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Introduction: Integrative nursing interventions (INI) play a significant role in healthcare, particularly in the prevention and treatment of chronic diseases. Integrating evidence-based INI into healthcare aligns with global initiatives such as the WHO's Decade of Healthy Aging 2020-2030. Many INI are low-threshold practices, empowering patients to independently manage health. However, the extent to which INI are used by home-care nursing-services (HNS) remains largely unknown. This study aims to explore the field of INI in German HNS regarding nurses' use of INI as well as attitudes, subjective knowledge, and information needs on the subject., Methods: A cross-sectional anonymous online survey with 29 Likert scale items and two open-ended questions was conducted between April 2023 and July 2023. The survey targeted nurse managers of HNS in Baden-Württemberg, Germany. Descriptive analysis was performed for quantitative data, while content analysis according to Kuckartz was applied to analyze open-ended text responses., Results: In total, n  = 68 out of n  = 1,331 HNS took part in the survey yielding a response rate of 5.1%. Their overall attitude toward INI was clearly positive (10-point Likert scale M ± SD: 8.37 ± 2.22). The average self-assessed knowledge level about INI was moderate (M ± SD: 5.39 ± 2.76). Almost half of the participants (45.6%) declared to incorporate INI in patient care. Most participants (84.2%) lacked employees with additional qualifications in INI. The INI used most were medicinal herbal teas (61%), compresses (57%), and aromatherapy (48%). Acupressure showed the greatest disparity between actual use in participating HNS (4.3%) and interest in further education (61%). The most common symptoms for which INI are used are pain, respiratory problems, anxiety, and palliative care. The main challenges reported for the use of INI in HNS are financial aspects, qualification and limited resources (staff and time)., Discussion: This exploratory study provides the first insights into nurses' attitudes, self-assessed knowledge, and utilization of INI in German HNS. Overall response rate was low (5.1%), therefore, the results should be interpreted with caution. Urgent action is needed to address financial aspects and further education on INI, to promote integration of INI in HNS to the best possible extent., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Stolz, Klocke, Mahler, Valentini and Joos.)

Introduction: The use of Complementary and Integrative Medicine (CIM) is very popular among the general population in Germany. However, international studies show that nurses, physicians, and other health care professionals (HCPs) at hospitals often do not feel sufficiently informed about different CIM approaches. Moreover, they do not feel trained enough to counsel their patients appropriately. In the German-speaking context, particularly within university hospitals, research on this subject is scarce. Therefore, the aim of this explorative study was to evaluate attitudes, subjective knowledge, and needs regarding CIM among HCPs with direct patient interaction across all four university hospitals in the federal state of Baden-Württemberg, Germany (Tübingen, Ulm, Freiburg, Heidelberg)., Methods: The multicenter, cross-sectional, anonymous full survey was conducted online using a self-developed, semi-structured, web-based questionnaire. Recruitment took place via all-inclusive e-mail distribution lists of all four university hospitals., Results: A total of n  = 2,026 participants (response rate varied by location from about 5 to 14%) fully answered the questionnaire. Nurses constituted the largest professional group ( n  = 1,196; 59%), followed by physicians ( n  = 567; 28%), physiotherapists ( n  = 54), psychologists ( n  = 48), midwives ( n  = 37), and other professions ( n  = 124). More than two-thirds (71%, n  = 1,437) of the participants were female and 14% ( n  = 286) reported additional training in CIM. The overall attitude toward CIM (10-point Likert scale, 10 = "very favorable") was clearly positive ( M  ±  SD : 7.43 ± 2.33), with notable differences between professional groups: midwives (9.05 ± 1.18), physiotherapists (8.44 ± 1.74), and nurses (8.08 ± 1.95) expressed the highest support, whereas physicians (5.80 ± 2.39) the lowest. 42% of the participants incorporated CIM in patient care (from 33% of physicians to 86% of midwives). Overall, relaxation therapy ( n  = 1,951; 96%), external applications ( n  = 1,911; 94%), massage ( n  = 1,836; 91%), and meditation/mindfulness ( n  = 1,812; 89%) were rated as useful or rather useful for patients. The average self-assessed knowledge level about CIM was moderate (M ± SD: 5.83 ± 2.03). Most of the participants found CIM training at university hospitals important and saw research about CIM as one of the tasks of university hospitals. The participants expressed the highest interest in education for acupuncture/acupressure, relaxation therapies, and manual medicine., Discussion: This comprehensive survey of health care professionals (HCPs) at university hospitals in Germany reveals a clearly positive disposition toward CIM, aligning with findings from other hospital-based surveys and highlighting differences among professional groups. While most therapies deemed beneficial for patient care are supported by positive evidence, further research is required for others. Given the average self-reported knowledge of CIM, targeted education is essential to meet the needs of both HCPs and patients and to ensure the provision of evidence-based information on the risks and benefits of CIM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hesmert, Klocke, Stolz, Huber, Samstag, Hübner, Simmet, Syrovets, Joos and Valentini.)

