Sleep is fundamental to health and well-being, yet relatively little research attention has been paid to sleep quality. This paper addresses how socio-economic circumstances and gender are associated ...with sleep problems. We examine (i) socio-economic status (SES) patterning of reported sleep problems, (ii) whether SES differences in sleep problems can be explained by socio-demographic characteristics, smoking, worries, health and depression, and (iii) gender differences in sleep problems, addressing the relative contribution of SES, smoking, worries, health and depression in explaining these differences. Logistic regression is used to analyse the British
Psychiatric Morbidity Survey 2000, which interviewed 8578 men and women aged 16–74. Strong independent associations are found between sleep problems and four measures of SES: household income, educational qualifications, living in rented housing and not being in paid employment. Income differences in sleep problems were no longer significant when health and other characteristics were adjusted. The higher odds of sleep problems among the unemployed and adults with low education remained significant following adjustment. Women reported significantly more sleep problems than men, as did the divorced and widowed compared with married respondents. Gender differences in sleep problems were halved following adjustment for socio-economic characteristics, suggesting that SES inequalities play a major part in accounting for gender differences in sleep problems. Our study casts doubt on the primacy of physiological explanations underlying these gender differences. Since disadvantaged socio-economic characteristics are strongly associated with sleep problems, we conclude that disrupted sleep may be a mechanism through which low SES is linked to poor health.
Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR ...structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP−BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.
The inhibitor-of-apoptosis proteins (IAPs) regulate programmed cell death by inhibiting members of the caspase family of enzymes. Recently, a mammalian protein called Smac (also named DIABLO) was ...identified that binds to the IAPs and promotes caspase activation. Although undefined in the X-ray structure, the amino-terminal residues of Smac are critical for its function. To understand the structural basis for molecular recognition between Smac and the IAPs, we determined the solution structure of the BIR3 domain of X-linked IAP (XIAP) complexed with a functionally active nine-residue peptide derived from the N terminus of Smac. The peptide binds across the third β-strand of the BIR3 domain in an extended conformation with only the first four residues contacting the protein. The complex is stabilized by four intermolecular hydrogen bonds, an electrostatic interaction involving the N terminus of the peptide, and several hydrophobic interactions. This structural information, along with the binding data from BIR3 and Smac peptide mutants reported here, should aid in the design of small molecules that may be used for the treatment of cancers that overexpress IAPs.
Discovering High-Affinity Ligands for Proteins: SAR by NMR Shuker, Suzanne B.; Hajduk, Philip J.; Meadows, Robert P. ...
Science (American Association for the Advancement of Science),
11/1996, Letnik:
274, Številka:
5292
Journal Article
Recenzirano
A nuclear magnetic resonance (NMR)-based method is described in which small organic molecules that bind to proximal subsites of a protein are identified, optimized, and linked together to produce ...high-affinity ligands. The approach is called "SAR by NMR" because structure-activity relationships (SAR) are obtained from NMR. With this technique, compounds with nanomolar affinities for the FK506 binding protein were rapidly discovered by tethering two ligands with micromolar affinities. The method reduces the amount of chemical synthesis and time required for the discovery of high-affinity ligands and appears particularly useful in target-directed drug research.
Considerable attention has been paid to inequalities in health. More recently, focus has also turned to inequalities in ‘recovery’; with research, for example, suggesting that lower grade of ...employment is strongly associated with slower recovery from both poor physical and poor mental health. However, this research has tended to operationalise recovery as ‘return to baseline’, and we know less about patterns and predictors when recovery is situated as a ‘process’. This paper seeks to address this gap. Drawing on data from the UK Household Longitudinal Study, we operationalise recovery as both an ‘outcome’ and as a ‘process’ and compare patterns and predictors across the two models. Our analysis demonstrates that the determinants of recovery from poor health, measured by the SF-12, are robust, regardless of whether recovery is operationalised as an outcome or as a process. For example, being employed and having a higher degree were found to increase the odds of recovery both from poor physical and mental health functioning, when recovery was operationalised as an outcome. These variables were also important in distinguishing health functioning trajectories following a poor health episode. At one and the same time, our analysis does suggest that understandings of inequalities in recovery will depend in part on how we define it. When recovery is operationalised as a simple transition from poor health state to good, it loses sight of the fact that there may be inequalities (i) within a ‘poor health’ state, (ii) in how individuals are able to step into the path of recovery, and (iii) in whether health states are maintained over time. We therefore need to remain alert to the additional nuance in understanding which comes from situating recovery as a process; as well as possible methodological artefacts in population research which come from how recovery is operationalised.
