ABSTRACT
BACKGROUND: Diagnostic rates and risk factors for the subsequent development of chronic thromboembolic pulmonary hypertension (CTEPH) following pulmonary embolism (PE) are not well defined. METHODS: Over a 10-year period (2010-2020), consecutive patients attending a PE follow-up clinic in Sheffield, UK (population 554 600) and all patients diagnosed with CTEPH at a pulmonary hypertension (PH) referral centre in Sheffield (referral population estimated 15-20 million) were included. RESULTS: Of 1956 patients attending the Sheffield PE clinic 3â months following a diagnosis of acute PE, 41 were diagnosed with CTEPH with a cumulative incidence of 2.10%, with 1.89% diagnosed within 2â years. Of 809 patients presenting with pulmonary hypertension (PH) and diagnosed with CTEPH, 32 were Sheffield residents and 777 were non-Sheffield residents. Patients diagnosed with CTEPH at the PE follow-up clinic had shorter symptom duration (p<0.01), better exercise capacity (p<0.05) and less severe pulmonary haemodynamics (p<0.01) compared with patients referred with suspected PH. Patients with no major transient risk factors present at the time of acute PE had a significantly higher risk of CTEPH compared with patients with major transient risk factors (OR 3.6, 95% CI 1.11-11.91; p=0.03). The presence of three computed tomography (CT) features of PH in combination with two or more out of four features of chronic thromboembolic pulmonary disease at the index PE was found in 19% of patients who developed CTEPH and in 0% of patients who did not. Diagnostic rates and pulmonary endarterectomy (PEA) rates were higher at 13.2 and 3.6 per million per year, respectively, for Sheffield residents compared with 3.9-5.2 and 1.7-2.3 per million per year, respectively, for non-Sheffield residents. CONCLUSIONS: In the real-world setting a dedicated PE follow-up pathway identifies patients with less severe CTEPH and increases population-based CTEPH diagnostic and PEA rates. At the time of acute PE diagnosis the absence of major transient risk factors, CT features of PH and chronic thromboembolism are risk factors for a subsequent diagnosis of CTEPH.
Subject(s)
Hypertension, Pulmonary , Pulmonary Embolism , Thromboembolism , Humans , Hypertension, Pulmonary/complications , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/epidemiology , Follow-Up Studies , Pulmonary Embolism/complications , Pulmonary Embolism/diagnosis , Pulmonary Embolism/epidemiology , Risk Factors , Thromboembolism/complications , Thromboembolism/diagnosis , Registries , Chronic DiseaseABSTRACT
The Parkinson's disease (PD) risk gene GTP cyclohydrolase 1 (GCH1) catalyzes the rate-limiting step in tetrahydrobiopterin (BH4) synthesis, an essential cofactor in the synthesis of monoaminergic neurotransmitters. To investigate the mechanisms by which GCH1 deficiency may contribute to PD, we generated a loss of function zebrafish gch1 mutant (gch1-/-), using CRISPR/Cas technology. gch1-/- zebrafish develop marked monoaminergic neurotransmitter deficiencies by 5 d postfertilization (dpf), movement deficits by 8 dpf and lethality by 12 dpf. Tyrosine hydroxylase (Th) protein levels were markedly reduced without loss of ascending dopaminergic (DAergic) neurons. L-DOPA treatment of gch1-/- larvae improved survival without ameliorating the motor phenotype. RNAseq of gch1-/- larval brain tissue identified highly upregulated transcripts involved in innate immune response. Subsequent experiments provided morphologic and functional evidence of microglial activation in gch1-/- The results of our study suggest that GCH1 deficiency may unmask early, subclinical parkinsonism and only indirectly contribute to neuronal cell death via immune-mediated mechanisms. Our work highlights the importance of functional validation for genome-wide association studies (GWAS) risk factors and further emphasizes the important role of inflammation in the pathogenesis of PD.SIGNIFICANCE STATEMENT Genome-wide association studies have now identified at least 90 genetic risk factors for sporadic Parkinson's disease (PD). Zebrafish are an ideal tool to determine the mechanistic role of genome-wide association studies (GWAS) risk genes in a vertebrate animal model. The discovery of GTP cyclohydrolase 1 (GCH1) as a genetic risk factor for PD was counterintuitive, GCH1 is the rate-limiting enzyme in the synthesis of dopamine (DA), mutations had previously been described in the non-neurodegenerative movement disorder dopa-responsive dystonia (DRD). Rather than causing DAergic cell death (as previously hypothesized by others), we now demonstrate that GCH1 impairs tyrosine hydroxylase (Th) homeostasis and activates innate immune mechanisms in the brain and provide evidence of microglial activation and phagocytic activity.
