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1.
J Clin Psychol ; 80(7): 1490-1503, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38447035

ABSTRACT

OBJECTIVE: This study examined the contributions of shame and posttraumatic stress disorder (PTSD) symptoms to two dimensions of social problem-solving. METHOD: A sample of 426 women who were seeking mental health assistance following experiences of intimate partner violence completed self-report and clinician measures. Separate path analyses were conducted for problem orientation and problem-solving styles. RESULTS: In the model examining problem orientation, higher levels of shame were significantly associated with lower levels of positive problem orientation (f2 = 0.32) and higher levels of negative problem orientation (f2 = 0.92), with large effects noted. PTSD symptoms were significantly, positively associated with negative problem orientation (f2 = 0.3, large effect). When examining problem-solving styles, shame showed a significant negative association with rational style (f2 = 0.08, small effect) and significant positive associations with impulsive style (f2 = 0.45, large effect) and avoidant style (f2 = 0.48, large effect). PTSD symptoms did not return significant associations with any of the three problem-solving styles. CONCLUSION: Results indicate that shame holds notable associations with both dimensions of social problem-solving, relative to PTSD symptoms, and are discussed in light of current models of post-trauma functioning. Implications for clinical care and early intervention efforts are highlighted.


Subject(s)
Intimate Partner Violence , Problem Solving , Shame , Stress Disorders, Post-Traumatic , Humans , Female , Stress Disorders, Post-Traumatic/psychology , Adult , Intimate Partner Violence/psychology , Middle Aged , Young Adult , Crime Victims/psychology
2.
JAMA ; 328(8): 719-727, 2022 08 23.
Article in English | MEDLINE | ID: mdl-35997730

ABSTRACT

Importance: There remains a lack of randomized trials investigating aspirin monotherapy for symptomatic venous thromboembolism (VTE) prophylaxis following total hip arthroplasty (THA) or total knee arthroplasty (TKA). Objective: To determine whether aspirin was noninferior to enoxaparin in preventing symptomatic VTE after THA or TKA. Design, Setting, and Participants: Cluster-randomized, crossover, registry-nested trial across 31 hospitals in Australia. Clusters were hospitals performing greater than 250 THA or TKA procedures annually. Patients (aged ≥18 years) undergoing hip or knee arthroplasty procedures were enrolled at each hospital. Patients receiving preoperative anticoagulation or who had a medical contraindication to either study drug were excluded. A total of 9711 eligible patients were enrolled (5675 in the aspirin group and 4036 in the enoxaparin group) between April 20, 2019, and December 18, 2020. Final follow-up occurred on August 14, 2021. Interventions: Hospitals were randomized to administer aspirin (100 mg/d) or enoxaparin (40 mg/d) for 35 days after THA and for 14 days after TKA. Crossover occurred after the patient enrollment target had been met for the first group. All 31 hospitals were initially randomized and 16 crossed over prior to trial cessation. Main Outcomes and Measures: The primary outcome was symptomatic VTE within 90 days, including pulmonary embolism and deep venous thrombosis (DVT) (above or below the knee). The noninferiority margin was 1%. Six secondary outcomes are reported, including death and major bleeding within 90 days. Analyses were performed by randomization group. Results: Enrollment was stopped after an interim analysis determined the stopping rule was met, with 9711 patients (median age, 68 years; 56.8% female) of the prespecified 15 562 enrolled (62%). Of these, 9203 (95%) completed the trial. Within 90 days of surgery, symptomatic VTE occurred in 256 patients, including pulmonary embolism (79 cases), above-knee DVT (18 cases), and below-knee DVT (174 cases). The symptomatic VTE rate in the aspirin group was 3.45% and in the enoxaparin group was 1.82% (estimated difference, 1.97%; 95% CI, 0.54%-3.41%). This failed to meet the criterion for noninferiority for aspirin and was significantly superior for enoxaparin (P = .007). Of 6 secondary outcomes, none were significantly better in the enoxaparin group compared with the aspirin group. Conclusions and Relevance: Among patients undergoing hip or knee arthroplasty for osteoarthritis, aspirin compared with enoxaparin resulted in a significantly higher rate of symptomatic VTE within 90 days, defined as below- or above-knee DVT or pulmonary embolism. These findings may be informed by a cost-effectiveness analysis. Trial Registration: ANZCTR Identifier: ACTRN12618001879257.


