Time in Grief: How do Bereaved Parents Mentalize It?

In this multimethod study, we examine bereaved parents’ capacity for mentalizing the temporal dimension of their grief. The theoretical assumptions of our study draw on the clinical and anthropological perspectives on the passage of time in grief. Parents’ mentalization of their experience of grief was measured both in the attachment context, using the Adult Attachment Interview (AAI) and using the narrative Child Loss Interview (CLI). We used thematic analysis to code parents’ mentalizing utterances in order to categorize time-related changes during the grieving process. Parents generally mentalize their grief-related experiences at a lower level of reflective functioning than their general attachment experiences. However, a higher general ability to mentalize contributes to a higher level of RF and greater coherence in mentalizing their grief. Parents experience time in grief through oscillation between the past with the deceased child and a restricted form of existence in the present reality.

The Glucocorticoid Receptor-Dependent Stress Response in Human Erythropoiesis Is BCL11A-Dependent

Extrapolations from data in mouse models and from human erythroid cells expanded ex vivo with the glucocorticoid receptor (GR) agonist Dexamethasone (Dex), suggest that GR plays an important role in the regulation of stress erythropoiesis 1. However, the mechanistic details of stress erythropoiesis are still poorly understood. By exploring the effects of Dex on erythroid expansion of CD34+ cells from a large number of healthy adult donors (n=25), we documented that Dex expands a population of immature erythroid cells which express high levels of BCL11A. In addition, in these cells BCL11A is mostly in the nuclei, compared to cells grown without Dex. These results suggest that GR regulates the transcriptional activity of BCL11A. To validate the role of BCL11A in the Dex response, we made observations in cells from patients with BCL11A deficiencies 2. We found that BCL11A-deficient CD34+ cells generate lower numbers of maturing erythroid cells compared to controls with Dex addition, suggesting that they respond poorly to Dex (Fig 1). Of note, RNAseq analyses indicate that erythroid cells expanded from the patients express levels of BCL11A lower than that of their parent cells while the levels of expression of other genes known to mediate the response to Dex of erythroid cells (ZFP36L2, CDKNIC and PPARA 3-5) expressed by these cells is normal. Further we extended our observations to Cushing's patients with highier cortisol levels, before(V1) and after their treatment(V2) using concurrent age and weight matched healthy controls (MC). There is no significant difference in frequency of CD34+ cells among V1, V2 and MC (range 0.3-2% in all cases). CD34 pos cells from all groups express similar levels of cKIT, IL-3Rβ, CXCR4 and CALR. However, a greater proportion of CD34+ cells from V1 express CD36 and CD110 (the thrombospondin and thrombopoietin receptor) and CD133 (the hematopoietic stem cell marker prominin) than those from V2 and MC (60-80% vs 10-20%), suggesting that the circulating progenitor cells from active Cushing's patients are a unique population likely generated in response to their high cortisol levels given that the phenotype of CD34+ cells from the blood of V2 patients is similar to that found in MC. The phenotype of CD34+ cells from Cushing's patients in vivo is similar to that of CD34+ cells generated in vitro after 2-4 days of culture with Dex 3,6,7. V1 progenitor cells generate similarly large number of immature erythroid cells in culture with and without Dex. By contrast with normal cells, these active cells also express lower levels of the cytoplasm-restricted form of GRα (GRS203) and greater levels of GILZ and BCL11A than normal or V2 cells. In conclusion, the data presented here indicate that GR activation switches the erythroid differentiation program from the steady-state to the stress mode and that activation of BCL11A is part of the response of erythroid cells to Dex. References 1) Varricchio et al Am J Blood Res. 2014;4:53; 2) Funnell et al Blood 2015; 126:89; 3) Ashley et al JCI 2020;130:2097; 4) Zhang L et al Nature 2013;499:92; 5) Lee et al Nature 2015;522:474; 6) Heideveld et al Haematologica 2015; 100:1396; 7) Xiang et al Blood 2015;125:1803. Figure 1 Figure 1. Disclosures Migliaccio: Dompe farmaceutici Spa R&D: Other: received funding for reserach .

