Розробка нейромережевої інтелектуальної системи для прогнозування енергетичних центрів плямових зображень у процесах профілювання лазерного променя

Здійснено розробку нейромережевої інтелектуальної системи для прогнозування енергетичних центрів (ЕЦ) плямових зображень у процесах профілювання лазерного променя (ЛП). Обґрунтовано актуальність задачі прогнозування координат ЕЦ профілю ЛП. Розглянуто методи прогнозування та обґрунтовано доцільність застосування нейромережевої моделі. Здійснено комп’ютерне моделювання системи прогнозування, а також на основі отриманих результатів сформульовано вимоги та здійснено програмну реалізацію інтелектуальної системи.Выполнено разработку нейросетевой интеллектуальной системы для прогнозирования энергетических центров (ЭЦ) пятенных зображений в процесах профилирования лазерного луча (ЛЛ). Обоснована актуальность задачи прогнозирования координат ЭЦ профиля ЛЛ. Рассмотрены методы прогнозирования и обоснована целесообразность применения нейросетевой модели. Выполнено компьютерное моделирование системы прогнозирования, а также на основе полученных результатов сформулированы требования и выполнено программную реализацию интеллектуальной системы.The development of a neural net intellectual system for energy centers (EC) spot images forecasting in the processes of laser beam profiling (LB) is done. Actuality of the problem of coordinates forecasting of EC of laser beam profile is proved. Methods of forecasting are considered and the appropriateness of usage the neural net model is justified. Computer simulation of forecasting system is carried out and also on the basis of the obtained results the requirements are formulated and software implementation of intelligent system is performed

Acid ceramidase regulates innate immune memory

Innate immune memory, also called “trained immunity,” is a functional state of myeloid cells enabling enhanced immune responses. This phenomenon is important for host defense, but also plays a role in various immune-mediated conditions. We show that exogenously administered sphingolipids and inhibition of sphingolipid metabolizing enzymes modulate trained immunity. In particular, we reveal that acid ceramidase, an enzyme that converts ceramide to sphingosine, is a potent regulator of trained immunity. We show that acid ceramidase regulates the transcription of histone-modifying enzymes, resulting in profound changes in histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation. We confirm our findings by identifying single-nucleotide polymorphisms in the region of ASAH1, the gene encoding acid ceramidase, that are associated with the trained immunity cytokine response. Our findings reveal an immunomodulatory effect of sphingolipids and identify acid ceramidase as a relevant therapeutic target to modulate trained immunity responses in innate immune-driven disorders.</p

Acid ceramidase regulates innate immune memory

Innate immune memory, also called “trained immunity,” is a functional state of myeloid cells enabling enhanced immune responses. This phenomenon is important for host defense, but also plays a role in various immune-mediated conditions. We show that exogenously administered sphingolipids and inhibition of sphingolipid metabolizing enzymes modulate trained immunity. In particular, we reveal that acid ceramidase, an enzyme that converts ceramide to sphingosine, is a potent regulator of trained immunity. We show that acid ceramidase regulates the transcription of histone-modifying enzymes, resulting in profound changes in histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation. We confirm our findings by identifying single-nucleotide polymorphisms in the region of ASAH1, the gene encoding acid ceramidase, that are associated with the trained immunity cytokine response. Our findings reveal an immunomodulatory effect of sphingolipids and identify acid ceramidase as a relevant therapeutic target to modulate trained immunity responses in innate immune-driven disorders.</p

Professional identity formation in the transition from medical school to working life:a qualitative study of group-coaching courses for junior doctors

BACKGROUND: The transition from student to medical doctor is challenging and stressful to many junior doctors. To practice with confidence and professionalism the junior doctors have to develop a strong professional identity. Various suggestions on how to facilitate formation of professional identity have been offered including the possible positive effect of group-coaching courses. The purpose of this study was to explore how group-coaching might facilitate professional identity formation among junior doctors in the transition period. METHODS: Group-coaching courses comprising three whole-day sessions and five 2 h sessions during a period of 4 months were offered to junior doctors in the first years after graduation. The purpose was to support the participants’ professional development, ability to relate to patients, relatives and staff and career development. The coaches in this study had a background as health professionals combined with coaching educations. Data was obtained through observations, open-ended questionnaires and interviews. A generic thematic analysis was applied. RESULTS: Forty-five doctors participated in six coaching groups. The three main themes emerging in the sessions were: Adoption to medical culture, career planning, and work/life-balance. The junior doctors found the coaching intervention highly useful in order to cope with these challenges. Furthermore, the group was a forum where the junior doctors could share thoughts and feelings with colleagues without being afraid that this would endanger their professional career. Many found new ways to respond to everyday challenges mainly through a new awareness of patterns of thinking and feeling. CONCLUSIONS: The participants found that the group-coaching course supported their professional identity formation (thinking, feeling and acting as a doctor), adoption to medical culture, career planning and managing a healthy work/life-balance. Further studies in different contexts are recommended as well as studies using other methods to test the results of this qualitative study. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12909-016-0684-3) contains supplementary material, which is available to authorized users

Multiparametric Immunoimaging Maps Inflammatory Signatures in Murine Myocardial Infarction Models.