Subject(s)
Brain/enzymology , GTP Cyclohydrolase/deficiency , Homeostasis/physiology , Immunity, Innate/physiology , Tyrosine 3-Monooxygenase/metabolism , Animals , Animals, Genetically Modified , Brain/immunology , Dopaminergic Neurons/enzymology , Dopaminergic Neurons/immunology , GTP Cyclohydrolase/genetics , Genetic Predisposition to Disease/genetics , Parkinson Disease/enzymology , Parkinson Disease/genetics , Parkinson Disease/immunology , Sequence Analysis, RNA/methods , Tyrosine 3-Monooxygenase/antagonists & inhibitors , Tyrosine 3-Monooxygenase/genetics , ZebrafishABSTRACT
BACKGROUND: Cardiac magnetic resonance (CMR) is the gold standard technique to assess biventricular volumes and function, and is increasingly being considered as an end-point in clinical studies. Currently, with the exception of right ventricular (RV) stroke volume and RV end-diastolic volume, there is only limited data on minimally important differences (MIDs) reported for CMR metrics. Our study aimed to identify MIDs for CMR metrics based on US Food and Drug Administration recommendations for a clinical outcome measure that should reflect how a patient "feels, functions or survives". METHODS: Consecutive treatment-naïve patients with pulmonary arterial hypertension (PAH) between 2010 and 2022 who had two CMR scans (at baseline prior to treatment and 12â months following treatment) were identified from the ASPIRE registry. All patients were followed up for 1 additional year after the second scan. For both scans, cardiac measurements were obtained from a validated fully automated segmentation tool. The MID in CMR metrics was determined using two distribution-based (0.5sd and minimal detectable change) and two anchor-based (change difference and generalised linear model regression) methods benchmarked to how a patient "feels" (emPHasis-10 quality of life questionnaire), "functions" (incremental shuttle walk test) or "survives" for 1-year mortality to changes in CMR measurements. RESULTS: 254 patients with PAH were included (mean±sd age 53±16â years, 79% female and 66% categorised as intermediate risk based on the 2022 European Society of Cardiology/European Respiratory Society risk score). We identified a 5% absolute increase in RV ejection fraction and a 17â mL decrease in RV end-diastolic or end-systolic volumes as the MIDs for improvement. Conversely, a 5% decrease in RV ejection fraction and a 10â mL increase in RV volumes were associated with worsening. CONCLUSIONS: This study establishes clinically relevant CMR MIDs for how a patient "feels, functions or survives" in response to PAH treatment. These findings provide further support for the use of CMR as a clinically relevant clinical outcome measure and will aid trial size calculations for studies using CMR.
Plain language summaryPulmonary arterial hypertension (PAH) is a disease of the vessels of the lung that causes their narrowing and stiffening. As a result, the heart pumping blood into these diseased lung vessels has to work harder and eventually gets worn out. PAH can affect patients' ability to function in daily activities and impact their quality of life. It also reduces their life expectancy dramatically. Patients are, therefore, often monitored and undergo several investigations to adapt treatment according to their situation. These investigations include a survey of how a patient feels (the emPHasis-10 questionnaire), functions (walking test) and how well the heart is coping with the disease (MRI of the heart). Until now, it is unclear how changes on MRI of the heart reflect changes in how a patient feels and functions. Our study identified patients that had the emPHasis-10 questionnaire, walking test and MRI of the heart at both the time of PAH diagnosis and one year later. This allowed us to compare how the changes in the different tests relate to each other. And because previous research identified thresholds for important changes in the emPHasis-10 questionnaire and the walking tests, we were able to use these tests as a benchmark for changes in the MRI of the heart. Our study identified thresholds for change on heart MRI that might indicate whether a patient has improved or worsened. This finding might have implications for how patients are monitored in clinical practice and future research on PAH treatments.