While immune checkpoint inhibitors show success in treating a subset of patients with certain late-stage cancers, these treatments fail in many other patients as a result of mechanisms that have yet to be fully characterized. The process of CD8 T cell exhaustion, by which T cells become dysfunctional in response to prolonged antigen exposure, has been implicated in immunotherapy resistance. Single-cell RNA sequencing (scRNA-seq) produces an abundance of data to analyze this process; however, due to the complexity of the process, contributions of other cell types to a process within a single cell type cannot be simply inferred. We constructed an analysis framework to first rank human skin tumor samples by degree of exhaustion in tumor-infiltrating CD8 T cells and then identify immune cell type-specific gene-regulatory network patterns significantly associated with T cell exhaustion. Using this framework, we further analyzed scRNA-seq data from human tumor and chronic viral infection samples to compare the T cell exhaustion process between these two contexts. In doing so, we identified transcription factor activity in the macrophages of both tissue types associated with this process. Our framework can be applied beyond the tumor immune microenvironment to any system involving cell-cell communication, facilitating insights into key biological processes that underpin the effective treatment of cancer and other complicated diseases.

Some patients develop multiple protracted sequelae after infection with SARS-CoV-2, collectively known as post-COVID syndrome or long COVID. To date, there is no evidence showing benefit of specific therapies for this condition, and patients likely resort to self-initiated therapies. We aimed to obtain information about therapies used by and needs of this population via inductive crowdsourcing research. Patients completed an online questionnaire about their symptoms and experiences with therapeutic approaches. Responses of 499 participants suggested few approaches (eg, mind-body medicine, respiratory therapy) had positive effects and showed a great need for patient-centered communication (eg, more recognition of this syndrome). Our findings can help design clinical studies and underscore the importance of the holistic approach to care provided by family medicine., (© 2023 Annals of Family Medicine, Inc.)

Background: Uveal melanoma is an aggressive cancer with high metastatic risk. Recently, we identified a circulating cancer cell population that co-expresses neoplastic and leukocyte antigens, termed circulating hybrid cells (CHCs). In other cancers, CHCs are more numerous and better predict oncologic outcomes compared to circulating tumor cells (CTCs). We sought to investigate the potential of CHCs as a prognostic biomarker in uveal melanoma. Methods: We isolated peripheral blood monocular cells from uveal melanoma patients at the time of primary treatment and used antibodies against leukocyte and melanoma markers to identify and enumerate CHCs and CTCs by immunocytochemistry. Results: Using a multi-marker approach to capture the heterogeneous disseminated tumor cell population, detection of CHCs was highly sensitive in uveal melanoma patients regardless of disease stage. CHCs were detected in 100% of stage I-III uveal melanoma patients (entire cohort, n = 68), whereas CTCs were detected in 58.8% of patients. CHCs were detected at levels statically higher than CTCs across all stages (p = 0.05). Moreover, CHC levels, but not CTCs, predicted 3 year progression-free survival (p < 0.03) and overall survival (p < 0.04). Conclusion: CHCs are a novel and promising prognostic biomarker in uveal melanoma.