Subject(s)
Anticoagulants , Arthroplasty, Replacement, Hip , Arthroplasty, Replacement, Knee , Aspirin , Enoxaparin , Venous Thromboembolism , Aged , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Arthroplasty, Replacement, Hip/adverse effects , Arthroplasty, Replacement, Knee/adverse effects , Aspirin/adverse effects , Aspirin/therapeutic use , Australia , Chemoprevention , Enoxaparin/adverse effects , Enoxaparin/therapeutic use , Female , Humans , Male , Osteoarthritis/surgery , Postoperative Complications/prevention & control , Pulmonary Embolism/etiology , Pulmonary Embolism/prevention & control , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & control
3.
Intern Med J ; 51(5): 712-724, 2021 May.
Article in English | MEDLINE | ID: mdl-32359019

ABSTRACT

BACKGROUND: Understanding the health profile, service and medicine use of Australians in the aged care sector will help inform appropriate service provision for our ageing population. AIMS: To examine the 2006-2015 trends in (i) comorbidities and frailty of individuals accessing aged care, and (ii) health services, medicine use and mortality after entry into long-term care. METHODS: Cross-sectional and population-based trend analyses were conducted using the Registry of Senior Australians. RESULTS: From 2006 to 2015, 509 944 individuals accessed permanent residential care, 206 394 home care, 283 014 respite and 124 943 transition care. Over this time, the proportion of individuals accessing permanent residential care with high frailty scores (≥0.3) increased (19.7-49.7%), as did the proportion with 5-9 comorbidities (46.4-54.5%), with similar trends observed for those accessing other services. The median number of medicines dispensed in the year after entering permanent residential care increased from 9 (interquartile range (IQR) 6-12) to 10 (IQR 7-14), while remaining stable in home care (2006: 9, IQR 5-12, 2015: 9, IQR 6-13). Short-term (within 100 days) mortality in those accessing permanent care was higher in 2006 (15.6%, 95% CI 15.2-16.0) than 2015 (14.6%, 95% CI 14.3-14.9). Longer term (101-1095 days, 2006: 44.3%, 95% CI 43.7-45.0, 2015: 46.4%, 95% CI 45.8-46.9) mortality was higher in 2015 compared to 2006. Mortality in individuals accessing home care did not change. CONCLUSION: The health of older Australians accessing aged care programmes has declined while frailty increased, with an increasing use of medicine and worse long-term mortality in some. Funding and care models need to adapt to this changing profile.


Subject(s)
Delivery of Health Care , Health Status , Aged , Australia/epidemiology , Cross-Sectional Studies , Humans , Registries
4.
Article in English | MEDLINE | ID: mdl-29784838

ABSTRACT

Antibiotics with novel bactericidal mechanisms of action are urgently needed. The antibiotic acyldepsipeptide 4 (ADEP4) activates the ClpP protease and causes cells to self-digest. The effects of ADEP4 and ClpP activation have not been characterized sufficiently for the enterococci, which are important pathogens known for high levels of acquired and intrinsic antibiotic resistance. In the present study, ADEP4 was found to be potently active against both Enterococcus faecalis and Enterococcus faecium, with MIC90s of 0.016 µg/ml and 0.031 µg/ml, respectively. ClpP purified from E. faecium was found to bind ADEP4 in a surface plasmon resonance analysis, and ClpP activation by ADEP4 was demonstrated biochemically with a ß-casein digestion assay. In addition, E. faecium ClpP was crystallized in the presence of ADEP4, revealing ADEP4 binding to ClpP in the activated state. These results confirm that the anti-enterococcal activity of ADEP4 occurs through ClpP activation. In killing curve assays, ADEP4 was found to be bactericidal against stationary-phase vancomycin-resistant E. faecalis (VRE) strain V583, and resistance development was prevented when ADEP4 was combined with multiple classes of approved antibiotics. ADEP4 in combination with partnering antibiotics also eradicated mature VRE biofilms within 72 h of treatment. Biofilm killing with ADEP4 antibiotic combinations was superior to that with the clinically used combinations ampicillin-gentamicin and ampicillin-daptomycin. In a murine peritoneal septicemia model, ADEP4 alone was as effective as ampicillin. ADEP4 coadministered with ampicillin was significantly more effective than either drug alone. These data suggest that ClpP-activating antibiotics may be useful for treating enterococcal infections.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Proteins/chemistry , Depsipeptides/pharmacology , Endopeptidase Clp/chemistry , Enterococcus faecalis/drug effects , Enterococcus faecium/drug effects , Vancomycin-Resistant Enterococci/drug effects , Ampicillin/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Bacterial Proteins/agonists , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Binding Sites , Biofilms/drug effects , Biofilms/growth & development , Crystallography, X-Ray , Depsipeptides/chemistry , Disease Models, Animal , Drug Combinations , Endopeptidase Clp/genetics , Endopeptidase Clp/metabolism , Enterococcus faecalis/enzymology , Enterococcus faecalis/genetics , Enterococcus faecalis/growth & development , Enterococcus faecium/enzymology , Enterococcus faecium/genetics , Enterococcus faecium/growth & development , Enzyme Activation/drug effects , Female , Gene Expression , Gram-Positive Bacterial Infections/drug therapy , Gram-Positive Bacterial Infections/microbiology , Mice , Microbial Sensitivity Tests , Models, Molecular , Protein Binding , Protein Interaction Domains and Motifs , Protein Structure, Secondary , Sepsis/drug therapy , Sepsis/microbiology , Vancomycin/pharmacology , Vancomycin-Resistant Enterococci/enzymology , Vancomycin-Resistant Enterococci/genetics , Vancomycin-Resistant Enterococci/growth & development
5.
J Phys Chem A ; 121(18): 3327-3339, 2017 May 11.
Article in English | MEDLINE | ID: mdl-28388049

