Memory Category Fluency, Memory Specificity, and the Fading Affect Bias for Positive and Negative Autobiographical Events: Performance on a Good Day- Bad Day Task in Healthy and Depressed Individuals

In mentally healthy individuals, autobiographical memory is typically biased toward positive events, which may help to maintain psychological well-being. Our aim was to assess a range of important positive memory biases in the mentally healthy and explore the possibility that these biases are mitigated in those with mental health problems. We administered a novel recall paradigm that required recollection of multiple good and bad past events (the Good Day-Bad Day task) to healthy and depressed individuals. This allowed us to explore differences in memory category fluency (i.e., the ability to generate integrated sets of associated events) for positive and negative memories, along with memory specificity, and fading affect bias-a greater reduction in the intensity of memory-related affect over time for negative versus positive events. We found that healthy participants demonstrated superior category fluency for positive relative to negative events but that this effect was absent in depressed participants. Healthy participants exhibited a strong fading affect bias that was significantly mitigated, although still present, in depression. Finally, memory specificity was reduced in depression for both positive and negative memories. Findings demonstrate that the positive bias associated with mental health is maintained by multiple autobiographical memory processes and that depression is as much a function of the absence of these positive biases as it is the presence of negative biases. Results provide important guidance for developing new treatments for improving mental health.This research was supported by the UK Medical Research Council (Grant: SUAG/006/RG91365) and the UK National Institute of Health Research Cambridge Biomedical Research Centre

Barbed suture vs conventional tenorrhaphy: biomechanical analysis in an animal model.

BACKGROUND: The advantages of barbed suture for tendon repair could be to eliminate the need for a knot and to better distribute the load throughout the tendon so as to reduce the deformation at the repair site. The purpose of this study was to evaluate the breaking force and the repair site deformation of a new barbed tenorrhaphy technique in an animal model. MATERIALS AND METHODS: Sixty porcine flexor tendons were divided randomly into three groups and repaired with one of the following techniques: a new 4-strand barbed technique using 2/0 polypropylene Quill™ SRS or 2/0 polydioxanone Quill™ SRS and a modified Kessler technique using 3/0 prolene. All tendons underwent mechanical testing to assess the 2-mm gap formation force, the breaking force and the mode of failure. The percentage change in tendon cross-sectional area before and after repair was calculated. RESULTS: The two-sample Student t-test demonstrated a significant increase in 2-mm gap formation force and in breaking force with barbed sutures, independently from suture material, when compared to traditional Kessler suture. Concerning the tendon profile, we registered less bunching at the repair site in the two barbed groups compared with the Kessler group. CONCLUSIONS: This study confirms the promising results achieved in previous ex vivo studies about the use of barbed suture in flexor tendon repair. In our animal model, tenorrhaphy with Quill™ SRS suture guarantees a breaking force of repair that exceeds the 40-50 N suggested as sufficient to initiate early active motion, and a smoother profile at the repair site. LEVEL OF EVIDENCE: Not applicable

The Search for Invariance: Repeated Positive Testing Serves the Goals of Causal Learning

Positive testing is characteristic of exploratory behavior, yet it seems to be at odds with the aim of information seeking. After all, repeated demonstrations of one’s current hypothesis often produce the same evidence and fail to distinguish it from potential alternatives. Research on the development of scientific reasoning and adult rule learning have both documented and attempted to explain this behavior. The current chapter reviews this prior work and introduces a novel theoretical account—the Search for Invariance (SI) hypothesis—which suggests that producing multiple positive examples serves the goals of causal learning. This hypothesis draws on the interventionist framework of causal reasoning, which suggests that causal learners are concerned with the invariance of candidate hypotheses. In a probabilistic and interdependent causal world, our primary goal is to determine whether, and in what contexts, our causal hypotheses provide accurate foundations for inference and intervention—not to disconfirm their alternatives. By recognizing the central role of invariance in causal learning, the phenomenon of positive testing may be reinterpreted as a rational information-seeking strategy

Intrinsic Capability of Budding Yeast Cofilin to Promote Turnover of Tropomyosin-Bound Actin Filaments

The ability of actin filaments to function in cell morphogenesis and motility is closely coupled to their dynamic properties. Yeast cells contain two prominent actin structures, cables and patches, both of which are rapidly assembled and disassembled. Although genetic studies have shown that rapid actin turnover in patches and cables depends on cofilin, how cofilin might control cable disassembly remains unclear, because tropomyosin, a component of actin cables, is thought to protect actin filaments against the depolymerizing activity of ADF/cofilin. We have identified cofilin as a yeast tropomyosin (Tpm1) binding protein through Tpm1 affinity column and mass spectrometry. Using a variety of assays, we show that yeast cofilin can efficiently depolymerize and sever yeast actin filaments decorated with either Tpm1 or mouse tropomyosins TM1 and TM4. Our results suggest that yeast cofilin has the intrinsic ability to promote actin cable turnover, and that the severing activity may rely on its ability to bind Tpm1