Background: The results of recent surveys indicate that more than 50% of the German population has experience with complementary and alternative medicine (CAM) or uses CAM regularly. This study investigated the CAM usage and CAM-related needs of hospitalized patients at university medical centres in the state of Baden-Württemberg, Germany., Methods: A multi-centre, paper-based, pseudonymous survey was carried out by the members of the Academic Centre for Complementary and Integrative Medicine. Patients of all ages, regardless of sex, diagnosis and treatment, who were hospitalized in the Department of Cardiology, Gastroenterology, Oncology, Gynaecology or Surgery at the university medical centres in Freiburg, Heidelberg, Tübingen and Ulm were eligible for inclusion., Results: Of the 1275 eligible patients, 67% (n = 854) consented to participate in the survey. Forty-eight percent of the study participants stated that they were currently using CAM. The most frequently used therapies were exercise (63%), herbal medicine (54%) and dietary supplements (53%). Only 16% of the patients discussed CAM usage with their attending physician. Half of the patients (48%) were interested in CAM consultations. More than 80% of the patients desired reliable CAM information and stated that physicians should be better informed about CAM., Conclusions: The frequency of CAM usage and the need for CAM counselling among hospitalized patients at university medical centres in Baden-Württemberg are high. To better meet patients' needs, CAM research and physician education should be intensified., Trial Registration: German Clinical Trial register ( DRKS00015445 )., (© 2021. The Author(s).)

Background: Complementary and integrative medical procedures (CIM) play an important role in general practice (GP). Consequently, in some countries (e.g. USA, Australia) specific curricula for the integration of CIM competencies in GP postgraduate education exist. Although Germany is one of the countries where CIM is strongly integrated in general practice, no such catalogue exists up to date. The aim of this study was to define a set of CIM competencies that are seen as relevant and feasible for postgraduate education in the German general practice setting., Methods: We used a multi-step, peer-based approach combining four different steps. Firstly, a survey among GP trainees (n = 138) was performed in order to assess needs and attitudes towards CIM. Then, existing competency-based CIM curricula were identified in international literature, translated into German and compared with the needs assessment from the survey. In a next step, we performed a survey among the CIM working group of the German Society for General Medicine and Family Medicine (DEGAM). As a last step, in a peer-based survey, GP trainers, GP trainees, and members of professional CIM associations (n = 131) evaluated a list of CIM competencies according to relevance and feasibility for general practice., Results: Within this multistage process, a final catalogue of 16 competencies was defined, covering the following areas: Medical knowledge, patient care and communication, practice-based learning, professionalism, and competencies based on the German healthcare system., Conclusion: The final catalogue of CIM competencies is intended to serve for GP training complementing the German competency-based curriculum for general practice. These competencies cover basic skills and are not intended to replace existing additional qualifications awarded by the medical associations in specific CIM methods, such as acupuncture or manual medicine. Therefore, a list of relevant competencies on CIM is available in order to serve as add-on for postgraduate education in general practice in Germany., (© 2021. The Author(s).)

Neurobehavioral studies have produced contradictory findings concerning the function of neurogenesis in the adult dentate gyrus. Previous studies have proved inconsistent across several behavioral endpoints thought to be dependent on dentate neurogenesis, including memory acquisition, short-term and long-term retention of memory, pattern separation, and reversal learning. We hypothesized that the main function of dentate neurogenesis is long-term memory formation because we assumed that a newly formed and integrated neuron would have a long-term impact on the local neural network. We used a cyclin D2-knock-out (cyclin D2 -/- ) mouse model of endogenously deficient dentate neurogenesis to test this hypothesis. We found that cyclin D2 -/- mice had robust and sustained loss of long-term memory in two separate behavioral tasks, Morris water maze (MWM) and touchscreen intermediate pattern separation. Moreover, after adjusting for differences in brain volumes determined by magnetic resonance (MR) imaging, reduced dentate neurogenesis moderately correlated with deficits in memory retention after 24 hours. Importantly, cyclin D2 -/- mice did not show deficits in learning acquisition in a touchscreen paradigm of intermediate pattern separation or MWM platform location, indicating intact short-term memory. Further evaluation of cyclin D2 -/- mice is necessary to confirm that deficits are specifically linked to dentate gyrus neurogenesis since cyclin D2 -/- mice also have a reduced size of the olfactory bulb, hippocampus, cerebellum and cortex besides reduced dentate gyrus neurogenesis.

