A Concept Development for the Symptom Science Model 2.0.

BACKGROUND: The National Institute of Nursing Research developed the National Institutes of Health symptom science model (SSM) in 2015 as a parsimonious conceptual model to guide symptom science research. OBJECTIVES: This concept development paper synthesizes justifications to strengthen the original model. METHODS: A literature review was performed, discussions with symptom science content expert stakeholders were held, and opportunities for expanding the current model were identified. Concept elements for a revised conceptual model-the SSM 2.0-were developed. RESULTS: In addition to the four original concept elements (complex symptom presentation, phenotypic characterization, biobehavioral factors [previously biomarker discovery], and clinical applications), three new concept elements are proposed, including social determinants of health, patient-centered experience, and policy/population health. DISCUSSION: There have been several calls to revise the original SSM from the nursing scientific community to expand its utility to other healthcare settings. Incorporating three additional concept elements can facilitate a broader variety of translational nursing research symptom science collaborations and applications, support additional scientific domains for symptom science activities, and produce more translatable symptom science to a wider audience of nursing research scholars and stakeholders during recovery from the COVID-19 pandemic. The revised SSM 2.0 with newly incorporated social determinants of health, patient-centered experience, and policy/population health components now empowers nursing scientists and scholars to address specific symptom science public health challenges particularly faced by vulnerable and underserved populations.

Integrative Behavioral Health (IBH) Model at the Intersections of the Philippine Mental Health Law, Education, and Policy: For COVID-19 Recovery and Beyond.

The COVID-19 pandemic has impacted the mental health of Philippine citizens. The authors propose the Integrative Behavioral Health (IBH) model to help facilitate the country's eventual recovery from a health psychology perspective. Findings were integrated from a faculty consultation from a private university's psychology department, a literature review, and a survey of students who are learning online. The survey results revealed that living with family members negatively correlated with readiness to learn online, r = -.37, p < .05. Further research is needed. Furthermore, combining themes gathered from the consultation, literature review, and variables used from the survey served as anchor words for the IBH model: 1. Emancipatory Education; 2) Filipino Psychology; 3) Contextualization; 4.) Philippine Mental Health Law; 5). Symptom Science; and 6) Social Determinants of Health (SDH). The constructs were implemented into an online health psychology course. The proposed curriculum design provides for an effective mental health response towards post-pandemic recovery.

Disentangling fatigue from anhedonia: a scoping review.

Fatigue and anhedonia are commonly reported, co-occurring clinical symptoms associated with chronic illnesses. Fatigue is a multidimensional construct that is defined as a distressing, persistent, subjective sense of physical, cognitive, or emotional tiredness that interferes with usual functioning. Anhedonia is a component of depressive disorders and other psychiatric conditions, such as schizophrenia, and is defined by the reduced ability to experience pleasure. Both symptoms greatly affect the health-related quality of life of patients with chronic illnesses. Although fatigue and anhedonia are commonly associated with each other, understanding the differences between the two constructs is necessary for diagnosis and clinical treatment. A scoping review was conducted based on published guidance, starting with a comprehensive search of existing literature to understand the similarities and differences between fatigue and anhedonia. An initial search of PubMed using fatigue and anhedonia as medical subject headings yielded a total of 5254 articles. A complete full-text review of the final 21 articles was conducted to find articles that treated both constructs similarly and articles that presented fatigue and anhedonia as distinct constructs. About 60% of the reviewed articles consider both constructs as distinct, but a considerable number of the reviewed articles found these constructs indistinguishable. Nomenclature and biology were two themes from the reviewed articles supporting the idea that anhedonia and fatigue are indistinguishable constructs. The information generated from this review is clinically relevant to optimize the management of fatigue related to anhedonia from other fatigue subtypes.

Structure-activity relationship of biaryl acylsulfonamide analogues on the human EP(3) prostanoid receptor.

Potent and selective ligands for the human EP3 prostanoid receptor are described. Biaryl compounds bearing a tethered ortho substituted acidic moiety were identified as potent EP3 antagonists based on the SAR described herein. The binding affinity of key compounds on all eight human prostanoid receptors is reported.

The utilization of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs.

Stable cell lines that individually express the eight known human prostanoid receptors (EP(1), EP(2), EP(3), EP(4), DP, FP, IP and TP) have been established using human embryonic kidney (HEK) 293(EBNA) cells. These recombinant cell lines have been employed in radioligand binding assays to determine the equilibrium inhibitor constants of known prostanoid receptor ligands at these eight receptors. This has allowed, for the first time, an assessment of the affinity and selectivity of several novel compounds at the individual human prostanoid receptors. This information should facilitate interpretation of pharmacological studies that employ these ligands as tools to study human tissues and cell lines and should, therefore, result in a greater understanding of prostanoid receptor biology.

New class of biphenylene dibenzazocinones as potent ligands for the human EP1 prostanoid receptor.

A new class of potent and selective ligands for the human EP1 prostanoid receptor is described. SAR studies reported herein allowed the identification of several potent dibenzazocinones bearing an acylsulfonamide side chain. The binding affinity of these compounds on all eight human prostanoid receptors is reported.

Prostaglandin E2-bisphosphonate conjugates: potential agents for treatment of osteoporosis.

Conjugates of bisphosphonates (potential bone resorption inhibitors) and prostaglandin E2 (a bone formation enhancer) were prepared and evaluated for their ability to bind to bone and to liberate, enzymatically, free PGE2. The conjugate 3, an amide at C-1 of PGE2 proved to be too stable in vivo while conjugate 6, a thioester, was too labile. Several PGE2, C-15 ester-linked conjugates (18, 23, 24 and 31) were prepared and conjugate 23 was found to bind effectively to bone in vitro and in vivo and to liberate PGE2 at an acceptable rate. A 4-week study in a rat model of osteoporosis showed that 23 was better tolerated and more effective as a bone growth stimulant than daily maximum tolerated doses of free PGE2.

