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This paper deals with a methodology for the implementation of cloud manufacturing (CM) architecture. CM is a current paradigm in which dynamically scalable and virtualized resources are provided to users as services over the Internet. CM is based on the concept of coud computing, which is essential in the Industry 4.0 trend. A CM architecture is employed to map users and providers of manufacturing resources. It reduces costs and development time during a product lifecycle. Some providers use different descriptions of their services, so we propose taking advantage of semantic web technologies such as ontologies to tackle this issue. Indeed, robust tools are proposed for mapping providers’ descriptions and user requests to find the most appropriate service. The ontology defines the stages of the product lifecycle as services. It also takes into account the features of coud computing (storage, computing capacity, etc.). The CM ontology will contribute to intelligent and automated service discovery. The proposed methodology is inspired by the ASDI framework (analysis–specification–design–implementation), which has already been used in the supply chain, healthcare and manufacturing domains. The aim of the new methodology is to propose an easy method of designing a library of components for a CM architecture. An example of the application of this methodology with a simulation model, based on the CloudSim software, is presented. The result can be used to help the industrial decision-makers who want to design CM architectures.

Despite recent advances in the treatment of melanoma, many patients with metastatic disease still succumb to their disease. To identify tumor-intrinsic modulators of immunity to melanoma, we performed a whole-genome CRISPR screen in melanoma and identified Setdb1 as well as all components of the human silencing hub complex. We found that loss of Setdb1 leads to increased immunogenicity and complete tumor clearance in a CD8+ T cell-dependent manner. Mechanistically, loss of Setdb1 causes de-repression of endogenous retroviruses (ERV) in melanoma cells and triggers tumor cell-intrinsic type I IFN signaling, upregulation of MHC-I expression, and increased CD8+ T-cell infiltration. Importantly, spontaneous immune clearance observed in Setdb1-/- tumors results in subsequent protection from other ERV-expressing tumor lines, supporting the functional antitumor role of ERV-specific CD8+ T cells found in the Setdb1-/- microenvironment. Blocking the type I IFN receptor in mice grafted with Setdb1-/- tumors decreases immunogenicity by decreasing MHC-I expression, leading to decreased T-cell infiltration and increased melanoma growth, comparable with Setdb1wt tumors. Together, these results provide key in vivo evidence of a critical role for Setdb1 and type I IFNs in generating an inflamed tumor microenvironment and potentiating tumor cell-intrinsic immunogenicity in melanoma. This study further emphasizes regulators of ERV expression and type I IFN expression as potential therapeutic targets for augmenting anticancer immune responses., (©2024 American Association for Cancer Research.)

Context: Nonsmall Cell Lung Cancer (NSCLC) treatment relies on first-line immunotherapy as single agent or combined with chemotherapy. Oligoprogression may be observed in this setting., Material and Method: We performed a European multicentric retrospective study on patients treated with first-line immunotherapy, who presented with oligoprogressive disease, treated with a local ablative treatment., Results: A total of 61 patients were retrospectively included between 2018 and 2022. Twenty-four patients (39%) received immunotherapy as single agent, and 37 (61%) chemo-immunotherapy. First oligoprogression occurred more frequently in pre-existing metastatic sites (47% of patients). Median PFS1 (defined as time to first oligoprogression) was 11.5 months [IC95%: 10.0-12.3]. We observed that 37 patients (61%) progressed after first oligoprogression, and 20 (54%) from them presented second oligoprogression. Median OS for the whole cohort was 72.0 months [IC95%: 19.3-124.8], with positive correlation between OS and PFS1 (R=0.65, P < .0001). After loco-ablative treatment with radiotherapy, disease control rate was 89% with ablative radiotherapy: 88% with conventional radiotherapy, and 89% with stereotactic radiotherapy., Conclusion: Patients with oligoprogression under/after immunotherapy have better prognosis with a high risk of subsequent oligoprogression., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Thyroid cancers are on the rise, but the associated vital prognosis and long-term survival rates are very good. Therefore, treated patients' quality of life and psychological well-being are important considerations. The treatment usually involves surgery and radioactive iodine (radioiodine) ablation. This study aims to investigate potential effects of radioiodine ablation therapy on health-related quality of life, anxiety and depression symptoms, and nutritional status at 6 months post-therapy., Methods: This study included 136 patients diagnosed with thyroid cancer. Absorbed doses to the salivary glands were estimated from dosimeters worn by patients. Patient health-related quality of life, psychological status and nutritional status were assessed before and 6 months after therapy using standardized questionnaires (including SF-36, Hospital Anxiety and Depression (HAD) scale). Statistical analyses included random-effects logistic and linear regressions adjusted for potential confounders., Results: While no significant association was found between radioiodine exposure and anxiety or depression symptoms, or nutritional status, a significant increase in the SF-36 role physical sub- score was observed in relation with the salivary gland dose (β= 6.54, 95%CI 2.71;10.36 for a 1-Gy increase)., Conclusions: The findings suggest an improved physical health-related quality of life, namely reduced pain and functional impairment, 6 months after radioiodine therapy in thyroid cancer patients. No significant association was found between radioiodine exposure and mental health-related quality of life, anxiety or depression scores nor nutritional status. This study does not provide any evidence that radioiodine therapy has a potentially adverse effect on patient health-related quality of life., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Ultra-high dose rate external beam radiotherapy (UHDR-RT) uses dose rates of several tens to thousands of Gy/s, compared with the dose rate of the order of a few Gy/min for conventional radiotherapy techniques, currently used in clinical practice. The use of such dose rate is likely to improve the therapeutic index by obtaining a radiobiological effect, known as the "FLASH" effect. This would maintain tumor control while enhancing tissues protection. To date, this effect has been achieved using beams of electrons, photons, protons, and heavy ions. However, the conditions required to achieve this "FLASH" effect are not well defined, and raise several questions, particularly with regard to the definition of the prescription, including dose fractionation, irradiated volume and the temporal structure of the pulsed beam. In addition, the dose delivered over a very short period induces technical challenges, particularly in terms of detectors, which must be mastered to guarantee safe clinical implementation. IRSN has carried out an in-depth literature review of the UHDR-RT technique, covering various aspects relating to patient radiation protection: the radiobiological mechanisms associated with the FLASH effect, the used temporal structure of the UHDR beams, accelerators and dose control, the properties of detectors to be used with UHDR beams, planning, clinical implementation, and clinical studies already carried out or in progress., (Copyright © 2024 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Background: Risk management programs targeting women with genetic predispositions to breast cancer (BC), eg, BRCA1 and BRCA2, are effective assuming full adherence with the program protocol. However, high risk to BC in women and equal access to care may not result in high and uniform adherence with the program., Objective: To elucidate factors influencing adherence with screening program in women with genetic predispositions to BC., Material and Methods: We retrieved data from a multicenter pathogenic-related BC surveillance program across 4 French regions. We used multilevel logistic modeling to analyze factors of adherence with the program, with "on-time" or postponed screening as the dependent variable., Results: Seven hundred and seventy-eight participants were followed for a 4.7-year median. We observed 2796 annual screening rounds and 5.4% postponed rounds with a 6-month margin. Women with prevalent BC and carriers of BRCA1 and BRCA2 mutations did not have on-time annual screenings any more than women low cancer risk. Better adherence was observed with screenings after the 2nd round, with higher total number of rounds. Having one or more recalls was significantly associated with worse adherence. No contextual factors affected adherence. Furthermore, postponed rounds increased between 2018 and 2020 compared to 2015 and 2017., Conclusion: Having a higher BC risk status does not result in better adherence to the risk management program. However, factors directly related to screening rounds reduced postponements. Future research should address the benefits of screening-related organizational factors that contribute to adherence improvement., (© The Author(s) 2024. Published by Oxford University Press.)

