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Abstract Inflammasome activation results in the cleavage of gasdermin D (GSDMD) by pro-inflammatory caspases. The N-terminal domains (GSDMDNT) oligomerize and assemble pores penetrating the target membrane. As methods to study pore formation in living cells are insufficient, the order of conformational changes, oligomerization, and membrane insertion remained unclear. We have raised nanobodies (VHHs) against human GSDMD and find that cytosolic expression of VHHGSDMD-1 and VHHGSDMD-2 prevents oligomerization of GSDMDNT and pyroptosis. The nanobody-stabilized GSDMDNT monomers partition into the plasma membrane, suggesting that membrane insertion precedes oligomerization. Inhibition of GSDMD pore formation switches cell death from pyroptosis to apoptosis, likely driven by the enhanced caspase-1 activity required to activate caspase-3. Recombinant antagonistic nanobodies added to the extracellular space prevent pyroptosis and exhibit unexpected therapeutic potential. They may thus be suitable to treat the ever-growing list of diseases caused by activation of (non-) canonical inflammasomes.

The ER chaperone BiP is regulated by FICD-mediated AMPylation and deAMPylation. Here, the authors characterise the structure of mammalian AMPylated BiP bound to FICD, by X-ray crystallography and neutron scattering, providing insights into the mechanism of BiP AMPylation and deAMPylation.

The role of mesencephalic astrocyte-derived neurotrophic factor (MANF) in maintenance of protein folding homeostasis inside the ER has remained unclear. Here the authors determine the structure of the complex between MANF and the ER-localized chaperone BiP and provide evidence that MANF serves as an anti-nucleotide exchange factor for BiP.

Most female meiotic spindles undergo striking morphological changes while transitioning from metaphase to anaphase. The ultra-structure of meiotic spindles, and how changes to this structure correlate with such dramatic spindle rearrangements remains largely unknown. To address this, we applied light microscopy, large-scale electron tomography and mathematical modeling of female meiotic Caenorhabditis elegans spindles. Combining these approaches, we find that meiotic spindles are dynamic arrays of short microtubules that turn over within seconds. The results show that the metaphase to anaphase transition correlates with an increase in microtubule numbers and a decrease in their average length. Detailed analysis of the tomographic data revealed that the microtubule length changes significantly during the metaphase-to-anaphase transition. This effect is most pronounced for microtubules located within 150 nm of the chromosome surface. To understand the mechanisms that drive this transition, we developed a mathematical model for the microtubule length distribution that considers microtubule growth, catastrophe, and severing. Using Bayesian inference to compare model predictions and data, we find that microtubule turn-over is the major driver of the spindle reorganizations. Our data suggest that in metaphase only a minor fraction of microtubules, those closest to the chromosomes, are severed. The large majority of microtubules, which are not in close contact with chromosomes, do not undergo severing. Instead, their length distribution is fully explained by growth and catastrophe. This suggests that the most prominent drivers of spindle rearrangements are changes in nucleation and catastrophe rate. In addition, we provide evidence that microtubule severing is dependent on katanin.

The metazoan endoplasmic reticulum (ER) serves both as a hub for maturation of secreted proteins and as an intracellular calcium storage compartment, facilitating calcium-release-dependent cellular processes. ER calcium depletion robustly activates the unfolded protein response (UPR). However, it is unclear how fluctuations in ER calcium impact organellar proteostasis. Here, we report that calcium selectively affects the dynamics of the abundant metazoan ER Hsp70 chaperone BiP, by enhancing its affinity for ADP. In the calcium-replete ER, ADP rebinding to post-ATP hydrolysis BiP-substrate complexes competes with ATP binding during both spontaneous and co-chaperone-assisted nucleotide exchange, favouring substrate retention. Conversely, in the calcium-depleted ER, relative acceleration of ADP-to-ATP exchange favours substrate release. These findings explain the rapid dissociation of certain substrates from BiP observed in the calcium-depleted ER and suggest a mechanism for tuning ER quality control and coupling UPR activity to signals that mobilise ER calcium in secretory cells.

Quantitative photoacoustic tomography aims to recover the spatial distribution of absolute chromophore concentrations and their ratios from deep tissue, high-resolution images. In this study, a model-based inversion scheme based on a Monte-Carlo light transport model is experimentally validated on 3-D multispectral images of a tissue phantom acquired using an all-optical scanner with a planar detection geometry. A calibrated absorber allowed scaling of the measured data during the inversion, while an acoustic correction method was employed to compensate the effects of limited view detection. Chromophore- and fluence-dependent step sizes and Adam optimization were implemented to achieve rapid convergence. High resolution 3-D maps of absolute concentrations and their ratios were recovered with high accuracy. Potential applications of this method include quantitative functional and molecular photoacoustic tomography of deep tissue in preclinical and clinical studies. Keywords: Quantitative photoacoustic imaging, Blood oxygen saturation, Inverse problem, Model based inversion, Monte Carlo, Spectral unmixing

Chromosome segregation during male meiosis is tailored to rapidly generate multitudes of sperm. Little is known about mechanisms that efficiently partition chromosomes to produce sperm. Using live imaging and tomographic reconstructions of spermatocyte meiotic spindles in Caenorhabditis elegans, we find the lagging X chromosome, a distinctive feature of anaphase I in C. elegans males, is due to lack of chromosome pairing. The unpaired chromosome remains tethered to centrosomes by lengthening kinetochore microtubules, which are under tension, suggesting that a ‘tug of war’ reliably resolves lagging. We find spermatocytes exhibit simultaneous pole-to-chromosome shortening (anaphase A) and pole-to-pole elongation (anaphase B). Electron tomography unexpectedly revealed spermatocyte anaphase A does not stem solely from kinetochore microtubule shortening. Instead, movement of autosomes is largely driven by distance change between chromosomes, microtubules, and centrosomes upon tension release during anaphase. Overall, we define novel features that segregate both lagging and paired chromosomes for optimal sperm production.

