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Electrically conductive polymeric materials have recently garnered significant interest from researchers due to their potential applications in the biomedical field, including medical implants, tissue engineering, flexible electronic devices, and biosensors. Poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) is considered the most successful conducting polymer due to its higher electrical conductivity and chemical stability, but it suffers from limited solubility in common organic solvents, poor mechanical properties, and low biocompatibility. An area of tremendous interest is in combining PEDOT:PSS with another polymer to form a blend or composite material in order to access the beneficial properties of both materials. However, the hydrophilic nature of PEDOT:PSS makes it difficult to produce composites with non-polar polymers. In order to overcome these problems, we have specifically designed and synthesized two new sulfonated polyurethanes (PUS) with high sulfonic acid functionality. The two polyurethanes, one water-soluble (PUS1) and one water-insoluble (PUS2), were used to make blends with two commercially available PEDOT:PSS formulations (CleviosTM FET and PH1000). Solvent cast films on glass substrates were made from water-soluble PEDOT:PSS/PUS1 blends while free-standing films of PEDOT:PSS/PUS2 blends were fabricated by compression-moulding. Ethylene glycol was used as conductivity enhancer, which showed an increase in the conductivity by several orders of magnitude in most of the compositions investigated. The highest conductivity of 438 S cm−1 was achieved for the blend with 80 wt% of PEDOT:PSS (PH1000) in PUS1.

Abstract Although liver transplantation (LT) is an effective therapy for cirrhosis, the risk of post-LT NASH is alarmingly high and is associated with accelerated progression to fibrosis/cirrhosis, cardiovascular disease and decreased survival. Lack of risk stratification strategies hampers early intervention against development of post-LT NASH fibrosis. The liver undergoes significant remodeling during inflammatory injury. During such remodeling, degraded peptide fragments (i.e., ‘degradome’) of the ECM and other proteins increase in plasma, making it a useful diagnostic/prognostic tool in chronic liver disease. To investigate whether liver injury caused by post-LT NASH would yield a unique degradome profile that is predictive of severe post-LT NASH fibrosis, a retrospective analysis of 22 biobanked samples from the Starzl Transplantation Institute (12 with post-LT NASH after 5 years and 10 without) was performed. Total plasma peptides were isolated and analyzed by 1D-LC–MS/MS analysis using a Proxeon EASY-nLC 1000 UHPLC and nanoelectrospray ionization into an Orbitrap Elite mass spectrometer. Qualitative and quantitative peptide features data were developed from MSn datasets using PEAKS Studio X (v10). LC–MS/MS yielded ~ 2700 identifiable peptide features based on the results from Peaks Studio analysis. Several peptides were significantly altered in patients that later developed fibrosis and heatmap analysis of the top 25 most significantly changed peptides, most of which were ECM-derived, clustered the 2 patient groups well. Supervised modeling of the dataset indicated that a fraction of the total peptide signal (~ 15%) could explain the differences between the groups, indicating a strong potential for representative biomarker selection. A similar degradome profile was observed when the plasma degradome patterns were compared being obesity sensitive (C57Bl6/J) and insensitive (AJ) mouse strains. The plasma degradome profile of post-LT patients yielded stark difference based on later development of post-LT NASH fibrosis. This approach could yield new “fingerprints” that can serve as minimally-invasive biomarkers of negative outcomes post-LT.

Efficient repair of skeletal muscle relies upon the precise coordination of cells between the satellite cell niche and innate immune cells that are recruited to the site of injury. The expression of pro-inflammatory cytokines and chemokines such as TNFα, IFNγ, CXCL1, and CCL2, by muscle and tissue resident immune cells recruits neutrophils and M1 macrophages to the injury and activates satellite cells. These signal cascades lead to highly integrated temporal and spatial control of muscle repair. Despite the therapeutic potential of these factors for improving tissue regeneration after traumatic and chronic injuries, their transcriptional regulation is not well understood. The transcription factor Mohawk (Mkx) functions as a repressor of myogenic differentiation and regulates fiber type specification. Embryonically, Mkx is expressed in all progenitor cells of the musculoskeletal system and is expressed in human and mouse myeloid lineage cells. An analysis of mice deficient for Mkx revealed a delay in postnatal muscle repair characterized by impaired clearance of necrotic fibers and smaller newly regenerated fibers. Further, there was a delay in the expression of inflammatory signals such as Ccl2, Ifnγ, and Tgfß. This was coupled with impaired recruitment of pro-inflammatory macrophages to the site of muscle damage. These studies demonstrate that Mkx plays a critical role in adult skeletal muscle repair that is mediated through the initial activation of the inflammatory response.