Subject(s)
Pulmonary Arterial Hypertension , Ventricular Dysfunction, Right , Humans , Female , Adult , Middle Aged , Aged , Male , Pulmonary Arterial Hypertension/diagnostic imaging , Quality of Life , Magnetic Resonance Imaging/methods , Stroke Volume/physiology , Familial Primary Pulmonary Hypertension , Ventricular Function, Right , Predictive Value of TestsABSTRACT
A requirement for PKCε in exiting from the Aurora B dependent abscission checkpoint is associated with events at the midbody, however, the recruitment, retention and action of PKCε in this compartment are poorly understood. Here, the prerequisite for 14-3-3 complex assembly in this pathway is directly linked to the phosphorylation of Aurora B S227 at the midbody. However, while essential for PKCε control of Aurora B, 14-3-3 association is shown to be unnecessary for the activity-dependent enrichment of PKCε at the midbody. This localisation is demonstrated to be an autonomous property of the inactive PKCε D532N mutant, consistent with activity-dependent dissociation. The C1A and C1B domains are necessary for this localisation, while the C2 domain and inter-C1 domain (IC1D) are necessary for retention at the midbody. Furthermore, it is shown that while the IC1D mutant retains 14-3-3 complex proficiency, it does not support Aurora B phosphorylation, nor rescues division failure observed with knockdown of endogenous PKCε. It is concluded that the concerted action of multiple independent events facilitates PKCε phosphorylation of Aurora B at the midbody to control exit from the abscission checkpoint.
Subject(s)
14-3-3 Proteins/metabolism , Aurora Kinase B/metabolism , Cytokinesis , Protein Kinase C-epsilon/metabolism , 14-3-3 Proteins/genetics , Aurora Kinase B/genetics , HEK293 Cells , Humans , Phosphorylation , Protein Kinase C-epsilon/genetics , Signal Transduction , Spindle ApparatusABSTRACT
Bi-allelic mutations in the glucocerebrosidase gene (GBA1) cause Gaucher's disease, the most common human lysosomal storage disease. We previously reported a marked increase in miR-155 transcript levels and early microglial activation in a zebrafish model of Gaucher's disease (gba1-/-). miR-155 is a master regulator of inflammation and has been implicated in a wide range of different neurodegenerative disorders. The observed miR-155 upregulation preceded the subsequent development of widespread pathology with marked neuroinflammation, closely resembling human Gaucher's disease pathology. We now report similar increases of miR-155 expression in mammalian models of GD, confirming that miR-155 upregulation is a shared feature in glucocerebrosidase (GCase) deficiency across different species. Using CRISPR/Cas9 mutagenesis we then generated a miR-155 mutant zebrafish line (miR-155-/-) with completely abolished miR-155 expression. Unexpectedly, loss of miR-155 did not mitigate either the reduced lifespan or the robust inflammatory phenotypes of gba1-/- mutant zebrafish. Our data demonstrate that neither neuroinflammation nor disease progression in GCase deficiency are dependent on miR-155 and suggest that miR-155 inhibition would not be a promising therapeutic target in Gaucher's disease.
