Cellular responses elicited by cell surface receptors differ depending on stimulus strength. We investigated how the high affinity receptor for IgE modulates the response of mast cells to a high- or low-affinity stimulus. Although both high- and low-affinity stimuli elicited similar receptor phosphorylation; receptor cluster size, mobility, distribution, and the cells’ effector responses differed. Low-affinity stimulation increased receptor association with the Src family kinase Fgr, and shifted signals from the adapter LAT1 to the related adapter LAT2. LAT1-dependent calcium signals required for mast cell degranulation were dampened, but the role of LAT2 in chemokine production was enhanced altering immune cell recruitment at the site of inflammation. The findings uncover how receptor discrimination of stimulus strength can be interpreted into distinct in vivo outcomes.

We investigated the relationships between the trans-cytoplasmic-membrane chemiosmotic parameters, viz. the membrane potential and the pH difference, and the toxicity of anions and organic acids in the acidophile Thiobacillus jerrooxidans. Organic acids accumulated in the cytoplasm in response to the transmembrane pH difference and inorganic anions could be caused to accumulate in response to the membrane potential. The distribution of the organic acids was unaffected by the membrane potential and that of the anions was not influenced by the pH difference. These accumulations may be toxic because of a direct effect of a high concentration of the anion in the cytoplasm or by acidification of the cytoplasm. The point of inhibition of respiration was at the level of the respiratory chain cytochrome oxidase when Fe(I1) was the respiratory substrate.

Mice overexpressing B cell activating factor of the TNF family (BAFF) develop systemic autoimmunity characterized by class-switched anti-nuclear antibodies. Transmembrane activator and CAML interactor (TACI) signals are critical for BAFF-mediated autoimmunity, but the B cell developmental subsets undergoing TACI-dependent activation in settings of excess BAFF remains unclear. We now report that, whereas surface TACI expression is usually limited to mature B cells, excess BAFF promotes the expansion of TACI-expressing transitional B cells. TACIhi transitional cells from BAFF-Tg mice are characterized by an activated, cycling phenotype; and the TACIhi cell subset is specifically enriched for autoreactivity, expresses activation-induced cytidine deaminase (AID) and T-bet and exhibits evidence of somatic hypermutation. Consistent with a potential contribution to BAFF-mediated humoral autoimmunity, TACIhi transitional B cells from BAFF-Tg mice spontaneously produce class-switched autoantibodies ex vivo. These combined findings highlight a novel mechanism whereby BAFF promotes humoral autoimmunity via direct, TACI-dependent activation of transitional B cells.

Cancer pain is estimated to occur in 30% to 70% of patients with early-stage cancer and 60% to 95% with advanced cancer. Current research shows that cancer pain continues to be undertreated despite the availability of analgesics and established guidelines to maximize their effectiveness. The purpose of this study was to describe oncology patients' pain experience during an episode of hospitalization with particular emphasis on exploring the relationship between oncology patients' beliefs about pain and the treatment they received. Consecutive patients (n = 126) were interviewed 48 hours after admission to an urban and a regional hospital in Australia; 47.6% of patients had experienced moderate to severe pain in the previous 24 hours but had only received 40.4% of available analgesic. Patients held varying beliefs about pain and pain treatments in particular, 41% held strong beliefs about the potential for addiction to narcotics. Patients who held this belief reported higher current pain, worst pain intensity, and higher average pain intensity in the previous 24 hours. Effective pain management in the inpatient oncology setting continues to be an important clinical issue, and patients do not receive all available pain treatment. There may be an important association between patients' beliefs about pain and pain management and the pain management they receive.