Although banned from production for decades, PCBs remain a significant risk to human health. A primary target of concern is the developing brain. Epidemiological studies link PCB exposures in utero or during infancy to increased risk of neuropsychiatric deficits in children. Nonclinical studies of legacy congeners found in PCB mixtures synthesized prior to the ban on PCB production suggest that non-dioxin-like (NDL) congeners are predominantly responsible for the developmental neurotoxicity associated with PCB exposures. Mechanistic studies suggest that NDL PCBs alter neurodevelopment via ryanodine receptor-dependent effects on dendritic arborization. Lightly chlorinated congeners, which were not present in the industrial mixtures synthesized prior to the ban on PCB production, have emerged as contemporary environmental contaminants, but there is a paucity of data regarding their potential developmental neurotoxicity. PCB 11, a prevalent contemporary congener, is found in the serum of children and their mothers, as well as in the serum of pregnant women at increased risk for having a child diagnosed with a neurodevelopmental disorder (NDD). Recent data demonstrates that PCB 11 modulates neuronal morphogenesis via mechanisms that are convergent with and divergent from those implicated in the developmental neurotoxicity of legacy NDL PCBs. This review summarizes these data and discusses their relevance to adverse neurodevelopmental outcomes in humans.

Despite being banned from production for decades, polychlorinated biphenyls (PCBs) continue to pose a significant risk to human health. This is due to not only the continued release of legacy PCBs from PCB-containing equipment and materials manufactured prior to the ban on PCB production, but also the inadvertent production of PCBs as byproducts of contemporary pigment and dye production. Evidence from human and animal studies clearly identifies developmental neurotoxicity as a primary endpoint of concern associated with PCB exposures. However, the relative role(s) of specific PCB congeners in mediating the adverse effects of PCBs on the developing nervous system, and the mechanism(s) by which PCBs disrupt typical neurodevelopment remain outstanding questions. New questions are also emerging regarding the potential developmental neurotoxicity of lower chlorinated PCBs that were not present in the legacy commercial PCB mixtures, but constitute a significant proportion of contemporary human PCB exposures. Here, we review behavioral and mechanistic data obtained from experimental models as well as recent epidemiological studies that suggest the non-dioxin-like (NDL) PCBs are primarily responsible for the developmental neurotoxicity associated with PCBs. We also discuss emerging data demonstrating the potential for non-legacy, lower chlorinated PCBs to cause adverse neurodevelopmental outcomes. Molecular targets, the relevance of PCB interactions with these targets to neurodevelopmental disorders, and critical data gaps are addressed as well., Competing Interests: The authors declare no conflicts of interest.