Abstract The correct spatio-temporal organization of the proteome is essential for cellular homeostasis. However, a detailed mechanistic understanding of this organization and how it is altered in response to external stimuli in the intact cellular environment is as-yet unrealized. ‘Protein painting methods provide a means to address this gap in knowledge by monitoring the conformational status of proteins within cells at the proteome-wide scale. Here, we demonstrate the ability of a protein painting method employing tetraphenylethene maleimide (TPE-MI) to reveal proteome network remodeling in whole cells in response to a cohort of commonly used pharmacological stimuli of varying specificity. We report specific, albeit heterogeneous, responses to individual stimuli that coalesce on a conserved set of core cellular machineries. This work expands our understanding of proteome conformational remodeling in response to cellular stimuli, and provides a blueprint for assessing how these conformational changes may contribute to disorders characterized by proteostasis imbalance.

Proteomics can define features of proteome foldedness by assessing the reactivity of surface exposed amino acids. Here, the authors show that such exposure patterns yield insight to structural changes in chaperones as they bind to unfolded proteins in urea-denatured mammalian cell lysate.

Many countries have started their transition to a net-zero economy. Lithium-ion batteries (LIBs) play an ever-increasing role towards this transition as a rechargeable energy storage medium. Initially, LIBs were developed for consumer electronics and portable devices but have seen dramatic growth in their use in electric vehicles (EVs) and via the gradual uptake in battery energy storage systems (BESSs) over the last decade. As such, critical metals (Li, Co, Ni, and Mn) and chemicals (polymers, electrolytes, Cu, Al, PVDF, LiPF6, LiBF4, and graphite) needed for LIBs are currently in great demand and are susceptible to global supply shortages. Dramatic increases in raw material prices, coupled with predicted exponential growth in global demand (e.g., United States graphite demand from 2022 7000 t to ~145,000 t), means that LIBs will not be sustainable if only sourced from raw materials. LIBs degrade over time. When their performance can no longer meet the requirement of their intended application (e.g., EVs in the 8–12 year range), opportunities exist to extract and recover battery materials for re-use in new batteries or to supply other industrial chemical sectors. This paper compares the challenges, barriers, opportunities, and successes of the United States of America and Australia as they transition to renewable energy storage and develop a battery supply chain to support a circular economy around LIBs.

Although most work has focused on resolution of collagen ECM, fibrosis resolution involves changes to several ECM proteins. The purpose of the current study was twofold: 1) to examine the role of MMP12 and elastin; and 2) to investigate the changes in degraded proteins in plasma (i.e., the “degradome”) in a preclinical model of fibrosis resolution. Fibrosis was induced by 4 weeks carbon tetrachloride (CCl4) exposure, and recovery was monitored for an additional 4 weeks. Some mice were treated with daily MMP12 inhibitor (MMP408) during the resolution phase. Liver injury and fibrosis was monitored by clinical chemistry, histology and gene expression. The release of degraded ECM peptides in the plasma was analyzed using by 1D-LC-MS/MS, coupled with PEAKS Studio (v10) peptide identification. Hepatic fibrosis and liver injury rapidly resolved in this mouse model. However, some collagen fibrils were still present 28d after cessation of CCl4. Despite this persistent collagen presence, expression of canonical markers of fibrosis were also normalized. The inhibition of MMP12 dramatically delayed fibrosis resolution under these conditions. LC-MS/MS analysis identified that several proteins were being degraded even at late stages of fibrosis resolution. Calpains 1/2 were identified as potential new proteases involved in fibrosis resolution. CONCLUSION. The results of this study indicate that remodeling of the liver during recovery from fibrosis is a complex and highly coordinated process that extends well beyond the degradation of the collagenous scar. These results also indicate that analysis of the plasma degradome may yield new insight into the mechanisms of fibrosis recovery, and by extension, new “theragnostic” targets. Lastly, a novel potential role for calpain activation in the degradation and turnover of proteins was identified.