ABSTRACT

Aerosol and molecular processing in the atmosphere occurs in a complex and variable environment consisting of multiple phases and interfacial regions. To explore the effects of such conditions on the reactivity of chemical systems, we employ an environmental simulation chamber to investigate the multiphase photolysis of pyruvic acid, which photoreacts in the troposphere in aqueous particles and in the gas phase. Upon irradiation of nebulized pyruvic acid, acetic acid and carbon dioxide are rapidly generated, which is consistent with previous literature on the bulk phase photolysis reactions. Additionally, we identify a new C6 product, zymonic acid, a species that has not previously been reported from pyruvic acid photolysis under any conditions. Its observation here, and corresponding spectroscopic signatures, indicates it could be formed by heterogeneous reactions at the droplet surface. Prior studies of the aqueous photolysis of pyruvic acid have shown that high-molecular-weight compounds are formed via radical reactions; however, they are inhibited by the presence of oxygen, leading to doubt as to whether the chemistry would occur in the atmosphere. Identification of dimethyltartaric acid from the photolysis of multiphase pyruvic acid in air confirms radical polymerization chemistry can compete with oxygen reactions to some extent under aerobic conditions. Evidence of additional polymerization within the particles during irradiation is suggested by the increasing viscosity and organic content of the particles. The implications of multiphase specific processes are then discussed within the broader scope of atmospheric science.

6.
Bioorg Med Chem Lett ; 26(16): 3950-4, 2016 08 15.
Article in English | MEDLINE | ID: mdl-27423480

ABSTRACT

The sulfonamide class of antibiotics has been in continuous use for over 70years. They are thought to act by directly inhibiting dihydropteroate synthase (DHPS), and also acting as prodrugs that sequester pterin pools by forming dead end pterin-sulfonamide conjugates. In this study, eight pterin-sulfonamide conjugates were synthesized using a novel synthetic strategy and their biochemical and microbiological properties were investigated. The conjugates were shown to competitively inhibit DHPS, and inhibition was enhanced by the presence of pyrophosphate that is crucial to catalysis and is known to promote an ordering of the DHPS active site. The co-crystal structure of Yersinia pestis DHPS bound to one of the more potent conjugates revealed a mode of binding that is similar to that of the enzymatic product analog pteroic acid. The antimicrobial activities of the pterin-sulfonamide conjugates were measured against Escherichia coli in the presence and absence of folate precursors and dependent metabolites. These results show that the conjugates have appreciable antibacterial activity and act by an on target, anti-folate pathway mechanism rather than as simple dead end products.


Subject(s)
Anti-Bacterial Agents/chemistry , Dihydropteroate Synthase/antagonists & inhibitors , Pterins/chemistry , Sulfonamides/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Dihydropteroate Synthase/metabolism , Escherichia coli/drug effects , Folic Acid/chemistry , Molecular Docking Simulation , Structure-Activity Relationship , Yersinia pestis/enzymology
7.
Proc Natl Acad Sci U S A ; 110(29): 11714-9, 2013 Jul 16.
Article in English | MEDLINE | ID: mdl-23821751