Hsp60 accelerates the maturation of pro-caspase-3 by upstream activator proteases during apoptosis.

The activation of caspases represents a critical step in the pathways leading to the biochemical and morphological changes that underlie apoptosis. Multiple pathways leading to caspase activation appear to exist and vary depending on the death-inducing stimulus. We demonstrate that the activation of caspase-3, in Jurkat cells stimulated to undergo apoptosis by a Fas-independent pathway, is catalyzed by caspase-6. Caspase-6 was found to co-purify with caspase-3 as part of a multiprotein activation complex from extracts of camptothecin-treated Jurkat cells. A biochemical analysis of the protein constituents of the activation complex showed that Hsp60 was also present. Furthermore, an interaction between Hsp60 and caspase-3 could be demonstrated by co-immunoprecipitation experiments using HeLa as well as Jurkat cell extracts. Using a reconstituted in vitro system, Hsp60 was able to substantially accelerate the maturation of procaspase-3 by different upstream activator caspases and this effect was dependent on ATP hydrolysis. We propose that the ATP-dependent 'foldase' activity of Hsp60 improves the vulnerability of pro-caspase-3 to proteolytic maturation by upstream caspases and that this represents an important regulatory event in apoptotic cell death.

Inhibition of human caspases by peptide-based and macromolecular inhibitors.

Studies with peptide-based and macromolecular inhibitors of the caspase family of cysteine proteases have helped to define a central role for these enzymes in inflammation and mammalian apoptosis. A clear interpretation of these studies has been compromised by an incomplete understanding of the selectivity of these molecules. Here we describe the selectivity of several peptide-based inhibitors and the coxpox serpin CrmA against 10 human caspases. The peptide aldehydes that were examined (Ac-WEHD-CHO, Ac-DEVD-CHO, Ac-YVAD-CHO, t-butoxycarbonyl-IETD-CHO, and t-butoxycarbonyl-AEVD-CHO) included several that contain the optimal tetrapeptide recognition motif for various caspases. These aldehydes display a wide range of selectivities and potencies against these enzymes, with dissociation constants ranging from 75 pM to >10 microM. The halomethyl ketone benzyloxycarbonyl-VAD fluoromethyl ketone is a broad specificity irreversible caspase inhibitor, with second-order inactivation rates that range from 2.9 x 10(2) M-1 s-1 for caspase-2 to 2.8 x 10(5) M-1 s-1 for caspase-1. The results obtained with peptide-based inhibitors are in accord with those predicted from the substrate specificity studies described earlier. The cowpox serpin CrmA is a potent (Ki < 20 nM) and selective inhibitor of Group I caspases (caspase-1, -4, and -5) and most Group III caspases (caspase-8, -9, and -10), suggesting that this virus facilitates infection through inhibition of both apoptosis and the host inflammatory response.

The three-dimensional structure of apopain/CPP32, a key mediator of apoptosis.

Cysteine proteases related to mammalian interleukin-1 beta converting enzyme (ICE) and to its Caenorhabditis elegans homologue, CED-3, play a critical role in the biochemical events that culminate in apoptosis. We have determined the three-dimensional structure of a complex of the human CED-3 homologue CPP32/apopain with a potent tetrapeptide-aldehyde inhibitor. The protein resembles ICE in overall structure, but its S4 subsite is strikingly different in size and chemical composition. These differences account for the variation in specificity between the ICE- and CED-3-related proteases and enable the design of specific inhibitors that can probe the physiological functions of the proteins and disease states with which they are associated.

Non-natural 14-hydroxy steroids. II. 13 alpha,14 alpha and 13 beta,14 beta isomers of methyl 14-hydroxy-1,7,17-trioxo-5 beta-androst-8-ene-19-oate.

C20H24O6, Mr = 360.41 lambda (Cu K alpha) = 1.54056 A, room temperature. (I) (5 beta,10 beta,13 alpha,14 alpha)-Methyl 14-hydroxy-1,7,17-trioxoandrost-8-ene-19-oate, triclinic, P1, a = 7.9514 (5), b = 9.2892 (5), c = 12.8534 (12) A, alpha = 81.256 (6), beta = 75.796 (6), gamma = 77.908 (5) degrees, V = 894.85 (11) A3, Z = 2, Dx = 1.338 Mg m-3, mu = 0.77 mm-1, F(000) = 383.96, final R = 0.043 for 2912 observed reflections. (II) (5 beta, 10 beta, 13 beta,14 beta)-Methyl 14-hydroxy-1,7,17-trioxoandrost-8-ene-19-oate, monoclinic, P21/n, a = 12.8704 (9), b = 10.4481 (9), c = 13.1482 (5) A, beta = 104.103 (5) degrees, V = 1714.77 (20) A3, Z = 4, Dx = 1.396 Mg m-3, mu = 0.81 mm-1, F(000) = 767.92, final R = 0.055 for 2516 observed reflections. These two non-natural steroids bear a methoxycarbonyl group at C(10). In both molecules the relative stereo-chemistry is cis for the A/B ring junction and cis for the C/D ring junction. The relative orientations of MeO2C--C(10) and HO--C(14) are anti for (I) and syn for (II). The methoxycarbonyl group lies at the axial position for (I) and equatorial for (II), relative to ring A. The energies of possible conformations for (I) and (II) are evaluated, wherein the A rings adopt a chair conformation.