Ageing is associated with a pronounced shift in mortality from cancer to degenerative diseases. Here, the authors show that in concordance with this shift, conserved transcriptional alterations during ageing across four vertebrates align with degenerative diseases but are opposite to those in cancer.

A connection between centrosomes and chromosomes is a key feature of mitotic spindles. Here the authors generate 3D reconstructions of whole mitotic spindles in earlyC. elegansembryos and show that chromosomes are anchored by the entire spindle network and that connections through kinetochore microtubules are few and likely very transient.

The endoplasmic reticulum (ER)-localized Hsp70 chaperone BiP contributes to protein folding homeostasis by engaging unfolded client proteins in a process that is tightly coupled to ATP binding and hydrolysis. The inverse correlation between BiP AMPylation and the burden of unfolded ER proteins suggests a post-translational mechanism for adjusting BiP’s activity to changing levels of ER stress, but the underlying molecular details are unexplored. We present biochemical and crystallographic studies indicating that irrespective of the identity of the bound nucleotide AMPylation biases BiP towards a conformation normally attained by the ATP-bound chaperone. AMPylation does not affect the interaction between BiP and J-protein co-factors but appears to allosterically impair J protein-stimulated ATP-hydrolysis, resulting in the inability of modified BiP to attain high affinity for its substrates. These findings suggest a molecular mechanism by which AMPylation serves as a switch to inactivate BiP, limiting its interactions with substrates whilst conserving ATP.

Many biological structures show recurring tiling patterns on one structural level or the other. Current image acquisition techniques are able to resolve those tiling patterns to allow quantitative analyses. The resulting image data, however, may contain an enormous number of elements. This renders manual image analysis infeasible, in particular when statistical analysis is to be conducted, requiring a larger number of image data to be analyzed. As a consequence, the analysis process needs to be automated to a large degree. In this paper, we describe a multi-step image segmentation pipeline for the automated segmentation of the calcified cartilage into individual tesserae from computed tomography images of skeletal elements of stingrays.Besides applying state-of-the-art algorithms like anisotropic diffusion smoothing, local thresholding for foreground segmentation, distance map calculation, and hierarchical watershed, we exploit a graph-based representation for fast correction of the segmentation. In addition, we propose a new distance map that is computed only in the plane that locally best approximates the calcified cartilage. This distance map drastically improves the separation of individual tesserae. We apply our segmentation pipeline to hyomandibulae from three individuals of the round stingray (Urobatis halleri), varying both in age and size.Each of the hyomandibula datasets contains approximately 3000 tesserae. To evaluate the quality of the automated segmentation, four expert users manually generated ground truth segmentations of small parts of one hyomandibula. These ground truth segmentations allowed us to compare the segmentation quality w.r.t. individual tesserae. Additionally, to investigate the segmentation quality of whole skeletal elements, landmarks were manually placed on all tesserae and their positions were then compared to the segmented tesserae. With the proposed segmentation pipeline, we sped up the processing of a single skeletal element from days or weeks to a few hours.

The original version of this Article contained an error in the spelling of the author Jule Müller, which was incorrectly given as Julia Müller. Additionally, in Fig. 4a, the blue-red colour scale for fold change in ageing/disease regulation included a blue stripe in place of a red stripe at the right-hand end of the scale. These errors have been corrected in both the PDF and HTML versions of the Article.

To target oncolytic measles viruses (MV) to tumors, we exploit the binding specificity of designed ankyrin repeat proteins (DARPins). These DARPin-MVs have high tumor selectivity while maintaining excellent oncolytic potency. Stability, small size, and efficacy of DARPins allowed the generation of MVs simultaneously targeted to tumor marker HER2/neu and cancer stem cell (CSC) marker EpCAM. For optimization, the linker connecting both DARPins was varied in flexibility and length. Flexibility had no impact on fusion helper activity whereas length had. MVs with bispecific MV-H are genetically stable and revealed the desired double-target specificity. In vitro, the cytolytic activity of bispecific MVs was superior or comparable to mono-targeted viruses depending on the target cells. In vivo, therapeutic efficacy of the bispecific viruses was validated in an orthotopic ovarian carcinoma model revealing an effective reduction of tumor mass. Finally, the power of bispecific targeting was demonstrated on cocultures of different tumor cells thereby mimicking tumor heterogeneity in vitro, more closely reflecting real tumors. Here, bispecific excelled monospecific viruses in efficacy. DARPin-based targeting domains thus allow the generation of efficacious oncolytic viruses with double specificity, with the potential to handle intratumoral variation of antigen expression and to simultaneously target CSCs and the bulk tumor mass.

The endoplasmic reticulum (ER)-localized Hsp70 chaperone BiP affects protein folding homeostasis and the response to ER stress. Reversible inactivating covalent modification of BiP is believed to contribute to the balance between chaperones and unfolded ER proteins, but the nature of this modification has so far been hinted at indirectly. We report that deletion of FICD, a gene encoding an ER-localized AMPylating enzyme, abolished detectable modification of endogenous BiP enhancing ER buffering of unfolded protein stress in mammalian cells, whilst deregulated FICD activity had the opposite effect. In vitro, FICD AMPylated BiP to completion on a single residue, Thr518. AMPylation increased, in a strictly FICD-dependent manner, as the flux of proteins entering the ER was attenuated in vivo. In vitro, Thr518 AMPylation enhanced peptide dissociation from BiP 6-fold and abolished stimulation of ATP hydrolysis by J-domain cofactor. These findings expose the molecular basis for covalent inactivation of BiP.