From Binary Groups to Terminal Rings

Binary groups are a meaningful step up from non-associative rings and nearrings. It makes sense to study them in terms of their nearrings of zero-fixing polynomial maps. As this involves algebras of a more specialized nature these are looked into in sections three and four. One of the main theorems of this paper occurs in section five where it is shown that a binary group V is a P0(V) ring module if, and only if, it is a rather restricted form of non-associative ring. Properties of these non-associative rings (called terminal rings) are investigated in sections six and seven. The finite case is of special interest since here terminal rings of odd order really are quite restricted. Sections eight to thirteen are taken up with the study of terminal rings of order pn (p an odd prime and n ≥ 1 an integer ≤ 7).

Convergent loss of the necroptosis pathway in disparate mammalian lineages shapes virus countermeasures

Programmed cell death is a vital process in the life cycle of an organism. Necroptosis, an evolutionary restricted form of programmed necrosis, contributes to the innate immune response by killing pathogen-infected cells. This virus-host interaction pathway is organized around two key components: the receptor-interacting protein kinase 3 (RIPK3), which recruits and phosphorylates the mixed lineage kinase-like protein (MLKL), thus inducing cellular plasma membrane rupture and cell death. Critically, the presence of necroptotic inhibitors in viral genomes validates necroptosis as an important host defense mechanism. Here, we show, counterintuitively, that in different mammalian lineages of mammalian, central components of the necroptotic pathway, such as RIPK3 and MLKL genes, are deleted or display inactivating mutations. Frameshifts or premature stop codons are observed in all the studied species of cetaceans and leporids. In carnivores' genomes, the MLKL gene is deleted, while in a small number of species from afrotheria and rodentia premature stop codons are observed in RIPK3 and/or MLKL. Interestingly, we also found a strong correlation between the disruption of necroptosis in leporids and cetaceans and the absence of the C-terminal domain of E3-like homologs (responsible for necroptosis inhibition) in their naturally infecting poxviruses. Overall, our study provides the first comprehensive picture of the molecular evolution of necroptosis in mammals. The loss of necroptosis multiple times during mammalian evolution highlights the importance of gene/pathway loss for species adaptation and suggests that necroptosis is not required for normal mammalian development. Moreover, this study highlights a co-evolutionary relationship between poxviruses and their hosts, emphasizing the role of host adaptation in shaping virus evolution.

Towards integrated photonic interposers for processing octave-spanning microresonator frequency combs

Microcombs—optical frequency combs generated in microresonators—have advanced tremendously in the past decade, and are advantageous for applications in frequency metrology, navigation, spectroscopy, telecommunications, and microwave photonics. Crucially, microcombs promise fully integrated miniaturized optical systems with unprecedented reductions in cost, size, weight, and power. However, the use of bulk free-space and fiber-optic components to process microcombs has restricted form factors to the table-top. Taking microcomb-based optical frequency synthesis around 1550 nm as our target application, here, we address this challenge by proposing an integrated photonics interposer architecture to replace discrete components by collecting, routing, and interfacing octave-wide microcomb-based optical signals between photonic chiplets and heterogeneously integrated devices. Experimentally, we confirm the requisite performance of the individual passive elements of the proposed interposer—octave-wide dichroics, multimode interferometers, and tunable ring filters, and implement the octave-spanning spectral filtering of a microcomb, central to the interposer, using silicon nitride photonics. Moreover, we show that the thick silicon nitride needed for bright dissipative Kerr soliton generation can be integrated with the comparatively thin silicon nitride interposer layer through octave-bandwidth adiabatic evanescent coupling, indicating a path towards future system-level consolidation. Finally, we numerically confirm the feasibility of operating the proposed interposer synthesizer as a fully assembled system. Our interposer architecture addresses the immediate need for on-chip microcomb processing to successfully miniaturize microcomb systems and can be readily adapted to other metrology-grade applications based on optical atomic clocks and high-precision navigation and spectroscopy.

