An Overview of Research on Acceptance and Commitment Therapy.

This review summarized recent systematic reviews and meta-analyses on randomized controlled trials evaluating acceptance and commitment therapy (ACT). Although the strength of evidence varies, overall there is plausible evidence for the efficacy of ACT for a wide range of areas including depression, anxiety disorders, obsessive-compulsive and related disorders, psychosis, substance use disorders, chronic pain, coping with chronic health conditions, obesity, stigma, and stress and burnout. ACT is also efficacious when delivered in digital self-help formats. Reviews of mediation research indicate ACT works through increasing psychological flexibility.

Self-Amputating and Interfusing Machines.

Biological organisms exhibit phenomenal adaptation through morphology-shifting mechanisms including self-amputation, regeneration, and collective behavior. For example, reptiles, crustaceans, and insects amputate their own appendages in response to threats. Temporary fusion between individuals enables collective behaviors, such as in ants that temporarily fuse to build bridges. The concept of morphological editing, involving the addition and subtraction of mass can be linked to modular robotics, wherein synthetic body morphology may be revised by rearranging parts. In this work, we  introduce a reversible cohesive interface made of thermoplastic elastomer that allows for strong attachment and easy detachment of distributed soft robot modules without direct human handling. The reversible joint boasts a modulus similar to materials commonly used in soft robotics, and can thus be distributed throughout soft robot bodies without introducing mechanical incongruities. To demonstrate utility, we  exploit the reversible joint in two embodiments: a soft quadruped robot that self-amputates a limb when stuck, and a cluster of three soft-crawling robots that fuse to cross a land-gap. This work points toward future robots capable of radical shape-shifting via changes in mass through autotomy and interfusion, as well as highlighting the crucial role that interfacial stiffness change plays in autotomizable biological and artificial systems. This article is protected by copyright. All rights reserved.

Aging as a loss of morphostatic information: A developmental bioelectricity perspective.

Maintaining order at the tissue level is crucial throughout the lifespan, as failure can lead to cancer and an accumulation of molecular and cellular disorders. Perhaps, the most consistent and pervasive result of these failures is aging, which is characterized by the progressive loss of function and decline in the ability to maintain anatomical homeostasis and reproduce. This leads to organ malfunction, diseases, and ultimately death. The traditional understanding of aging is that it is caused by the accumulation of molecular and cellular damage. In this article, we propose a complementary view of aging from the perspective of endogenous bioelectricity which has not yet been integrated into aging research. We propose a view of aging as a morphostasis defect, a loss of biophysical prepattern information, encoding anatomical setpoints used for dynamic tissue and organ homeostasis. We hypothesize that this is specifically driven by abrogation of the endogenous bioelectric signaling that normally harnesses individual cell behaviors toward the creation and upkeep of complex multicellular structures in vivo. Herein, we first describe bioelectricity as the physiological software of life, and then identify and discuss the links between bioelectricity and life extension strategies and age-related diseases. We develop a bridge between aging and regeneration via bioelectric signaling that suggests a research program for healthful longevity via morphoceuticals. Finally, we discuss the broader implications of the homologies between development, aging, cancer and regeneration and how morphoceuticals can be developed for aging.

Antibody-Mediated Depletion of Autoreactive T Lymphocytes through PD-1 Improves Disease Outcomes and Visualizes T Cell Activation in Experimental Autoimmune Encephalomyelitis.

