Expression of Ifnlr1 on intestinal epithelial cells is critical to the antiviral effects of IFN-lambda against norovirus and reovirus

Lambda interferon (IFN-λ) has potent antiviral effects against multiple enteric viral pathogens, including norovirus and rotavirus, in both preventing and curing infection. Because the intestine includes a diverse array of cell types, however, the cell(s) upon which IFN-λ acts to exert its antiviral effects is unclear. Here, we sought to identify IFN-λ-responsive cells by generation of mice with lineage-specific deletion of the receptor for IFN-λ, Ifnlr1. We found that expression of IFNLR1 on intestinal epithelial cells (IECs) in the small intestine and colon is required for enteric IFN-λ antiviral activity. IEC Ifnlr1 expression also determines the efficacy of IFN-λ in resolving persistent murine norovirus (MNoV) infection and regulates fecal shedding and viral titers in tissue. Thus, the expression of Ifnlr1 by IECs is necessary for the response to both endogenous and exogenous IFN-λ. We further demonstrate that IEC Ifnlr1 expression is required for the sterilizing innate immune effects of IFN-λ by extending these findings in Rag1-deficient mice. Finally, we assessed whether our findings pertained to multiple viral pathogens by infecting mice specifically lacking IEC Ifnlr1 expression with reovirus. These mice phenocopied Ifnlr1-null animals, exhibiting increased intestinal tissue titers and enhanced reovirus fecal shedding. Thus, IECs are the critical cell type responding to IFN-λ to control multiple enteric viruses. This is the first genetic evidence that supports an essential role for IECs in IFN-λ-mediated control of enteric viral infection, and these findings provide insight into the mechanism of IFN-λ-mediated antiviral activity. IMPORTANCE Human noroviruses (HNoVs) are the leading cause of epidemic gastroenteritis worldwide. Type III interferons (IFN-λ) control enteric viral infections in the gut and have been shown to cure mouse norovirus, a small-animal model for HNoVs. Using a genetic approach with conditional knockout mice, we identified IECs as the dominant IFN-λ-responsive cells in control of enteric virus infection in vivo. Upon murine norovirus or reovirus infection, Ifnlr1 depletion in IECs largely recapitulated the phenotype seen in Ifnlr1(−/−) mice of higher intestinal tissue viral titers and increased viral shedding in the stool. Moreover, IFN-λ-mediated sterilizing immunity against murine norovirus requires the capacity of IECs to respond to IFN-λ. These findings clarify the mechanism of action of this cytokine and emphasize the therapeutic potential of IFN-λ for treating mucosal viral infections

How to Motivate Your Dragon: Teaching Goal-Driven Agents to Speak and Act in Fantasy Worlds.

We seek to create agents that both act and communicate with other agents in pursuit of a goal. Towards this end, we extend LIGHT (Urbanek et al. 2019)—a large-scale crowd-sourced fantasy text-game—with a dataset of quests. These contain natural language motivations paired with in-game goals and human demonstrations; completing a quest might require dialogue or actions (or both). We introduce a reinforcement learning system that (1) incorporates large-scale language modeling-based and commonsense reasoning-based pre-training to imbue the agent with relevant priors; and (2) leverages a factorized action space of action commands and dialogue, balancing between the two. We conduct zero-shot evaluations using held-out human expert demonstrations, showing that our agents are able to act consistently and talk naturally with respect to their motivations

Amino acid substitution equivalent to human chorea-acanthocytosis I2771R in yeast Vps13 protein affects its binding to phosphatidylinositol 3-phosphate

The rare human disorder chorea-acanthocytosis (ChAc) is caused by mutations in hVPS13A gene. The hVps13A protein interacts with actin and regulates the level of phosphatidylinositol 4-phosphate (PI4P) in the membranes of neuronal cells. Yeast Vps13 is involved in vacuolar protein transport and, like hVps13A, participates in PI4P metabolism. Vps13 proteins are conserved in eukaryotes, but their molecular function remains unknown. One of the mutations found in ChAc patients causes amino acids substitution I2771R which affects the localization of hVps13A in skeletal muscles. To dissect the mechanism of pathogenesis of I2771R, we created and analyzed a yeast strain carrying the equivalent mutation. Here we show that in yeast, substitution I2749R causes dysfunction of Vps13 protein in endocytosis and vacuolar transport, although the level of the protein is not affected, suggesting loss of function. We also show that Vps13, like hVps13A, influences actin cytoskeleton organization and binds actin in immunoprecipitation experiments. Vps13-I2749R binds actin, but does not function in the actin cytoskeleton organization. Moreover, we show that Vps13 binds phospholipids, especially phosphatidylinositol 3-phosphate (PI3P), via its SHR_BD and APT1 domains. Substitution I2749R attenuates this ability. Finally, the localization of Vps13-GFP is altered when cellular levels of PI3P are decreased indicating its trafficking within the endosomal membrane system. These results suggest that PI3P regulates the functioning of Vps13, both in protein trafficking and actin cytoskeleton organization. Attenuation of PI3P-binding ability in the mutant hVps13A protein may be one of the reasons for its mislocalization and disrupted function in cells of patients suffering from ChAc