Acute flaccid myelitis: long-term outcomes recorded in the CAPTURE study compared with paediatric transverse myelitis

BackgroundSince 2014, the USA has documented three outbreaks of acute flaccid myelitis (AFM). Unique features and treatment responses of this myelitis variant have not been prospectively studied. This study prospectively measured outcomes in paediatric myelitis patients relative to treatments.MethodsThis was a prospective, multicentre, non-randomised, observational cohort study. The study duration was 5 years and the length of follow-up was 1 year. This study collected data from children and families in North America. Patients were enrolled at academic centres with expertise in myelitis or online via a web portal. Paediatric patients diagnosed with myelitis were eligible for enrolment in the study within 6 months of onset of symptoms. Patients were characterised as transverse myelitis (TM) or the AFM variant based on clinical and radiographic findings.ResultsThe cohort of 90 patients included patients with AFM and TM. Of the 51 patients with AFM there was evidence of two clinically relevant patterns. This included a grey matter restricted form of AFM and a cohort with concomitant white matter that could explain lower extremity motor deficits in patients with lesions restricted to the cervical spine. The improvement in deficits with the use of corticosteroids was similar to what was observed in the TM cohort (p=0.97).ConclusionsClinicians should consider on a case by case basis the approach to therapy for AFM patients. Prospective controlled studies of long-term outcomes would be useful in this growing patient population.

PML-Dependent Memory of Type I Interferon Treatment Results in a Restricted Form of HSV Latency

Herpes simplex virus (HSV) establishes latent infection in long-lived neurons. During initial infection, neurons are exposed to multiple inflammatory cytokines but the effects of immune signaling on the nature of HSV latency is unknown. We show that initial infection of primary murine neurons in the presence of type I interferon (IFN) results in a form of latency that is restricted for reactivation. We also found that the subnuclear condensates, promyelocytic leukemia-nuclear bodies (PML-NBs), are absent from primary sympathetic and sensory neurons but form with type I IFN treatment and persist even when IFN signaling resolves. HSV-1 genomes colocalized with PML-NBs throughout a latent infection of neurons only when type I IFN was present during initial infection. Depletion of PML prior to or following infection did not impact the establishment latency; however, it did rescue the ability of HSV to reactivate from IFN-treated neurons. This study demonstrates that viral genomes possess a memory of the IFN response during de novo infection, which results in differential subnuclear positioning and ultimately restricts the ability of genomes to reactivate.

Free Choice Permission in Defeasible Deontic Logic

Free Choice Permission is one of the challenges for the formalisation of norms. In this paper, we follow a novel approach that accepts Free Choice Permission in a restricted form. The intuition behind the guarded form is strongly aligned with the idea of defeasibility. Accordingly, we investigate how to model the guarded form in Defeasible Deontic Logic extended with disjunctive permissions.

Mīmāṃsā deontic reasoning using specificity: a proof theoretic approach

Over the course of more than two millennia the philosophical school of Mīmāṃsā has thoroughly analyzed normative statements. In this paper we approach a formalization of the deontic system which is applied but never explicitly discussed in Mīmāṃsā to resolve conflicts between deontic statements by giving preference to the more specific ones. We first extend with prohibitions and recommendations the non-normal deontic logic extracted in Ciabattoni et al. (in: TABLEAUX 2015, volume 9323 of LNCS, Springer, 2015) from Mīmāṃsā texts, obtaining a multimodal dyadic version of the deontic logic $$\mathsf {MD}$$ MD . Sequent calculus is then used to close a set of prima-facie injunctions under a restricted form of monotonicity, using specificity to avoid conflicts. We establish decidability and complexity results, and investigate the potential use of the resulting system for Mīmāṃsā philosophy and, more generally, for the formal interpretation of normative statements.