DnaK/Hsp70 chaperones form oligomers of poorly understood structure and functional significance. Site-specific proteolysis and crosslinking were used to probe the architecture of oligomers formed by the endoplasmic reticulum (ER) Hsp70, BiP. These were found to consist of adjacent protomers engaging the interdomain linker of one molecule in the substrate binding site of another, attenuating the chaperone function of oligomeric BiP. Native gel electrophoresis revealed a rapidly-modulated reciprocal relationship between the burden of unfolded proteins and BiP oligomers and slower equilibration between oligomers and inactive, covalently-modified BiP. Lumenal ER calcium depletion caused rapid oligomerization of mammalian BiP and a coincidental diminution in substrate binding, pointing to the relative inertness of the oligomers. Thus, equilibration between inactive oligomers and active monomeric BiP is poised to buffer fluctuations in ER unfolded protein load on a rapid timescale attainable neither by inter-conversion of active and covalently-modified BiP nor by the conventional unfolded protein response.

Tracing microtubule centerlines in serial section electron tomography requires microtubules to be stitched across sections, that is lines from different sections need to be aligned, endpoints need to be matched at section boundaries to establish a correspondence between neighboring sections, and corresponding lines need to be connected across multiple sections. We present computational methods for these tasks: 1) An initial alignment is computed using a distance compatibility graph. 2) A fine alignment is then computed with a probabilistic variant of the iterative closest points algorithm, which we extended to handle the orientation of lines by introducing a periodic random variable to the probabilistic formulation. 3) Endpoint correspondence is established by formulating a matching problem in terms of a Markov random field and computing the best matching with belief propagation. Belief propagation is not generally guaranteed to converge to a minimum. We show how convergence can be achieved, nonetheless, with minimal manual input. In addition to stitching microtubule centerlines, the correspondence is also applied to transform and merge the electron tomograms. We applied the proposed methods to samples from the mitotic spindle in C. elegans, the meiotic spindle in X. laevis, and sub-pellicular microtubule arrays in T. brucei. The methods were able to stitch microtubules across section boundaries in good agreement with experts' opinions for the spindle samples. Results, however, were not satisfactory for the microtubule arrays. For certain experiments, such as an analysis of the spindle, the proposed methods can replace manual expert tracing and thus enable the analysis of microtubules over long distances with reasonable manual effort.

Cellular senescence is described to be a consequence of telomere erosion during the replicative life span of primary human cells. Quiescence should therefore not contribute to cellular aging but rather extend lifespan. Here we tested this hypothesis and demonstrate that cultured long-term quiescent human fibroblasts transit into senescence due to similar cellular mechanisms with similar dynamics and with a similar maximum life span as proliferating controls, even under physiological oxygen conditions. Both, long-term quiescent and senescent fibroblasts almost completely fail to undergo apoptosis. The transition of long-term quiescent fibroblasts into senescence is also independent of HES1 which protects short-term quiescent cells from becoming senescent. Most significantly, DNA damage accumulates during senescence as well as during long-term quiescence at physiological oxygen levels. We suggest that telomere-independent, potentially maintenance driven gradual induction of cellular senescence during quiescence is a counterbalance to tumor development.

Glucose restriction mimicked by feeding the roundworm Caenorhabditis elegans with 2-deoxy-D-glucose (DOG) - a glucose molecule that lacks the ability to undergo glycolysis - has been found to increase the life span of the nematodes considerably. To facilitate understanding of the molecular mechanisms behind this life extension, we analyzed transcriptomes of DOG-treated and untreated roundworms obtained by RNA-seq at different ages. We found that, depending on age, DOG changes the magnitude of the expression values of about 2 to 24 percent of the genes significantly, although our results reveal that the gross changes introduced by DOG are small compared to the age-induced changes. We found that 27 genes are constantly either up- or down-regulated by DOG over the whole life span, among them several members of the cytochrome P450 family. The monotonic change with age of the temporal expression patterns of the genes was investigated, leading to the result that 21 genes reverse their monotonic behaviour under impaired glycolysis. Put simply, the DOG-treatment reduces the gross transcriptional activity but increases the interconnectedness of gene expression. However, a detailed analysis of network parameters discloses that the introduced changes differ remarkably between individual signalling pathways. We found a reorganization of the hubs of the mTOR pathway when standard diet is replaced by DOG feeding. By constructing correlation based difference networks, we identified those signalling pathways that are most vigorously changed by impaired glycolysis. Taken together, we have found a number of genes and pathways that are potentially involved in the DOG-driven extension of life span of C. elegans. Furthermore, our results demonstrate how the network structure of ageing-relevant signalling pathways is reorganised under impaired glycolysis.

Five institutional partners participated in an interlaboratory comparison of nucleic acid extraction, RNA preservation and quantitative Real-Time PCR (qPCR) based assays for biogas biocenoses derived from different grass silage digesting laboratory and pilot scale fermenters. A kit format DNA extraction system based on physical and chemical lysis with excellent extraction efficiency yielded highly reproducible results among the partners and clearly outperformed a traditional CTAB/chloroform/isoamylalcohol based method. Analytical purpose, sample texture, consistency and upstream pretreatment steps determine the modifications that should be applied to achieve maximum efficiency in the trade-off between extract purity and nucleic acid recovery rate. RNA extraction was much more variable, and the destination of the extract determines the method to be used. RNA stabilization with quaternary ammonium salts was an as satisfactory approach as flash freezing in liquid N2. Due to co-eluted impurities, spectrophotometry proved to be of limited value for nucleic acid qualification and quantification in extracts obtained with the kit, and picoGreen® based quantification was more trustworthy. Absorbance at 230 nm can be extremely high in the presence of certain chaotropic guanidine salts, but guanidinium isothiocyanate does not affect (q)PCR. Absolute quantification by qPCR requires application of a reliable internal standard for which correct PCR efficiency and Y-intercept values are important and must be reported.

