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Theories of embodied cognition hypothesize interdependencies between psychological well-being and physical posture. The purpose of this study was to assess the feasibility of objectively measuring posture, and to explore the relationship between posture and affect and other patient centered outcomes in breast cancer survivors (BCS) with persistent postsurgical pain (PPSP) over a 12-week course of therapeutic Qigong mind-body training. Twenty-one BCS with PPSP attended group Qigong training. Clinical outcomes were pain, fatigue, self-esteem, anxiety, depression, stress and exercise self-efficacy. Posture outcomes were vertical spine and vertical head angles in the sagittal plane, measured with a 3D motion capture system in three conditions: eyes open (EO), eyes open relaxed (EOR) and eyes closed (EC). Assessments were made before and after the Qigong training. The association between categorical variables (angle and mood) was measured by Cramer’s V. In the EO condition, most participants who improved in fatigue and anxiety scales also had better vertical head values. For the EOR condition, a moderate correlation was observed between changes in vertical head angle and changes in fatigue scale. In the EC condition, most of the participants who improved in measures of fatigue also improved vertical head angle. Additionally, pain severity decreased while vertical spine angle improved. These preliminary findings support that emotion and other patient centered outcomes should be considered within an embodied framework, and that Qigong may be a promising intervention for addressing biopsychosocially complex interventions such as PPSP in BCSs.

Intimate partner violence is underreported to police. A study was conducted utilizing focus group methodology to identify women's perceptions of the barriers to seeking police help for intimate partner violence (IPV). Facilitators used a structured format with open-ended questions for five focus group sessions that were recorded and subsequently analyzed using Ethnograph software. Participants were 41 women identified from social service agencies in an urban setting serving IPV women with diverse ethnic and cultural backgrounds. Participants identified many barriers for victims, which fell within the following three themes: (1) Predisposing characteristics - situational and personal factors; (2) fears and negative experiences with police response; and (3) fears of possible repercussions. Participants also described positive experiences with police and generated a 'wish list' for improving police response to IPV. Policies and actions that can be taken by police and social service agencies to address the barriers IPV victims face in seeking police help are discussed. [ABSTRACT FROM AUTHOR]

Body awareness is an attentional focus on and awareness of internal body sensations. This study aimed to validate German versions of the Body Awareness Questionnaire (BAQ) and the Body Responsiveness Questionnaire (BRQ) in chronic pain patients and to assess their associations with pain-related variables and to assess their responsiveness to intervention. The instruments were translated to German and administered to 512 chronic pain patients (50.3±11.4 years, 91.6% female) to assess their factor structure and reliability. Cronbach's α for the BAQ total score was 0.86. Factor analysis of the BRQ revealed the two factors Importance of Interoceptive Awareness (Cronbach's α = 0.75) and Perceived Connection (Cronbach's α = 0.75) and the single-item Suppression of Bodily Sensations. The BAQ was independently associated with lower mindfulness, self-esteem, stress, and depression; Importance of Interoceptive Awareness with mindfulness, self-acceptance, self-esteem, and physical contact; Perceived Connection with self-acceptance, vitality, and lower sensory pain; Suppression of Bodily Sensations with lower self-esteem, physical contact, and higher depressive symptoms. After a 10-week multimodal mind-body program (n = 202), the BAQ and Importance of Interoceptive Awareness increased and pain intensity and Suppression of Bodily Sensation decreased. In conclusion, body awareness and body responsiveness are associated with pain-related variables in patients with chronic pain. Mind-body interventions may positively influence both pain and body awareness, hinting at a potential mechanism of action of these interventions to be tested in further research.

BACKGROUND:Current dementia medications have small effect sizes, many adverse effects and do not change the disease course. Therefore, it is critically important to study alternative treatment strategies. The goal of this study was to pilot-test a novel, integrative group exercise program for individuals with mild-to-moderate dementia called Preventing Loss of Independence through Exercise (PLIÉ), which focuses on training procedural memory for basic functional movements (e.g., sit-to-stand) while increasing mindful body awareness and facilitating social connection. METHODS:We performed a 36-week cross-over pilot clinical trial to compare PLIÉ with usual care (UC) at an adult day program for individuals with dementia in San Francisco, CA. Assessments of physical performance, cognitive function, physical function, dementia-related behaviors, quality of life and caregiver burden were performed by blinded assessors at baseline, 18 weeks (cross-over) and 36 weeks. Our primary outcomes were effect sizes based on between-group comparisons of change from baseline to 18 weeks; secondary outcomes were within-group comparisons of change before and after cross-over. RESULTS:Twelve individuals enrolled (7 PLIÉ, 5 UC) and 2 withdrew (1 PLIÉ, 18 weeks; 1 UC, 36 weeks). Participants were 82% women (mean age, 84 ± 4 years); caregivers were 82% daughters (mean age, 56 ± 13 years). Effect sizes were not statistically significant but suggested potentially clinically meaningful (≥ 0.25 SDs) improvement with PLIÉ versus UC for physical performance (Cohen's D: 0.34 SDs), cognitive function (0.76 SDs) and quality of life (0.83 SDs) as well as for caregiver measures of participant's quality of life (0.33 SDs) and caregiver burden (0.49 SDs). Results were similar when within-group comparisons were made before and after cross-over. CONCLUSIONS:PLIÉ is a novel, integrative exercise program that shows promise for improving physical function, cognitive function, quality of life and caregiver burden in individuals with mild-to-moderate dementia. Larger randomized, controlled trials are warranted. TRIAL REGISTRATION:ClinicalTrials.gov NCT01371214.