ABSTRACT

The study of organic chemistry in atmospheric aerosols and cloud formation is of interest in predictions of air quality and climate change. It is now known that aqueous phase chemistry is important in the formation of secondary organic aerosols. Here, the photoreactivity of pyruvic acid (PA; CH3COCOOH) is investigated in aqueous environments characteristic of atmospheric aerosols. PA is currently used as a proxy for α-dicarbonyls in atmospheric models and is abundant in both the gas phase and the aqueous phase (atmospheric aerosols, fog, and clouds) in the atmosphere. The photoreactivity of PA in these phases, however, is very different, thus prompting the need for a mechanistic understanding of its reactivity in different environments. Although the decarboxylation of aqueous phase PA through UV excitation has been studied for many years, its mechanism and products remain controversial. In this work, photolysis of aqueous PA is shown to produce acetoin (CH3CHOHCOCH3), lactic acid (CH3CHOHCOOH), acetic acid (CH3COOH), and oligomers, illustrating the progression from a three-carbon molecule to four-carbon and even six-carbon molecules through direct photolysis. These products are detected using vibrational and electronic spectroscopy, NMR, and MS, and a reaction mechanism is presented accounting for all products detected. The relevance of sunlight-initiated PA chemistry in aqueous environments is then discussed in the context of processes occurring on atmospheric aerosols.


Subject(s)
Aerosols/chemistry , Atmosphere/chemistry , Light , Photochemistry/methods , Pyruvic Acid/chemistry , Water/chemistry , Acetic Acid/chemistry , Acetoin/chemistry , Lactic Acid/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Structure , Photolysis
8.
Proc Natl Acad Sci U S A ; 109(39): 15697-701, 2012 Sep 25.
Article in English | MEDLINE | ID: mdl-22927374

ABSTRACT

We report unambiguous spectroscopic evidence of peptide bond formation at the air-water interface, yielding a possible mechanism providing insight into the formation of modern ribosomal peptide bonds, and a means for the emergence of peptides on early Earth. Protein synthesis in aqueous environments, facilitated by sequential amino acid condensation forming peptides, is a ubiquitous process in modern biology, and a fundamental reaction necessary in prebiotic chemistry. Such reactions, however, are condensation reactions, requiring the elimination of a water molecule for every peptide bond formed, and are thus unfavorable in aqueous environments both from a thermodynamic and kinetic point of view. We use the hydrophobic environment of the air-water interface as a favorable venue for peptide bond synthesis, and demonstrate the occurrence of this chemistry with in situ techniques using Langmuir-trough methods and infrared reflection absorption spectroscopy. Leucine ethyl ester (a small amino acid ester) first partitions to the water surface, then coordinates with Cu(2+) ions at the interface, and subsequently undergoes a condensation reaction selectively forming peptide bonds at the air-water interface.


Subject(s)
Air , Peptides/chemistry , Water/chemistry , Copper/chemistry , Hydrophobic and Hydrophilic Interactions
9.
J Am Chem Soc ; 136(10): 3784-7, 2014 Mar 12.
Article in English | MEDLINE | ID: mdl-24559493

ABSTRACT

The aqueous photochemistry of 2-oxooctanoic acid (a single-tailed surfactant) results in the synthesis of a double-tailed surfactant product followed by spontaneous self-assembly into vesicles. The photochemical mechanism is detailed here, and the reaction products are identified using mass spectrometry. Then, the self-assembled vesicles are characterized using dynamic light scattering, fluorescence microscopy, and NMR. Further, their stability over time and in the presence of MgCl2 salt is demonstrated. This work contributes to membrane evolution through the provision of a prebiotic route for the synthesis of plausible membrane components and subsequent self-assembly of a primitive enclosure.

10.
J Phys Chem A ; 118(37): 8505-16, 2014 Sep 18.
Article in English | MEDLINE | ID: mdl-24725260

ABSTRACT

Pyruvic acid in the atmosphere is found in both the gas and aqueous phases, and its behavior gives insight into that of other α-keto acids. Photolysis is a significant degradation pathway for this molecule in the environment, and in aqueous solution the major photoproducts are higher-molecular-weight compounds that may contribute to secondary organic aerosol mass. The kinetics of the aqueous-phase photolysis of pyruvic acid under aerobic and anaerobic conditions was investigated in order to calculate the first-order rate constant, Jaq, in solution. Analysis of the exponential decay of pyruvic acid was performed by monitoring both pyruvic acid and its photolytic products over the course of the reaction by (1)H NMR spectroscopy. Detection of major and minor products in the 0.1, 0.05, and 0.02 M pyruvic acid photolyses clearly demonstrates that the primary reaction pathways are highly dependent on the initial pyruvic acid concentration and the presence of dissolved oxygen. The Jaq values were calculated with approximations based on the dominant pathways for limiting cases of the mechanism. Finally, a model study using the calculated rate constants demonstrates the importance of aqueous-phase photolysis as a sink for pyruvic acid in the atmosphere, compared with gas-phase photolysis and OH oxidation.