Background: The number of persons living with dementia will increase. So far, pharmacological management is limited because of small effect sizes and side effects of the drugs. Therefore, it is important to assess non-pharmacological treatment options such as massage, which have nearly no side effects and are easy for caregivers to apply., Objectives: To conduct a systematic review with meta-analysis, aiming to pool the evidence for the efficacy of manual massage for persons living with dementia., Design: A systematic review and meta-analysis., Data Sources: EMBASE, Medline, PubMed, PSYinfo, BIOSIS, EBM, PSYCINDEX, Osteopathic Research Web, and OSTMED.DR were searched, regardless of publication year, through August 2017., Review Methods: Randomized controlled trials (RCTs) evaluating manual massage in patients with dementia with or without using (aromatic) oil were included. The intervention of the control group had to guarantee no physical contact between caregiver and patient. Only studies assessing behavioural and psychological symptoms of dementia, cognitive abilities or depressive symptoms with validated instruments were included. Two reviewers independently extracted data and assessed risk of bias using The Cochrane Collaboration's 'Risk of bias' tool. Continuous outcomes are given as standardized mean difference (SMD), with 95% confidence intervals (CI) if different scaling of outcome measurement was used, and as mean difference (MD), with 95% confidence intervals (CI) for identical scaling. Data were pooled using the random-effects model. Sensitivity analysis considered type of massage, oil and outcome. Funnel plots were performed., Results: Eleven RCTs, with a total of 825 persons living with dementia, were eligible for qualitative synthesis and nine for quantitative synthesis. Two studies, with a total of 95 participants, had a high risk of bias. A pooled analysis of the mean change showed a benefit of manual massage compared to the control group using the Cohen Mansfield Agitation Inventory (SMD = -0.56, 95% CI [-0.95, -0.17], P = 0.005), which included six studies with 395 participants, and using the Cornell Scale of Depression in Dementia (MD = -6.14 [-8.66, -3.61], P < 0.00001), which included three studies with 193 participants. No significant effect could be demonstrated using the Neuropsychiatric Inventory and Mini Mental State Examination. Subgroup analysis of 'acupressure' did not show significant group differences., Conclusions: Manual massage may serve as a non-pharmacological strategy to improve behavioural and psychological symptoms in persons living with dementia. Thus, healthcare professionals and family caregivers should be encouraged to apply massage to their patients and relatives. More research is needed, however, to provide clearer recommendations with respect to frequency and types of massage., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Epidemiological studies have reported associations of air pollution exposures with various neurodevelopmental disorders such as autism spectrum disorder (ASD), attention deficit and schizophrenia, all of which are male-biased in prevalence. Our studies of early postnatal exposure of mice to the ultrafine particle (UFP) component of air pollution, considered the most reactive component, provide support for these epidemiological associations, demonstrating male-specific or male-biased neuropathological changes and cognitive and impulsivity deficits consistent with these disorders. Since these neurodevelopmental disorders also include altered social behavior and communication, the current study examined the ability of developmental UFP exposure to reproduce these social behavior deficits and to determine whether any observed alterations reflected changes in steroid hormone concentrations. Elevated plus maze, social conditioned place preference, and social novelty preference were examined in adult mice that had been exposed to concentrated (10-20x) ambient UFPs averaging approximately 45 ug/m 3 particle mass concentrations from postnatal day (PND) 4-7 and 10-13 for 4 h/day. Changes in serum testosterone (T) and corticosterone where measured at postnatal day (P)14 and approximately P120. UFP exposure decreased serum T concentrations on PND 14 and social nose-to-nose sniff rates with novel males in adulthood, suggesting social communication deficits in unfamiliar social contexts. Decreased sniff rates were not accounted for by alterations in fear-mediated behaviors and occurred without overt deficits in social preference, recognition or communication with a familiar animal or alterations in corticosterone. Adult T serum concentrations were positively correlated with nose to nose sniff rates. Collectively, these studies confirm another feature of male-biased neurodevelopmental disorders following developmental exposures to even very low levels of UFP air pollution that could be related to alterations in sex steroid programming of brain function., (Copyright © 2018. Published by Elsevier B.V.)

Accumulating evidence indicates the developing central nervous system (CNS) is a target of air pollution toxicity. Epidemiological reports increasingly demonstrate that exposure to the particulate matter (PM) fraction of air pollution during neurodevelopment is associated with an increased risk of neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD). These observations are supported by animal studies demonstrating prenatal exposure to concentrated ambient PM induces neuropathologies characteristic of ASD, including ventriculomegaly and aberrant corpus callosum (CC) myelination. Given the role of the CC and cerebellum in ASD etiology, this study tested whether prenatal exposure to concentrated ambient particles (CAPs) produced pathological features in offspring CC and cerebella consistent with ASD. Analysis of cerebellar myelin density revealed male-specific hypermyelination in CAPs-exposed offspring at postnatal days (PNDs) 11-15 without alteration of cerebellar area. Atomic absorption spectroscopy (AAS) revealed elevated iron (Fe) in the cerebellum of CAPs-exposed female offspring at PNDs 11-15, which connects with previously observed elevated Fe in the female CC. The presence of Fe inclusions, along with aluminum (Al) and silicon (Si) inclusions, were confirmed at nanoscale resolution in the CC along with ultrastructural myelin sheath damage. Furthermore, RNAseq and gene ontology (GO) enrichment analyses revealed cerebellar gene expression was significantly affected by sex and prenatal CAPs exposure with significant enrichment in inflammation and transmembrane transport processes that could underlie observed myelin and metal pathologies. Overall, this study highlights the ability of PM exposure to disrupt myelinogenesis and elucidates novel molecular targets of PM-induced developmental neurotoxicity.