Abstract Unsafe abortion's significant contribution to maternal mortality and morbidity was a critical factor leading to liberalization of Nepal's restrictive abortion law in 2002. Careful, comprehensive planning among a range of multisectoral stakeholders, led by Nepal's Ministry of Health and Population, enabled the country subsequently to introduce and scale up safe abortion services in a remarkably short timeframe. This paper examines factors that contributed to rapid, successful implementation of legal abortion in this mountainous republic, including deliberate attention to the key areas of policy, health system capacity, equipment and supplies, and information dissemination. Important elements of this successful model of scaling up safe legal abortion include: the pre-existence of postabortion care services, through which health-care providers were already familiar with the main clinical technique for safe abortion; government leadership in coordinating complementary contributions from a wide range of public- and private-sector actors; reliance on public-health evidence in formulating policies governing abortion provision, which led to the embrace of medical abortion and authorization of midlevel providers as key strategies for decentralizing care; and integration of abortion care into existing Safe Motherhood and the broader health system. While challenges remain in ensuring that all Nepali women can readily exercise their legal right to early pregnancy termination, the national safe abortion program has already yielded strong positive results. Nepal's experience making high-quality abortion care widely accessible in a short period of time offers important lessons for other countries seeking to reduce maternal mortality and morbidity from unsafe abortion and to achieve Millennium Development Goals.

Competing Interests: Declaration of interests We declare no competing interests.

The last two decades have witnessed substantial advances in identifying synaptic plasticity responsible for behavioral changes in animal models of substance use disorder. We have learned the most about cocaine-induced plasticity in the nucleus accumbens and its relationship to cocaine seeking, so that is the focus in this review. Synaptic plasticity pointing to potential therapeutic targets has been identified mainly using two drug self-administration models: extinction-reinstatement and abstinence models. A relationship between cocaine seeking and potentiated AMPAR transmission in nucleus accumbens is indicated by both models. In particular, an atypical subpopulation-Ca2+-permeable or CP-AMPARs-mediates cue-induced seeking that persists even after long periods of abstinence, modeling the persistent vulnerability to relapse that represents a major challenge in treating substance use disorder. We review strategies to reverse CP-AMPAR plasticity; strategies targeting other components of excitatory synapses, including dysregulated glutamate uptake and release; and behavioral interventions that can be augmented by harnessing synaptic plasticity.

Rationale: Incubation of cocaine craving refers to the progressive intensification of cue-induced craving during abstinence from cocaine self-administration. We showed previously that homomeric GluA1 Ca 2+ -permeable AMPARs (CP-AMPAR) accumulate in excitatory synapses of nucleus accumbens core (NAcc) medium spiny neurons (MSN) after ∼1 month of abstinence and thereafter their activation is required for expression of incubation. Therefore, it is important to understand mechanisms underlying CP-AMPAR plasticity., Objectives: We hypothesize that CP-AMPAR upregulation represents a retinoic acid (RA)-dependent form of homeostatic plasticity, previously described in other brain regions, in which a reduction in neuronal activity disinhibits RA synthesis, leading to GluA1 translation and CP-AMPAR synaptic insertion. We tested this using viral vectors to bidirectionally manipulate RA signaling in NAcc during abstinence following extended-access cocaine self-administration., Results: We used shRNA targeted to the RA degradative enzyme Cyp26b1 to increase RA signaling. This treatment accelerated incubation; rats expressed incubation on abstinence day (AD) 15, when it is not yet detected in control rats. It also accelerated CP-AMPAR synaptic insertion measured with slice physiology. CP-AMPARs were detected in Cyp26b1 shRNA-expressing MSN, but not control MSN, on AD15-18. Next, we used shRNA targeted to the major RA synthetic enzyme Aldh1a1 to reduce RA signaling. In MSN expressing Aldh1a1 shRNA, synaptic CP-AMPARs were reduced in late withdrawal (AD42-60) compared to controls. However, we did not detect an effect of this manipulation on incubated cocaine seeking (AD40)., Conclusions: These findings support the hypothesis that increased RA signaling during abstinence contributes to CP-AMPAR accumulation and incubation of cocaine craving., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cytochromes P450 (P450s) are a superfamily of heme-containing enzymes possessing a broad range of monooxygenase activities. One such activity is O-demethylation, an essential and rate-determining step in emerging strategies to valorize lignin that employ carbon-carbon bond cleavage. We recently identified PbdA, a P450 from Rhodococcus jostii RHA1, and PbdB, its cognate reductase, which catalyze the O-demethylation of para-methoxylated benzoates (p-MBAs) to initiate growth of RHA1 on these compounds. PbdA had the highest affinity (K d  = 3.8 ± 0.6 μM) and apparent specificity (k cat /K M  = 20,000 ± 3000 M -1  s -1 ) for p-MBA. The enzyme also O-demethylated two related lignin-derived aromatic compounds with remarkable efficiency: veratrate and isovanillate. PbdA also catalyzed the hydroxylation and dehydrogenation of p-ethylbenzoate even though RHA1 did not grow on this compound. Atomic-resolution structures of PbdA in complex with p-MBA, p-ethylbenzoate, and veratrate revealed a cluster of three residues that form hydrogen bonds with the substrates' carboxylate: Ser87, Ser237, and Arg84. Substitution of these residues resulted in lower affinity and O-demethylation activity on p-MBA as well as increased affinity for the acetyl analog, p-methoxyacetophenone. The S87A and S237A variants of PbdA also catalyzed the O-demethylation of an aldehyde analog of p-MBA, p-methoxy-benzaldehyde, while the R84M variant did not, despite binding this compound with high affinity. These results suggest that Ser87, Ser237, and Arg84 are not only important determinants of specificity but also help to orientate that substrate correctly in the active site. This study facilitates the design of biocatalysts for lignin valorization., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Relapse represents a consistent clinical problem for individuals with substance use disorder. In the incubation of craving model of persistent craving and relapse, cue-induced drug seeking progressively intensifies or "incubates" during the first weeks of abstinence from drug self-administration and then remains high for months. Previously, we and others have demonstrated that expression of incubated cocaine craving requires strengthening of excitatory synaptic transmission in the nucleus accumbens core (NAcc). However, despite the importance of dopaminergic signaling in the NAcc for motivated behavior, little is known about the role that dopamine (DA) plays in the incubation of cocaine craving. Here we used fiber photometry to measure DA transients in the NAcc of male and female rats during cue-induced seeking tests conducted in early abstinence from cocaine self-administration, prior to incubation, and late abstinence, after incubation of craving has plateaued. We observed DA transients time-locked to cue-induced responding but their magnitude did not differ significantly when measured during early versus late abstinence seeking tests. Next, we tested for a functional role of these DA transients by injecting DA receptor antagonists into the NAcc just before the cue-induced seeking test. Blockade of either D1 or D2 DA receptors reduced cue-induced cocaine seeking after but not before incubation. We found no main effect of sex or significant interaction of sex with other factors in our experiments. These results suggest that DA contributes to incubated cocaine seeking but the emergence of this role reflects changes in postsynaptic responsiveness to DA rather than presynaptic alterations., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