•There is no consensus on what recovery is and how it should be operationalised.•Understanding of inequalities in recovery across health conditions remains scarce.•We operationalised recovery both as an outcome and as a process.•We found robust inequalities in recovery across the two approaches.•Considering recovery as a process revealed more nuanced patterns in inequalities.
Background
Artificial intelligence (AI) is said to be “transforming mental health”. AI-based technologies and technique are now considered to have uses in almost every domain of mental health care: ...including decision-making, assessment and healthcare management. What remains underexplored is whether/how mental health recovery is situated within these discussions and practices.
Method
Taking conversational agents as our point of departure, we explore the ways official online materials explain and make sense of chatbots, their imagined functionality and value for (potential) users. We focus on three chatbots for mental health: Woebot, Wysa and Tess.
Findings
“Recovery” is largely missing as an overt focus across materials. However, analysis does reveal themes that speak to the struggles over practice, expertise and evidence that the concept of recovery articulates. We discuss these under the headings “troubled clinical responsibility”, “extended virtue of (technological) self-care” and “altered ontologies and psychopathologies of time”.
Conclusions
Ultimately, we argue that alongside more traditional forms of recovery, chatbots may be shaped by, and shaping, an increasingly individualised form of a “personal recovery imperative”.
Interest in all-optical spin switching (AOS) is growing rapidly. The recent discovery of AOS in Mn2RuGa provides a much needed clean case of crystalline ferrimagnets for theoretical simulations. ...Here, we attempt to simulate it using the state-of-the-art first-principles method combined with the Heisenberg exchange model. We first compute the spin moments at two inequivalent manganese sites and then feed them into our model Hamiltonian. We employ an ultrafast laser pulse to switch the spins. We find that there is a similar optimal laser field amplitude to switch spins. However, we find that the exchange interaction has a significant effect on the system switchability. Weakening the exchange interaction could make the system unswitchable. This provides a crucial insight into the switching mechanism in ferrimagnets.
The inhibitor-of-apoptosis (IAP) family of proteins, originally identified in baculoviruses, regulate programmed cell death in a variety of organisms. IAPs inhibit specific enzymes (caspases) in the ...death cascade and contain one to three modules of a common 70-amino-acid motif called the BIR domain. Here we describe the nuclear magnetic resonance structure of a region encompassing the second BIR domain (BIR2) of a human IAP family member, XIAP (also called hILP or MIHA). The structure of the BIR domain consists of a three-stranded antiparallel β-sheet and four α-helices and resembles a classical zinc finger. Unexpectedly, conserved amino acids within the linker region between the BIR1 and BIR2 domains were found to be critical for inhibiting caspase-3. The absence or presence of these residues may explain the differences in caspase inhibition observed for different truncated and full-length IAPs. Our data further indicate that these residues may bind to the active site and that the BIR domain may interact with an adjacent site on the enzyme.
THE Bcl-2 family of proteins regulate programmed cell death by an unknown mechanism. Here we describe the crystal and solution structures of a Bcl-2 family member, Bcl-xL (ref. 2). The structures ...consist of two central, primarily hydrophobic alpha-helices, which are surrounded by amphipathic helices. A 60-residue loop connecting helices alpha1 and alpha2 was found to be flexible and non-essential for anti-apoptotic activity. The three functionally important Bcl-2 homology regions (BH1, BH2 and BH3) are in close spatial proximity and form an elongated hydrophobic cleft that may represent the binding site for other Bcl-2 family members. The arrangement of the alpha-helices in Bcl-xL is reminiscent of the membrane translocation domain of bacterial toxins, in particular diphtheria toxin and the colicins. The structural similarity may provide a clue to the mechanism of action of the Bcl-2 family of proteins.
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