Background: People with disabilities (PWD) commonly experience difficulties in accessing their environments, which can lead to restricted participation in outdoor leisure-time physical activity. Participating in outdoor leisure-time physical activity (OLTPA) provides health and social benefits to PWD and benefits to the communities in which they live., Objective: The aim of the study was to identify features existing in digital platforms that facilitate access to OLTPA for PWD., Methods: A scoping review was conducted in four library databases and in Google advance search to identify relevant scientific and grey literature, and websites. Each step of the review was independently conducted by two co-authors who confirmed consensus of results. Descriptive data analyses were performed., Results: Seven scientific studies and ten websites were included in the scoping review. Seven presented mobile apps, nine presented a website and one presented an online database. Sources reported five main obstacles to using digital platforms that support access to physical activities (e.g., lack of digital literacy, technical issues, unintuitive design), and 10 facilitators (e.g., possibility to personalize your online space, accessibility features of the navigation). Among these sources, a trend emerged in the most important factors and features to consider for the visuals and navigation of the platforms., Conclusion: The features of digital platforms that facilitate access to OLTPA include intuitive design compliant with accessibility guidelines and supported by navigation tools, personalization of the online space, and features for social interactions., Competing Interests: Declaration of competing interest All authors confirm that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: In order to ensure adequate radiation protection of critical groups such as staff, caregivers and the general public coming into proximity of nuclear medicine (NM) patients, it is necessary to consider the impact of the radiation emitted by the patients during their stay at the hospital or after leaving the hospital. Current risk assessments are based on ambient dose rate measurements in a single position at a specified distance from the patient and carried out at several time points after administration of the radiopharmaceutical to estimate the whole-body retention. The limitations of such an approach are addressed in this study by developing and validating a more advanced computational dosimetry approach using Monte Carlo (MC) simulations in combination with flexible and realistic computational phantoms and time activity distribution curves from reference biokinetic models., Results: Measurements of the ambient dose rate equivalent Ḣ * (10) at 1 m from the NM patient have been successfully compared against MC simulations with 5 different codes using the ICRP adult reference computational voxel phantoms, for typical clinical procedures with 99m Tc-HDP/MDP, 18 FDG and Na 131 I. All measurement data fall in the 95% confidence intervals, determined for the average simulated results. Moreover, the different MC codes (MCNP-X, PHITS, GATE, GEANT4, TRIPOLI-4®) have been compared for a more realistic scenario where the effective dose rate Ė of an exposed individual was determined in positions facing and aside the patient model at 30 cm, 50 cm and 100 cm. The variation between codes was lower than 8% for all the radiopharmaceuticals at 1 m, and varied from 5 to 16% for the face-to face and side-by-side configuration at 30 cm and 50 cm. A sensitivity study on the influence of patient model morphology demonstrated that the relative standard deviation of Ḣ * (10) at 1 m for the range of included patient models remained under 16% for time points up to 120 min post administration., Conclusions: The validated computational approach will be further used for the evaluation of effective dose rates per unit administered activity for a variety of close-contact configurations and a range of radiopharmaceuticals as part of risk assessment studies. Together with the choice of appropriate dose constraints this would facilitate the setting of release criteria and patient restrictions., (© 2024. The Author(s).)

Purpose: To assess a large panel of MR compatible detectors on the full range of measurements required for a 0.35 T MR-linac commissioning by using a specific statistical method represented as a continuum of comparison with the Monte Carlo (MC) TPS calculations. This study also describes the commissioning tests and the secondary MC dose calculation validation., Material and Methods: Plans were created on the Viewray TPS to generate MC reference data. Absolute dose points, PDD, profiles and output factors were extracted and compared to measurements performed with ten different detectors: PTW 31010, 31021, 31022, Markus 34045 and Exradin A28 MR ionization chambers, SN Edge shielded diode, PTW 60019 microdiamond, PTW 60023 unshielded diode, EBT3 radiochromic films and LiF µcubes. Three commissioning steps consisted in comparison between calculated and measured dose: the beam model validation, the output calibration verification in four different phantoms and the commissioning tests recommended by the IAEA-TECDOC-1583., Main Results: The symmetry for the high resolution detectors was higher than the TPS data of about 1%. The angular responses of the PTW 60023 and the SN Edge were - 6.6 and - 11.9% compared to the PTW 31010 at 60°. The X/Y-left and the Y-right penumbras measured by the high resolution detectors were in good agreement with the TPS values except for the PTW 60023 for large field sizes. For the 0.84 × 0.83 cm 2 field size, the mean deviation to the TPS of the uncorrected OF was - 1.7 ± 1.6% against - 4.0 ± 0.6% for the corrected OF whereas we found - 4.8 ± 0.8% for passive dosimeters. The mean absolute dose deviations to the TPS in different phantoms were 0 ± 0.4%, - 1.2 ± 0.6% and 0.5 ± 1.1% for the PTW 31010, PTW 31021 and Exradin A28 MR respectively., Conclusions: The magnetic field effects on the measurements are considerably reduced at low magnetic field. The PTW 31010 ionization chamber can be used with confidence in different phantoms for commissioning and QA tests requiring absolute dose verifications. For relative measurements, the PTW 60019 presented the best agreement for the full range of field size. For the profile assessment, shielded diodes had a behaviour similar to the PTW 60019 and 60023 while the ionization chambers were the most suitable detectors for the symmetry. The output correction factors published by the IAEA TRS 483 seem to be applicable at low magnetic field pending the publication of new MR specific values., (© 2024. The Author(s).)