BACKGROUND: Cellular senescence is induced either internally, for example by replication exhaustion and cell division, or externally, for example by irradiation. In both cases, cellular damages accumulate which, if not successfully repaired, can result in senescence induction. Recently, we determined the transcriptional changes combined with the transition into replicative senescence in primary human fibroblast strains. Here, by γ-irradiation we induced premature cellular senescence in the fibroblast cell strains (HFF and MRC-5) and determined the corresponding transcriptional changes by high-throughput RNA sequencing. RESULTS: Comparing the transcriptomes, we found a high degree of similarity in differential gene expression in replicative as well as in irradiation induced senescence for both cell strains suggesting, in each cell strain, a common cellular response to error accumulation. On the functional pathway level, "Cell cycle" was the only pathway commonly down-regulated in replicative and irradiation-induced senescence in both fibroblast strains, confirming the tight link between DNA repair and cell cycle regulation. However, "DNA repair" and "replication" pathways were down-regulated more strongly in fibroblasts undergoing replicative exhaustion. We also retrieved genes and pathways in each of the cell strains specific for irradiation induced senescence. CONCLUSION: We found the pathways associated with "DNA repair" and "replication" less stringently regulated in irradiation induced compared to replicative senescence. The strong regulation of these pathways in replicative senescence highlights the importance of replication errors for its induction.

Autonomic nervous system dysfunction is increasingly recognized as a common sequela of traumatic brain injury (TBI). Heart rate variability (HRV) is a specific measure of autonomic nervous system functioning that can be used to measure beat-to-beat changes in heart rate following TBI. The objective of this systematic review was to determine the state of the literature on HRV dysfunction following TBI, assess the level of support for HRV dysfunction following TBI, and determine if HRV dysfunction predicts mortality and the severity and subsequent recovery of TBI symptoms. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two raters coded each article and provided quality ratings with discrepancies resolved by consensus. Eighty-nine papers met the inclusion criteria. Findings indicated that TBI of any severity is associated with decreased (i.e., worse) HRV; the severity of TBI appears to moderate the relationship between HRV and recovery; decreased HRV following TBI predicts mortality beyond age; HRV disturbances may persist beyond return-to-play and symptom resolution following mild TBI. Overall, current literature suggests HRV is decreased following TBI and may be a good indicator of physiological change and predictor of important outcomes including mortality and symptom improvement following TBI., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Research on the psychophysiology of stress is expanding rapidly, but the field lacks a clear integrative framework to help translate research findings into empirically supported stress interventions. The Research Domain Criteria (RDoC) is an excellent candidate to explore as a framework to integrate stress research. The RDoC framework is a dimensional, multi-modal approach to psychopathology proposed as an alternative to categorical approaches used by the International Classification of Diseases (ICD) and the Diagnostic and Statistical Manual (DSM). The goal of this paper is to explore the RDoC as a framework to integrate psychophysiology research into therapeutic interventions for stress. The RDoC consists of six domains: negative valence systems, positive valence systems, cognitive systems, social processes systems, arousal/regulatory systems, and sensorimotor systems, and provides an excellent structure for integrating information from multiple levels of functioning including physiology, behavior, and self-report, as well as genes, molecules, cells, and brain circuits. Integrating psychophysiological research on stress using the RDoC framework can direct and amplify stress management and psychotherapeutic interventions. First, the RDoC provides a clear foundation for conceptualizing the stress response in terms of important concepts such as allostasis and adaptation. In this perspective, the terms "allostatic response" or "adaptation response" are more descriptive terms than "stress response" in understanding bodily responses to life threats and challenges. Second, psychophysiological approaches can be used in the context of modalities such as biofeedback and mindfulness to both collect psychophysiological data and then integrate that data into a broader therapeutic framework. Heart rate variability (HRV) biofeedback is being used more frequently as part of a therapeutic intervention package with stress management and psychotherapy, and HRV data is also used to provide outcome evidence on the efficacy of treatment. Mindfulness practices are commonly used in combination with stress management and psychotherapy, and psychophysiological data (HRV, EEG, blood pressure, etc.) is often collected to explore and understand mind/body relationships. In conclusion, the lack of a clear framework to assess and understand mind/body functioning limits current stress research and interventions. The RDoC provides a strong framework to assess and integrate physiological and psychological data and improve stress interventions., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Steffen.)

Objective: Autonomic nervous system dysregulation is a common consequence of traumatic brain injury (TBI). Heart rate variability (HRV) is a cost-effective measure of autonomic nervous system functioning, with studies suggesting decreased HRV following moderate-to-severe TBI. HRV biofeedback treatment may improve post-TBI autonomic nervous system functioning and post-injury emotional and cognitive functioning. We provide a systematic evidence-based review of the state of the literature and effectiveness of HRV biofeedback following TBI., Method: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two coders coded each article and provided quality ratings. Seven papers met inclusion criteria. All studies included a measure of emotional functioning and 5 studies (63%) included neuropsychological outcomes., Results: Participants completed 11 sessions of HRV biofeedback on average (range = 1 to 40). HRV biofeedback was associated with improved HRV following TBI. There was a positive relationship between increased HRV and TBI recovery following biofeedback, including improvements in cognitive and emotional functioning, and physical symptoms such as headaches, dizziness, and sleep problems., Conclusion: The literature on HRV biofeedback for TBI is promising, but in its infancy; effectiveness is unclear due to poor-to-fair study quality, and potential publication bias (all studies reported positive results).

Theory impacts how research is conducted. A popular theory used to conceptualize brain functioning is the triune brain theory. The triune brain theory is an evolutionary theory of brain development that emphasizes three key brain regions consisting of the brainstem, the limbic system, and the cortex that function relatively independently in coping with stress via fight or flight, emotion, and cognition, respectively. However, modern neuroscience research demonstrates that the triune brain theory does not accurately explain how the brain functions in everyday life or during the stress response. Specifically, emotion and cognition are interdependent and work together, the limbic system is not a purely emotional center nor are there purely emotional circuits in the brain, and the cortex is not a purely cognitive center nor are there purely cognitive circuits in the brain. We propose a new evolutionarily based model, the adaptive brain, that is founded on adaptive prediction resulting from interdependent brain networks using interoception and exteroception to balance current needs, and the interconnections among homeostasis, allostasis, emotion, cognition, and strong social bonds in accomplishing adaptive goals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Steffen, Hedges and Matheson.)