Topical Treatment of Nonhealing Venous Leg Ulcer with Propolis Ointment

An investigation of effectiveness of topical treatment of nonhealing chronic venous leg ulcers with propolis ointment was conducted. 56 patients were included in the study and randomized into two groups. In group 1, there were 28 patients (ulceration area: 6.9–9.78 cm2) treated by means of topical propolis ointment application and short stretch bandage compression. In group 2, there were 29 patients (ulceration area: 7.2–9.4 cm2) treated by means of Unna boot leg compression without topical propolis treatment. In the study, the efficacy of both treatment methods in patients with resistive venous leg ulcers was compared. The ulceration of patients from group 1 healed completely after 6 weeks of therapy in all cases. In all patients from group 2, the process of healing was longer but successfully completed after 16 weeks of the therapy. We found that an adjunctive propolis ointment treatment increases the efficacy of the short stretch bandage compression stocking, and this combined treatment is more effective than Unna’s boot compression alone

You ≠ Me: Individual differences in the structure of social cognition

This study investigated the structure of social cognition, and how it is influenced by personality; specifically, how various socio-cognitive capabilities, and the pattern of inter-relationships and co-dependencies among them differ between divergent personality styles. To measure social cognition, a large non-clinical sample (n = 290) undertook an extensive battery of self-report and performance-based measures of visual perspective taking, imitative tendencies, affective empathy, interoceptive accuracy, emotion regulation, and state affectivity. These same individuals then completed the Personality Styles and Disorders Inventory. Latent Profile Analysis revealed two dissociable personality profiles that exhibited contrasting cognitive and affective dispositions, and multivariate analyses indicated further that these profiles differed on measures of social cognition; individuals characterised by a flexible and adaptive personality profile expressed higher action orientation (emotion regulation) compared to those showing more inflexible tendencies, along with better visual perspective taking, superior interoceptive accuracy, less imitative tendencies, and lower personal distress and negativity. These characteristics point towards more efficient self-other distinction, and to higher cognitive control more generally. Moreover, low-level cognitive mechanisms served to mediate other higher level socio-emotional capabilities. Together, these findings elucidate the cognitive and affective underpinnings of individual differences in social behaviour, providing a data-driven model that should guide future research in this area

Stan Scheller: The Forerunner of Clinical Studies on Using Propolis for Poor and Chronic Nonhealing Wounds

For hundreds of years poor and chronic nonhealing wounds have constituted a serious problem to medicine. What is more, treating such wounds is an expensive let alone a long-lasting process. The following paper describes Professor Scheller's achievements in using propolis for poor and chronic non-healing wounds. The authors' intention was to present the results connected with the use of the ethanolic extract propolis, in the treatment of patients suffering from burns, venous crural ulceration, local sacral bone pressure ulcers, suppurative osteitis and arthritis, suppurative postoperative local wound complications, and infected traumatic wounds

Recurrent versus first cervical artery dissection - a retrospective study of clinical and vascular characteristics

Background and purpose Most recurrent cervical artery dissection (CeAD) events occur shortly after the acute first CeAD. This study compared the characteristics of recurrent and first CeAD events and searched for associations between subsequent events of an individual person. Methods Cervical artery dissection patients with a new CeAD event occurring during a 3-6 month follow-up were retrospectively selected in seven specialized stroke centers. Clinical and vascular characteristics of the initial and the recurrent CeADs were compared. Results The study sample included 76 patients. Recurrent CeADs were occlusive in one (1.3%) patient, caused cerebral ischaemia in 13 (17.1%) and were asymptomatic in 39 (51.3%) patients, compared to 29 (38.2%) occlusive, 42 (55.3%) ischaemic and no asymptomatic first CeAD events. In 52 (68.4%) patients, recurrent dissections affected both internal carotid arteries or both vertebral arteries, whilst 24 (31.6%) patients had subsequent dissections in both types of artery. Twelve (28.6%) of 42 patients with an ischaemic first dissection had ischaemic symptoms due to the recurrent CeADs, too. However, only one (1.3%) of 34 patients with a non-ischaemic first CeAD suffered ischaemia upon recurrence. Conclusion Recurrent CeAD typically affects the same site of artery. It causes ischaemic events less often than the first CeAD. The risk that patients who presented with solely non-ischaemic symptoms of a first CeAD will have ischaemic symptoms in the case of a recurrent CeAD seems very small.Peer reviewe

Ocena właściwości mechanicznych tętnic ludzkich poddanych procesowi wyjałowienia oraz kontrolowanego zamrażania przy wykorzystaniu krioprotektora