The filamentous actin (F-actin) cytoskeleton is a composite material consisting of cortical actin and bundled F-actin stress fibers, which together mediate the mechanical behaviors of the cell, from cell division to cell migration. However, as mechanical forces are typically measured upon transmission to the extracellular matrix, the internal distribution of forces within the cytoskeleton is unknown. Likewise, how distinct F-actin architectures contribute to the generation and transmission of mechanical forces is unclear. Therefore, we have developed a molecular tension sensor that embeds into the F-actin cytoskeleton. Using this sensor, we measure tension within stress fibers and cortical actin, as the cell is subject to uniaxial stretch. We find that the mechanical response, as measured by FRET, depends on the direction of applied stretch relative to the cell's axis of alignment. When the cell is aligned parallel to the direction of the stretch, stress fibers and cortical actin both accumulate tension. By contrast, when aligned perpendicular to the direction of stretch, stress fibers relax tension while the cortex accumulates tension, indicating mechanical anisotropy within the cytoskeleton. We further show that myosin inhibition regulates this anisotropy. Thus, the mechanical anisotropy of the cell and the coordination between distinct F-actin architectures vary and depend upon applied load., (© 2023. The Author(s).)

Many people living with diabetes also have nonalcoholic fatty liver disease (NAFLD). Interleukin-6 (IL-6) is involved in both diseases, interacting with both membrane-bound (classical) and circulating (trans-signaling) soluble receptors. We investigated whether secretion of IL-6 trans-signaling coreceptors are altered in NAFLD by diabetes and whether this might associate with the severity of fatty liver disease. Secretion patterns were investigated with use of human hepatocyte, stellate, and monocyte cell lines. Associations with liver pathology were investigated in two patient cohorts: 1) biopsy-confirmed steatohepatitis and 2) class 3 obesity. We found that exposure of stellate cells to high glucose and palmitate increased IL-6 and soluble gp130 (sgp130) secretion. In line with this, plasma sgp130 in both patient cohorts positively correlated with HbA1c, and subjects with diabetes had higher circulating levels of IL-6 and trans-signaling coreceptors. Plasma sgp130 strongly correlated with liver stiffness and was significantly increased in subjects with F4 fibrosis stage. Monocyte activation was associated with reduced sIL-6R secretion. These data suggest that hyperglycemia and hyperlipidemia can directly impact IL-6 trans-signaling and that this may be linked to enhanced severity of NAFLD in patients with concomitant diabetes., Article Highlights: IL-6 and its circulating coreceptor sgp130 are increased in people with fatty liver disease and steatohepatitis. High glucose and lipids stimulated IL-6 and sgp130 secretion from hepatic stellate cells. sgp130 levels correlated with HbA1c, and diabetes concurrent with steatohepatitis further increased circulating levels of all IL-6 trans-signaling mediators. Circulating sgp130 positively correlated with liver stiffness and hepatic fibrosis. Metabolic stress to liver associated with fatty liver disease might shift the balance of IL-6 classical versus trans-signaling, promoting liver fibrosis that is accelerated by diabetes., (© 2023 by the American Diabetes Association.)

A 75-year-old woman with a history of chronic hydrocephalus due to stenosis of the aqueduct of Sylvius was examined at the emergency department for altered mental status. There was placement of a ventriculoperitoneal shunt in 1970 complicated by meningitis, leading to removal of the material and ventriculociternostomy as definitive treatment in 2004. About one month previously, she had undergone a laparoscopic cholecystectomy complicated by an intra-abdominal collection. Clinical examination at the emergency department revealed a Glasgow score of 8 (E3 V1 M4). In the emergency department the patient presented a tonic-clonic seizure before a cerebral CT scan was performed showing a massive compressive pneumocephalus, then a second seizure. The patient was finally admitted to the neurosurgery department and underwent surgery., Learning Points: Changes in mental status in a patient with a history of chronic hydrocephalus should alert clinicians to a possible complication.This case reflects the delayed diagnosis of a critically ill patient in the emergency department., Competing Interests: Conflicts of Interests: The Authors declare that there are no competing interests., (© EFIM 2023.)

It is well known that foetuses are highly sensitive to ionising radiation and special attention to justification and optimisation of radiological procedures involving a pregnant patient is required. A task to review, validate and compare different approaches to managing the pregnant patient and to estimating the associated foetal doses arising from a diagnostic or interventional radiology (DIR) procedure was designed in the framework of EURADOS working group 12. As a first step, a survey of radiation protection practice including dosimetry considerations among EURADOS members was performed using online questionnaire. Then, to evaluate the possible differences in the estimated foetal doses, a comparison of assessed dose values was made for three cases of pregnant patients that underwent different CT procedures. More than 120 professionals from 108 institutions and 17 countries that are involved in managing pregnant patients undergoing DIR procedures answered the questionnaire. Most of the respondents use national or hospital guidelines on the management of pregnant patients undergoing DIR procedures. However, the guidelines differ considerably among respondents. Comparison of foetal dose assessments performed by dosimetry experts showed the variety of methods used as well as large variability of estimated foetal doses in all three cases. Although European and International commission on radiation protection guidelines already exist, they are more than 20 years old and, in some aspects, they are obsolete. This paper shows that there is a need to revise and update these guidelines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Background: Understanding of changes in salivary and lacrimal gland functions after radioactive iodine therapy ( 131 I-therapy) remains limited, and, to date, no studies have evaluated dose-response relationships between absorbed dose from 131 I-therapy and dysfunctions of these glands. This study investigates salivary/lacrimal dysfunctions in differentiated thyroid cancer (DTC) patients six months after 131 I-therapy, identifies 131 I-therapy-related risk factors for salivary/lacrimal dysfunctions, and assesses the relationships between 131 I-therapy radiation dose and these dysfunctions. Methods: A cohort study was conducted involving 136 DTC patients treated by 131 I-therapy of whom 44 and 92 patients received 1.1 and 3.7 GBq, respectively. Absorbed dose to the salivary glands was estimated using a dosimetric reconstruction method based on thermoluminescent dosimeter measurements. Salivary and lacrimal functions were assessed at baseline (T0, i.e., immediately before 131 I-therapy) and six months later (T6) using validated questionnaires and salivary samplings, with and without stimulation of the salivary glands. Statistical analyses included descriptive analyses and random-effects multivariate logistic and linear regressions. Results: There was no difference between T0 and T6 in the level of parotid gland pain, nor was there difference in the number of patients with hyposalivation, but there were significantly more patients with dry mouth sensation and dry eyes after therapy compared with baseline. Age, menopause, depression and anxiety symptoms, history of systemic disease, and not taking painkillers in the past three months were found to be significantly associated with salivary or lacrimal disorders. Significant associations were found between 131 I-exposure and salivary disorders adjusted on the previous variables: for example, per 1-Gy increase in mean dose to the salivary glands, odds ratio = 1.43 [CI 1.02 to 2.04] for dry mouth sensation, ß = -0.08 [CI -0.12 to -0.02] mL/min for stimulated saliva flow, and ß = 1.07 [CI 0.42 to 1.71] mmol/L for salivary potassium concentration. Conclusions: This study brings new knowledge on the relationship between the absorbed dose to the salivary glands from 131 I-therapy and salivary/lacrimal dysfunctions in DTC patients six months after 131 I-therapy. Despite the findings of some dysfunctions, the results do not show any obvious clinical disorders after the 131 I-therapy. Nevertheless, this study raises awareness of the risk factors for salivary disorders, and calls for longer follow-up. Clinical Trials Registration: Number NCT04876287 on the public website (ClinicalTrials.gov).