Stress influences many health-related behaviors including diet and nutrition intake, often resulting in increased calorie intake, fewer healthy eating behaviors, and poorer nutrition. Food intake is modulated by inhibitory control and has important implications for our physical, mental, and emotional health. Yet, little is known about the relationship between stress and food-related inhibitory control. We tested the influence of a short-term experimental stressor on behavioral and event-related potential (ERP; N2 and P3 components) measures of food-related inhibitory control. Ninety-seven healthy participants were randomly assigned to complete the Trier Social Stress Test (TSST) (n = 48, 27 females [52.9%]) or a neutral control condition (n = 49, 35 females [70%]) immediately followed by food-specific go/no-go and neutral go/no-go tasks while electroencephalogram (EEG) data were recorded. Stress levels were successfully manipulated, with heightened self-report and physiological measures (heart rate and systolic blood pressure) of the stress response in individuals who completed the TSST compared to control. As expected, the high calorie food-specific go/no-go task elicited larger N2 amplitude than the neutral task. N2 component amplitude was also significantly larger following the TSST relative to the control task. There were no significant between-group or task differences for P3 amplitude or behavioral measures. Findings suggest heightened N2 amplitude following psychological stress that is not specific to food or inhibition processes and may reflect heightened arousal following stress. Future research in individuals with overweight/obesity or experiencing chronic stress will further clarify the role of stress in food-related inhibitory control., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Heart rate variability (HRV) is considered an index of self-regulatory capacity, and trait compassion predicts healthy HRV and self-regulation. Compassion focused psychotherapy interventions have been shown to increase levels of compassion in the general population but no studies to date have examined if these interventions also increase HRV in a distressed clinical sample. The present study examined whether a 12-week compassion focused therapy intervention administered in group format would improve resting HRV and impact HRV reactivity during self-critical writing and self-compassion writing tasks administered before and after the intervention. A total of 31 participants in a university counseling center completed the intervention and HRV assessments. Resting HRV did not significantly change over the course of the intervention in the overall sample. Only those who showed a reliable increase in self-compassion also had a significant increase in resting HRV post-intervention. Additionally, the self-critical writing task was associated with a significant decrease in HRV, with HRV staying low during self-compassionate writing and then significantly increasing during recovery. Reliable change in self-compassion predicted increased HRV reactivity to self-critical and self-compassion writing tasks following the intervention, indicating greater engagement with the task. Findings support the idea that increased self-compassion increases HRV reactivity and potentially strengthens ability to engage with difficult emotions in psychotherapy.

Introduction: Approaches to improve heart rate variability and reduce stress such as breathing retraining are more frequently being integrated into psychotherapy but little research on their effectiveness has been done to date. Specifically, no studies to date have directly compared using a breathing pacer at 6 breaths per minute with compassion focused soothing rhythm breathing., Current Study: In this randomized controlled experiment, 6 breaths per minute breathing using a pacer was compared with compassion focused soothing rhythm breathing, with a nature video being used as a control group condition., Methods: Heart rate variability (HRV) measures were assessed via electrocardiogram (ECG) and respiration belt, and an automated blood pressure machine was used to measure systolic diastolic blood pressure, and heart rate (HR). A total of 96 participants were randomized into the three conditions. Following a 5-min baseline, participants engaged in either 6 breath per minute breathing, soothing rhythm breathing, or watched a nature video for 10 min. To induce a stressful state, participants then wrote for 5 min about a time they felt intensely self-critical. Participants then wrote for 5 min about a time they felt self-compassionate, and the experiment ended with a 10-min recovery period., Results: Conditions did not significantly differ at baseline. Overall, HRV, as measured by standard deviation of NN intervals (SDNN), low frequency HRV (LF HRV), and LF/HF ratio, increased during the intervention period, decreased during self-critical writing, and then returned to baseline levels during the recovery period. High frequency HRV (HF HRV) was not impacted by any of the interventions. The participants in the 6 breath per minute pacer condition were unable to consistently breathe at that rate and averaged about 12 breaths per minute. Time by Condition analyses revealed that both the 6 breaths per minute pacer and soothing breathing rhythm conditions lead to significantly higher SDNN than the nature video condition during breathing practice but there were no significant differences between conditions in response to the self-critical and self-compassionate writing or recovery periods. The 6 breath per minute pacer condition demonstrated a higher LF HRV and LF/HF ratio than the soothing rhythm breathing condition, and both intervention conditions had a higher LF HRV and LF/HF ratio than the nature video., Conclusions: Although the 6 breath per minute pacer condition participants were not able to breath consistently at the low pace, both the participants attempting to breathe at 6 breaths per minute as well as those in the soothing rhythm breathing condition effectively increased HR variability as measured by SDNN, and attempting to breathe at 6 breaths per minute led to the highest LF HRV and LF/HF ratio. Both breathing approaches impacted HRV more than watching a relaxing nature video and can potentially be used as key adjuncts in psychotherapy to aid in regulating physiological functioning, although it appears that consistent breathing practice would be needed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Steffen, Bartlett, Channell, Jackman, Cressman, Bills and Pescatello.)