Occupational and environmental exposures to industrial chemicals are well known to cause hepatotoxicity and liver injury. However, despite extensive evidence showing that exposure can lead to disease, current research approaches and regulatory policies fail to address the possibility that subtle changes caused by low level exposure to chemicals may also enhance preexisting conditions. In recent years, the conceptual understanding of the contribution of environmental chemicals to liver disease has progressed significantly. Mitochondria are often target of toxicity of environmental toxicants resulting in multisystem disorders involving different cells, tissues, and organs. Here, we review persistent maladaptive changes to mitochondria in response to environmental toxicant exposure as a mechanism of hepatotoxicity. With better understanding of the mechanism(s) and risk factors that mediate the initiation and progression of toxicant-induced liver disease, rational targeted therapy can be developed to better predict risk, as well as to treat or prevent this disease.

Liver diseases are considered to predominantly possess an inherited or xenobiotic etiology. However, inheritance drives the ability to appropriately adapt to environmental stressors, and disease is the culmination of a maladaptive response. Thus “pure” genetic and “pure” xenobiotic liver diseases are modified by each other and other factors, identified or unknown. The purpose of this review is to highlight the knowledgebase of environmental exposure as a potential risk modifying agent for the development of liver disease by other causes. This exercise is not to argue that all liver diseases have an environmental component, but to challenge the assumption that the current state of our knowledge is sufficient in all cases to conclusively dismiss this as a possibility. This review also discusses key new tools and approaches that will likely be critical to address this question in the future. Taken together, identifying the key gaps in our understanding is critical for the field to move forward, or at the very least to “know what we don't know.”

Recent reports have clearly demonstrated a tight correlation between obesity and elevated circulating uric acid levels (hyperuricemia). However, nearly all preclinical work in this area has been completed with male mice, leaving the field with a considerable gap in knowledge regarding female responses to obesity and hyperuricemia. This deficiency in sex as a biological variable extends beyond unknowns regarding uric acid (UA) to several important comorbidities associated with obesity including nonalcoholic fatty liver disease (NAFLD). To attempt to address this issue, herein we describe both phenotypic and metabolic responses to diet-induced obesity (DIO) in female mice. Six-week-old female C57BL/6J mice were fed a high-fat diet (60% calories derived from fat) for 32 weeks. The DIO female mice had significant weight gain over the course of the study, higher fasting blood glucose, impaired glucose tolerance, and elevated plasma insulin levels compared to age-matched on normal chow. While these classic indices of DIO and NAFLD were observed such as increased circulating levels of ALT and AST, there was no difference in circulating UA levels. Obese female mice also demonstrated increased hepatic triglyceride (TG), cholesterol, and cholesteryl ester. In addition, several markers of hepatic inflammation were significantly increased. Also, alterations in the expression of redox-related enzymes were observed in obese mice compared to lean controls including increases in extracellular superoxide dismutase (Sod3), heme oxygenase (Ho)-1, and xanthine dehydrogenase (Xdh). Interestingly, hepatic UA levels were significantly elevated (∼2-fold) in obese mice compared to their lean counterparts. These data demonstrate female mice assume a similar metabolic profile to that reported in several male models of obesity in the context of alterations in glucose tolerance, hepatic steatosis, and elevated transaminases (ALT and AST) in the absence of hyperuricemia affirming the need for further study.

