The prevalence and incidence of mental ill-health in adults with autism and intellectual disabilities

The prevalence, and incidence, of mental ill-health in adults with intellectual disabilities and autism were compared with the whole population with intellectual disabilities, and with controls, matched individually for age, gender, ability-level, and Down syndrome. Although the adults with autism had a higher point prevalence of problem behaviours compared with the whole adult population with intellectual disabilities, compared with individually matched controls there was no difference in prevalence, or incidence of either problem behaviours or other mental ill-health. Adults with autism who had problem behaviours were less likely to recover over a two-year period than were their matched controls. Apparent differences in rates of mental ill-health are accounted for by factors other than autism, including Down syndrome and ability level

Aristotle’s assertoric syllogistic and modern relevance logic

This paper sets out to evaluate the claim that Aristotle’s Assertoric Syllogistic is a relevance logic or shows significant similarities with it. I prepare the grounds for a meaningful comparison by extracting the notion of relevance employed in the most influential work on modern relevance logic, Anderson and Belnap’s Entailment. This notion is characterized by two conditions imposed on the concept of validity: first, that some meaning content is shared between the premises and the conclusion, and second, that the premises of a proof are actually used to derive the conclusion. Turning to Aristotle’s Prior Analytics, I argue that there is evidence that Aristotle’s Assertoric Syllogistic satisfies both conditions. Moreover, Aristotle at one point explicitly addresses the potential harmfulness of syllogisms with unused premises. Here, I argue that Aristotle’s analysis allows for a rejection of such syllogisms on formal grounds established in the foregoing parts of the Prior Analytics. In a final section I consider the view that Aristotle distinguished between validity on the one hand and syllogistic validity on the other. Following this line of reasoning, Aristotle’s logic might not be a relevance logic, since relevance is part of syllogistic validity and not, as modern relevance logic demands, of general validity. I argue that the reasons to reject this view are more compelling than the reasons to accept it and that we can, cautiously, uphold the result that Aristotle’s logic is a relevance logic

Multi‐dimensional biodiversity hotspots and the future of taxonomic, ecological and phylogenetic diversity: A case study of North American rodents

AimWe investigate geographic patterns across taxonomic, ecological and phylogenetic diversity to test for spatial (in)congruency and identify aggregate diversity hotspots in relationship to present land use and future climate. Simulating extinctions of imperilled species, we demonstrate where losses across diversity dimensions and geography are predicted.LocationNorth America.Time periodPresent day, future.Major taxa studiedRodentia.MethodsUsing geographic range maps for rodent species, we quantified spatial patterns for 11 dimensions of diversity: taxonomic (species, range weighted), ecological (body size, diet and habitat), phylogenetic (mean, variance, and nearest‐neighbour patristic distances, phylogenetic distance and genus‐to‐species ratio) and phyloendemism. We tested for correlations across dimensions and used spatial residual analyses to illustrate regions of pronounced diversity. We aggregated diversity hotspots in relationship to predictions of land‐use and climate change and recalculated metrics following extinctions of IUCN‐listed imperilled species.ResultsTopographically complex western North America hosts high diversity across multiple dimensions: phyloendemism and ecological diversity exceed predictions based on taxonomic richness, and phylogenetic variance patterns indicate steep gradients in phylogenetic turnover. An aggregate diversity hotspot emerges in the west, whereas spatial incongruence exists across diversity dimensions at the continental scale. Notably, phylogenetic metrics are uncorrelated with ecological diversity. Diversity hotspots overlap with land‐use and climate change, and extinctions predicted by IUCN status are unevenly distributed across space, phylogeny or ecological groups.Main conclusionsComparison of taxonomic, ecological and phylogenetic diversity patterns for North American rodents clearly shows the multifaceted nature of biodiversity. Testing for geographic patterns and (in)congruency across dimensions of diversity facilitates investigation into underlying ecological and evolutionary processes. The geographic scope of this analysis suggests that several explicit regional challenges face North American rodent fauna in the future. Simultaneous consideration of multi‐dimensional biodiversity allows us to assess what critical functions or evolutionary history we might lose with future extinctions and maximize the potential of our conservation efforts.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154236/1/geb13050.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154236/2/geb13050_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154236/3/geb13050-sup-0001-Supinfo1.pd

Evolutionarily Conserved Linkage between Enzyme Fold, Flexibility, and Catalysis

Proteins are intrinsically flexible molecules. The role of internal motions in a protein's designated function is widely debated. The role of protein structure in enzyme catalysis is well established, and conservation of structural features provides vital clues to their role in function. Recently, it has been proposed that the protein function may involve multiple conformations: the observed deviations are not random thermodynamic fluctuations; rather, flexibility may be closely linked to protein function, including enzyme catalysis. We hypothesize that the argument of conservation of important structural features can also be extended to identification of protein flexibility in interconnection with enzyme function. Three classes of enzymes (prolyl-peptidyl isomerase, oxidoreductase, and nuclease) that catalyze diverse chemical reactions have been examined using detailed computational modeling. For each class, the identification and characterization of the internal protein motions coupled to the chemical step in enzyme mechanisms in multiple species show identical enzyme conformational fluctuations. In addition to the active-site residues, motions of protein surface loop regions (>10 Å away) are observed to be identical across species, and networks of conserved interactions/residues connect these highly flexible surface regions to the active-site residues that make direct contact with substrates. More interestingly, examination of reaction-coupled motions in non-homologous enzyme systems (with no structural or sequence similarity) that catalyze the same biochemical reaction shows motions that induce remarkably similar changes in the enzyme–substrate interactions during catalysis. The results indicate that the reaction-coupled flexibility is a conserved aspect of the enzyme molecular architecture. Protein motions in distal areas of homologous and non-homologous enzyme systems mediate similar changes in the active-site enzyme–substrate interactions, thereby impacting the mechanism of catalyzed chemistry. These results have implications for understanding the mechanism of allostery, and for protein engineering and drug design