Accumulating studies indicate that the brain is a direct target of air pollution exposure during the fetal period. We have previously demonstrated that exposure to concentrated ambient particles (CAPs) during gestation produces ventriculomegaly, periventricular hypermyelination, and enlargement of the corpus callosum (CC) during postnatal development in mice. This study aimed to further characterize the cellular basis of the observed hypermyelination and determine if this outcome, among other effects, persisted as the brain matured. Analysis of CC-1 + mature oligodendrocytes in the CC at postnatal days (PNDs) 11-15 suggest a premature maturational shift in number and proportion of total cells in prenatally CAPs-exposed males and females, with no overall change in total CC cellularity. The overall number of Olig2 + lineage cells in the CC was not affected in either sex at the same postnatal timepoint. Assessment of myelin status at early brain maturity (PNDs 57-61) revealed persistent hypermyelination in CAPs-exposed animals of both sexes. In addition, ventriculomegaly was persistent in CAPs-treated females, with possible amelioration of ventriculomegaly in CAPs-exposed males. When oligodendrocyte precursor cell (OPC) pool status was analyzed at PNDs 57-61, there were significant CAPs-induced alterations in cycling Ki67 + /Olig2 + cell number and proportion of total cells in the female CC. Total CC cellularity was slightly elevated in CAPs-exposed males at PNDs 57-61. Overall, these data support a growing body of evidence that demonstrate the vulnerability of the developing brain to environmental insults such as ambient particulate matter. The sensitivity of oligodendrocytes and myelin, in particular, to such an insult warrants further investigation into the mechanistic underpinnings of OPC and myelin disruption by constituent air pollutants., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Increasing evidence indicates that the central nervous system (CNS) is a target of air pollution. We previously reported that postnatal exposure of mice to concentrated ambient ultrafine particles (UFP; ≤100 nm) via the University of Rochester HUCAPS system during a critical developmental window of CNS development, equivalent to human 3rd trimester, produced male-predominant neuropathological and behavioral characteristics common to multiple neurodevelopmental disorders, including autism spectrum disorder (ASD), in humans. The current study sought to determine whether vulnerability to fine (≤2.5 μm) and UFP air pollution exposure extends to embryonic periods of brain development in mice, equivalent to human 1st and 2nd trimesters. Pregnant mice were exposed 6 h/day from gestational days (GDs) 0.5-16.5 using the New York University VACES system to concentrated ambient fine/ultrafine particles at an average concentration of 92.69 μg/m3 over the course of the exposure period. At postnatal days (PNDs) 11-15, neuropathological consequences were characterized. Gestational air pollution exposures produced ventriculomegaly, increased corpus callosum (CC) area and reduced hippocampal area in both sexes. Both sexes demonstrated CC hypermyelination and increased microglial activation and reduced total CC microglia number. Analyses of iron deposition as a critical component of myelination revealed increased iron deposition in the CC of exposed female offspring, but not in males. These findings demonstrate that vulnerability of the brain to air pollution extends to gestation and produces features of several neurodevelopmental disorders in both sexes. Further, they highlight the importance of the commonalities of components of particulate matter exposures as a source of neurotoxicity and common CNS alterations., (© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Prenatal stress and nutrition are well-known to alter a broad range of physiological systems, notably metabolic, endocrine and neurobehavioral function. Commonly used methods for oral administration of xenobiotics can, by acting as a stressor or altering normal nutrition intake, alter these physiological systems as well. Taken together, oral administration methods may unintentionally introduce confounding physiological effects that can mask or enhance toxicity of xenobiotics, particularly if they share biological targets. Consequently, it should be preferable to develop alternative methods without these potential confounds. The aim of this study was to determine the suitability of mealworms as an alternative treat-based method to deliver xenobiotics via the orogastric route. Accurate oral administration is contingent on motivation and preference; mice reliably preferred mealworms over wafer cookie treats. Further, ingestion of wafer cookies significantly increased mouse blood glucose levels, whereas unaltered mealworms produced no such change. Mealworms functioned effectively to orally administer glucose, as glucose-spiked mealworms produced a rise in blood glucose equivalent to the ingestion of the wafer cookie. Mealworms did not interfere with the physiological function of orally administered d-amphetamine, as both mealworm and oral gavage administered d-amphetamine showed similar alterations in locomotor behavior (mice did not fully consume d-amphetamine-dosed cookies and thus could not be compared). Collectively, the findings indicate that mealworms are a preferred and readily consumed treat, which importantly mimics environmental-relevant nutritional intake, and mealworms per se do not alter glucose metabolic pathways. Additionally, mealworms accurately delivered xenobiotics into blood circulation and did not interfere with the physiological function of administered xenobiotics. Thus mealworm-based oral administration may be a preferable and accurate route of xenobiotic administration that eliminates physiological alterations associated with other methods of delivery., (Copyright © 2016. Published by Elsevier Inc.)