In the 'incubation of cocaine craving' model of relapse, rats exhibit progressive intensification (incubation) of cue-induced craving over several weeks of forced abstinence from cocaine self-administration. The expression of incubated craving depends on plasticity of excitatory synaptic transmission in nucleus accumbens core (NAcC) medium spiny neurons (MSN). Previously, we found that the maintenance of this plasticity and the expression of incubation depends on ongoing protein translation, and the regulation of translation is altered after incubation of cocaine craving. Here we used male and female rats that express Cre recombinase in either dopamine D1 receptor- or adenosine 2a (A2a) receptor-expressing MSN to express a GFP-tagged ribosomal protein in a cell-type specific manner, enabling us to use Translating Ribosome Affinity Purification (TRAP) to isolate actively translating mRNAs from both MSN subtypes for analysis by RNA-seq. We compared rats that self-administered saline or cocaine. Saline rats were assessed on abstinence day (AD) 1, while cocaine rats were assessed on AD1 or AD40-50. For both D1-MSN and A2a-MSN, there were few differentially translated genes between saline and cocaine AD1 groups. In contrast, pronounced differences in the translatome were observed between cocaine rats on AD1 and AD40-50, and this was far more robust in D1-MSN. Notably, all comparisons revealed sex differences in translating mRNAs. Sequencing results were validated by qRT-PCR for several genes of interest. This study, the first to combine TRAP-seq, transgenic rats, and a cocaine self-administration paradigm, identifies translating mRNAs linked to incubation of cocaine craving in D1-MSN and A2a-MSN of the NAcC., Competing Interests: Competing Interests: The authors have nothing to disclose.

Background: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but severe complication following vaccination with adenovirus vector-based COVID-19 vaccines. Antibodies directed against platelet factor 4 (PF4) are thought to be responsible for platelet activation and subsequent thromboembolic events in these patients. Since a single vaccination does not lead to sufficient immunization, subsequent vaccinations against COVID-19 have been recommended. However, concerns exist regarding the possible development of a new thromboembolic episode after subsequent vaccinations in VITT patients. Methods: We prospectively analyzed follow-up data from four VITT patients (three women and one man; median age, 44 years [range, 22 to 62 years]) who subsequently received additional COVID-19 vaccines. Platelet counts, anti-PF4/heparin antibody level measurements, and a functional platelet activation assay were performed at each follow-up visit. Additionally, we conducted a literature review and summarized similar reports on the outcome of subsequent vaccinations in patients with VITT. Results: The patients had developed thrombocytopenia and thrombosis 4 to 17 days after the first vaccination with ChAdOx1 nCoV-19. The optical densities (ODs) of anti-PF4/heparin antibodies decreased with time, and three out of four patients tested negative within 4 months. One patient remained positive even after 10 months post first vaccination. All four patients received an mRNA-based vaccine as a second vaccination against SARS-CoV-2. No significant drop in platelet count or new thromboembolic complications were observed during follow-up. We identified seven publications reporting subsequent COVID-19 vaccination in VITT patients. None of the patients developed thrombocytopenia or thrombosis after the subsequent vaccination. Conclusion: Subsequent vaccination with an mRNA vaccine appears to be safe in VITT patients.