Psychological stress is increasingly associated with alterations in performance and affect. Yet, the relationship between experimentally induced psychological stress and neural indices of performance monitoring and error processing, as well as response inhibition, are unclear. Using scalp-recorded event-related potentials (ERPs), we tested the relationship between experimental stress, using the Trier Social Stress Test (TSST), and the error-related negativity (ERN), error positivity (Pe), and N2 ERP components. A final sample of 71 undergraduate students were randomly assigned to go through the TSST ( n = 36; 18 female) or a brief mindfulness relaxation exercise ( n = 35; 16 female) immediately followed by a go/no-go task while electroencephalogram (EEG) data were collected. Salivary cortisol, heart rate, and blood pressure confirmed increased physiological stress in the TSST group relative to control. Reaction times, accuracy, and post-error slowing did not differ by stress group. Two-group (TSST, control) by 2-trial type (correct, incorrect for ERN/Pe; go correct, no-go correct for N2) repeated measures ANOVAs for the ERN, Pe, and N2 showed the expected main effects of trial type; neither the ERN nor the N2 ERP components showed interactions with the stress manipulation. In contrast, the Pe component showed a significant Group by Trial interaction, with reduced Pe amplitude following the stress condition relative to control. Pe amplitude did not, however, correlate with cortisol reactivity. Findings suggest a reduction in Pe amplitude following experimental stress that may be associated with reduced error awareness or attention to errors following the TSST. Given the variability in the extant literature on the relationship between experimentally induced stress and neurophysiological reflections of performance monitoring, we provide another point of data and conclude that better understanding of moderating variables is needed followed by high-powered replication studies to get at the nuance that is not yet understood in the relationship between induced stress and performance monitoring/response inhibition processes., (Copyright © 2020 Rodeback, Hedges-Muncy, Hunt, Carbine, Steffen and Larson.)

It is not wise to generalize psychophysiological findings from WEIRD (Western, Educated, Industrialized, Rich, Democratic) samples to all people and yet this occurs frequently in research. Case-in-point is our understanding of psychophysiological responses to stress which suggest universality despite our knowledge that these pathways are moderated by factors such as ethnicity and culture. Here we discuss the epidemiological phenomenon commonly referred to as the Hispanic health paradox to illustrate the importance of culture in understanding stress. We posit that despite high stress exposure, Hispanics may experience relatively low levels of stress contributing to their paradoxical health advantages. Building on our prior work, we present a new, culturally-tailored stress theory model to illustrate how sociocultural factors may moderate the experience of stress (through appraisals) with downstream effects on psychophysiological mechanisms. We support the model with available data and end this paper with a call for research that more carefully considers cultural and ethnic factors in psychophysiological research., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Heart rate variability (HRV) is a significant marker of health outcomes with decreased HRV predicting increased disease risk. HRV is decreased in major depressive disorder (MDD) but existing treatments for depression do not return heart rate variability to normal levels even with successful treatment of depression. Heart rate variability biofeedback (HRVB) increases heart rate variability but no studies to date have examined whether combining HRVB with psychotherapy improves outcome in MDD treatment. The present study used a randomized controlled design to compare the effects of HRVB combined with psychotherapy on MDD relative to a psychotherapy treatment as usual group and to a non-depressed control group. The HRVB+psychotherapy group showed a larger increase in HRV and a larger decrease in depressive symptoms relative to the other groups over a six-week period, whereas the psychotherapy group only did not improve HRV. Results support the supplementation of psychotherapy with HRVB in the treatment of MDD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Heart rate variability biofeedback (HRVB) significantly improves heart rate variability (HRV). Breathing at resonance frequency (RF, approximately 6 breaths/min) constitutes a key part of HRVB training and is hypothesized to be a pathway through which biofeedback improves HRV. No studies to date, however, have experimentally examined whether RF breathing impacts measures of HRV. The present study addressed this question by comparing three groups: the RF group breathed at their determined RF for 15 min; the RF + 1 group breathed at 1 breath/min higher than their determined RF for 15 min; and the third group sat quietly for 15 min. After this 15-min period, all groups participated in the Paced Auditory Serial Addition Task (PASAT) for 8 min, and then sat quietly during a 10-min recovery period. HRV, blood pressure, and mood were measured throughout the experiment. Groups were not significantly different on any of the measures at baseline. After the breathing exercise, the RF group reported higher positive mood than the other two groups and a significantly higher LF/HF HRV ratio relative to the control group, a key goal in HRVB training ( p  < 0.05). Additionally, the RF group showed lower systolic blood pressure during the PASAT and during the recovery period relative to the control group, with the RF + 1 group not being significantly different from either group ( p  < 0.05). Overall, RF breathing appears to play an important role in the positive effect HRVB has on measures of HRV.

Religious service attendance predicts increased well-being across a number of studies. It is not clear, however, whether this relationship is due to religious factors such as intrinsic religiosity or due to nonreligious factors such as social support or socially desirable responding. The purpose of the present study was to examine the relationship between religious service attendance and well-being while simultaneously examining intrinsic religiosity, social support, and socially desirable responding as potential mediators of the relationship. A sample of 855 participants (71 % female, average age 19.5) completed questionnaires assessing religiosity, social support, socially desirable responding, and well-being. Path models were estimated using maximum likelihood estimation to analyze the data. Intrinsic religiosity was the strongest mediator of the relationship between religious service attendance and depressive and anxiety symptoms. This suggests that the mental health benefits of religious service attendance are not simply the result of increased social support or a certain response style on questionnaires; rather, it appears that the relationship is at least partly the result of people trying to live their religion in their daily lives.

Objective: Mexican immigrants have lower cardiovascular disease risk than US citizens, but risk increases with level of acculturation. Our study investigated whether job stress and financial strain would be related to inflammation (C-reactive protein), lipids, and blood pressure, and if they would play a role in the acculturation process in Mexican immigrants., Methods: A sample of 310 Mexican immigrants living in the United States were studied on measures of job stress, financial strain, acculturation, and cardiovascular disease risk factors (C-reactive protein, lipids, and blood pressure)., Results: Job instability, financial strain, and acculturation, were related to inflammation, but psychological demands and decision latitude were not related. Lipids and blood pressure were not related to the variables of interest. Body mass index (BMI) was related to both increased acculturation and inflammation, and when controlling for BMI, acculturation was no longer a significant predictor of inflammation. Job instability and financial strain remained significant predictors of inflammation after controlling for BMI, sex, and age. Job instability and financial strain were not related to acculturation, suggesting that these factors are significant stressors for both newly arrived and more established immigrants., Conclusions: Job instability and financial strain predict increased inflammation in Mexican immigrants but they do not play a role in the relationship between acculturation and C-reactive protein. The effects of acculturation on inflammation in this study were mediated by BMI.