Mechanical and kinetic effects of shortened tropomyosin reconstituted into myofibrils

The effects of tropomyosin on muscle mechanics and kinetics were examined in skeletal myofibrils using a novel method to remove tropomyosin (Tm) and troponin (Tn) and then replace these proteins with altered versions. Extraction employed a low ionic strength rigor solution, followed by sequential reconstitution at physiological ionic strength with Tm then Tn. SDS-PAGE analysis was consistent with full reconstitution, and fluorescence imaging after reconstitution using Oregon-green-labeled Tm indicated the expected localization. Myofibrils remained mechanically viable: maximum isometric forces of myofibrils after sTm/sTn reconstitution (control) were comparable (~84%) to the forces generated by non-reconstituted preparations, and the reconstitution minimally affected the rate of isometric activation (kact), calcium sensitivity (pCa50), and cooperativity (nH). Reconstitutions using various combinations of cardiac and skeletal Tm and Tn indicated that isoforms of both Tm and Tn influence calcium sensitivity of force development in opposite directions, but the isoforms do not otherwise alter cross-bridge kinetics. Myofibrils reconstituted with Δ23Tm, a deletion mutant lacking the second and third of Tm’s seven quasi-repeats, exhibited greatly depressed maximal force, moderately slower kact rates and reduced nH. Δ23Tm similarly decreased the cooperativity of calcium binding to the troponin regulatory sites of isolated thin filaments in solution. The mechanisms behind these effects of Δ23Tm also were investigated using Pi and ADP jumps. Pi and ADP kinetics were indistinguishable in Δ23Tm myofibrils compared to controls. The results suggest that the deleted region of tropomyosin is important for cooperative thin filament activation by calcium

Glycomics Analysis of Mammalian Heparan Sulfates Modified by the Human Extracellular Sulfatase HSulf2

The Sulfs are a family of endosulfatases that selectively modify the 6O-sulfation state of cell-surface heparan sulfate (HS) molecules. Sulfs serve as modulators of cell-signaling events because the changes they induce alter the cell surface co-receptor functions of HS chains. A variety of studies have been aimed at understanding how Sulfs modify HS structure, and many of these studies utilize Sulf knockout cell lines as the source for the HS used in the experiments. However, genetic manipulation of Sulfs has been shown to alter the expression levels of HS biosynthetic enzymes, and in these cases an assessment of the fine structural changes induced solely by Sulf enzymatic activity is not possible. Therefore, the present work aims to extend the understanding of substrate specificities of HSulf2 using in vitro experiments to compare HSulf2 activities on HS from different organ tissues.To further the understanding of Sulf enzymatic activity, we conducted in vitro experiments where a variety of mammalian HS substrates were modified by recombinant human Sulf2 (HSulf2). Subsequent to treatment with HSulf2, the HS samples were exhaustively depolymerized and analyzed using size-exclusion liquid chromatography-mass spectrometry (SEC-LC/MS). We found that HSulf2 activity was highly dependent on the structural features of the HS substrate. Additionally, we characterized, for the first time, the activity of HSulf2 on the non-reducing end (NRE) of HS chains. The results indicate that the action pattern of HSulf2 at the NRE is different compared to internally within the HS chain.The results of the present study indicate that the activity of Sulfs is dependent on the unique structural features of the HS populations that they edit. The activity of HSulf2 at HS NREs implicates the Sulfs as key regulators of this region of the chains, and concomitantly, the protein-binding events that occur there

A longitudinal examination of the relationship between trauma-related cognitive factors and internalising and externalising psychopathology in physically injured children