Many parasitic worms have a major adverse impact on human and animal populations worldwide due to the chronicity of their infections. There is a growing body of evidence indicating that extracellular vesicles (EVs) are intimately involved in modulating (suppressing) inflammatory/immune host responses and parasitism. As one of the most pathogenic nematodes of livestock animals, Haemonchus contortus is an ideal model system for EV exploration. Here, employing a multi-step enrichment process (in vitro culture, followed by ultracentrifugation, size exclusion and filtration), we enriched EVs from H. contortus and undertook the first comprehensive (qualitative and quantitative) multi-omic investigation of EV proteins and lipids using advanced liquid chromatography–mass spectrometry and informatics methods. We identified and quantified 561 proteins and 446 lipids in EVs and compared these molecules with those of adult worms. We identified unique molecules in EVs, such as proteins linked to lipid transportation and lipid species (i.e., sphingolipids) associated with signalling, indicating the involvement of these molecules in parasite-host cross-talk. This work provides a solid starting point to explore the functional roles of EV-specific proteins and lipids in modulating parasite-host cross-talk, and the prospect of finding ways of disrupting or interrupting this relationship to suppress or eliminate parasite infection.

BackgroundIt has been identified that military veterans have distinct experiences of loneliness and social isolation and, when comparing this community to other client groups with a PTSD diagnosis, veterans respond less favorably to treatment. However, the link between PTSD and loneliness for veterans remains insufficiently researched and it is unclear if there are effective interventions tackling this distinct experience of loneliness.AimsThis systematic narrative review aimed to synthesize existing evidence incorporating elements of social connection, social isolation, and loneliness within interventions for military veterans with a diagnosis of PTSD, consequently aiming to examine the impact of such interventions upon this community.MethodsSix databases were searched, utilizing relevant search criteria, with no date restrictions. Articles were included if they involved intervention or treatment for military veterans with PTSD and considered elements of social connection, social isolation, and/or loneliness. The initial search returned 202 papers. After exclusions, removal of duplications, and a reference/citation search, 28 papers remained and were included in this review.ResultsFrom the 28 studies, 11 directly addressed social isolation and two studies directly addressed loneliness. Six themes were generated: (i) rethinking the diagnosis of PTSD, (ii) holistic interventions, (iii) peer support, (iv) social reintegration, (v) empowerment through purpose and community, and (vi) building trust.ConclusionsA direct focus upon social reintegration and engagement, psychosocial functioning, building trust, peer support, group cohesiveness and empowerment through a sense of purpose and learning new skills may mitigate experiential loneliness and social isolation for veterans with PTSD. Future research and practice should further explore the needs of the PTSD-diagnosed veteran community, seek to explore and identify potential common routes toward the development of PTSD within this community and consider bespoke interventions for tackling loneliness.

As an adaptive survival response to exogenous stress, bacteria undergo dynamic remodelling of their lipid metabolism pathways to alter the composition of their cellular membranes. Here, using Escherichia coli as a well characterised model system, we report the development and application of a ‘multi-omics’ strategy for comprehensive quantitative analysis of the temporal changes in the lipidome and proteome profiles that occur under exponential growth phase versus stationary growth phase conditions i.e., nutrient depletion stress. Lipidome analysis performed using ‘shotgun’ direct infusion-based ultra-high resolution accurate mass spectrometry revealed a quantitative decrease in total lipid content under stationary growth phase conditions, along with a significant increase in the mol% composition of total cardiolipin, and an increase in ‘odd-numbered’ acyl-chain length containing glycerophospholipids. The inclusion of field asymmetry ion mobility spectrometry was shown to enable the enrichment and improved depth of coverage of low-abundance cardiolipins, while ultraviolet photodissociation-tandem mass spectrometry facilitated more complete lipid structural characterisation compared with conventional collision-induced dissociation, including unambiguous assignment of the odd-numbered acyl-chains as containing cyclopropyl modifications. Proteome analysis using data-dependent acquisition nano-liquid chromatography mass spectrometry and tandem mass spectrometry analysis identified 83% of the predicted E. coli lipid metabolism enzymes, which enabled the temporal dependence associated with the expression of key enzymes responsible for the observed adaptive lipid metabolism to be determined, including those involved in phospholipid metabolism (e.g., ClsB and Cfa), fatty acid synthesis (e.g., FabH) and degradation (e.g., FadA/B,D,E,I,J and M), and proteins involved in the oxidative stress response resulting from the generation of reactive oxygen species during β-oxidation or lipid degradation.

