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The blocking effect, canonical in the study of associativelearning, is often explained as a failure of the blocked cue tobecome associated with the outcome. However, thisperspective fails to explain recent findings that suggestlearning about a blocked cue is superior to a different type ofredundant cue. We report an experiment designed to test theproposal that blocking is not a failure of association, but aperformance effect arising from a comparator process(Denniston, Savastano, & Miller, 2001). Participants receivedA+ AX+ BY+ CY- training containing a blocked cue X andanother redundant cue Y, before rating outcome expectanciesfor individual cues. These ratings were inconsistent with theassociation-failure view. After subsequent A- Y+ training,participants rated cues again. Ratings in the second test wereinconsistent with the comparator theory. Our data suggest thatneither perspective is likely to provide a complete account ofcausal learning.

Hepatocellular carcinoma (HCC) is difficult to detect, carries a poor prognosis, and is one of few cancers with an increasing yearly incidence. Molecular defects in complement factor H (CFH), a critical regulatory protein of the complement alternative pathway (AP), are typically associated with inflammatory diseases of the eye and kidney. Little is known regarding the role of CFH in controlling complement activation within the liver. While studying aging CFH-deficient ([fH.sup.-/-]) mice, we observed spontaneous hepatic tumor formation in more than 50% of aged [fH.sup.-/-] males. Examination of [fH.sup.-/-] livers (3-24 months) for evidence of complement-mediated inflammation revealed widespread deposition of complement-activation fragments throughout the sinusoids, elevated transaminase levels, increased hepatic CD8* and F4/80* cells, overexpression of hepatic mRNA associated with inflammatory signaling pathways, steatosis, and increased collagen deposition. Immunostaining of human HCC biopsies revealed extensive deposition of complement fragments within the tumors. Investigating the Cancer Genome Atlas also revealed that increased CFH mRNA expression is associated with improved survival in patients with HCC, whereas mutations are associated with worse survival. These results indicate that CFH is critical for controlling complement activation in the liver, and in its absence, AP activation leads to chronic inflammation and promotes hepatic carcinogenesis., Introduction Key functions of the immune system are the ability to discriminate self from nonself, and to rapidly eliminate invasive pathogens while causing minimal injury to the host. Rapid induction [...]

During pregnancy the maternal pancreatic islets of Langerhans undergo adaptive changes to compensate for gestational insulin resistance. The lactogenic hormones are well established to play a key role in regulating the islet adaptation to pregnancy, and one of the mechanisms through which they act is through upregulating β-cell serotonin production. During pregnancy islet serotonin levels are significantly elevated, where it is released from the β-cells to drive the adaptive response through paracrine and autocrine effects. We have previously shown that placental kisspeptin (KP) also plays a role in promoting the elevated insulin secretion and β-cell proliferation observed during pregnancy, although the precise mechanisms involved are unclear. In the present study we investigated the effects of KP on expression of pro-proliferative genes and serotonin biosynthesis within rodent islets. Whilst KP had limited effect on pro-proliferative gene expression at the time points tested, KP did significantly stimulate expression of the serotonin biosynthesis enzyme Tph-1. Furthermore, the islets of pregnant β-cell-specific GPR54 knockdown mice were found to contain significantly fewer serotonin-positive β-cells when compared to pregnant controls. Our previous studies suggested that reduced placental kisspeptin production, with consequent impaired kisspeptin-dependent β-cell compensation, may be a factor in the development of GDM in humans. These current data suggest that, similar to the lactogenic hormones, KP may also contribute to serotonin biosynthesis and subsequent islet signalling during pregnancy. Furthermore, upregulation of serotonin biosynthesis may represent a common mechanism through which multiple signals might influence the islet adaptation to pregnancy. [ABSTRACT FROM AUTHOR]

Background: Folk medicines are attractive therapeutic agents for treating type 2 diabetes mellitus (T2DM). Most plant extracts that have been suggested to restore β-cells function were tested in vivo. Some only have been tested in vitro to determine whether they have a direct effect on β-cells islets of Langerhans. Currently, there are no defined criteria for screening of β-cell-directed plant-based remedies as potential antidiabetic agents. Summary: In this review, we have identified certain criteria/characteristics that can be used to generate a "screening portfolio" to identify plant extracts as potential β-cell-directed agents for the treatment of T2DM. To validate our screening method, we studied the potential therapeutic efficacy of a Gymnema sylvestre (GS) extract using the screening criteria detailed in the review. Six criteria have been identified and validated using OSA®, a GS extract. By using this screening method, we show that OSA® fulfilled most of the criteria identified for an effective β-cell-directed antidiabetic therapy, being an effective insulin-releasing agent at nontoxic concentrations; maintaining β-cell insulin content by stimulating a concomitant increase in insulin gene transcription; maintaining β-cell mass by protecting against apoptosis; and being effective at maintaining normoglycemia in vivo in a mouse model and a human cohort with T2DM. Key messages: The present review has highlighted the importance of having a screening portfolio for plant extracts that have potential antidiabetic effects in the treatment of T2DM. We propose that this screening method should be adopted for future studies to identify new β-cell-directed antidiabetic plant derived agents. [ABSTRACT FROM AUTHOR]

To combine paleopathological and biomechanical analysis to reconstruct the impact that a severe skeletal injury had on an individual's ability to function and participate in medieval society. Three medieval individuals from Cambridge, England with ante-mortem fractures to the lower limb were analyzed. Plain X-rays were used to determine the degree of malunion, rotation and overlap of each fracture. Cortical bone architecture of the injured individuals and 28 uninjured controls were analyzed using micro-computed tomography (µCT). Clinical and functional consequences were examined using the Bioarcheology of Care framework. The mechanism of injury, the secondary complications, and the extent of the care received was reconstructed for each individual. Bilateral asymmetry in the cortical bone architecture revealed the long-term alterations to each individual's gait. Each of these individuals survived a severe injury resulting in chronic physical impairment, though not all would have been considered 'disabled'. This research contributes to the discussion about medieval care provision and social constructions of disability by illustrating how an interdisciplinary approach provides insight into the experiences of those with physical impairments. The integration of µCT imaging within the Bioarcheology of Care model is a novel approach with great potential for application across the field. Biomechanical analysis was restricted to cortical geometry. Further study of bilateral asymmetry in trabecular architecture could complement our understanding of altered loading modalities in past societies. [ABSTRACT FROM AUTHOR]