Subject(s)
Encephalitis/metabolism , Gaucher Disease/metabolism , MicroRNAs/metabolism , Nerve Degeneration/metabolism , Animals , Animals, Genetically Modified , Clustered Regularly Interspaced Short Palindromic Repeats , Cytokines/metabolism , Disease Models, Animal , Disease Progression , Encephalitis/genetics , Encephalitis/pathology , Gaucher Disease/genetics , Gaucher Disease/pathology , Glucosylceramidase/genetics , Glucosylceramidase/metabolism , Mice , MicroRNAs/genetics , Mutation , Nerve Degeneration/genetics , Nerve Degeneration/pathology , Neurons/metabolism , Neurons/pathology , Up-Regulation , ZebrafishABSTRACT
BACKGROUND: Rehabilitative exercise for critically ill patients may have many benefits; however, it is unknown what intensive care unit (ICU) clinicians perceive to be important rationale for the implementation of rehabilitative exercise in critical care settings. OBJECTIVE: To identify which rationales for rehabilitative exercise interventions were perceived by ICU clinicians to be important and determine whether perceptions were consistent across nursing, medical and physiotherapy clinicians. METHODS: A cross-sectional study was undertaken among clinicians (nursing, medical, physiotherapy) working in a mixed medical surgical ICU in an Australian metropolitan tertiary hospital. Participants completed a customised web-based questionnaire developed by a clinician working-group. The questionnaire consisted of 11 plausible rationales for commencing rehabilitative exercise in ICUs based on prior literature and their own clinical experiences grouped into 4 over-arching categories (musculoskeletal, respiratory, psychological and facilitation of discharge). Participants rated their perceived importance for each potential rationale on a 5-point Likert scale. RESULTS: Participants (n=76) with a median (interquartile range) 4.8 (1.5, 15.5) years of experience working in ICUs completed the questionnaire. Responses were consistent across professional disciplines. Clinicians rated rehabilitative exercise as either 'very much' or 'somewhat' important for facilitating discharge (n=76, 100%), reducing muscle atrophy (n=76, 100%), increasing muscle strength (n=76, 100%), prevention of contractures (n=73, 96%), reducing the incidence of ICU acquired weakness (n=62, 82%), increasing oxygenation (n=71, 93%), facilitating weaning (n=72, 97%), reducing anxiety (n=60, 80%), reducing depression (n=64, 84%), reducing delirium (n=53, 70%), and increasing mental alertness (n=65, 87%). CONCLUSIONS: Any shortcoming in implementation of rehabilitation exercise is unlikely attributable to a lack of perceived importance by nursing, medical or physiotherapy clinicians who are the most likely clinicians to influence rehabilitation practices in ICUs. It is noteworthy that this study examined self-reported perceptions, not physiological or scientific legitimacy of rationales, or clinician behaviours in practice.
Subject(s)
Critical Care , Critical Illness/rehabilitation , Exercise Therapy , Medical Staff, Hospital , Cross-Sectional Studies , Humans , Intensive Care Units , Surveys and QuestionnairesABSTRACT
In addition to guiding proteins to defined genomic loci, DNA can act as an allosteric ligand that influences protein structure and activity. Here we compared genome-wide binding, transcriptional regulation, and, using NMR, the conformation of two glucocorticoid receptor (GR) isoforms that differ by a single amino acid insertion in the lever arm, a domain that adopts DNA sequence-specific conformations. We show that these isoforms differentially regulate gene expression levels through two mechanisms: differential DNA binding and altered communication between GR domains. Our studies suggest a versatile role for DNA in both modulating GR activity and also in directing the use of GR isoforms. We propose that the lever arm is a "fulcrum" for bidirectional allosteric signaling, conferring conformational changes in the DNA reading head that influence DNA sequence selectivity, as well as conferring changes in the dimerization domain that connect functionally with remote regulatory surfaces, thereby influencing which genes are regulated and the magnitude of their regulation.