Cognitive models of posttraumatic stress disorder (PTSD) highlight maladaptive posttrauma appraisals, trauma memory qualities, and coping strategies, such as rumination or thought suppression, as key processes that maintain PTSD symptoms. Anxiety, depression and externalising symptoms can also present in children in the aftermath of trauma, yet there has been little empirical investigation of the potential relevance of posttrauma cognitive processes for such difficulties. Here, we examined whether: a) acute maladaptive cognitive processes (specifically, maladaptive appraisals, memory qualities, and cognitive coping) were associated with symptoms of PTSD, internalising, and externalising at 1-month posttrauma (T1); and b) changes in these cognitive processes predicted symptom change at a follow-up assessment 6 months later (T2). We recruited 132 6–13 year old children and their parents from emergency departments following the child’s experience of an acute trauma. Children self-reported on their maladaptive appraisals, trauma-memory and cognitive coping strategies, along with symptoms of PTSD, anxiety and depression. Parents also rated children’s internalising and externalising symptoms. We found each cognitive process to be robustly associated with PTSD and non-PTSD internalising symptoms at T1, and change in each predicted change in symptoms to T2. Maladaptive appraisals and cognitive coping were unique predictors of children’s posttrauma internalising. Effects were partially retained even controlling for co-occurring PTSD symptoms. There was less evidence that trauma-specific cognitive processes were associated with externalising symptoms. Findings suggest aspects of cognitive models of PTSD are applicable to broader posttrauma psychopathology, and have implications for how we understand and target children’s posttrauma psychological adjustment

Comparative Lipidomics of Azole Sensitive and Resistant Clinical Isolates of Candida albicans Reveals Unexpected Diversity in Molecular Lipid Imprints

Although transcriptome and proteome approaches have been applied to determine the regulatory circuitry behind multidrug resistance (MDR) in Candida, its lipidome remains poorly characterized. Lipids do acclimatize to the development of MDR in Candida, but exactly how the acclimatization is achieved is poorly understood. In the present study, we have used a high-throughput mass spectrometry-based shotgun approach and analyzed the lipidome of genetically matched clinical azole-sensitive (AS) and -resistant (AR) isolates of C. albicans. By comparing the lipid profiling of matched isolates, we have identified major classes of lipids and determined more than 200 individual molecular lipid species among these major classes. The lipidome analysis has been statistically validated by principal component analysis. Although each AR isolate was similar with regard to displaying a high MIC to drugs, they had a distinct lipid imprint. There were some significant commonalities in the lipid profiles of these pairs, including molecular lipid species ranging from monounsaturated to polyunsaturated fatty acid-containing phosphoglycerides. Consistent fluctuation in phosphatidyl serine, mannosylinositolphosphorylceramides, and sterol esters levels indicated their compensatory role in maintaining lipid homeostasis among most AR isolates. Notably, overexpression of either CaCdr1p or CaMdr1p efflux pump proteins led to a different lipidomic response among AR isolates. This study clearly establishes the versatility of lipid metabolism in handling azole stress among various matched AR isolates. This comprehensive lipidomic approach will serve as a resource for assessing strategies aimed at disrupting the functions of Candida lipids, particularly the functional interactions between lipids and MDR determinants

Target 2035-update on the quest for a probe for every protein

Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function. Accordingly, a subset of human proteins has been at the heart of research interests of scientists over the centuries, and we have accumulated varying degrees of knowledge about approximately 65% of the human proteome. Nevertheless, a large proportion of proteins in the human proteome (∼35%) remains uncharacterized, and less than 5% of the human proteome has been successfully targeted for drug discovery. This highlights the profound disconnect between our abilities to obtain genetic information and subsequent development of effective medicines. Target 2035 is an international federation of biomedical scientists from the public and private sectors, which aims to address this gap by developing and applying new technologies to create by year 2035 chemogenomic libraries, chemical probes, and/or biological probes for the entire human proteome

BarA-UvrY Two-Component System Regulates Virulence of Uropathogenic E. coli CFT073

Uropathogenic Escherichia coli (UPEC), a member of extraintestinal pathogenic E. coli, cause ∼80% of community-acquired urinary tract infections (UTI) in humans. UPEC initiates its colonization in epithelial cells lining the urinary tract with a complicated life cycle, replicating and persisting in intracellular and extracellular niches. Consequently, UPEC causes cystitis and more severe form of pyelonephritis. To further understand the virulence characteristics of UPEC, we investigated the roles of BarA-UvrY two-component system (TCS) in regulating UPEC virulence. Our results showed that mutation of BarA-UvrY TCS significantly decreased the virulence of UPEC CFT073, as assessed by mouse urinary tract infection, chicken embryo killing assay, and cytotoxicity assay on human kidney and uroepithelial cell lines. Furthermore, mutation of either barA or uvrY gene reduced the production of hemolysin, lipopolysaccharide (LPS), proinflammatory cytokines (TNF-α and IL-6) and chemokine (IL-8). The virulence phenotype was restored similar to that of wild-type by complementation of either barA or uvrY gene in trans. In addition, we discussed a possible link between the BarA-UvrY TCS and CsrA in positively and negatively controlling virulence in UPEC. Overall, this study provides the evidences for BarA-UvrY TCS regulates the virulence of UPEC CFT073 and may point to mechanisms by which virulence regulations are observed in different ways may control the long-term survival of UPEC in the urinary tract