Long-term therapeutic outcomes of multiple sclerosis (MS) remain hindered by the chronic nature of immune cell stimulation toward self-antigens. Development of novel methods to target and deplete autoreactive T lymphocytes remains an attractive target for therapeutics for MS. We developed a programmed cell death 1 (PD-1)-targeted radiolabeled mAb and assessed its ability to deplete activated PD-1+ T lymphocytes in vitro and its ability to reduce disease burden of the myelin oligodendrocyte glycoprotein 35-55 experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice. We also investigated the upregulation of PD-1 on infiltrating lymphocytes in an animal model of MS. Finally, we demonstrate the (to our knowledge) first reported positron-emission tomography/computed tomography imaging of activated PD-1+ cells in the EAE animal model of MS. We found that the 177Lu radioisotope-labeled anti-PD-1 mAb demonstrated significant in vitro cytotoxicity toward activated CD4+PD-1+ T lymphocytes and led to significant reduction in overall disease progression in the EAE animal model. Our results show high expression of PD-1 on infiltrating lymphocytes in the spinal cords of EAE diseased animals. Positron-emission tomography/computed tomography imaging of the anti-PD-1 mAb demonstrated significant uptake in the cervical draining lymph nodes highlighting accumulation of activated lymphocytes. Targeted depletion of T lymphocytes using T cell activation markers such as PD-1 may present a novel method to reduce autoimmune attack and inflammation in autoimmune diseases such as MS. Development of multimodal nuclear theranostic agents may present the opportunity to monitor T cell activation via imaging radioisotopes and simultaneously treat MS using therapeutic radioisotopes.

Recommendations for asthma monitoring in children: A PeARL document endorsed by APAPARI, EAACI, INTERASMA, REG, and WAO.

Monitoring is a major component of asthma management in children. Regular monitoring allows for diagnosis confirmation, treatment optimization, and natural history review. Numerous factors that may affect disease activity and patient well-being need to be monitored: response and adherence to treatment, disease control, disease progression, comorbidities, quality of life, medication side-effects, allergen and irritant exposures, diet and more. However, the prioritization of such factors and the selection of relevant assessment tools is an unmet need. Furthermore, rapidly developing technologies promise new opportunities for closer, or even "real-time," monitoring between visits. Following an approach that included needs assessment, evidence appraisal, and Delphi consensus, the PeARL Think Tank, in collaboration with major international professional and patient organizations, has developed a set of 24 recommendations on pediatric asthma monitoring, to support healthcare professionals in decision-making and care pathway design.

Electroceuticals: emerging applications beyond the nervous system and excitable tissues.

Electroceuticals have evolved beyond devices manipulating neuronal signaling for symptomatic treatment, becoming more precise and disease modulating and expanding beyond the nervous system. These advancements promise transformative applications in arthritis, cancer treatment, tissue regeneration, and more. Here, we discuss these recent advances and offer insights for future research.

Unraveling the Enigma of Organismal Death: Insights, Implications, and Frontiers.

Significant knowledge gaps exist regarding the responses of cells, tissues, and organs to organismal death. Examining the survival mechanisms influenced by metabolism and environment, this research has the potential to transform regenerative medicine, redefine legal death, and provide insights into life's physiological limits, paralleling inquiries in embryogenesis.

The energetics of cellular life transitions.

Major life transitions are always difficult because change costs energy. Recent findings have demonstrated how mitochondrial oxidative phosphorylation (OxPhos) defects increase the energetic cost of living, and that excessive integrated stress response (ISR) signaling may prevent cellular identity transitions during development. In this perspective, we discuss general bioenergetic principles of life transitions and the costly molecular processes involved in reprograming the cellular hardware/software as cells shift identity. The energetic cost of cellular differentiation has not been directly quantified, representing a gap in knowledge. We propose that the ISR is an energetic checkpoint evolved to i) prevent OxPhos-deficient cells from engaging in excessively costly transitions, and ii) allow ISR-positive cells to recruit systemic energetic resources by signaling via the brain.

Examining processes of change for acceptance and commitment therapy and cognitive behavioral therapy self-help books with depressed college students.

Given the prevalence of depression, it is worthwhile to consider a variety of treatment approaches to reach as many sufferers as possible, including highly accessible formats such as self-help books. Books based in acceptance and commitment therapy (ACT) and cognitive behavioral therapy (CBT) propose to treat depression through distinct processes of change, though the degree to which these treatments are distinguishable in this format is unclear. Furthermore, it is possible that some individuals may respond better to therapeutic processes from one approach over the other based on personal preferences. We tested the effects of ACT and CBT self-help books on processes of change in a sample of 139 depressed college students in which some participants were given a choice of treatment and others were randomized. Cognitive fusion, which improved better in the ACT group, was the only process of change that distinguished the two treatments. Additionally, early improvements in cognitive fusion were associated with less depression-related stigma at posttreatment. Lastly, randomization, instead of choosing a treatment, led to greater improvements in almost all processes of change. We discuss how these findings inform personalized care, tangible differences between ACT and CBT, and effective practices for treating depression at large scale.