Incubation of cocaine craving, a translationally relevant model for the persistence of drug craving during abstinence, ultimately depends on strengthening of nucleus accumbens core (NAcc) synapses through synaptic insertion of homomeric GluA1 Ca 2+ -permeable AMPA receptors (CP-AMPARs). Here we tested the hypothesis that CP-AMPAR upregulation results from a form of homeostatic plasticity, previously characterized in vitro and in other brain regions, that depends on retinoic acid (RA) signaling in dendrites. Under normal conditions, ongoing synaptic transmission maintains intracellular Ca 2+ at levels sufficient to suppress RA synthesis. Prolonged blockade of neuronal activity results in disinhibition of RA synthesis, leading to increased GluA1 translation and synaptic insertion of homomeric GluA1 CP-AMPARs. Using slice recordings, we found that increasing RA signaling in NAcc medium spiny neurons (MSN) from drug-naïve rats rapidly upregulates CP-AMPARs, and that this pathway is operative only in MSN expressing the D1 dopamine receptor. In MSN recorded from rats that have undergone incubation of craving, this effect of RA is occluded; instead, interruption of RA signaling in the slice normalizes the incubation-associated elevation of synaptic CP-AMPARs. Paralleling this in vitro finding, interruption of RA signaling in the NAcc of 'incubated rats' normalizes the incubation-associated elevation of cue-induced cocaine seeking. These results suggest that RA signaling becomes tonically active in the NAcc during cocaine withdrawal and, by maintaining elevated CP-AMPAR levels, contributes to the incubation of cocaine craving., Competing Interests: Conflict of interest statement: Dr. Wolf and OHSU have a financial interest in Eleutheria Pharmaceuticals LLC, a company that may have a commercial interest in results related to the research described herein. This potential conflict of interest has been reviewed and managed by OHSU. The other authors declare no competing interests.

Ethylene glycol (EG) is a widely used industrial chemical with manifold applications and also generated in the degradation of plastics such as polyethylene terephthalate. Rhodococcus jostii RHA1 (RHA1), a potential biocatalytic chassis, grows on EG. Transcriptomic analyses revealed four clusters of genes potentially involved in EG catabolism: the mad locus, predicted to encode m ycofactocin-dependent a lcohol d egradation, including the catabolism of EG to glycolate; two GCL clusters, predicted to encode glycolate and glyoxylate catabolism; and the mft genes, predicted to specify mycofactocin biosynthesis. Bioinformatic analyses further revealed that the mad and mft genes are widely distributed in mycolic acid-producing bacteria such as RHA1. Neither Δ madA nor Δ mftC RHA1 mutant strains grew on EG but grew on acetate. In resting cell assays, the Δ madA mutant depleted glycolaldehyde but not EG from culture media. These results indicate that madA encodes a mycofactocin-dependent alcohol dehydrogenase that initiates EG catabolism. In contrast to some mycobacterial strains, the mad genes did not appear to enable RHA1 to grow on methanol as sole substrate. Finally, a strain of RHA1 adapted to grow ~3× faster on EG contained an overexpressed gene, aldA2 , predicted to encode an aldehyde dehydrogenase. When incubated with EG, this strain accumulated lower concentrations of glycolaldehyde than RHA1. Moreover, ecotopically expressed aldA2 increased RHA1's tolerance for EG further suggesting that glycolaldehyde accumulation limits growth of RHA1 on EG. Overall, this study provides insights into the bacterial catabolism of small alcohols and aldehydes and facilitates the engineering of Rhodococcus for the upgrading of plastic waste streams.IMPORTANCEEthylene glycol (EG), a two-carbon (C2) alcohol, is produced in high volumes for use in a wide variety of applications. There is burgeoning interest in understanding and engineering the bacterial catabolism of EG, in part to establish circular economic routes for its use. This study identifies an EG catabolic pathway in Rhodococcus , a genus of bacteria well suited for biocatalysis. This pathway is responsible for the catabolism of methanol, a C1 feedstock, in related bacteria. Finally, we describe strategies to increase the rate of degradation of EG by increasing the transformation of glycolaldehyde, a toxic metabolic intermediate. This work advances the development of biocatalytic strategies to transform C2 feedstocks., Competing Interests: The authors declare no conflict of interest.

Antiphospholipid syndrome (APS) is known as a rare etiology of embolic ischemic stroke. In individuals below 50 years, up to 20% of strokes are associated with APS, whereas in patients >50 years, it is considered a very seldom cause of stroke. We describe the course of a 66-year-old white woman, who experienced four embolic strokes with large vessel occlusion over a period of 2 years, which were repeatedly and successfully treated by mechanical thrombectomy. Initially attributed to atrial fibrillation and treated with direct oral anticoagulants, the patient was finally diagnosed with primary APS due to isolated anti-beta 2-glycoprotein antibodies and successfully treated after several stroke recurrences. After initiation of Vitamin K antagonist therapy, no further strokes occurred. For recurrent embolic stroke despite oral anticoagulation, late-onset APS might be considered a rare etiology also in the elderly., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Brain Circulation.)