Despite recent advances in the treatment of melanoma, many patients with metastatic disease still succumb to their disease. To identify tumor-intrinsic modulators of immunity to melanoma, we performed a whole-genome CRISPR screen in melanoma and identified multiple components of the HUSH complex, including Setdb1 , as hits. We found that loss of Setdb1 leads to increased immunogenicity and complete tumor clearance in a CD8+ T-cell dependent manner. Mechanistically, loss of Setdb1 causes de-repression of endogenous retroviruses (ERVs) in melanoma cells and triggers tumor-cell intrinsic type-I interferon signaling, upregulation of MHC-I expression, and increased CD8+ T-cell infiltration. Furthermore, spontaneous immune clearance observed in Setdb1 -/- tumors results in subsequent protection from other ERV-expressing tumor lines, supporting the functional anti-tumor role of ERV-specific CD8+ T-cells found in the Setdb1 -/- microenvironment. Blocking the type-I interferon receptor in mice grafted with Setdb1 -/- tumors decreases immunogenicity by decreasing MHC-I expression, leading to decreased T-cell infiltration and increased melanoma growth comparable to Setdb1 wt tumors. Together, these results indicate a critical role for Setdb1 and type-I interferons in generating an inflamed tumor microenvironment, and potentiating tumor-cell intrinsic immunogenicity in melanoma. This study further emphasizes regulators of ERV expression and type-I interferon expression as potential therapeutic targets for augmenting anti-cancer immune responses.

Purpose: To evaluate the effectiveness of currently available radioprotective (RP) devices in reducing the dose to interventional cardiology staff, especially to the eye lens and brain., Methods: The performances of five RP devices (masks, caps, patient drapes, staff lead and lead-free aprons and Zero-Gravity (ZG) suspended radiation protection system) were assessed by means of Monte Carlo (MC) simulations. A geometry representative of an interventional cardiology setup was modelled and several configurations, including beam projections and staff distance from the source, were investigated. In addition, measurements on phantoms were performed for masks and drapes., Results: An average dose reduction of 65% and 25% to the eyes and the brain respectively was obtained for the masks by MC simulations but a strong influence of the design was observed. The cap effectiveness for the brain ranges on average between 13% and 37%. Nevertheless, it was shown that only some upper parts of the brain were protected. There was no significant difference between the effectiveness of lead and lead-free aprons. Of all the devices, the ZG system offered the highest protection to the brain and eye lens and a protection level comparable to the apron for the organs normally covered., Conclusion: All investigated devices showed potential for dose reduction to specific organs. However, for masks, caps and drapes, it strongly depends on the design, exposure conditions and staff position. Therefore, for a clinical use, it is recommended to evaluate their effectiveness in the planned conditions of use., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Fibronectin (FN) is an essential structural and regulatory component of the extracellular matrix (ECM), and its binding to integrin receptors supports cell adhesion, migration, and signaling. Here, using live-cell microscopy of fibroblasts expressing FN tagged with a pH-sensitive fluorophore, we show that FN is secreted predominantly at the ventral surface of cells in an integrin-independent manner. Locally secreted FN then undergoes β1 integrin-dependent fibrillogenesis. We find that the site of FN secretion is regulated by cell polarization, which occurs in bursts under stabilized lamellipodia at the leading edge. Moreover, analysis of FN secretion and focal adhesion dynamics suggest that focal adhesion formation precedes FN deposition and that deposition continues during focal adhesion disassembly. Lastly, we show that the polarized FN deposition in spreading and migrating cells requires both intact microtubules and myosin II-mediated contractility. Thus, while FN secretion does not require integrin binding, the site of exocytosis is regulated by membrane and cytoskeletal dynamics with secretion occurring after new adhesion formation., (© 2022 Huet-Calderwood et al.)

In a large retrospective study, we assessed the putative use of circulating microvesicles (MVs), as innovative biomarkers of radiation toxicity in a cohort of 208 patients with prostate adenocarcinoma overexposed to radiation. The level of platelet (P)-, monocyte (M)- and endothelial (E)-derived MVs were assessed by flow cytometry. Rectal bleeding toxicity scores were collected at the time of blood sampling and during the routine follow-up and were tested for association with MVs using a multivariate logistic regression. MVs dosimetric correlation was investigated using dose volume histograms information available for a subset of 36 patients. The number of PMVs was significantly increased in patients with highest toxicity grades compared to lower grades. Risk prediction analysis revealed that increased numbers of PMVs, and an increased amount of MMVs relative to EMVs, were associated with worst rectal bleeding grade compared to the time of blood sampling. Moreover, a significant correlation was found between PMV and MMV numbers, with the range of doses up to the median exposure (40 Gy) of bladder/rectum and anterior rectal wall, respectively. MVs could be considered as new biomarkers to improve the identification of patients with high toxicity grade and may be instrumental for the prognosis of radiation therapy complications., (© 2023. The Author(s).)