11.
Nurs Res ; 63(2): 75-82, 2014.
Article in English | MEDLINE | ID: mdl-24589644

ABSTRACT

BACKGROUND: Loss of muscle mass and strength (i.e., sarcopenia) in the older adults is a strong predictor of falls, with subsequent morbidity and inability to execute activities of daily living. Use of biomarkers may enhance assessment of effects of community-based exercise interventions aimed at improving muscle strength. OBJECTIVE: The aim of this study was to investigate the use of troponin as a newly proposed biomarker of skeletal muscle health when determining the outcomes of strength-training programs designed for community-dwelling adults over the age of 65 years. METHODS: Outcomes of two strength training programs ("Peer Exercise Program Promotes Independence" and "Stay Strong, Stay Healthy") were assessed using physical performance tests designed for senior fitness evaluation, grip strength, and changes in serum levels of skeletal muscle-specific troponin T (sTnT). RESULTS: Improvement in physical performance, including a significant increase in grip strength, was associated with a significant reduction in serum levels of sTnT. DISCUSSION: Findings from these studies suggest that, when "Peer Exercise Program Promotes Independence" and "Stay Strong, Stay Healthy" are implemented for at least 10 weeks, significant gains in strength are achieved. This strength improvement was associated with a reduction in serum levels of troponin, supporting the use of troponin as a novel biomarker of muscle health in the assessment of strength training programs for the older adults. Reduced sTnT after exercise intervention suggests that skeletal muscles become stronger and less susceptible to damage because of the exercise regimens.


Subject(s)
Accidental Falls/prevention & control , Muscle Strength/physiology , Muscle, Skeletal/metabolism , Resistance Training , Troponin T/blood , Age Factors , Aged , Aged, 80 and over , Biomarkers/blood , Female , Health Status , Humans , Male , Outcome Assessment, Health Care , Weight-Bearing/physiology
12.
Trauma Violence Abuse ; 25(2): 1468-1483, 2024 04.
Article in English | MEDLINE | ID: mdl-37427484

ABSTRACT

Substantial comorbidity exists between posttraumatic stress disorder and sleep disturbances/disorders. Such comorbidities are understudied in minority groups, including Asian Indians residing in countries outside India. Thus, we synthesized the existing literature specific to this group of Asian Indians to determine (a) prevalence estimates of posttraumatic stress disorder (PTSD) and sleep disturbances/disorders; and (b) PTSD-sleep comorbidity estimates. For this systematic review, we searched four databases (PubMed, PsycInfo, PTSDpubs, Web of Science) using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Of 3,796 screened articles, 9 articles (10 studies) met inclusion criteria. Study sample sizes ranged from 11 to 2,112 Asian Indians; studies were conducted in Singapore or Malaysia. No reviewed study examined PTSD. All studies examined sleep disturbances/disorders among Asian Indians; prevalence estimates were: 8.3% to 70.4% for short sleep duration, 2.0% to 22.9% for long sleep duration, 25.9% to 56.3% for poor sleep quality, 3.4% to 67.5% for insomnia diagnosis or probable insomnia, 7.7% for excessive daytime sleepiness, 3.8% to 54.6% for obstructive sleep apnea (OSA) diagnosis or high OSA risk, and 5.1% to 11.1% for sleep-disordered breathing. Specific to Asian Indians residing in countries outside India, this review advances PTSD-sleep literature by (a) suggesting substantial prevalence of sleep disturbances/disorders; (b) highlighting the need for culturally relevant sleep interventions; and (c) highlighting research gaps (e.g., no PTSD-focused research).