Electrically conductive polymeric materials have recently garnered significant interest from researchers due to their potential applications in the biomedical field, including medical implants, tissue engineering, flexible electronic devices, and biosensors. Poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) is considered the most successful conducting polymer due to its higher electrical conductivity and chemical stability, but it suffers from limited solubility in common organic solvents, poor mechanical properties, and low biocompatibility. An area of tremendous interest is in combining PEDOT:PSS with another polymer to form a blend or composite material in order to access the beneficial properties of both materials. However, the hydrophilic nature of PEDOT:PSS makes it difficult to produce composites with non-polar polymers. In order to overcome these problems, we have specifically designed and synthesized two new sulfonated polyurethanes (PUS) with high sulfonic acid functionality. The two polyurethanes, one water-soluble (PUS1) and one water-insoluble (PUS2), were used to make blends with two commercially available PEDOT:PSS formulations (CleviosTM FET and PH1000). Solvent cast films on glass substrates were made from water-soluble PEDOT:PSS/PUS1 blends while free-standing films of PEDOT:PSS/PUS2 blends were fabricated by compression-moulding. Ethylene glycol was used as conductivity enhancer, which showed an increase in the conductivity by several orders of magnitude in most of the compositions investigated. The highest conductivity of 438 S cm−1 was achieved for the blend with 80 wt% of PEDOT:PSS (PH1000) in PUS1. [ABSTRACT FROM AUTHOR]

In recent years, in an effort to reach Net Zero Emissions, there has been growing interest by various academic and industry communities to develop chemicals and industrial processes that are circular, sustainable and green. We report the rapid, simple and effective surface modification of a porous metal oxide with organic dyes using supercritical carbon dioxide (scCO2). Titanium dioxide (TiO2) photoanodes were coated in very short times, under mild conditions and the excess dye recovered afterwards for reuse. The process obviates the need for conventional toxic solvents, the generation of unwanted waste streams, and more importantly, we see an unexpected device performance enhancement of 212 and 163 % for TerCOOTMS, 2 a and TerCN/COOTBDMS, 4 dyes, respectively, when compared to the conventional solvent deposition method. [ABSTRACT FROM AUTHOR]

The hepatic extracellular matrix (ECM) is most accurately depicted as a dynamic compartment that comprises a diverse range of players that work bidirectionally with hepatic cells to regulate overall homeostasis. Although the classic meaning of the ECM referred to only proteins directly involved in generating the ECM structure, such as collagens, proteoglycans, and glycoproteins, the definition of the ECM is now broader and includes all components associated with this compartment. The ECM is critical in mediating phenotype at the cellular, organ, and even organismal levels. The purpose of this review is to summarize the prevailing mechanisms by which ECM mediates hepatic phenotype and discuss the potential or established role of this compartment in the response to hepatic injury in the context of steatotic liver disease. [ABSTRACT FROM AUTHOR]

The B‐cell lymphoma 2 (BCL2) family members, BCL2‐associated protein X (BAX) and BCL2 homologous antagonist killer (BAK), are required for programmed cell death via the mitochondrial pathway. When cells are stressed, damaged or redundant, the balance of power between the BCL2 family of proteins shifts towards BAX and BAK, allowing their transition from an inactive, monomeric state to a membrane‐active oligomeric form that releases cytochrome c from the mitochondrial intermembrane space. That oligomeric state has an essential intermediate, a symmetric homodimer of BAX or BAK. Here we describe crystal structures of dimers of the core domain of BAX, comprising its helices α2–α5. These structures provide an atomic resolution description of the interactions that drive BAX homo‐dimerisation and insights into potential interaction between core domain dimers and membrane lipids. The previously identified BAK lipid‐interacting sites are not conserved with BAX and are likely to determine the differences between them in their interactions with lipids. We also describe structures of heterodimers of BAK/BAX core domains, yielding further insight into the differences in lipid binding between BAX and BAK. [ABSTRACT FROM AUTHOR]