Bioactive degradable scaffolds that facilitate bone healing while fighting off initial bacterial infection have the potential to change established strategies of dealing with traumatic bone injuries. To achieve this a composite material made from calcium phosphate graphene (CaPG), and MXene was synthesized. CaPG was created by functionalizing graphene oxide with phosphate groups in the presence of CaBr with a Lewis acid catalyst. Through this transformation, Ca 2+ and PO 4 3- inducerons are released as the material degrades thereby aiding in the process of osteogenesis. The 2D MXene sheets, which have shown to have antibacterial properties, were made by etching the Al from a layered Ti 3 AlC 2 (MAX phase) using HF. The hot-pressed scaffolds made of these materials were designed to combat the possibility of infection during initial surgery and failure of osteogenesis to occur. These two failure modes account for a large percentage of issues that can arise during the treatment of traumatic bone injuries. These scaffolds were able to retain induceron-eluting properties in various weight percentages and bring about osteogenesis with CaPG alone and 2 wt% MXene scaffolds demonstrating increased osteogenic activity as compared to no treatment. Additionally, added MXene provided antibacterial properties that could be seen at as little as 2 wt%. This CaPG and MXene composite provides a possible avenue for developing osteogenic, antibacterial materials for treating bone injuries., (© 2024 The Author(s). Journal of Biomedical Materials Research Part B: Applied Biomaterials published by Wiley Periodicals LLC.)

Objectives: Deep brain stimulation (DBS) is a well-established surgical therapy for movement disorders that comprises implantation of stimulation electrodes and a pacemaker. These procedures can be performed separately, leaving the possibility of externalizing the electrodes for local field potential recording or testing multiple targets for therapeutic efficacy. It is still debated whether the temporary externalization of DBS electrodes leads to an increased risk of infection. We therefore aimed to assess the risk of infection during and after lead externalization in DBS surgery., Materials and Methods: In this retrospective study, we analyzed a consecutive series of 624 DBS surgeries, including 266 instances with temporary externalization of DBS electrodes for a mean of 6.1 days. Patients were available for follow-up of at least one year, except in 15 instances. In 14 patients with negative test stimulation, electrodes were removed. All kinds of infections related to implantation of the neurostimulation system were accounted for., Results: Overall, infections occurred in 22 of 624 surgeries (3.5%). Without externalization of electrodes, infections were noted after 7 of 358 surgeries (2.0%), whereas with externalization, 15 of 252 infections were found (6.0%). This difference was significant (p = 0.01), but it did not reach statistical significance when comparing groups within different diagnoses. The rate of infection with externalized electrodes was highest in psychiatric disorders (9.1%), followed by Parkinson's disease (7.3%), pain (5.7%), and dystonia (5.5%). The duration of the externalization of the DBS electrodes was comparable in patients who developed an infection (6.1 ± 3.1 days) with duration in those who did not (6.0 ± 3.5 days)., Conclusions: Although infection rates were relatively low in our study, there was a slightly higher infection rate when DBS electrodes were externalized. On the basis of our results, the indication for electrode externalization should be carefully considered, and patients should be informed about the possibility of a higher infection risk when externalization of DBS electrodes is planned., Competing Interests: Conflict of Interest Joachim Runge received travel grants from Medtronic. Thomas M. Kinfe is a consultant to Medtronic and Abbott. Assel Saryyeva received travel grants from Medtronic. Joachim K. Krauss is a consultant to Medtronic, Boston Scientific, Aleva, and Inomed. The remaining authors report no conflict of interest., (Copyright © 2023 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Dopamine (DA) plays multiple roles in a wide range of physiological and pathological processes via a large network of dopaminergic projections. To dissect the spatiotemporal dynamics of DA release in both dense and sparsely innervated brain regions, we developed a series of green and red fluorescent G-protein-coupled receptor activation-based DA (GRAB DA ) sensors using a variety of DA receptor subtypes. These sensors have high sensitivity, selectivity and signal-to-noise ratio with subsecond response kinetics and the ability to detect a wide range of DA concentrations. We then used these sensors in mice to measure both optogenetically evoked and behaviorally relevant DA release while measuring neurochemical signaling in the nucleus accumbens, amygdala and cortex. Using these sensors, we also detected spatially resolved heterogeneous cortical DA release in mice performing various behaviors. These next-generation GRAB DA sensors provide a robust set of tools for imaging dopaminergic activity under a variety of physiological and pathological conditions., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Emergent strategies to valorize lignin, an abundant but underutilized aromatic biopolymer, include tandem processes that integrate chemical depolymerization and biological catalysis. To date, aromatic monomers from C-O bond cleavage of lignin have been converted to bioproducts, but the presence of recalcitrant C-C bonds in lignin limits the product yield. A promising chemocatalytic strategy that overcomes this limitation involves phenol methyl protection and autoxidation. Incorporating this into a tandem process requires microbial cell factories able to transform the p -methoxylated products in the resulting methylated lignin stream. In this study, we assessed the ability of Rhodococcus jostii RHA1 to catabolize the major aromatic products in a methylated lignin stream and elucidated the pathways responsible for this catabolism. RHA1 grew on a methylated pine lignin stream, catabolizing the major aromatic monomers: p -methoxybenzoate ( p -MBA), veratrate, and veratraldehyde. Bioinformatic analyses suggested that a cytochrome P450, PbdA, and its cognate reductase, PbdB, are involved in p -MBA catabolism. Gene deletion studies established that both pbdA and pbdB are essential for growth on p -MBA and several derivatives. Furthermore, a deletion mutant of a candidate p- hydroxybenzoate ( p -HBA) hydroxylase, Δ pobA , did not grow on p -HBA. Veratraldehyde and veratrate catabolism required both vanillin dehydrogenase (Vdh) and vanillate O -demethylase (VanAB), revealing previously unknown roles of these enzymes. Finally, a Δ pcaL strain grew on neither p -MBA nor veratrate, indicating they are catabolized through the β-ketoadipate pathway. This study expands our understanding of the bacterial catabolism of aromatic compounds and facilitates the development of biocatalysts for lignin valorization.IMPORTANCELignin, an abundant aromatic polymer found in plant biomass, is a promising renewable replacement for fossil fuels as a feedstock for the chemical industry. Strategies for upgrading lignin include processes that couple the catalytic fractionation of biomass and biocatalytic transformation of the resulting aromatic compounds with a microbial cell factory. Engineering microbial cell factories for this biocatalysis requires characterization of bacterial pathways involved in catabolizing lignin-derived aromatic compounds. This study identifies new pathways for lignin-derived aromatic degradation in Rhodococcus , a genus of bacteria well suited for biocatalysis. Additionally, we describe previously unknown activities of characterized enzymes on lignin-derived compounds, expanding their utility. This work advances the development of strategies to replace fossil fuel-based feedstocks with sustainable alternatives., Competing Interests: The authors declare no conflict of interest.