Predictors of adherence to a publicly available self-guided digital mental health intervention.

Low adherence to self-guided digital mental health interventions (DMHIs) have raised concerns about their real-world effectiveness. Naturalistic data from self-guided DMHIs are often not available, hindering our ability to assess adherence among real-world users. This study aimed to analyze 3 years of user data from the public launch of an empirically supported 12-session self-guided DMHI, to assess overall program adherence rates and explore predictors of adherence. Data from 984 registered users were analyzed. Results showed that only 14.8% of users completed all 12 modules and 68.6% completed less than half of the modules. Users who were younger, had milder depression, had never seen a mental health provider, and who rejected signing-up for weekly program emails completed significantly more modules. Results add to concerns about the generalizability of controlled research on DMHIs due to lower adherence outside of research trials. This study highlights the potential of user data in identifying key factors that may be related to adherence. By examining adherence patterns among different sub-sets of users, we can pinpoint and focus on individuals who may adhere and benefit more from self-guided programs. Findings could also have implications for guiding intervention personalization for individuals who struggle to complete DMHIs.

Principled Limitations on Self-Representation for Generic Physical Systems.

The ideas of self-observation and self-representation, and the concomitant idea of self-control, pervade both the cognitive and life sciences, arising in domains as diverse as immunology and robotics. Here, we ask in a very general way whether, and to what extent, these ideas make sense. Using a generic model of physical interactions, we prove a theorem and several corollaries that severely restrict applicable notions of self-observation, self-representation, and self-control. We show, in particular, that adding observational, representational, or control capabilities to a meta-level component of a system cannot, even in principle, lead to a complete meta-level representation of the system as a whole. We conclude that self-representation can at best be heuristic, and that self models cannot, in general, be empirically tested by the systems that implement them.

Collective intelligence: A unifying concept for integrating biology across scales and substrates.

A defining feature of biology is the use of a multiscale architecture, ranging from molecular networks to cells, tissues, organs, whole bodies, and swarms. Crucially however, biology is not only nested structurally, but also functionally: each level is able to solve problems in distinct problem spaces, such as physiological, morphological, and behavioral state space. Percolating adaptive functionality from one level of competent subunits to a higher functional level of organization requires collective dynamics: multiple components must work together to achieve specific outcomes. Here we overview a number of biological examples at different scales which highlight the ability of cellular material to make decisions that implement cooperation toward specific homeodynamic endpoints, and implement collective intelligence by solving problems at the cell, tissue, and whole-organism levels. We explore the hypothesis that collective intelligence is not only the province of groups of animals, and that an important symmetry exists between the behavioral science of swarms and the competencies of cells and other biological systems at different scales. We then briefly outline the implications of this approach, and the possible impact of tools from the field of diverse intelligence for regenerative medicine and synthetic bioengineering.

Host gene expression signatures to identify infection type and organ dysfunction in children evaluated for sepsis: a multicentre cohort study.

