APCs in acquired tolerance induced by low dose soluble protein Ags, normal and B cell-deficient adult mice were injected i.v. with repeated low doses (10 microgram) of deaggregated OVA, then challenged with OVA in CFA. In animals treated with deaggregated OVA, the in vitro proliferative responses of lymph node T cells to OVA were significantly reduced, and production of the Th1 cytokine, IFN-gamma, in response to OVA was reduced to undetectable levels. This occurred in both normal and B cell-deficient treated animals. B cells were also unnecessary for self tolerance of T cells to the transgenic self Ag, hen egg lysozyme, in a strain with a very low serum lysozyme concentration. Partial low zone tolerance induced by deaggregated, low dose OVA was selective for T cell responses as measured by in vitro proliferation and IL-2 and IFN-gamma production, because Ab responses of B cell-sufficient mice to this T cell-dependent Ag were largely unaffected. Both treated and untreated animals produced equivalent titers of anti-OVA Abs, predominantly of the IgG1 and IgG2b isotypes, following challenge with OVA in CFA.

To investigate a role for B cells as tolerogenic APCs in peripheral lymphoid organs, we have developed a system in which B cells from mice transgenic for the membrane-bound form of human mu-chain are transferred into nontransgenic recipients. Mice injected with B cells expressing human mu-chain became profoundly tolerant to human mu-chain, as shown by greatly reduced Ab responses following challenge with human mu-chain in adjuvant. Adoptive transfer experiments showed that the recipient's Th cell response to human mu-chain was impaired. When the human mu transgenic spleen cells were activated with LPS before transfer, they no longer induced tolerance. Spleen cells from double-transgenic mice expressing both human mu-chain and the costimulatory molecule B7-1 (CD80) also failed to induce tolerance to human mu-chain. However, neither human mu transgenic LPS blasts nor double-transgenic B cells induced an Ab response or primed for a secondary Ab response to Ag in adjuvant. Therefore, we find that expression of B7-1 together with Ag can interfere with tolerance induction without inducing Ab formation or priming for a secondary Ab response.