An experimental study to examine the effects of CardioWaves interval training (CWIT) and continuous training (CT) on resting blood pressure, resting heart rate, and mind-body wellness. Fifty-two normotensive (blood pressure <120/80 mmHg), pre-hypertensive (120-139/80-89 mmHg), and hypertensive (>140/90 mmHg) participants were randomly assigned and equally divided between the CWIT and CT groups. Both groups participated in the assigned exercise protocol 30 minutes per day, four days per week for eight weeks. Resting blood pressure, resting heart rate, and mind-body wellness were measured pre- and post-intervention. A total of 47 participants (15 females and 32 males) were included in the analysis. The CWIT group had a non-significant trend of reduced systolic blood pressure (SBP) and increased diastolic blood pressure (DBP) while the CT group had a statistically significant decrease in awake SBP (p = 0.01) and total SBP (p = 0.01) and a non-significant decrease in DBP. With both groups combined, the female participants had a statistically significant decrease in awake SBP (p = 0.002), asleep SBP (p = 0.01), total SBP (p = 0.003), awake DBP (p = 0.02), and total DBP (p = 0.05). The male participants had an increase in SBP and DBP with total DBP showing a statistically significant increase (p = 0.05). Neither group had a consistent change in resting heart rate. Both groups showed improved mind-body wellness. CWIT and CT reduced resting blood pressure, with CT having a greater effect. Resting heart rate did not change in either group. Additionally, both CWIT and CT improved mind-body wellness.

The effects of religiosity on well-being appear to depend on religious orientation, with intrinsic orientation being related to positive outcomes and extrinsic orientation being related to neutral or negative outcomes. It is not clear, however, why intrinsic and extrinsic religiosity has the relationships they do. Self-determination theory may provide a useful framework of intrinsic and extrinsic aspirations that may help to answer this question. The purpose of the present study was to examine whether intrinsic and extrinsic religiosity would be related to intrinsic and extrinsic life aspirations. We hypothesized that intrinsic religiosity would be positively related to intrinsic life aspirations and negatively related with extrinsic life aspirations, and that extrinsic religiosity would be positively related to extrinsic life aspirations and negatively related to intrinsic aspirations, and that life aspirations would partially mediate the relationships between religious orientation and outcome. To study these hypotheses, a random national sample (total number of 425, average age of 52, 59 % female) completed the measures of religious orientation, life aspirations, affect, and life satisfaction. It was found that intrinsic religiosity was positively related to positive affect, life satisfaction, and intrinsic life aspirations and was negatively related to negative affect and extrinsic life aspirations. Extrinsic religiosity was positively related to extrinsic life aspirations and was not related to the intrinsic life aspirations. When both religious orientation and life aspiration variables were included together in the model predicting outcome, both remained significant indicating that religious orientation and life aspirations are independent predictors of outcome. In conclusion, although religious orientation and life aspirations are significantly related to each other and to outcome, life aspirations did not mediate the effects of religious orientation. Therefore, self-determination theory does not appear to completely account for the effects of religious orientation.

Religiosity is related to positive health and life satisfaction but the pathways through which this occurs have not been clearly delineated. The purpose of this study was to examine potential mediators of the relationships between intrinsic and extrinsic religiosity and negative affect and life satisfaction. Perfectionism and life aspirations are two possible pathways through which religious orientation is related to outcome. It was hypothesized that adaptive perfectionism and intrinsic life aspirations would act as mediators between intrinsic religiosity and negative affect and life satisfaction, and that maladaptive perfectionism and extrinsic life aspirations would act as mediators between the extrinsic religiosity and negative affect and life satisfaction. Two consecutive samples of religious college students (N = 540 and N = 485) completed measures of the Age Universal Religious Orientation Index, the Frost Multi-Dimensional Perfectionism Scale, the Aspiration Index, the Beck Depression Inventory-II, the Spielberger State-Trait Anxiety Inventory, and the Satisfaction with Life Scale. Intrinsic religiosity had a direct negative relationship with negative affect and positive relationship with life satisfaction. Contrary to the hypotheses, intrinsic religiosity had its strongest indirect effect via maladaptive perfectionism such that increased intrinsic religiosity was related to decreased maladaptive perfectionism which in turn lead to better negative affect and life satisfaction. Extrinsic religiosity was related to increased maladaptive perfectionism and thereby indirectly contributed to worse negative affect and life satisfaction. Interestingly, when the effects of maladaptive perfectionism were controlled, the direct effects of extrinsic religiosity were related to reduced negative affect and increased life satisfaction. Overall, the strongest mediator in this study of both intrinsic and extrinsic religiosity was maladaptive perfectionism, with intrinsic religiosity related to decreased maladaptive perfectionism and extrinsic religiosity related to increased maladaptive perfectionism.

Accumulating evidence indicates that psychotherapy participants show increased physiological responsiveness to stress. The purpose of the present study was to examine differences between individuals participating in outpatient psychotherapy and matched controls using an experimental design. Forty-two psychotherapy participants and 48 matched controls were assessed on cardiovascular and cortisol functioning at baseline, during the Trier Social Stress Test (TSST), and during a 20-min recovery period. Psychotherapy participants and matched controls did not differ at baseline or during the TSST on the physiological measures but psychotherapy participants had higher cortisol and heart rate (HR) during the recovery period. In regards to reactivity, cortisol increased during the recovery period for the psychotherapy participants but decreased for those in the matched control group. Psychotherapy participants experiencing clinically significant levels of distress displayed elevated systolic and diastolic blood pressure and HR during the TSST when compared to psychotherapy participants not experiencing clinically significant levels of distress. Overall, physiological reactivity to stress appears to be an important issue for those in psychotherapy and directly addressing this issue may help improve psychotherapy outcomes.