Subject(s)
Alternative Splicing/genetics , Amino Acids/genetics , Gene Expression Regulation/genetics , Models, Molecular , Protein Conformation , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/physiology , Cell Line, Tumor , Chromatin Immunoprecipitation , Electrophoretic Mobility Shift Assay , Humans , Immunoblotting , Microarray Analysis , Mutagenesis, Insertional/genetics , Protein Isoforms/genetics , Protein Isoforms/physiology , Real-Time Polymerase Chain Reaction , Transcription, Genetic/geneticsABSTRACT
Approved therapies for the treatment of patients with pulmonary arterial hypertension (PAH) mediate pulmonary vascular vasodilatation by targeting distinct biological pathways. International guidelines recommend that patients with an inadequate response to dual therapy with a phosphodiesterase type-5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), are recommended to either intensify oral therapy by adding a selective prostacyclin receptor (IP) agonist (selexipag), or switching from PDE5i to a soluble guanylate-cyclase stimulator (sGCS; riociguat). The clinical equipoise between these therapeutic choices provides the opportunity for evaluation of individualized therapeutic effects. Traditionally, invasive/hospital-based investigations are required to comprehensively assess disease severity and demonstrate treatment benefits. Regulatory-approved, minimally invasive monitors enable equivalent measurements to be obtained while patients are at home. In this 2 × 2 randomized crossover trial, patients with PAH established on guideline-recommended dual therapy and implanted with CardioMEMS™ (a wireless pulmonary artery sensor) and ConfirmRx™ (an insertable cardiac rhythm monitor), will receive ERA + sGCS, or PDEi + ERA + IP agonist. The study will evaluate clinical efficacy via established clinical investigations and remote monitoring technologies, with remote data relayed through regulatory-approved online clinical portals. The primary aim will be the change in right ventricular systolic volume measured by magnetic resonance imaging (MRI) from baseline to maximal tolerated dose with each therapy. Using data from MRI and other outcomes, including hemodynamics, physical activity, physiological measurements, quality of life, and side effect reporting, we will determine whether remote technology facilitates early evaluation of clinical efficacy, and investigate intra-patient efficacy of the two treatment approaches.
ABSTRACT
While CBT is an effective treatment for depression, uptake can be low. This is largely due to attitudinal barriers. Accordingly, the goals of the current investigation were to (a) tailor and develop persuasive psychoeducational materials to match dominant cultural beliefs about the causes of depression and (b) examine the effectiveness of tailored CBT descriptions in improving CBT perceptions. We examined the believability of CBT mechanisms by invoking commonly endorsed etiological models of depression and investigated whether tailoring CBT descriptions to match etiological beliefs about depression influences perceptions of CBT. Participants were recruited using TurkPrime. In Study 1, participants (n = 425) read a CBT description that was generic or framed to match an etiological model of depression (biological, stress/environmental, or relationship/interpersonal). The participants indicated believability of each model as adopted by CBT. In study 2, the participants (n = 449) selected what they believed was the most important cause of depression. Subsequently, the participants were randomised to receive either a CBT description tailored to their endorsed model or a generic CBT description, and they provided ratings for CBT's acceptability, credibility, and expectancy. In Study 1, the believability of biological CBT mechanisms was low across conditions, but participants reported greater believability when receiving a biological description than when receiving other mechanistic descriptions. Participants who received the stress- and relationship-focused descriptions did not rate the respective models as more believable than those who received a generic description. In study 2, there were no differences in the perceptions of acceptability, credibility and expectancy between participants who received a tailored description and those who received a generic description. Our findings suggest that CBT is believed to be a psychologically appropriate treatment; however, the believability of biological mechanisms is improved by presenting a biology-focused description.
Subject(s)
Cognitive Behavioral Therapy , Depression , Humans , Depression/therapy , Treatment Outcome , Drugs, GenericABSTRACT
Heterozygous variants in GBA1, encoding glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson's disease (PD). Moreover, sporadic PD patients also have a substantial reduction of GCase activity. Genetic variants of SMPD1 are also overrepresented in PD cohorts, whereas a reduction of its encoded enzyme (acid sphingomyelinase or ASM) activity is linked to an earlier age of PD onset. Despite both converging on the ceramide pathway, how the combined deficiencies of both enzymes might interact to modulate PD has yet to be explored. Therefore, we created a double-knockout (DKO) zebrafish line for both gba1 (or gba) and smpd1 to test for an interaction in vivo, hypothesising an exacerbation of phenotypes in the DKO line compared to those for single mutants. Unexpectedly, DKO zebrafish maintained conventional swimming behaviour and had normalised neuronal gene expression signatures compared to those of single mutants. We further identified rescue of mitochondrial Complexes I and IV in DKO zebrafish. Despite having an unexpected rescue effect, our results confirm ASM as a modifier of GBA1 deficiency in vivo. Our study highlights the need for validating how genetic variants and enzymatic deficiencies may interact in vivo.