Background: Assessment of the mechanical properties of human arteries after cryopreservation processing protocol including antibiotic sterilisation and controlled freezing with the use of cryoprotector (10% DMSO). Material and methods: 12 aortic and 9 femoral artery segments were investigated; the donor age ranged from 18 to 42 years, the time of the storage in the liquid nitrogen vapours was from 1 to 36 months. The stretching tests of vessel specimens (using INSTRON tensile testing machine) and manometric investigations were performed. The mechanical resistance (breaking stress) and elastic moduli were evaluated (at maximal stress value and at the stress of 300 kPa). The results were compared with fresh homograft specimens. Results: The mechanical resistance (breaking stress) of the investigated cryopreserved aortic segments ranged from 1.5 MPa (± 0.34) (if stretched perpendicular to the vessel long axis) to 1.05 MPa (± 0.3) (if stretching was performed in parallel). For the femoral artery specimens the respective values were 2.4 MPa (± 0.93) and 1.35 MPa (± 0.5). Elastic moduli at the stress of 300 kPa in aortic specimens achieved 1.38 (± 0.4) and 1.8 (± 0.85). For the attained femoral arteries respective values were 2.83 (± 1.34) and 1.47 (± 0.9). There were no significant differences concerning mechanical properties between fresh and cryopreserved aortic wall segments. Conclusions: 1. Cryopreserved allogenic arteries (aorta, femoral arteries) maintain high mechanical resistance against breaking stress and intra-arterial pressure. 2. Despite vessel preparation (including sterilisation and control freezing protocols), cryopreserved arteries maintain elastic properties, justifying an implementation of this material in human circulatory system. 3. The use of arterial segments with low number of collaterals and their correct suture or ligation can influence the allograft mechanical stress resistance

Expression of SMARCD1 interacts with age in association with asthma control on inhaled corticosteroid therapy.

BackgroundGlobal gene expression levels are known to be highly dependent upon gross demographic features including age, yet identification of age-related genomic indicators has yet to be comprehensively undertaken in a disease and treatment-specific context.MethodsWe used gene expression data from CD4+ lymphocytes in the Asthma BioRepository for Integrative Genomic Exploration (Asthma BRIDGE), an open-access collection of subjects participating in genetic studies of asthma with available gene expression data. Replication population participants were Puerto Rico islanders recruited as part of the ongoing Genes environments & Admixture in Latino Americans (GALA II), who provided nasal brushings for transcript sequencing. The main outcome measure was chronic asthma control as derived by questionnaires. Genomic associations were performed using regression of chronic asthma control score on gene expression with age in years as a covariate, including a multiplicative interaction term for gene expression times age.ResultsThe SMARCD1 gene (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1) interacted with age to influence chronic asthma control on inhaled corticosteroids, with a doubling of expression leading to an increase of 1.3 units of chronic asthma control per year (95% CI [0.86, 1.74], p = 6 × 10- 9), suggesting worsening asthma control with increasing age. This result replicated in GALA II (p = 3.8 × 10- 8). Cellular assays confirmed the role of SMARCD1 in glucocorticoid response in airway epithelial cells.ConclusionFocusing on age-dependent factors may help identify novel indicators of asthma medication response. Age appears to modulate the effect of SMARCD1 on asthma control with inhaled corticosteroids

Phosphatidylinositol-3-phosphate regulates response of cells to proteotoxic stress

Human Nedd4 ubiquitin ligase, or its variants, inhibit yeast cell growth by disturbing the actin cytoskeleton organization and dynamics, and lead to an increase in levels of ubiquitinated proteins. In a screen for multicopy suppressors which rescue growth of yeast cells producing Nedd4 ligase with an inactive WW4 domain (Nedd4w4), we identified a fragment of ATG2 gene encoding part of the Atg2 core autophagy protein. Expression of the Atg2-C1 fragment (aa 1074-1447) improved growth, actin cytoskeleton organization, but did not significantly change the levels of ubiquitinated proteins in these cells. The GFP-Atg2-C1 protein in Nedd4w4-producing cells primarily localized to a single defined structure adjacent to the vacuole, surrounded by an actin filament ring, containing Hsp42 and Hsp104 chaperones. This localization was not affected in several atg deletion mutants, suggesting that it might be distinct from the phagophore assembly site (PAS). However, deletion of ATG18 encoding a phosphatidylinositol-3-phosphate (PI3P)-binding protein affected the morphology of the GFP-Atg2-C1 structure while deletion of ATG14 encoding a subunit of PI3 kinase suppressed toxicity of Nedd4w4 independently of GFP-Atg2-C1. Further analysis of the Atg2-C1 revealed that it contains an APT1 domain of previously uncharacterized function. Most importantly, we showed that this domain is able to bind phosphatidylinositol phosphates, especially PI3P, which is abundant in the PAS and endosomes. Together our results suggest that human Nedd4 ubiquitinates proteins in yeast and causes proteotoxic stress and, with some Atg proteins, leads to formation of a perivacuolar structure, which may be involved in sequestration, aggregation or degradation of proteins