Controlled exocytosis and endocytosis of integrin adhesion receptors is required for normal cell adhesion, migration, and signaling. In this chapter, we describe the design of functional β1 integrins carrying extracellular fluorescent or chemically traceable tags (ecto-tag) and methods for their use to image β1 integrin trafficking in cells. We provide approaches to generate cells in which endogenous β1 integrins are replaced by ecto-tagged integrins containing a pH-sensitive fluorophore pHluorin or a HaloTag and describe strategies using photobleaching, selective extracellular/intracellular labeling, and chase, quenching, and blocking to reveal β1 integrin exocytosis, endocytosis, and recycling by live total internal reflection fluorescence (TIRF) microscopy., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: The study aim was to analyse the influence of the lead free cap on doses received by interventional cardiologists. The impact of lead free cap on doses to the head were evaluated in number of studies. As different methods used to assess the attenuation properties of protective cap can lead to ambiguous results, a detailed study was performed., Material and Methods: The effectiveness of a lead free cap in reducing the doses to the skin was assessed in clinic by performing measurements with thermoluminescent dosimeters attached inside and outside the cap first during individual coronary angiography (CA) or CA/percutaneous transluminal coronary angioplasty (CA/PTCA) procedures and then cumulated during few procedures of the same type. In order to investigate the effect of the cap on reducing the doses to the brain additional measurements were performed with a male Alderson Rando and polymethyl methacrylate (PMMA) phantoms representing the physician and the patient, respectively for different projections. The brain dose per procedure, annual and cumulated during entire working practice were estimated for both cases working with and without the cap., Results: The dose reduction factor (RF) for the skin (the quotient of doses outside and inside the cap) vary from 1.1 up to 4.0 in clinical conditions; on average 2.3-fold reduction is observed in the most exposed left temple. The RFs determined for the part of the head covered by the cap range from 1.4 to 1.8 while for the brain from 1.0 to 1.1 depending on the projection. The estimated annual brain dose for interventional cardiologist performing yearly 550 CA/PTCA procedures without any protective shields is 7.2 mGy and it is reduced with the lead free cap by an average factor of 1.1., Conclusions: The study results proved the considerable effectiveness of lead free cap to protect the skin but very limited to protect the brain. Int J Occup Med Environ Health. 2022;35(5):549-60., (This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.)

Background: Following radioiodine ( 131 I) therapy of differentiated thyroid cancer, the salivary glands may become inflamed, leading to dysfunctions and decreases in patients' nutritional status and quality of life. The incidence of these dysfunctions after 131 I-therapy is poorly known, and no clinical or genetic factors have been identified to date to define at-risk patients, which would allow the delivered activity to be adapted to the expected risk of salivary dysfunctions., Objective: The aims of this study are to estimate the incidence of salivary dysfunctions, and consequences on the quality of life and nutritional status for patients after 131 I-therapy; to characterize at-risk patients of developing posttreatment dysfunctions using clinical, biomolecular, and biochemical factors; and to validate a dosimetric method to calculate the dose received at the salivary gland level for analyzing the dose-response relationship between absorbed doses to salivary glands and salivary dysfunctions., Methods: This prospective study aims to include patients for whom 131 I-therapy is indicated as part of the treatment for differentiated thyroid cancer in a Paris hospital (40 and 80 patients in the 1.1 GBq and 3.7 GBq groups, respectively). The follow-up is based on three scheduled visits: at inclusion (T0, immediately before 131 I-therapy), and at 6 months (T6) and 18 months (T18) posttreatment. For each visit, questionnaires on salivary dysfunctions (validated French tool), quality of life (Hospital Anxiety and Depression scale, Medical Outcomes Study 36-Item Short Form Survey), and nutritional status (visual analog scale) are administered by a trained clinical research associate. At T0 and T6, saliva samples and individual measurements of the salivary flow, without and with salivary glands stimulation, are performed. External thermoluminescent dosimeters are positioned on the skin opposite the salivary glands and at the sternal fork immediately before 131 I administration and removed after 5 days. From the doses recorded by the dosimeters, an estimation of the dose received at the salivary glands will be carried out using physical and computational phantoms. Genetic and epigenetic analyses will be performed to search for potential biomarkers of the predisposition to develop salivary dysfunctions after 131 I-therapy., Results: A total of 139 patients (99 women, 71.2%; mean age 47.4, SD 14.3 years) were enrolled in the study between September 2020 and April 2021 (45 and 94 patients in the 1.1 GBq and 3.7G Bq groups, respectively). T6 follow-up is complete and T18 follow-up is currently underway. Statistical analyses will assess the links between salivary dysfunctions and absorbed doses to the salivary glands, accounting for associated factors. Moreover, impacts on the patients' quality of life will be analyzed., Conclusions: To our knowledge, this study is the first to investigate the risk of salivary dysfunctions (using both objective and subjective indicators) in relation to organ (salivary glands) doses, based on individual dosimeter records and dose reconstructions. The results will allow the identification of patients at risk of salivary dysfunctions and will permit clinicians to propose a more adapted follow-up and/or countermeasures to adverse effects., Trial Registration: ClinicalTrials.gov NCT04876287; https://clinicaltrials.gov/ct2/show/NCT04876287., International Registered Report Identifier (irrid): DERR1-10.2196/35565., (©Clémence Baudin, Charlotte Lussey-Lepoutre, Alice Bressand, Camille Buffet, Fabrice Menegaux, Marine Soret, David Broggio, Céline Bassinet, Christelle Huet, Gemma Armengol, Laurence Leenhardt, Marie-Odile Bernier. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 22.07.2022.)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Providing touch-massage care to children in child psychiatry is a process that requires specific learning and a certain psychological and emotional availability. In this context, clinical training in nursing provides tools and resources for the caregiver. This type of care consolidates the relationship of trust and lays the foundations of the helping relationship. The bodily approach allows to approach the awareness of the emotions and to bring appeasement., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Tousled-like kinases (TLKs) are nuclear serine-threonine kinases essential for genome maintenance and proper cell division in animals and plants. A major function of TLKs is to phosphorylate the histone chaperone proteins ASF1a and ASF1b to facilitate DNA replication-coupled nucleosome assembly, but how TLKs selectively target these critical substrates is unknown. Here, we show that TLK2 selectivity towards ASF1 substrates is achieved in two ways. First, the TLK2 catalytic domain recognizes consensus phosphorylation site motifs in the ASF1 C-terminal tail. Second, a short sequence at the TLK2 N-terminus docks onto the ASF1a globular N-terminal domain in a manner that mimics its histone H3 client. Disrupting either catalytic or non-catalytic interactions through mutagenesis hampers ASF1 phosphorylation by TLK2 and cell growth. Our results suggest that the stringent selectivity of TLKs for ASF1 is enforced by an unusual interaction mode involving mutual recognition of a short sequence motifs by both kinase and substrate., (© 2022. The Author(s).)