Subject(s)
Sleep Apnea, Obstructive , Sleep Initiation and Maintenance Disorders , Sleep Wake Disorders , Stress Disorders, Post-Traumatic , Humans , Sleep , Sleep Apnea, Obstructive/epidemiology , Sleep Initiation and Maintenance Disorders/epidemiology , Sleep Wake Disorders/epidemiology , Stress Disorders, Post-Traumatic/epidemiology , Asian People , India
13.
Psychol Trauma ; 2024 Sep 26.
Article in English | MEDLINE | ID: mdl-39325419

ABSTRACT

OBJECTIVE: In trauma research, it is common for researchers to characterize participants as either "trauma exposed" or "not trauma exposed" regardless of nuanced differences of the potentially traumatic event (PTE). To our knowledge, no study has simultaneously examined differences across both PTEs and exposure types. METHOD: Using latent class analysis, we investigated latent homogeneous subgroups of individuals following experiences of 16 PTEs via three exposure types (i.e., direct, indirect, and/or occupational). We further examined class differences regarding posttraumatic stress disorder (PTSD) symptom clusters, event centrality, depression, and anxiety. Our sample included 2,663 participants (Mage = 22.33; 56.0% female). RESULTS: Results indicated four latent subgroups: (a) occupational trauma (OT), (b) direct interpersonal trauma (DIT), (c) indirect trauma (IT), and (d) low trauma exposure (LTE). Individuals in the OT class reported the highest levels of all symptoms except for PTSD avoidance and event centrality (which were highest in the DIT class), and individuals in the LTE class reported the lowest levels of all symptoms. Several nuanced between-class differences were found regarding posttrauma outcomes. CONCLUSIONS: Findings further support the notion that dichotomizing participants as "trauma exposed" or "not trauma exposed" is overly simplistic and ignores important variability in trauma research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

14.
J Anxiety Disord ; 101: 102806, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38061324

ABSTRACT

OBJECTIVE: Studies exploring latent profiles of mental health in trauma survivors have largely relied on self-report, making it unclear whether these patterns correspond with clinician-assessed psychopathology. The purpose of the current study was to examine latent profiles of self-reported PTSD, depression, and anxiety in a sample of 387 women who had experienced intimate partner violence (IPV) and investigate whether profiles mapped onto clinician-rated measures of the same outcomes. METHOD: Participants completed a series of semi-structured interviews and self-report measures assessing PTSD, depression, and anxiety. RESULTS: Latent profile analyses revealed a 3-profile solution characterized by Low (22.48 %), Moderate (37.98 %), and High (39.53 %) self-reported symptomology. Clinician ratings were significant predictors of membership in the low vs. moderate vs. high symptomology profiles. However, normalized means showed discrepancies between self-report and clinician assessment regarding which issue was rated most severe. CONCLUSIONS: Results suggest that while latent modeling approaches relying on self-report may adequately approximate common underlying patterns of psychopathology, they have limitations in identifying which disorders are most salient for clinical intervention.


Subject(s)
Intimate Partner Violence , Stress Disorders, Post-Traumatic , Female , Humans , Stress Disorders, Post-Traumatic/diagnosis , Stress Disorders, Post-Traumatic/psychology , Self Report , Depression/diagnosis , Depression/psychology , Anxiety/diagnosis , Anxiety/psychology , Intimate Partner Violence/psychology , Survivors
15.
Nat Commun ; 15(1): 8829, 2024 Oct 12.
Article in English | MEDLINE | ID: mdl-39396041

ABSTRACT

PROTAC® (proteolysis-targeting chimera) molecules induce proximity between an E3 ligase and protein-of-interest (POI) to target the POI for ubiquitin-mediated degradation. Cooperative E3-PROTAC-POI complexes have potential to achieve neo-substrate selectivity beyond that established by POI binding to the ligand alone. Here, we extend the collection of ubiquitin ligases employable for cooperative ternary complex formation to include the C-degron E3 KLHDC2. Ligands were identified that engage the C-degron binding site in KLHDC2, subjected to structure-based improvement, and linked to JQ1 for BET-family neo-substrate recruitment. Consideration of the exit vector emanating from the ligand engaged in KLHDC2's U-shaped degron-binding pocket enabled generation of SJ46421, which drives formation of a remarkably cooperative, paralog-selective ternary complex with BRD3BD2. Meanwhile, screening pro-drug variants enabled surmounting cell permeability limitations imposed by acidic moieties resembling the KLHDC2-binding C-degron. Selectivity for BRD3 compared to other BET-family members is further manifested in ubiquitylation in vitro, and prodrug version SJ46420-mediated degradation in cells. Selectivity is also achieved for the ubiquitin ligase, overcoming E3 auto-inhibition to engage KLHDC2, but not the related KLHDC1, KLHDC3, or KLHDC10 E3s. In sum, our study establishes neo-substrate-specific targeted protein degradation via KLHDC2, and provides a framework for developing selective PROTAC protein degraders employing C-degron E3 ligases.