A programmed cell death pathway in the malaria parasite Plasmodium falciparum has general features of mammalian apoptosis but is mediated by clan CA cysteine proteases

Several recent discoveries of the hallmark features of programmed cell death (PCD) in Plasmodium falciparum have presented the possibility of revealing novel targets for antimalarial therapy. Using a combination of cell-based assays, flow cytometry and fluorescence microscopy, we detected features including mitochondrial dysregulation, activation of cysteine proteases and in situ DNA fragmentation in parasites induced with chloroquine (CQ) and staurosporine (ST). The use of the pan-caspase inhibitor, z-Val-Ala-Asp-fmk (zVAD), and the mitochondria outer membrane permeabilization (MOMP) inhibitor, 4-hydroxy-tamoxifen, enabled the characterization of a novel CQ-induced pathway linking cysteine protease activation to downstream mitochondrial dysregulation, amplified protease activity and DNA fragmentation. The PCD features were observed only at high (μM) concentrations of CQ. The use of a new synthetic coumarin-labeled chloroquine (CM-CQ) showed that these features may be associated with concentration-dependent differences in drug localization. By further using cysteine protease inhibitors z-Asp-Glu-Val-Asp-fmk (zDEVD), z-Phe-Ala-fmk (zFA), z-Phe-Phe-fmk (zFF), z-Leu-Leu-Leu-fmk (zLLL), E64d and CA-074, we were able to implicate clan CA cysteine proteases in CQ-mediated PCD. Finally, CQ induction of two CQ-resistant parasite strains, 7G8 and K1, reveals the existence of PCD features in these parasites, the extent of which was less than 3D7. The use of the chemoreversal agent verapamil implicates the parasite digestive vacuole in mediating CQ-induced PCD

Discovery and Development of Toll-Like Receptor 4 (TLR4) Antagonists: A New Paradigm for Treating Sepsis and Other Diseases

Abstract. Sepsis remains the most common cause of death in intensive care units in the USA, with a current estimate of at least 750,000 cases per year, and 215,000 deaths annually. Despite extensive research still we do not quite understand the cellular and molecular mechanisms that are involved in triggering and propagation of septic injury. Endotoxin (lipopolysaccharide from Gram-negative bacteria, or LPS) has been implicated as a major cause of this syndrome. Inflammatory shock as a consequence of LPS release remains a serious clinical concern. In humans, inflammatory responses to LPS result in the release of cytokines and other cell mediators from monocytes and macrophages, which can cause fever, shock, organ failure and death. A number of different approaches have been investigated to try to treat and/or prevent the septic shock associated with infections caused by Gram-negative bacteria, including blockage of one or more of the cytokines induced by LPS. Recently several novel amphipathic compounds have been developed as direct LPS antagonists at the LPS receptor, TLR4. This review article will outline the current knowledge on the TLR4-LPS synthesis and discuss the signaling, in vitro pre-clinical and in vivo clinical evaluation of TLR4 antagonists and their potential use in sepsis and a variety of diseases such as atherosclerosis as well as hepatic and renal malfunction. KEY WORDS: drug discovery; LPS; sepsis; toll-like receptor antagonists

Cognitive behaviour therapy (CBT) for anxiety and depression in adults with mild intellectual disabilities (ID): a pilot randomised controlled trial

Background: Several studies have showed that people with intellectual disabilities (ID) have suitable skills to undergo cognitive behavioural therapy (CBT). Case studies have reported successful use of cognitive behavioural therapy techniques (with adaptations) in people with ID. Modified cognitive behavioural therapy may be a feasible and effective approach for the treatment of depression, anxiety, and other mood disorders in ID. To date, two studies have reported group-based manaulised cognitive behavioural treatment programs for depression in people with mild ID. However, there is no individual manualised programme for anxiety or depression in people with intellectual disabilities. The aims of the study are to determine the feasibility of conducting a randomised controlled trial for CBT in people with ID. The data will inform the power calculation and other aspects of carrying out a definitive randomised controlled trial.Methods: Thirty participants with mild ID will be allocated randomly to either CBT or treatment as usual (TAU). The CBT group will receive up to 20 hourly individual CBT over a period of 4 months. TAU is the standard treatment which is available to any adult with an intellectual disability who is referred to the intellectual disability service (including care management, community support, medical, nursing or social support). Beck Youth Inventories (Beck Anxiety Inventory & Beck Depression Inventory) will be administered at baseline; end of treatment (4 months) and at six months to evaluate the changes in depression and anxiety. Client satisfaction, quality of life and the health economics will be secondary outcomes.Discussion: The broad outcome of the study will be to produce clear guidance for therapists to apply an established psychological intervention and identify how and whether it works with people with intellectual disabilities