Objective: This study aimed to assess whether the hospital level of care where asphyxiated neonates treated with hypothermia were originally born influences their outcome., Study Design: We conducted a retrospective cohort study of all asphyxiated neonates treated with hypothermia in a large metropolitan area. Birth hospitals were categorized based on provincially predefined levels of care. Primary outcome was defined as death and/or brain injury on brain magnetic resonance imaging (adverse outcome) and was compared according to the hospital level of care., Results: The overall incidence of asphyxiated neonates treated with hypothermia significantly decreased as hospital level of care increased: 1 per 1,000 live births (109/114,627) in level I units; 0.9 per 1,000 live births (73/84,890) in level II units; and 0.7 per 1,000 live births (51/71,093) in level III units ( p  < 0.001). The rate of emergent cesarean sections and the initial pH within the first hour of life were significantly lower in level I and level II units compared with level III units (respectively, p  < 0.001 and p  = 0.002). In a multivariable analysis adjusting for the rates of emergent cesarean sections and initial pH within the first hour of life, being born in level I units was confirmed as an independent predictor of adverse outcome (adjusted odds ratio [OR] level I vs. level III 95% confidence interval [CI]: 2.13 [1.02-4.43], p  = 0.04) and brain injury (adjusted OR level I vs. level III 95% CI: 2.41 [1.12-5.22], p  = 0.02)., Conclusion: Asphyxiated neonates born in level I units and transferred for hypothermia treatment were less often born by emergent cesarean sections, had worse pH values within the first hour of life, and had a higher incidence of adverse outcome and brain injury compared with neonates born in level III units. Further work is needed to optimize the initial management of these neonates to improve outcomes, regardless of the location of their hospital of birth., Key Points: · The incidence of asphyxiated neonates treated with hypothermia varied by hospital level of care.. · Their rates of emergent cesarean sections and their initial pH within the first hour of life varied by hospital level of care.. · The hospital level of care was an independent predictor of their adverse outcome, defined as death and/or brain injury on brain MRI.., Competing Interests: None declared., (Thieme. All rights reserved.)

Free-breathing external beam radiotherapy remains challenging due to the complex elastic or irregular motion of abdominal organs, as imaging moving organs leads to the creation of motion blurring artifacts. In this paper, we propose a radial-based MRI reconstruction method from 3D free-breathing abdominal data using spatio-temporal geodesic trajectories, to quantify motion during radiotherapy. The prospective study was approved by the institutional review board and consent was obtained from all participants. A total of 25 healthy volunteers, 12 women and 13 men (38 years ± 12 [standard deviation]), and 11 liver cancer patients underwent imaging using a 3.0 T clinical MRI system. The radial acquisition based on golden-angle sparse sampling was performed using a 3D stack-of-stars gradient-echo sequence and reconstructed using a discretized piecewise spatio-temporal trajectory defined in a low-dimensional embedding, which tracks the inhale and exhale phases, allowing the separation between distinct motion phases. Liver displacement between phases as measured with the proposed radial approach based on the deformation vector fields was compared to a navigator-based approach. Images reconstructed with the proposed technique with 20 motion states and registered with the multiscale B-spline approach received on average the highest Likert scores for the overall image quality and visual SNR score 3.2 ± 0.3 (mean ± standard deviation), with liver displacement errors varying between 0.1 and 2.0 mm (mean 0.8 ± 0.6 mm). When compared to navigator-based approaches, the proposed method yields similar deformation vector field magnitudes and angle distributions, and with improved reconstruction accuracy based on mean squared errors. Schematic illustration of the proposed 4D-MRI reconstruction method based on radial golden-angle acquisitions and a respiration motion model from a manifold embedding used for motion tracking. First, data is extracted from the center of k-space using golden-angle sampling, which is then mapped onto a low-dimensional embedding, describing the relationship between neighboring samples in the breathing cycle. The trained model is then used to extract the respiratory motion signal for slice re-ordering. The process then improves the image quality through deformable image registration. Using a reference volume, the deformation vector field (DVF) of sequential motion states are extracted, followed by deformable registrations. The output is a 4DMRI which allows to visualize and quantify motion during free-breathing., (© 2021. International Federation for Medical and Biological Engineering.)

The need for personal protective equipment increased exponentially in response to the Covid-19 pandemic. To cope with the mask shortage during springtime 2020, a French consortium was created to find ways to reuse medical and respiratory masks in healthcare departments. The consortium addressed the complex context of the balance between cleaning medical masks in a way that maintains their safety and functionality for reuse, with the environmental advantage to manage medical disposable waste despite the current mask designation as single-use by the regulatory frameworks. We report a Workflow that provides a quantitative basis to determine the safety and efficacy of a medical mask that is decontaminated for reuse. The type IIR polypropylene medical masks can be washed up to 10 times, washed 5 times and autoclaved 5 times, or washed then sterilized with radiations or ethylene oxide, without any degradation of their filtration or breathability properties. There is loss of the anti-projection properties. The Workflow rendered the medical masks to comply to the AFNOR S76-001 standard as "type 1 non-sanitory usage masks". This qualification gives a legal status to the Workflow-treated masks and allows recommendation for the reuse of washed medical masks by the general population, with the significant public health advantage of providing better protection than cloth-tissue masks. Additionally, such a legal status provides a basis to perform a clinical trial to test the masks in real conditions, with full compliance with EN 14683 norm, for collective reuse. The rational reuse of medical mask and their end-of-life management is critical, particularly in pandemic periods when decisive turns can be taken. The reuse of masks in the general population, in industries, or in hospitals (but not for surgery) has significant advantages for the management of waste without degrading the safety of individuals wearing reused masks., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Treatment of accidental radiation-induced myelosuppression is primarily based on supportive care and requires specific treatment based on hematopoietic growth factors injection or hematopoietic cell transplantation for the most severe cases. The cytokines used consisted of pegylated erythropoietin (darbepoetin alfa) 500 IU once per week, pegylated G-CSF (pegfilgrastim) 6 mg × 2 once, stem cell factor 20 µg.kg-1 for five days, and romiplostim (TPO analog) 10 µg.kg -1 once per week, with different combinations depending on the accidents. As the stem cell factor did not have regulatory approval for clinical use in France, the French regulatory authorities (ANSM, formerly, AFSSAPS) approved their compassionate use as an investigational drug "on a case-by-case basis". According to the evolution and clinical characteristics, each patient's treatment was adopted on an individual basis. Daily blood count allows initiating G-CSF and SCF delivery when granulocyte <1,000/mm3, TPO delivery when platelets <50,000/mm3, and EPO when Hb<80 g/L. The length of each treatment was based on blood cell recovery criteria. The concept of "stimulation strategy" is linked to each patient's residual hematopoiesis, which varies among them, depending on the radiation exposure's characteristics and heterogeneity. This paper reports the medical management of 8 overexposed patients to ionizing radiation. The recovery of bone marrow function after myelosuppression was accelerated using growth factors, optimized by multiple-line combinations. Particularly in the event of prolonged exposure to ionizing radiation in dose ranges inducing severe myelosuppression (in the order of 5 to 8 Gy), with no indication of hematopoietic stem cell transplantation., (©2021 by Radiation Research Society. All rights of reproduction in any form reserved.)