In the past 2 decades, research on atherosclerotic cardiovascular disease has uncovered inflammation to be a key driver of the pathophysiological process. A pressing need therefore exists to quantitatively and longitudinally probe inflammation, in preclinical models and in cardiovascular disease patients, ideally using non-invasive methods and at multiple levels. Here, we developed and employed in vivo multiparametric imaging approaches to investigate the immune response following myocardial infarction. The myocardial infarction models encompassed either transient or permanent left anterior descending coronary artery occlusion in C57BL/6 and Apoe-/-mice. We performed nanotracer-based fluorine magnetic resonance imaging and positron emission tomography (PET) imaging using a CD11b-specific nanobody and a C-C motif chemokine receptor 2-binding probe. We found that immune cell influx in the infarct was more pronounced in the permanent occlusion model. Further, using 18F-fluorothymidine and 18F-fluorodeoxyglucose PET, we detected increased hematopoietic activity after myocardial infarction, with no difference between the models. Finally, we observed persistent systemic inflammation and exacerbated atherosclerosis in Apoe-/- mice, regardless of which infarction model was used. Taken together, we showed the strengths and capabilities of multiparametric imaging in detecting inflammatory activity in cardiovascular disease, which augments the development of clinical readouts.This work was supported by National Institute of Health grants R01HL143814 (to Dr Fayad), P01HL131478 (Drs Fayad and Mulder), P41EB025815 (Drs Liu and Gropler ), R35HL145212 (Dr Liu), and R35HL139598 (Dr Nahrendorf) and award K22CA226040 (Dr Rashidian). This work was also supported by an Innovation Research Fund Basic Research Award from the Dana-Farber Cancer Institute (Dr Rashidian). Dr Maier was supported by Deutsche Forschungsgemeinschaft grants (MA 7059/1 and MA 7059/3-1) and is part of SFB1425 funded by the Deutsche Forschungsgemeinschaft (project no. 422681845). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.S

A modular approach toward producing nanotherapeutics targeting the innate immune system.

Immunotherapies controlling the adaptive immune system are firmly established, but regulating the innate immune system remains much less explored. The intrinsic interactions between nanoparticles and phagocytic myeloid cells make these materials especially suited for engaging the innate immune system. However, developing nanotherapeutics is an elaborate process. Here, we demonstrate a modular approach that facilitates efficiently incorporating a broad variety of drugs in a nanobiologic platform. Using a microfluidic formulation strategy, we produced apolipoprotein A1-based nanobiologics with favorable innate immune system-engaging properties as evaluated by in vivo screening. Subsequently, rapamycin and three small-molecule inhibitors were derivatized with lipophilic promoieties, ensuring their seamless incorporation and efficient retention in nanobiologics. A short regimen of intravenously administered rapamycin-loaded nanobiologics (mTORi-NBs) significantly prolonged allograft survival in a heart transplantation mouse model. Last, we studied mTORi-NB biodistribution in nonhuman primates by PET/MR imaging and evaluated its safety, paving the way for clinical translation.This work was supported by NIH grants R01 CA220234, R01 HL144072, P01 HL131478, and NWO/ZonMW Vici 91818622 (to W.J.M.M.); R01 HL143814 and P01HL131478 (to Z.A.F.); R01 AI139623 (to J.O.); and P30 CA008748 (to T.R.). M.M.T.v.L. was supported by the American Heart Association (grant 19PRE34380423). M.G.N. was supported by a Spinoza grant from the Netherlands Organization for Scientific Research and an ERC Advanced Grant (no. 833247); L.A.B.J. was supported by a Competitiveness Operational Programme grant of the Romanian Ministry of European Funds (P_37_762, MySMIS 103587).S

Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells.

Immunoparalysis is a compensatory and persistent anti-inflammatory response to trauma, sepsis or another serious insult, which increases the risk of opportunistic infections, morbidity and mortality. Here, we show that in cultured primary human monocytes, interleukin-4 (IL4) inhibits acute inflammation, while simultaneously inducing a long-lasting innate immune memory named trained immunity. To take advantage of this paradoxical IL4 feature in vivo, we developed a fusion protein of apolipoprotein A1 (apoA1) and IL4, which integrates into a lipid nanoparticle. In mice and non-human primates, an intravenously injected apoA1-IL4-embedding nanoparticle targets myeloid-cell-rich haematopoietic organs, in particular, the spleen and bone marrow. We subsequently demonstrate that IL4 nanotherapy resolved immunoparalysis in mice with lipopolysaccharide-induced hyperinflammation, as well as in ex vivo human sepsis models and in experimental endotoxemia. Our findings support the translational development of nanoparticle formulations of apoA1-IL4 for the treatment of patients with sepsis at risk of immunoparalysis-induced complications.We thank M. Jaeger (Radboudumc) for kindly providing flourescein isothiocyanate-labelled Candida albicans. D. Williams (East Tennessee State University) provided the β-glucan we used in our initial experiments. H. Lemmers (Radboudumc) kindly prepared the purified lipopolysaccharide used for stimulation of primary human monocytes and macrophages. Part of the figures were prepared using (among other software) Biorender.com. B.N. is supported by a National Health and Medical Research Council (Australia) Investigator Grant (APP1173314). This work was supported by National Institutes of Health grants R01 HL144072, R01 CA220234 and P01 HL131478, as well as a Vici grant from the Dutch Research Council NWO and an ERC Advanced Grant (all to W.J.M.M.). M.G.N. was supported by a Spinoza grant from Dutch Research Council NWO and an ERC Advanced Grant (#833247).S

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Investigating supramolecular systems using Förster resonance energy transfer

Supramolecular systems have applications in areas as diverse as materials science, biochemistry, analytical chemistry, and nanomedicine. However, analyzing such systems can be challenging due to the wide range of time scales, binding strengths, distances, and concentrations at which non-covalent phenomena take place. Due to their versatility and sensitivity, Förster resonance energy transfer (FRET)-based techniques are excellently suited to meet such challenges. Here, we detail the ways in which FRET has been used to study non-covalent interactions in both synthetic and biological supramolecular systems. Among other topics, we examine methods to measure molecular forces, determine protein conformations, monitor assembly kinetics, and visualize in vivo drug release from nanoparticles. Furthermore, we highlight multiplex FRET techniques, discuss the field's limitations, and provide a perspective on new developments