Subject(s)
Niemann-Pick Disease, Type A , Parkinson Disease , Animals , Glucosylceramidase/genetics , Glucosylceramidase/metabolism , Zebrafish/genetics , Zebrafish/metabolism , Parkinson Disease/metabolism , Phenotype , alpha-Synuclein/metabolism , Mutation/geneticsABSTRACT
BACKGROUND: Microvascular abnormalities and impaired gas transfer have been observed in patients with COVID-19. The progression of pulmonary changes in these patients remains unclear. RESEARCH QUESTION: Do patients hospitalized with COVID-19 without evidence of architectural distortion on structural imaging exhibit longitudinal improvements in lung function measured by using 1H and 129Xe MRI between 6 and 52 weeks following hospitalization? STUDY DESIGN AND METHODS: Patients who were hospitalized with COVID-19 pneumonia underwent a pulmonary 1H and 129Xe MRI protocol at 6, 12, 25, and 51 weeks following hospital admission in a prospective cohort study between November 2020 and February 2022. The imaging protocol was as follows: 1H ultra-short echo time, contrast-enhanced lung perfusion, 129Xe ventilation, 129Xe diffusion-weighted, and 129Xe spectroscopic imaging of gas exchange. RESULTS: Nine patients were recruited (age 57 ± 14 [median ± interquartile range] years; six of nine patients were male). Patients underwent MRI at 6 (n = 9), 12 (n = 9), 25 (n = 6), and 51 (n = 8) weeks following hospital admission. Patients with signs of interstitial lung damage were excluded. At 6 weeks, patients exhibited impaired 129Xe gas transfer (RBC to membrane fraction), but lung microstructure was not increased (apparent diffusion coefficient and mean acinar airway dimensions). Minor ventilation abnormalities present in four patients were largely resolved in the 6- to 25-week period. At 12 weeks, all patients with lung perfusion data (n = 6) showed an increase in both pulmonary blood volume and flow compared with 6 weeks, although this was not statistically significant. At 12 weeks, significant improvements in 129Xe gas transfer were observed compared with 6-week examinations; however, 129Xe gas transfer remained abnormally low at weeks 12, 25, and 51. INTERPRETATION: 129Xe gas transfer was impaired up to 1 year following hospitalization in patients who were hospitalized with COVID-19 pneumonia, without evidence of architectural distortion on structural imaging, whereas lung ventilation was normal at 52 weeks.
Subject(s)
COVID-19 , Xenon Isotopes , Humans , Male , Adult , Middle Aged , Aged , Female , Prospective Studies , Magnetic Resonance Imaging/methods , Lung/diagnostic imagingABSTRACT
Background: Current European Society of Cardiology and European Respiratory Society guidelines recommend regular risk stratification with an aim of treating patients with pulmonary arterial hypertension (PAH) to improve or maintain low-risk status (<5% 1-year mortality). Methods: Consecutive patients with PAH who underwent cardiac magnetic resonance imaging (cMRI) were identified from the Assessing the Spectrum of Pulmonary hypertension Identified at a Referral centre (ASPIRE) registry. Kaplan-Meier survival curves, locally weighted scatterplot smoothing regression and multi-variable logistic regression analysis were performed. Results: In 311 consecutive, treatment-naïve patients with PAH undergoing cMRI including 121 undergoing follow-up cMRI, measures of right ventricular (RV) function including right ventricular ejection fraction (RVEF) and RV end systolic volume and right atrial (RA) area had prognostic value. However, only RV metrics were able to identify a low-risk status. Age (p < 0.01) and RVEF (p < 0.01) but not RA area were independent predictors of 1-year mortality. Conclusion: This study highlights the need for guidelines to include measures of RV function rather than RA area alone to aid the risk stratification of patients with PAH.