Subject(s)
Proteolysis , Transcription Factors , Ubiquitin-Protein Ligases , Humans , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , HEK293 Cells , Binding Sites , Ligands , Ubiquitination , Substrate Specificity , Protein Binding , Triazoles/chemistry , Triazoles/pharmacology , Triazoles/metabolism , Ubiquitin/metabolism , Azepines/pharmacology , Azepines/chemistry , Azepines/metabolism , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics , Degrons
16.
J Am Chem Soc ; 135(2): 710-6, 2013 Jan 16.
Article in English | MEDLINE | ID: mdl-23240998

ABSTRACT

The ionization state of organic molecules at the air-water interface and the related problem of the surface pH of water have significant consequences on the catalytic role of the surface in chemical reactions and are currently areas of intense research and controversy. In this work, infrared reflection-absorption spectroscopy (IRRAS) is used to identify changes in the ionization state of L-phenylalanine in the surface region versus the bulk aqueous solution. L-phenylalanine has the unique advantage of possessing two different hydrophilic groups, a carboxylic acid and an amine base, which can deprotonate and protonate respectively depending on the ionic environment they experience at the water surface. In this work, the polar group vibrations in the surface region are identified spectroscopically in varying bulk pH solutions, and are subsequently compared with the ionization state of the polar groups of molecules residing in the bulk environment. The polar groups of L-phenylalanine at the surface transition to their deprotonated state at bulk pH values lower than the molecules residing in the bulk, indicating a decrease in their pK(a) at the surface, and implying an enhanced hydroxide ion concentration in the surface region relative to the bulk.


Subject(s)
Phenylalanine/chemistry , Water/chemistry , Air , Hydrogen-Ion Concentration , Infrared Rays , Molecular Structure , Solutions/chemistry , Surface Properties , X-Ray Absorption Spectroscopy
17.
Acc Chem Res ; 45(12): 2106-13, 2012 Dec 18.
Article in English | MEDLINE | ID: mdl-22509900

ABSTRACT

The prebiotic conversion of simple organic molecules into complex biopolymers necessary for life can only have emerged on a stage set by geophysics. The transition between "prebiotic soup," the diverse mixture of small molecules, and complex, self-replicating organisms requires passing through the bottleneck of fundamental chemistry. In this Account, we examine how water-air interfaces, namely, the surfaces of lakes, oceans, and atmospheric aerosols on ancient Earth, facilitated the emergence of complex structures necessary for life. Aerosols are liquid or solid suspensions in air with a broad, power law size distribution. Collectively, these globally distributed atmospheric particles have an enormous surface area. Organic films at the interface between water and air offer advantages for biomolecular synthesis compared with the bulk and can simultaneously participate in the folding of biopolymers into primitive enclosed structures. We survey the advantages of the water-air interface for prebiotic chemistry in a geophysical context from three points of view. We examine the formation of biopolymers from simple organic precursors and describe the necessity and availability of enclosures. In addition, we provide a statistical mechanical approach to natural selection and emergence of complexity that proposes a link between these molecular mechanisms and macroscopic scales. Very large aerosol populations were ubiquitous on ancient Earth, and the surfaces of lakes, oceans, and atmospheric aerosols would have provided an auspicious environment for the emergence of complex structures necessary for life. These prebiotic reactors would inevitably have incorporated the products of chemistry into their anhydrous, two-dimensional organic films in the three-dimensional fluids of the gaseous atmosphere and the liquid ocean. The untrammeled operation of natural selection on these aerosols provided the likely location where condensation reactions could form biopolymers by elimination of water. The fluctuating exposure of the large, recycling aerosol populations to radiation, pressure, temperature, and humidity over geological time allows complexity to emerge from simple molecular precursors. We propose an approach that connects chemical statistical thermodynamics and the macroscopic world of the planetary ocean and atmosphere.