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a halogenated aromatic hydrocarbon that elicits toxicity through the aryl hydrocarbon receptor (AhR). In the liver, gross markers of TCDD toxicity are attributed to AhR activation in parenchymal hepatocytes. However, less is known regarding the consequences of TCDD treatment on non-parenchymal cells in the liver. Hepatic stellate cells (HSCs) are non-parenchymal cells that store vitamin A when quiescent. Upon liver injury, activated HSCs lose this storage ability and instead function in the development and maintenance of inflammation and fibrosis through the production of pro-inflammatory mediators and collagen type I. Reports that TCDD exposure disrupts hepatic retinoid homeostasis and dysregulates extracellular matrix remodeling in the liver led us to speculate that TCDD treatment may disrupt HSC activity. The human HSC line LX-2 was used to test the hypothesis that TCDD treatment directly activates HSCs. Results indicate that exposure to 10nM TCDD almost completely inhibited lipid droplet storage in LX-2 cells cultured with retinol and palmitic acid. TCDD treatment also increased LX-2 cell proliferation, expression of α-smooth muscle actin, and production of monocyte chemoattractant protein-1 (MCP-1), all of which are characteristics of activated HSCs. However, TCDD treatment had no effect on Col1a1 mRNA levels in LX-2 cells stimulated with the potent profibrogenic mediator, transforming growth factor-β. The TCDD-mediated increase in LX-2 cell proliferation, but not MCP-1 production, was abolished when phosphoinositide 3-kinase was inhibited. These results indicate that HSCs are susceptible to direct modulation by TCDD and that TCDD likely increases HSC activation through a multi-faceted mechanism., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Ubiquitin-calmodulin ligase (uCaM synthetase: EC 6.3.2.21), which has been detected in all tissues so far examined, catalyzes the Ca2+-dependent reversible synthesis of ubiquityl-calmodulin which is not directed to degradation by the ATP-dependent 26-S protease [Laub, M. & Jennissen, H. P. (1997) Biochim. Biophys. Acta 1357, 173-191]. As has been shown in the preceding paper in this journal, the uCaM synthetase holosystem can be separated into two essential protein components: uCaM Syn-F1, a ubiquitin-binding protein belonging to the ubiquitin-activating enzyme family (E1) and uCaM Syn-F2 which bestows the reaction specificity leading to the covalent modification of calmodulin with ubiquitin. UCaM Syn-F2, which binds to calmodulin-Sepharose in a Ca2+-dependent manner, has been purified over 3500-fold in seven steps from rabbit reticulocytes and has a native molecular mass of approximately 620 kDa. It binds calmodulin with a Km of 5 microM and to uCaM Syn-F1, i.e. ubiquitin-activating enzyme (E1), with a Km of 3 nM. The maximal specific activity obtained in enriched uCaM Syn-F2 is 6-8 pkat/mg. The pH optimum of uCaM synthetase lies at pH 8.5. In kinetic experiments the Km values for 125I-ubiquitin and ATP/Mg2+ were determined to be 8 microM and 16 nM, respectively, for the uCaM synthetase holosystem. The existence of a third separable protein component of uCaM synthetase, as is the case in E1, E2, E3 systems, is very unlikely since affinity chromatography on calmodulin-Sepharose, two ion-exchange chromatography steps and finally a gel-filtration step failed to indicate any additional protein component essential for synthetase activity. We therefore propose a two-component model for uCaM synthetase. This model is also supported by simple hyperbolic velocity curves in kinetic experiments based on the variation of these two components. The data suggests that uCaM Syn-F2 is neither an E2 nor an E3 but evidently combines the properties of both, making the Ca2+-dependent uCaM synthetase the member of a group of two-component ubiquitin ligase systems.