INTRODUCTION: Health-related factors can impact aviation safety. This study investigated the published, historical aviation accidents that have been investigated by the U.S. National Transportation Safety Board (NTSB) to understand medical conditions and medication use that have been determined to be causal to mishaps. METHODS: A two-part approach was adopted for this study: 1) a scoping review was conducted to provide an overview of the current medical literature addressing medical factors and flight safety; and 2) a comprehensive review of aviation accident reports from the NTSB database from January 2013 to October 2022. RESULTS: The literature review demonstrated that psychiatric, cardiovascular, and neurological medications were the major categories of medications reported in fatal aircraft accidents. Age was not found to be a risk factor. Review of the NTSB database demonstrated that, among 15,654 mishaps, medical factors were associated in 703 (4.5%) accidents. NTSB data showed that cardiovascular (1.3%), psychiatric (0.23%), and endocrine diseases (0.17%) were the most commonly reported diseases among pilots. In accident reports, cardiovascular medications (1.49%), sedating antihistamines (0.91%), and alcohol (0.70%) were the most commonly used medications at the time of the accidents. DISCUSSION: Health-related factors were a small yet likely underestimated proportion of the factors associated with accidents. Cardiovascular diseases and treatment were the most important factors. It is important to continue to investigate the association between health-related factors and the commission of mishaps. Zhu Y, Wolf ME, Alsibai RA, Abbas AS, Alsawaf Y, Saadi S, Farah MH, Wang Z, Murad MH. Health-related factors among pilots in aviation accidents . Aerosp Med Hum Perform. 2024; 95(2):79-83.

Oxygenases catalyze crucial reactions throughout all domains of life, cleaving molecular oxygen (O 2 ) and inserting one or two of its atoms into organic substrates. Many oxygenases, including those in the cytochrome P450 (P450) and Rieske oxygenase enzyme families, function as multicomponent systems, which require one or more redox partners to transfer electrons to the catalytic center. As the identity of the reductase can change the reactivity of the oxygenase, characterization of the latter with its cognate redox partners is critical. However, the isolation of the native redox partner or partners is often challenging. Here, we report the preparation and characterization of PbdB, the native reductase partner of PbdA, a bacterial P450 enzyme that catalyzes the O-demethylation of para-methoxylated benzoates. Through production in a rhodoccocal host, codon optimization, and anaerobic purification, this procedure overcomes conventional challenges in redox partner production and allows for robust oxygenase characterization with its native redox partner. Key lessons learned here, including the value of production in a related host and rare codon effects are applicable to a broad range of Fe-dependent oxygenases and their components., (Copyright © 2024. Published by Elsevier Inc.)

Cobalt-containing alloys are useful for orthopedic applications due to their low volumetric wear rates, corrosion resistance, high mechanical strength, hardness, and fatigue resistance. Unfortunately, these prosthetics release significant levels of cobalt ions, which was only discovered after their widespread implantation into patients requiring hip replacements. These cobalt ions can result in local toxic effects-including peri-implant toxicity, aseptic loosening, and pseudotumor-as well as systemic toxic effects-including neurological, cardiovascular, and endocrine disorders. Failing metal-on-metal (MoM) implants usually necessitate painful, risky, and costly revision surgeries. To treat metallosis arising from failing MoM implants, a synovial fluid-mimicking chelator was designed to remove these metal ions. Hyaluronic acid (HA), the major chemical component of synovial fluid, was functionalized with British anti-Lewisite (BAL) to create a chelator (BAL-HA). BAL-HA effectively binds cobalt and rescues in vitro cell vitality (up to 370% of cells exposed to IC 50 levels of cobalt) and enhances the rate of clearance of cobalt in vivo ( t 1/2 from 48 h to 6 h). A metallosis model was also created to investigate our therapy. Results demonstrate that BAL-HA chelator system is biocompatible and capable of capturing significant amounts of cobalt ions from the hip joint within 30 min, with no risk of kidney failure. This chelation therapy has the potential to mitigate cobalt toxicity from failing MoM implants through noninvasive injections into the joint.