Subject(s)
Atmosphere/chemistry , Oceans and Seas , Aerosols/chemistry , Air , Kinetics , Temperature , Thermodynamics , Water/chemistry
18.
Orig Life Evol Biosph ; 43(4-5): 341-52, 2013 Oct.
Article in English | MEDLINE | ID: mdl-24362712

ABSTRACT

Coupling chemical reactions to an energy source is a necessary step in the origin of life. Here, we utilize UV photons provided by a simulated sun to activate aqueous pyruvic acid and subsequently prompt chemical reactions mimicking some of the functions of modern metabolism. Pyruvic acid is interesting in a prebiotic context due to its prevalence in modern metabolism and its abiotic availability on early Earth. Here, pyruvic acid (CH3COCOOH, a C3 molecule) photochemically reacts to produce more complex molecules containing four or more carbon atoms. Acetoin (CH3CHOHCOCH3), a C4 molecule and a modern bacterial metabolite, is produced in this chemistry as well as lactic acid (CH3CHOHCOOH), a molecule which, when coupled with other abiotic chemical reaction pathways, can provide a regeneration pathway for pyruvic acid. This chemistry is discussed in the context of plausible environments on early Earth such as near the ocean surface and atmospheric aerosol particles. These environments allow for combination and exchange of reactants and products of other reaction environments (such as shallow hydrothermal vents). The result could be a contribution to the steady increase in chemical complexity requisite in the origin of life.


Subject(s)
Evolution, Chemical , Pyruvic Acid/chemistry , Ultraviolet Rays , Acetoin/chemistry , Aerosols/chemistry , Atmosphere/chemistry , Carbon/chemistry , Lactic Acid/chemistry , Magnetic Resonance Spectroscopy , Spectrophotometry, Ultraviolet , Water/chemistry
19.
Anxiety Stress Coping ; 36(2): 184-198, 2023 03.
Article in English | MEDLINE | ID: mdl-35266842

ABSTRACT

BACKGROUND: Coyne and Tennen [(2010). Positive psychology in cancer care: Bad science, exaggerated claims, and unproven medicine. Annals of Behavioral Medicine, 39(1), 16-26. https://doi.org/10.1007/s12160-009-9154-z] argue that completing self-reports of posttraumatic growth (PTG) requires four complicated cognitive steps. DESIGN: We conducted two experiments designed to (1) use mental chronometry (i.e., reaction times on cognitive tasks) to test whether respondents engage in multiple cognitive steps when completing self-reports of PTG, and (2) determine whether coaching participants to take these steps results in a more valid assessment. METHOD: In Experiment 1, 310 undergraduates were randomly assigned to complete either the Posttraumatic Growth Inventory (PTGI) or Stress-Related Growth Scale (SRGS), and its corresponding current version that requires only one cognitive step. In Experiment 2, 306 undergraduates were randomly assigned to complete either a guided-steps version of the SRGS or the original SRGS. RESULTS: Experiment 1 indicated a very small difference in completion time for the PTGI, but not the SRGS, in comparison to the current versions, suggesting respondents do not engage in the four required cognitive steps. In Experiment 2, participants reported less PTG when coached to go through the four cognitive steps, but the resulting scores were generally unrelated to measures of convergent and predictive validity. CONCLUSION: We conclude that individuals cannot accurately report PTG, even when explicitly coached.


Subject(s)
Posttraumatic Growth, Psychological , Stress Disorders, Post-Traumatic , Humans , Adaptation, Psychological , Cognition , Self Report , Stress Disorders, Post-Traumatic/psychology
20.
J Psychiatr Res ; 167: 37-45, 2023 Oct 06.
Article in English | MEDLINE | ID: mdl-37832202

ABSTRACT

BACKGROUND: Posttraumatic stress disorder (PTSD), sleep disturbances, and problematic alcohol use are frequently comorbid. Research shows that individuals with more PTSD symptom severity and poorer sleep are highly susceptible to drinking alcohol to cope with negative affect. The current study examined the number and nature of different subgroups of trauma-exposed college students based on endorsed PTSD symptoms and sleep disturbances; and how such subgroups relate to drinking to cope motives. METHOD: The sample included 474 trauma-exposed college students (Mage = 20.69 years; 75.50% female) who completed self-report surveys. RESULTS: Latent profile analyses revealed three subgroups: High PTSD-Sleep Disturbances (n = 71), Moderate PTSD-Sleep Disturbances (n = 135), and Low PTSD-Sleep Disturbances (n = 268). Results indicated that college students in the Low PTSD-Sleep Disturbances group endorsed the lowest amount of coping-related drinking motives; however, college students in the Moderate PTSD-Sleep Disturbances group did not endorse significantly different levels of coping-related drinking motives than college students in the High PTSD-Sleep Disturbances group. CONCLUSIONS: College students with subclinical presentations of psychopathology are at risk for endorsing risky drinking motives. As they adjust to a stressful environment with a culture of heavy drinking, providing context-relevant intervention efforts such as adaptive coping strategies, relaxation skills designed to facilitate restful sleep, and trauma-informed care may be highly beneficial for college students.

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