Meditation is associated with positive health behaviors and improved cognitive control. One mechanism for the relationship between meditation and cognitive control is changes in activity of the anterior cingulate cortex-mediated neural pathways. The error-related negativity (ERN) and error positivity (Pe) components of the scalp-recorded event-related potential (ERP) represent cingulate-mediated functions of performance monitoring that may be modulated by mindfulness meditation. We utilized a flanker task, an experimental design, and a brief mindfulness intervention in a sample of 55 healthy non-meditators (n = 28 randomly assigned to the mindfulness group and n = 27 randomly assigned to the control group) to examine autonomic nervous system functions as measured by blood pressure and indices of cognitive control as measured by response times, error rates, post-error slowing, and the ERN and Pe components of the ERP. Systolic blood pressure significantly differentiated groups following the mindfulness intervention and following the flanker task. There were non-significant differences between the mindfulness and control groups for response times, post-error slowing, and error rates on the flanker task. Amplitude and latency of the ERN did not differ between groups; however, amplitude of the Pe was significantly smaller in individuals in the mindfulness group than in the control group. Findings suggest that a brief mindfulness intervention is associated with reduced autonomic arousal and decreased amplitude of the Pe, an ERP associated with error awareness, attention, and motivational salience, but does not alter amplitude of the ERN or behavioral performance. Implications for brief mindfulness interventions and state vs. trait affect theories of the ERN are discussed. Future research examining graded levels of mindfulness and tracking error awareness will clarify relationship between mindfulness and performance monitoring.

Mexican Americans typically have better cardiovascular health than Caucasians, despite being relatively economically disadvantaged. Given research indicating the importance of relationship quality on one's health, our study examined whether certain relationship orientations (eg, communal or exchange) differed between Caucasians and Mexican Americans and if these orientations could help explain the Hispanic Paradox. We recruited 582 adults from a community being primarily Caucasian (40%) and foreign-born Mexican Americans (55%). Participants wore 24-hour ambulatory blood pressure (ABP) monitors and completed self-report measures of relationship satisfaction and relationship orientation. Results indicated that Caucasians tended to have more of a communal relationship orientation compared to foreign-born Mexican Americans. Communal orientation was predictive of higher relationship satisfaction and while higher relationship satisfaction predicted lower systolic blood pressure when ethnicity was added into the model this relationship was eliminated and foreign-born Mexican Americans had higher ABP compared to Caucasians. Even though communal and exchange relationship orientation don't seem to give us any more information to unravel the Hispanic Paradox, there are important ethnic differences in how we engage in marriage relationships and future research will need to examine the health effects of these differences.

Growing research has demonstrated a link between spiritual well-being and better health; however, little is known about possible physiological mechanisms. In a sample of highly religious healthy male and female adults (n = 100) ages 19-59 (m = 28.28) we examined the influence of spiritual well-being, as measured by the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being (FACIT-Sp-Ex), on physiological risk factors for heart disease. Specifically we examined 24-h ambulatory blood pressure (BP), inflammation (hs-C-reactive protein), fasting glucose, and blood lipids. Regression analyses reveal that higher levels of spiritual-wellness (total FACIT-Sp-Ex score) was significantly related to lower systolic ambulatory BP (β = -.345; P < .001), diastolic ambulatory BP (β = -.24; P = .02), hs-C-reactive protein (β = -.23; P = .04), fasting glucose (β = -.28; P = .006), and marginally lower triglycerides (β = -.21; P = .09) and VLDL (β = -.21; P = .10) controlling for age, gender, and church attendance. Results remained generally consistent across the Meaning, Peace, Faith and Additional Spiritual Concerns subscales of the FACIT-Sp-Ex. Spiritual well-being may be cardio protective.

Menopause represents an important life change, particularly for religious women whose identity is significantly related to family. Two competing hypotheses are examined: one, because religious women have their identity focused on family and child rearing, spirituality will be related to increased menopausal symptoms because menopause represents a loss of identity and purpose; and two, because spirituality can provide strength and comfort during difficult times, it will, therefore, be related to decreased menopausal symptoms. To test these competing hypotheses, questionnaires were administered to 218 women (average age 55, 35% premenopausal, 26% peri-menopausal, 39% postmenopausal) who were members of the Church of Jesus Christ of Latter Day Saints. Regression analyses indicated that higher levels of spiritual strength were related to decreased levels of reported menopausal symptoms. Spiritual strength was also related to increased benefit finding during menopause, decreased concern with body appearance, and increased use of adaptive coping strategies. We conclude that finding strength in spirituality may help religious women cope better with the life changes associated with menopause.

Objective: To determine whether the Social Role (SR) Scale of the Outcome Questionnaire (OQ) can predict work productivity., Methods: Employees at Utah State Hospital completed the OQ and the Work Productivity and Activity Impairment Scale (WPAI) once monthly for four months., Results: The SR predicted the WPAI Presenteeism and Activity Impairment scales., Conclusions: The SR can be used to estimate work productivity using tools like the Productivity Calculator. Specific relationships among measures and suggestions for future research are discussed.

A social gradient has been consistently demonstrated in Western countries with higher socioeconomic status (SES) related to lower blood pressure (BP). In non-Western countries, however, the social gradient is not always evident, with some countries appearing to show a reversed social gradient. It was hypothesized that culture moderates the social gradient, with the relationship between SES and BP differing as a function of culture. To investigate the idea of a "cultural gradient" a sample of Hispanic immigrants and Whites was studied. A total of 79 participants (30 Hispanic immigrant, 49 White) wore ambulatory blood pressure monitors for 24 h. The Hispanic immigrants also completed the Acculturation Rating Scale for Mexican Americans- II. Hispanic immigrants had lower SES and lower BP compared to Whites. A cultural gradient moderating the social gradient was evident with Hispanic immigrants displaying a positive relationship between SES and BP and Whites displaying a negative relationship. Among Hispanic immigrants, increased acculturation to Western culture decreased the positive relationship between SES and BP. Just as there is a social gradient with increasing socioeconomic status related to better cardiovascular health, there appears to be a cultural gradient with increasing acculturation to Western society related to worse cardiovascular health.