Introduction: Perinatal asphyxia remains a frequent cause of neonatal mortality and long-term neurodevelopmental sequelae, despite the introduction of therapeutic hypothermia. Specific maternal characteristics may predispose asphyxiated newborns treated with hypothermia to worse outcome., Objective: To investigate the possible association between specific maternal factors and adverse outcome in asphyxiated newborns treated with hypothermia., Methods: We conducted a retrospective review of our database of 215 asphyxiated newborns treated with hypothermia from 2008 to 2015. We collected maternal characteristics including parity and labor duration, and we defined adverse outcome as death and/or brain injury. We compared the maternal characteristics between the asphyxiated newborns who developed adverse outcome and those who did not., Results: Asphyxiated newborns born to nulliparous mothers had a significantly higher risk of adverse outcome (61%), compared to asphyxiated newborns born from primiparous (19%) and multiparous (20%) mothers ( p =  .002). Labor duration was longer in nulliparous mothers ( p =  .04). Among mothers who delivered vaginally, labor duration was significantly longer in newborns developing adverse outcome ( p =  .04). In multivariable analysis, parity was confirmed as an independent predictor of adverse outcome in all newborns, but labor duration showed a borderline non-significant association with adverse outcome ( p =  .051) only in newborns born vaginally. Labor duration beyond 12 h of life was associated with maximal sensitivity and specificity in detecting asphyxiated newborns at an increased risk of adverse outcome despite hypothermia treatment (AUC 0.62, p =  .044)., Conclusions: Newborns with evidence of perinatal asphyxia, born to nulliparous mothers, and especially to those in whom the duration of labor has been prolonged, might be at higher risk of death or brain injury despite the use of therapeutic hypothermia.

Glutamate dehydrogenases (GDHs) are widespread metabolic enzymes that play key roles in nitrogen homeostasis. Large glutamate dehydrogenases composed of 180 kDa subunits (L-GDHs 180 ) contain long N- and C-terminal segments flanking the catalytic core. Despite the relevance of L-GDHs 180 in bacterial physiology, the lack of structural data for these enzymes has limited the progress of functional studies. Here we show that the mycobacterial L-GDH 180 (mL-GDH 180 ) adopts a quaternary structure that is radically different from that of related low molecular weight enzymes. Intersubunit contacts in mL-GDH 180 involve a C-terminal domain that we propose as a new fold and a flexible N-terminal segment comprising ACT-like and PAS-type domains that could act as metabolic sensors for allosteric regulation. These findings uncover unique aspects of the structure-function relationship in the subfamily of L-GDHs.

Objective: The intestinal epithelial barrier (IEB) restricts the passage of microbes and potentially harmful substances from the lumen through the paracellular space, and rupture of its integrity is associated with a variety of gastrointestinal disorders and extra-digestive diseases. Increased IEB permeability has been linked to disruption of metabolic homeostasis leading to obesity and type 2 diabetes. Interestingly, recent studies have uncovered compelling evidence that the AMP-activated protein kinase (AMPK) signaling pathway plays an important role in maintaining epithelial cell barrier function. However, our understanding of the function of intestinal AMPK in regulating IEB and glucose homeostasis remains sparse., Methods: We generated mice lacking the two α1 and α2 AMPK catalytic subunits specifically in intestinal epithelial cells (IEC AMPK KO) and determined the physiological consequences of intestinal-specific deletion of AMPK in response to high-fat diet (HFD)-induced obesity. We combined histological, functional, and integrative analyses to ascertain the effects of gut AMPK loss on intestinal permeability in vivo and ex vivo and on the development of obesity and metabolic dysfunction. We also determined the impact of intestinal AMPK deletion in an inducible mouse model (i-IEC AMPK KO) by measuring IEB function, glucose homeostasis, and the composition of gut microbiota via fecal 16S rRNA sequencing., Results: While there were no differences in in vivo intestinal permeability in WT and IEC AMPK KO mice, ex vivo transcellular and paracellular permeability measured in Ussing chambers was significantly increased in the distal colon of IEC AMPK KO mice. This was associated with a reduction in pSer425 GIV phosphorylation, a marker of leaky gut barrier. However, the expression of tight junction proteins in intestinal epithelial cells and pro-inflammatory cytokines in the lamina propria were not different between genotypes. Although the HFD-fed AMPK KO mice displayed suppression of the stress polarity signaling pathway and a concomitant increase in colon permeability, loss of intestinal AMPK did not exacerbate body weight gain or adiposity. Deletion of AMPK was also not sufficient to alter glucose homeostasis or the acute glucose-lowering action of metformin in control diet (CD)- or HFD-fed mice. CD-fed i-IEC AMPK KO mice also presented higher permeability in the distal colon under homeostatic conditions but, surprisingly, this was not detected upon HFD feeding. Alteration in epithelial barrier function in the i-IEC AMPK KO mice was associated with a shift in the gut microbiota composition with higher levels of Clostridiales and Desulfovibrionales., Conclusions: Altogether, our results revealed a significant role of intestinal AMPK in maintaining IEB integrity in the distal colon but not in regulating glucose homeostasis. Our data also highlight the complex interaction between gut microbiota and host AMPK., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Purpose: First, this experimental study aims at comparing out-of-field doses delivered by three radiotherapy techniques (3DCRT, VMAT (two different accelerators), and tomotherapy) for a pediatric renal treatment. Secondly, the accuracy of treatment planning systems (TPS) for out-of-field calculation is evaluated., Methods: EBT3 films were positioned in pediatric phantoms (5 and 10 yr old). They were irradiated according to four plans: 3DCRT (Clinac 2100CS, Varian), VMAT (Clinac 2100CS and Halcyon, Varian), and tomotherapy for a same target volume. 3D dose determination was performed with an in-house Matlab tool using linear interpolation of film measurements. 1D and 3D comparisons were made between techniques. Finally, measurements were compared to the Eclipse (Varian) and Tomotherapy (Accuray) TPS calculations., Results: Advanced radiotherapy techniques (VMATs and tomotherapy) deliver higher out-of-field doses compared to 3DCRT due to increased beam-on time triggered by intensity modulation. Differences increase with distance to target and reach a factor of 3 between VMAT and 3DCRT. Besides, tomotherapy delivers lower doses than VMAT: although tomotherapy beam-on time is higher than in VMAT, the additional shielding of the Hi-Art system reduces out-of-field doses. The latest generation Halcyon system proves to deliver lower peripheral doses than conventional accelerators. Regarding TPS calculation, tomotherapy proves to be suitable for out-of-field dose determination up to 30 cm from field edge whereas Eclipse (AAA and AXB) largely underestimates those doses., Conclusion: This study shows that the high dose conformation allowed by advanced radiotherapy is done at the cost of higher peripheral doses. In the context of treatment-related risk estimation, the consequence of this increase might be significative. Modern systems require adapted head shielding and a particular attention has to be taken regarding on-board imaging dose. Finally, TPS advanced dose calculation algorithms do not certify dose accuracy beyond field edges, and thus, those doses are not suitable for risk assessment., (© 2021 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Working Group (WG) 6 'Computational Dosimetry' of the European Radiation Dosimetry Group promotes good practice in the application of computational methods for radiation dosimetry in radiation protection and the medical use of ionising radiation. Its cross-sectional activities within the association cover a large range of current topics in radiation dosimetry, including more fundamental studies of radiation effects in complex systems. In addition, WG 6 also performs scientific research and development as well as knowledge transfer activities, such as training courses. Monte Carlo techniques, including the use of anthropomorphic and other numerical phantoms based on voxelised geometrical models, play a strong part in the activities pursued in WG 6. However, other aspects and techniques, such as neutron spectra unfolding, have an important role as well. A number of intercomparison exercises have been carried out in the past to provide information on the accuracy with which computational methods are applied and whether best practice is being followed. Within the exercises that are still ongoing, the focus has changed towards assessing the uncertainty that can be achieved with these computational methods. Furthermore, the future strategy of WG 6 also includes an extension of the scope toward experimental benchmark activities and evaluation of cross-sections and algorithms, with the vision of establishing a gold standard for Monte Carlo methods used in medical and radiobiological applications., (© 2021 Society for Radiological Protection. Published on behalf of SRP by IOP Publishing Limited. All rights reserved.)