Objective: Functional stereotactic neurosurgery including deep brain stimulation (DBS) and radiofrequency lesioning is well established and widely used for treatment of movement disorders and various other neurological and psychiatric diseases. Although functional stereotactic neurosurgery procedures are considered relatively safe, intracranial hemorrhage resulting in permanent neurological deficits may occur in 1%-3% of patients. Microelectrode recording (MER) has been recognized as a valuable tool for refining the final target in functional stereotactic neurosurgery. Moreover, MER provides insight into the underlying neurophysiological pathomechanisms of movement disorders and other diseases. Nevertheless, there is an ongoing controversy on whether MER increases the risk for hemorrhage. The authors aimed to compare the risk of hemorrhage in functional stereotactic neurosurgical procedures with regard to the use of MER., Methods: The authors performed a comparative analysis on a consecutive series of 645 functional neurosurgery procedures, including 624 DBS surgeries and 21 radiofrequency lesionings, to evaluate whether the use of MER would increase the risk for hemorrhage. MER was performed in 396 procedures, while no MER was used in 249 cases. The MER technique involved the use of a guiding cannula and a single trajectory when feasible. Postoperative CT scans were obtained within 24 hours after surgery in all patients and screened for the presence of hemorrhage., Results: Twenty-one intracranial hemorrhages were detected on the postoperative CT scans (3.2%). Of the 21 intracranial hemorrhages, 14 were asymptomatic and 7 were symptomatic. Symptoms were transient except in 1 case. There was no statistically significant correlation between hemorrhage and the use of MER at any site (subdural, ventricle, trajectory, target, whether asymptomatic or symptomatic). There were 4 cases of symptomatic hemorrhage in the MER group (1%) and 3 cases in those without MER (1.2%)., Conclusions: Intraoperative MER did not increase the overall risk of hemorrhage in the authors' experience using primarily a single MER trajectory and a guiding cannula.

Relapse is a major problem in treating methamphetamine use disorder. "Incubation of craving" during abstinence is a rat model for persistence of vulnerability to craving and relapse. While methamphetamine incubation has previously been demonstrated in male and female rats, it has not been demonstrated after withdrawal periods greater than 51 d and most mechanistic work used males. Here, we address both gaps. First, although methamphetamine intake was higher in males during self-administration training (6 h/d × 10 d), incubation was similar in males and females, with "incubated" craving persisting through withdrawal day (WD)100. Second, using whole-cell patch-clamp recordings in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) core, we assessed synaptic levels of calcium-permeable AMPA receptors (CP-AMPARs), as their elevation is required for expression of incubation in males. In both sexes, compared with saline-self-administering controls, CP-AMPAR levels were significantly higher in methamphetamine rats across withdrawal, although this was less pronounced in WD100-135 rats than WD15-35 or WD40-75 methamphetamine rats. We also examined membrane properties and NMDA receptor (NMDAR) transmission. In saline controls, MSNs from males exhibited lower excitability than females. This difference was eliminated after incubation because of increased excitability of MSNs from males. NMDAR transmission did not differ between sexes and was not altered after incubation. In conclusion, incubation persists for longer than previously described and equally persistent CP-AMPAR plasticity in NAc core occurs in both sexes. Thus, abstinence-related synaptic plasticity in NAc is similar in males and females although other methamphetamine-related behaviors and neuroadaptations show differences., Competing Interests: M.E.W. is founder of Eleutheria Pharmaceuticals LLC. All other authors declare no competing financial interests., (Copyright © 2023 Funke et al.)

Wound dressings have been shifting toward a more active role in the wound-healing process. Hydrated environments with additives to aid in the healing process are currently being explored through the application of hydrocolloid dressings. However, these moist healing environments are also ideal for bacterial growth, leading to the widespread use of antibiotics with concerns of antibiotic resistance and toxicity. To overcome this concern, we present a hydrogel wound dressing consisting of hyaluronic acid (HA) cross-linked with gentamicin. This hydrogel treats bacterial infection locally, lowering the effective dose and reducing the concerns of antibiotic resistance and systemic exposure. Changing the cross-linking density, by using varied amounts of a cross-linker, created gels that provided a sustained release of gentamicin for up to 9 days with a range of adhesive and cohesive properties. Overall, this HA hydrogel could provide an important solution in treating local infection in burns and other dermal injuries.