ABSTRACT
OBJECTIVES: This research examined whether people's causal explanations of depression were associated with acceptability and efficacy-related treatment perceptions and likelihood to choose cognitive behavioural therapy (CBT) and antidepressant medication (ADM) as depression treatments. DESIGN: A cross-sectional internet-based design was used. METHODS: A general population sample was used over a clinical sample to study those who had not yet chosen to enter treatment. A total of 422 individuals were recruited through a crowdsourcing platform to complete an online survey. Measures included perceived causes of depression, perceived acceptability, efficacy and choice likelihood for ADM and CBT, and demographics. RESULTS: Those with biological causal explanations of depression were more favourable towards ADM on all three perceptual measures of acceptability, efficacy and likelihood to choose ADM as a treatment for depression. Personality/character-related causal explanations of depression were positively related to perceived efficacy and likelihood to choose CBT as a depression treatment. Those endorsing environmental stress causes of depression were more likely to choose CBT as a treatment for depression. CONCLUSIONS: Results indicated that people's beliefs about the causes of depression were related to their perceptions of and likelihoods to choose ADM and CBT as depression treatments. PRACTITIONER POINTS: Provides evidence of how different causal explanations of depression influence sufferers' likelihoods to choose ADM and CBT as possible treatments for their depression. Provides support for exploring potential patients' causal explanations about depression prior to recommending a treatment regimen.
Subject(s)
Cognitive Behavioral Therapy , Depression , Antidepressive Agents/therapeutic use , Cross-Sectional Studies , Humans , PerceptionABSTRACT
The maturing mutational landscape of cancer genomes, the development and application of clinical interventions and evolving insights into tumour-associated functions reveal unexpected features of the protein kinase C (PKC) family of serine/threonine protein kinases. These advances include recent work showing gain or loss-of-function mutations relating to driver or bystander roles, how conformational constraints and plasticity impact this class of proteins and how emergent cancer-associated properties may offer opportunities for intervention. The profound impact of the tumour microenvironment, reflected in the efficacy of immune checkpoint interventions, further prompts to incorporate PKC family actions and interventions in this ecosystem, informed by insights into the control of stromal and immune cell functions. Drugging PKC isoforms has offered much promise, but when and how is not obvious.
Subject(s)
Neoplasms/enzymology , Protein Kinase C/physiology , Animals , Humans , Isoenzymes/physiology , Mutation , Phosphorylation , Promoter Regions, Genetic , Protein Kinase C/antagonists & inhibitors , Protein Kinase C/genetics , Tumor MicroenvironmentABSTRACT
Induced pluripotent stem cell (iPSC)-derived neural cultures from amyotrophic lateral sclerosis (ALS) patients can model disease phenotypes. However, heterogeneity arising from genetic and experimental variability limits their utility, impacting reproducibility and the ability to track cellular origins of pathogenesis. Here, we present methodologies using single-cell RNA sequencing (scRNA-seq) analysis to address these limitations. By repeatedly differentiating and applying scRNA-seq to motor neurons (MNs) from healthy, familial ALS, sporadic ALS, and genome-edited iPSC lines across multiple patients, batches, and platforms, we account for genetic and experimental variability toward identifying unified and reproducible ALS signatures. Combining HOX and developmental gene expression with global clustering, we anatomically classified cells into rostrocaudal, progenitor, and postmitotic identities. By relaxing statistical thresholds, we discovered genes in iPSC-MNs that were concordantly dysregulated in postmortem MNs and yielded predictive ALS markers in other human and mouse models. Our approach thus revealed early, convergent, and MN-resolved signatures of ALS.
Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Induced Pluripotent Stem Cells/metabolism , Motor Neurons/metabolism , Animals , Disease Models, Animal , Humans , MiceABSTRACT
The majority of people with depression in the United States either never seek treatment or gravitate exclusively to antidepressant medication (ADM), despite the existence of other effective treatments, such as cognitive-behavioral therapy (CBT). Reluctance to use psychotherapy is partly due to lack of appropriate mental health literacy and perceptions of low treatment acceptability (appropriateness for a given problem) and credibility (treatment logicalness, and whether the patient expects improvement). In the current investigation, we examined whether providing psychoeducation about CBT for depression would change participant perceptions of the treatment's acceptability and credibility. We recruited 554 (female n = 314; 57%) participants across two online studies, and assessed their baseline perceptions of CBT and ADM using modified Treatment Acceptability (TAAS) and Treatment Credibility and Expectancy (CEQ) scales. Participants were subsequently presented with evidence-based, expert-vetted psychoeducational materials describing CBT and ADM, and were asked to recomplete the TAAS and CEQ. In Study 1, participants endorsed significantly higher CBT-CEQ (credibility/expectancy) scores postpsychoeducation. In Study 2, participants endorsed significantly lower CBT-TAAS (acceptability), and among those with no exposure to depression treatments, endorsed significantly higher CBT-CEQ scores postpsychoeducation. In both studies, there were no perceptual changes of ADM after the psychoeducation. Finally, in Study 2, endorsement of a biological model of depression and depressive symptoms were negatively predictive of CBT's acceptability and credibility and expectancy postpsychoeducation. Perceptions of credibility and expectancy of CBT for depression appear malleable even after exposure to brief psychoeducation, whereas shifting perceptions of CBT's acceptability may require more extensive intervention.
Subject(s)
Antidepressive Agents/administration & dosage , Cognitive Behavioral Therapy/methods , Adult , Cognition , Depression/therapy , Depressive Disorder/psychology , Depressive Disorder/therapy , Female , Humans , Male , Psychotherapy/methods , Treatment OutcomeABSTRACT
BACKGROUND: We previously reported up-regulation of tigarb (the zebrafish orthologue of human TIGAR, TP53 - Induced Glycolysis and Apoptosis Regulator) in a zebrafish pink1-/- model of Parkinson's disease (PD). Genetic inactivation of tigarb led to the rescue of dopaminergic neurons and mitochondrial function in pink-/- zebrafish. The aim of this study was to determine the relevance of TIGAR for human PD, investigate its disease specificity and identify relevant upstream and downstream mechanisms. MATERIALS AND METHODS: TIGAR Immunohistochemistry, using a range of antibodies, was undertaken for detailed assessment of TIGAR in formalin-fixed, paraffin-embedded tissue from post mortem brains of PD patients and other neurodegenerative disorders (nâ¯=â¯10 controls, 10 PD cases, 10 dementia with Lewy bodies, 5 motor neurone disease (MND), 3 multiple system atrophy (MSA)) and complemented by immunohistochemistry for p53, hexokinase I (HK-I) and hexokinase II (HK-II; nâ¯=â¯4 control, 4 PD, and 4 dementia with Lewy bodies). RESULTS: TIGAR was detected in Lewy bodies and Lewy neurites in the substantia nigra of sporadic PD and Dementia with Lewy bodies (DLB) patients. Staining of adjacent sections and double staining confirmed the presence of TIGAR alongside alpha-synuclein in these LB and neurites. In contrast, TIGAR-positive aggregates were not seen in cortical Lewy bodies. TIGAR protein was also absent in both TDP-43-positive inclusions in MND and glial cytoplasmic inclusions in MSA. Subsequent investigation of the TIGAR-upstream regulator p53 and the downstream targets HK-I and HK-II in PD brains suggested a possible mild increase in HK-I. CONCLUSIONS: TIGAR protein, is present in SN Lewy bodies of both sporadic PD and DLB. The absence of TIGAR protein in the pathological inclusions of MND or MSA suggests disease specificity and further raises the possibility that TIGAR may be involved in PD pathogenesis.