BACKGROUND: Sepsis is defined as dysregulated host response to infection that leads to life-threatening organ dysfunction. Biomarkers characterising the dysregulated host response in sepsis are lacking. We aimed to develop host gene expression signatures to predict organ dysfunction in children with bacterial or viral infection. METHODS: This cohort study was done in emergency departments and intensive care units of four hospitals in Queensland, Australia, and recruited children aged 1 month to 17 years who, upon admission, underwent a diagnostic test, including blood cultures, for suspected sepsis. Whole-blood RNA sequencing of blood was performed with Illumina NovaSeq (San Diego, CA, USA). Samples with completed phenotyping, monitoring, and RNA extraction by March 31, 2020, were included in the discovery cohort; samples collected or completed thereafter and by Oct 27, 2021, constituted the Rapid Paediatric Infection Diagnosis in Sepsis (RAPIDS) internal validation cohort. An external validation cohort was assembled from RNA sequencing gene expression count data from the observational European Childhood Life-threatening Infectious Disease Study (EUCLIDS), which recruited children with severe infection in nine European countries between 2012 and 2016. Feature selection approaches were applied to derive novel gene signatures for disease class (bacterial vs viral infection) and disease severity (presence vs absence of organ dysfunction 24 h post-sampling). The primary endpoint was the presence of organ dysfunction 24 h after blood sampling in the presence of confirmed bacterial versus viral infection. Gene signature performance is reported as area under the receiver operating characteristic curves (AUCs) and 95% CI. FINDINGS: Between Sept 25, 2017, and Oct 27, 2021, 907 patients were enrolled. Blood samples from 595 patients were included in the discovery cohort, and samples from 312 children were included in the RAPIDS validation cohort. We derived a ten-gene disease class signature that achieved an AUC of 94·1% (95% CI 90·6-97·7) in distinguishing bacterial from viral infections in the RAPIDS validation cohort. A ten-gene disease severity signature achieved an AUC of 82·2% (95% CI 76·3-88·1) in predicting organ dysfunction within 24 h of sampling in the RAPIDS validation cohort. Used in tandem, the disease class and disease severity signatures predicted organ dysfunction within 24 h of sampling with an AUC of 90·5% (95% CI 83·3-97·6) for patients with predicted bacterial infection and 94·7% (87·8-100·0) for patients with predicted viral infection. In the external EUCLIDS validation dataset (n=362), the disease class and disease severity predicted organ dysfunction at time of sampling with an AUC of 70·1% (95% CI 44·1-96·2) for patients with predicted bacterial infection and 69·6% (53·1-86·0) for patients with predicted viral infection. INTERPRETATION: In children evaluated for sepsis, novel host transcriptomic signatures specific for bacterial and viral infection can identify dysregulated host response leading to organ dysfunction. FUNDING: Australian Government Medical Research Future Fund Genomic Health Futures Mission, Children's Hospital Foundation Queensland, Brisbane Diamantina Health Partners, Emergency Medicine Foundation, Gold Coast Hospital Foundation, Far North Queensland Foundation, Townsville Hospital and Health Services SERTA Grant, and Australian Infectious Diseases Research Centre.

Evaluation of Plasma Biomarkers for Causal Association With Peripheral Artery Disease.

BACKGROUND: Hundreds of biomarkers for peripheral artery disease (PAD) have been reported in the literature; however, the observational nature of these studies limits causal inference due to the potential of reverse causality and residual confounding. We sought to evaluate the potential causal impact of putative PAD biomarkers identified in human observational studies through genetic causal inference methods. METHODS: Putative circulating PAD biomarkers were identified from human observational studies through a comprehensive literature search based on terms related to PAD using PubMed, Cochrane, and Embase. Genetic instruments were generated from publicly available genome-wide association studies of circulating biomarkers. Two-sample Mendelian randomization was used to test the association of genetically determined biomarker levels with PAD using summary statistics from a genome-wide association study of 31 307 individuals with and 211 753 individuals without PAD in the Veterans Affairs Million Veteran Program and replicated in data from FinnGen comprised of 11 924 individuals with and 288 638 individuals without PAD. RESULTS: We identified 204 unique circulating biomarkers for PAD from the observational literature, of which 173 were genetically instrumented using genome-wide association study results. After accounting for multiple testing (false discovery rate, <0.05), 10 of 173 (5.8%) biomarkers had significant associations with PAD. These 10 biomarkers represented categories including plasma lipoprotein regulation, lipid homeostasis, and protein-lipid complex remodeling. Observational literature highlighted different pathways including inflammatory response, negative regulation of multicellular organismal processes, and regulation of response to external stimuli. CONCLUSIONS: Integrating human observational studies and genetic causal inference highlights several key pathways in PAD pathophysiology. This work demonstrates that a substantial portion of biomarkers identified in observational studies are not well supported by human genetic evidence and emphasizes the importance of triangulating evidence to understand PAD pathophysiology. Although the identified biomarkers offer insights into atherosclerotic development in the lower limb, their specificity to PAD compared with more widespread atherosclerosis requires further study.

"Bioelectricity in Development, Regeneration, and Cancers" Cell Bio 2023: A Joint Meeting of the American Society of Cell Biology and European Molecular Biology Organization December 2-6, 2023, in Boston, MA, USA.