Background: Cue-induced cocaine craving progressively intensifies (incubates) during abstinence from cocaine self-administration. Expression of incubated cocaine craving depends on elevated calcium-permeable AMPA receptors (CP-AMPARs) on medium spiny neurons in the nucleus accumbens (NAc) core. After incubation has occurred, stimulation of NAc metabotropic glutamate 1 (mGlu 1 ) receptors or systemic administration of mGlu 1 positive allosteric modulators removes CP-AMPARs from NAc synapses via dynamin-dependent internalization (mGlu 1 long-term depression [LTD]) and thereby reduces incubated cocaine craving. Because mGlu 1 positive allosteric modulators are potential therapeutics for cocaine craving, it is important to further define the mechanism triggering this mGlu 1 -LTD., Methods: Male and female rats self-administered saline or cocaine (10 days) using a long access regimen (6 h/day). Following ≥40 days of abstinence, we assessed the ability of an mGlu 1 positive allosteric modulator to inhibit expression of incubated craving and remove CP-AMPARs from NAc synapses under control conditions, after blocking the integrated stress response (ISR), or after knocking down oligophrenin-1, a mediator of the ISR that can promote AMPAR endocytosis. AMPAR transmission in NAc medium spiny neurons was assessed with ex vivo slice recordings., Results: mGlu 1 stimulation reduced cue-induced craving and removed synaptic CP-AMPARs. When the ISR was blocked prior to mGlu 1 stimulation, there was no reduction in cue-induced craving, nor were CP-AMPARs removed from the synapse. Further, selective knockdown of oligophrenin-1 blocked mGlu 1 -LTD., Conclusions: Our results indicate that mGlu 1 -LTD in the NAc and consequently the reduction of cue-induced seeking occur through activation of the ISR, which induces translation of oligophrenin-1. We also demonstrate CP-AMPAR accumulation and mGlu 1 reversal in female rats, as previously shown in male rats., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Heavy aldehyde and ketone analogues, R 2 X═O (X = Si, Ge, Sn, or Pb), differ from their R 2 C═O counterparts due to their greater tendency to oligeramize as the X═O bond polarity increases as one goes down the periodic table. To date, H 2 Sn═O and H 2 Pb═O have eluded experimental detection. Herein we present the most rigorous theoretical study to date on these structures, providing CCSD(T)/pwCVTZ fundamental frequencies computed on CCSD(T)/CBS optimized structures for the H 2 X═O (X = Sn, Pb) potential energy surface. The focal point approach is employed to produce the CCSDTQ/CBS relative energies. For the Sn and Pb structures, the carbene-like cis -HXOH was the global minima, with the trans species being less than 0.6 and 1.1 kcal mol -1 above the cis structures, respectively. The formaldehyde-like H 2 X═O structure is in an energy well of at least 34.8 and 25.4 kcal mol -1 for Sn and Pb, respectively. Our results provide guidance for future work that may detect H 2 Sn═O or H 2 Pb═O for the first time.

One of the most challenging issues in the treatment of substance use disorder, including misuse of opioids such as oxycodone, is persistent vulnerability to relapse, often triggered by cues or contexts previously associated with drug use. In rats, cue-induced craving progressively intensifies ('incubates') during withdrawal from extended-access self-administration of several classes of misused drugs, including the psychostimulants cocaine and methamphetamine. For these psychostimulants, incubation is associated with strengthening of excitatory synapses in the nucleus accumbens (NAc) through incorporation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors that lack the GluA2 subunit and are therefore Ca 2+ -permeable (CP-AMPARs). Once CP-AMPAR upregulation occurs, their stimulation is required for expression of incubation. It is not known if a similar mechanism contributes to incubation of oxycodone craving. Using male rats, we established that incubation occurs by withdrawal day (WD) 15 and persists through WD30. Then, using cell-surface biotinylation, we found that surface levels of the AMPAR subunit GluA1 but not GluA2 are elevated in NAc core and shell of oxycodone rats on WD15, although this wanes by WD30. Next, using intra-NAc injection of the selective CP-AMPAR antagonist Naspm before a seeking test, we demonstrate that CP-AMPAR blockade in either subregion decreases oxycodone seeking on WD15 or WD30 (after incubation), but not WD1, and has no effect in saline self-administering animals. The Naspm results suggest CP-AMPARs persist in synapses through WD30 even if total cell surface levels wane. These results suggest that a common neurobiological mechanism contributes to expression of incubation of craving for oxycodone and psychostimulants., (© 2022 Society for the Study of Addiction.)

Coronavirus disease (COVID) toes are pernio-like skin lesions associated with severe acute respiratory syndrome coronavirus 2. We observed pernio-like skin findings presenting after a Pfizer BioNTech vaccine, which significantly worsened after an infusion of rituximab. This suggests that the mechanism for COVID toes is interferon activation. Military providers may avoid unnecessary referrals for this self-limiting condition by anticipating this adverse effect., (© The Association of Military Surgeons of the United States 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Biallelic variants in UCHL1 have been associated with a progressive early-onset neurodegenerative disorder, autosomal recessive spastic paraplegia type 79. In this study, we investigated heterozygous UCHL1 variants on the basis of results from cohort-based burden analyses., Methods: Gene-burden analyses were performed on exome and genome data of independent cohorts of patients with hereditary ataxia and spastic paraplegia from Germany and the United Kingdom in a total of 3169 patients and 33,141 controls. Clinical data of affected individuals and additional independent families were collected and evaluated. Patients' fibroblasts were used to perform mass spectrometry-based proteomics., Results: UCHL1 was prioritized in both independent cohorts as a candidate gene for an autosomal dominant disorder. We identified a total of 34 cases from 18 unrelated families, carrying 13 heterozygous loss-of-function variants (15 families) and an inframe insertion (3 families). Affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17). The mass spectrometry-based proteomics showed approximately 50% reduction of UCHL1 expression in patients' fibroblasts., Conclusion: Our bioinformatic analysis, in-depth clinical and genetic workup, and functional studies established haploinsufficiency of UCHL1 as a novel disease mechanism in spastic ataxia., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.)