Finding transition states and diffusion pathways is essential to understand the evolution of materials and chemical reactions. Such characterization is hampered by the heavy computation costs associated with exploring energy landscapes at ab initio accuracy. Here, we revisit the activation-relaxation technique (ARTn) to considerably reduce its costs when used with the density functional theory and propose three adapted versions of the algorithm to efficiently (i) explore the energy landscape of complex materials with the knowledge of a single minimum (ARTn); (ii) identify a transition state when two minima or a guess transition state is given (refining ART or r-ART); and (iii) reconstruct complex pathways between two given states (directed ART or d-ART). We show the application of these three variants on benchmark examples and on various complex defects in silicon. For the latter, the presented improvements to ART lead to much more precise transition states while being 2 to 6 times faster than the commonly used string methods such as the climbing image nudged elastic band method (CI-NEB).

The integrin family of transmembrane adhesion receptors coordinates complex signaling networks that control the ability of cells to sense and communicate with the extracellular environment. Kindlin proteins are a central cytoplasmic component of these networks, directly binding integrin cytoplasmic domains and mediating interactions with cytoskeletal and signaling proteins. The physiological importance of kindlins is well established, but how the scaffolding functions of kindlins are regulated at the molecular level is still unclear. Here, using a combination of GFP nanotrap association assays, pulldown and integrin-binding assays, and live-cell imaging, we demonstrate that full-length kindlins can oligomerize (self-associate) in mammalian cells, and we propose that this self-association inhibits integrin binding and kindlin localization to focal adhesions. We show that both kindlin-2 and kindlin-3 can self-associate and that kindlin-3 self-association is more robust. Using chimeric mapping, we demonstrate that the F2PH and F3 subdomains are important for kindlin self-association. Through comparative sequence analysis of kindlin-2 and kindlin-3, we identify kindlin-3 point mutations that decrease self-association and enhance integrin binding, affording mutant kindlin-3 the ability to localize to focal adhesions. Our results support the notion that kindlin self-association negatively regulates integrin binding., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Kadry et al.)

Ionic electroactive polymers (ionic EAPs) can greatly aid in biomedical applications where micro-sized actuators are required for delicate procedures. Since these types of actuators generally require platinum or gold metallic electrodes, they tend to be expensive and susceptible to delamination. Previous research has solved this problem by replacing the metallic electrodes with conductive polymers (CP) and forming an interpenetrating polymer network (IPN) between the conductive polymer (CP) and the solid polymer electrolyte (SPE). Since these actuators contain toxic ionic liquids, they are unsuitable for biological applications. In this study, we present a novel and facile method of fabricating a biocompatible and ionic liquid-free actuator that uses semi-IPN to hold the CP and Nafion-based SPE layers together. Surface activated fabrication treatment (SAFT) is applied to the precursor-Nafion membrane in order to convert the sulfonyl fluoride groups on the surface to sulfonate. Through template-assisted self-assembly, the CP electrodes from either polyaniline (PANI) or poly(3,4-ethylenedioxythiophene) (PEDOT) interlock with the surface treated precursor-Nafion membrane so that no delamination can occur. The electrodes growth pattern, interfacial layer's thickness, and shape can be controlled by adjusting the SAFT concentration and duration., (Copyright © 2020 Jo, Huet and Naguib.)

The cellular energy sensor AMP-activated protein kinase (AMPK) is a metabolic regulator that mediates adaptation to nutritional variations to maintain a proper energy balance in cells. We show here that suckling-weaning and fasting-refeeding transitions in rodents are associated with changes in AMPK activation and the cellular energy state in the liver. These nutritional transitions were characterized by a metabolic switch from lipid to glucose utilization, orchestrated by modifications in glucose levels and the glucagon/insulin ratio in the bloodstream. We therefore investigated the respective roles of glucose and pancreatic hormones on AMPK activation in mouse primary hepatocytes. We found that glucose starvation transiently activates AMPK, whereas changes in glucagon and insulin levels had no impact on AMPK. Challenge of hepatocytes with metformin-induced metabolic stress strengthened both AMPK activation and cellular energy depletion under limited-glucose conditions, whereas neither glucagon nor insulin altered AMPK activation. Although both insulin and glucagon induced AMPKα phosphorylation at its Ser 485/491 residue, they did not affect its activity. Finally, the decrease in cellular ATP levels in response to an energy stress was additionally exacerbated under fasting conditions and by AMPK deficiency in hepatocytes, revealing metabolic inflexibility and emphasizing the importance of AMPK for maintaining hepatic energy charge. Our results suggest that nutritional changes ( i.e. glucose availability), rather than the related hormonal changes ( i.e. the glucagon/insulin ratio), sensitize AMPK activation to the energetic stress induced by the dietary transition during fasting. This effect is critical for preserving the cellular energy state in the liver., (© 2020 Huet et al.)