Cell Bio conferences-organized jointly by the American Society of Cell Biology (ASCB) and European Molecular Biology Organization (EMBO)-showcase a diverse global community of the brightest researchers in Cell Biology and in emerging interdisciplinary topics, including bioelectricity. In this report, we briefly overview the Cell Bio 2023 subgroup meeting "Bioelectricity in Development, Regeneration, and Cancers." This subgroup meeting featured 12 talks (7 Principal Investigators and 5 junior scientists) exploring the role of bioelectricity in endogenous and diseased states in model systems ranging from cells in culture to single-cell organisms such as yeast all the way to mammalian systems (including tools and technology developed for exploring bioelectricity and electrotaxis in cells and tissues). The subgroup meeting concluded with a discussion on the current challenges and opportunities for the field of bioelectricity.

Proteomic Associations of Adverse Outcomes in Human Heart Failure.

BACKGROUND: Identifying novel molecular drivers of disease progression in heart failure (HF) is a high-priority goal that may provide new therapeutic targets to improve patient outcomes. The authors investigated the relationship between plasma proteins and adverse outcomes in HF and their putative causal role using Mendelian randomization. METHODS AND RESULTS: The authors measured 4776 plasma proteins among 1964 participants with HF with a reduced left ventricular ejection fraction enrolled in PHFS (Penn Heart Failure Study). Assessed were the observational relationship between plasma proteins and (1) all-cause death or (2) death or HF-related hospital admission (DHFA). The authors replicated nominally significant associations in the Washington University HF registry (N=1080). Proteins significantly associated with outcomes were the subject of 2-sample Mendelian randomization and colocalization analyses. After correction for multiple testing, 243 and 126 proteins were found to be significantly associated with death and DHFA, respectively. These included small ubiquitin-like modifier 2 (standardized hazard ratio [sHR], 1.56; P<0.0001), growth differentiation factor-15 (sHR, 1.68; P<0.0001) for death, A disintegrin and metalloproteinase with thrombospondin motifs-like protein (sHR, 1.40; P<0.0001), and pulmonary-associated surfactant protein C (sHR, 1.24; P<0.0001) for DHFA. In pathway analyses, top canonical pathways associated with death and DHFA included fibrotic, inflammatory, and coagulation pathways. Genomic analyses provided evidence of nominally significant associations between levels of 6 genetically predicted proteins with DHFA and 11 genetically predicted proteins with death. CONCLUSIONS: This study implicates multiple novel proteins in HF and provides preliminary evidence of associations between genetically predicted plasma levels of 17 candidate proteins and the risk for adverse outcomes in human HF.

Rickettsia species identified in adult, host-seeking Dermacentor occidentalis (Acari: Ixodidae) from Baja California, Mexico, and Oregon and Washington, United States.

The Pacific Coast tick (Dermacentor occidentalis Marx, 1892) is a frequently encountered and commonly reported human-biting tick species that has been recorded from most of California and parts of southwestern Oregon, southcentral Washington, and northwestern Mexico. Although previous investigators have surveyed populations of D. occidentalis for the presence of Rickettsia species across several regions of California, populations of this tick have not been surveyed heretofore for rickettsiae from Baja California, Oregon, or Washington. We evaluated 1,367 host-seeking, D. occidentalis adults collected from 2015 to 2022 by flagging vegetation at multiple sites in Baja California, Mexico, and Oregon and Washington, United States, using genus- and species-specific assays for spotted fever group rickettsiae. DNA of Rickettsia 364D, R. bellii, and R. tillamookensis was not detected in specimens from these regions. DNA of R. rhipicephali was detected in D. occidentalis specimens obtained from Ensenada Municipality in Baja California and southwestern Oregon, but not from Washington. All ompA sequences of R. rhipichephali that were amplified from individual ticks in southwestern Oregon were represented by a single genotype. DNA of the Ixodes pacificus rickettsial endosymbiont was amplified from specimens collected in southwestern Oregon and Klickitat County, Washington; to the best of our knowledge, this Rickettsia species has never been identified in D. occidentalis. Collectively, these data are consistent with a relatively recent introduction of Pacific Coast ticks in the northernmost extension of its recognized range.