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"Reid, Sarah"
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The deSUMOylase SENP7 promotes chromatin relaxation for homologous recombination DNA repair
SUMO conjugation is known to occur in response to double‐stranded DNA breaks in mammalian cells, but whether SUMO deconjugation has a role remains unclear. Here, we show that the SUMO/Sentrin/Smt3‐specific peptidase, SENP7, interacts with the chromatin repressive KRAB‐associated protein 1 (KAP1) through heterochromatin protein 1 alpha (HP1α). SENP7 promotes the removal of SUMO2/3 from KAP1 and regulates the interaction of the chromatin remodeler CHD3 with chromatin. Consequently, in the presence of CHD3, SENP7 is required for chromatin relaxation in response to DNA damage, for homologous recombination repair and for cellular resistance to DNA‐damaging agents. Thus, deSUMOylation by SENP7 is required to promote a permissive chromatin environment for DNA repair.
This study shows that SENP7 removes SUMO from KAP1, regulating the interaction of CHD3 with chromatin. In the presence of CHD3, SENP7 is required for chromatin relaxation in response to DNA damage, the ensuing repair and resistance to DNA damaging agents.
Journal Article
CXCL9 Contributes to Antimicrobial Protection of the Gut during Citrobacter rodentium Infection Independent of Chemokine-Receptor Signaling
Chemokines have been shown to be effective bactericidal molecules against a variety of bacteria and fungi in vitro. These direct antimicrobial effects are independent of their chemotactic activities involving immunological receptors. However, the direct biological role that these proteins may play in host defense, particularly against intestinal pathogens, is poorly understood. Here, we show that CXCL9, an ELR- chemokine, exhibits direct antimicrobial activity against Citrobacter rodentium, an attaching/effacing pathogen that infects the gut mucosa. Inhibition of this antimicrobial activity in vivo using anti-CXCL9 antibodies increases host susceptibility to C. rodentium infection with pronounced bacterial penetration into crypts, increased bacterial load, and worsened tissue pathology. Using Rag1(-/-) mice and CXCR3(-/-) mice, we demonstrate that the role for CXCL9 in protecting the gut mucosa is independent of an adaptive response or its immunological receptor, CXCR3. Finally, we provide evidence that phagocytes function in tandem with NK cells for robust CXCL9 responses to C. rodentium. These findings identify a novel role for the immune cell-derived CXCL9 chemokine in directing a protective antimicrobial response in the intestinal mucosa.
Journal Article
In vitro Characterization of Gut Microbiota-Derived Bacterial Strains With Neuroprotective Properties
Neurodegenerative diseases are disabling, incurable and progressive conditions characterized by neuronal loss and decreased cognitive function. Changes in gut microbiome composition have been linked to a number of neurodegenerative diseases, indicating a role for the gut-brain axis. Here, we show how specific gut-derived bacterial strains can modulate neuroinflammatory and neurodegenerative processes in vitro through the production of specific metabolites and discuss the potential therapeutic implications for neurodegenerative disorders. A panel of fifty gut bacterial strains was screened for their ability to reduce pro-inflammatory IL-6 secretion in U373 glioblastoma astrocytoma cells. Parabacteroides distasonis MRx0005 and Megasphaera massiliensis MRx0029 had the strongest capacity to reduce IL-6 secretion in vitro. Oxidative stress plays a crucial role in neuroinflammation and neurodegeneration, and both bacterial strains displayed intrinsic antioxidant capacity. While MRx0005 showed a general antioxidant activity on different brain cell lines, MRx0029 only protected differentiated SH-SY5Y neuroblastoma cells from chemically-induced oxidative stress. MRx0029 also induced a mature phenotype in undifferentiated neuroblastoma cells through upregulation of microtubule-associated protein 2. Interestingly, short-chain fatty acid analysis revealed that MRx0005 mainly produced C1-C3 fatty acids, while MRx0029 produced C4-C6 fatty acids, specifically butyric, valeric and hexanoic acid. None of the short-chain fatty acids tested protected neuroblastoma cells from chemically-induced oxidative stress. However, butyrate was able to reduce neuroinflammation in vitro, and the combination of butyrate and valerate induced neuronal maturation, albeit not to the same degree as the complex cell-free supernatant of MRx0029. This observation was confirmed by solvent extraction of cell-free supernatants, where only MRx0029 methanolic fractions containing butyrate and valerate showed an anti-inflammatory activity in U373 cells and retained the ability to differentiate neuroblastoma cells. In summary, our results suggest that the pleiotropic nature of live biotherapeutics, as opposed to isolated metabolites, could be a promising novel drug class in drug discovery for neurodegenerative disorders.
Journal Article
GogB Is an Anti-Inflammatory Effector that Limits Tissue Damage during Salmonella Infection through Interaction with Human FBXO22 and Skp1
Bacterial pathogens often manipulate host immune pathways to establish acute and chronic infection. Many Gram-negative bacteria do this by secreting effector proteins through a type III secretion system that alter the host response to the pathogen. In this study, we determined that the phage-encoded GogB effector protein in Salmonella targets the host SCF E3 type ubiquitin ligase through an interaction with Skp1 and the human F-box only 22 (FBXO22) protein. Domain mapping and functional knockdown studies indicated that GogB-containing bacteria inhibited IκB degradation and NFκB activation in macrophages, which required Skp1 and a eukaryotic-like F-box motif in the C-terminal domain of GogB. GogB-deficient Salmonella were unable to limit NFκB activation, which lead to increased proinflammatory responses in infected mice accompanied by extensive tissue damage and enhanced colonization in the gut during long-term chronic infections. We conclude that GogB is an anti-inflammatory effector that helps regulate inflammation-enhanced colonization by limiting tissue damage during infection.
Journal Article
Teaching Justice-Oriented Picturebooks Through Collaborative Discussion and ‘Slow Looking’: Implications for Initial Teacher Education Settings
Picturebooks have a long history as literature for literacy learning in initial teacher education (ITE) settings. Yet, the practice of “using” picturebooks solely to teach isolated skills becomes more alarming as pre-service teachers encounter classroom picturebook instruction that features diverse racial, linguistic, or ethnic communities as “plugged” into scripted curriculum without opportunities for students to respond to the socio-cultural portrayals encountered. Guidance for ITE programs is needed to ensure that the aesthetic and sociopolitical features of picturebooks are not only considered but deeply taught to pre-service teachers. Drawing from a qualitative analysis of a fifth-grade reader engaging with a picturebook featuring a character with a similar phenotype across ten days, an inductive and iterative process of data analysis identified salient moments of collaborative discussions and the ‘slow looking’ approaches she used to interact with justice-oriented picturebooks. Our findings highlight the visual, material, and multimodal ways these texts serve as mentor resources for writing and drawing, while also acting as identity-affirming texts. To conclude, we offer essential implications for ITE settings, instructors, and their students by unpacking the significance of instruction that matters most for supporting pre-service teachers as curators of justice-oriented picturebooks.
Journal Article
It Might Be Different from What We Think
Reid et al explore critical encounters with linguistically diverse picturebooks in an elementary classroom setting. They illustrate how critical encounters emerged in an elementary classroom through teacher and student discussions about language and identity with linguistically diverse picturebooks.
Journal Article
Friendship, bitching, and the making of ethical selves: what it means to be a good friend among girls in a London school
This article explores the relationship between friendship, personhood, and ethics among girls in a London school. While a Western ideal of friendship is posited as a personal, private, and spontaneous relationship between autonomous individuals, I argue that girls' friendships are a complex entanglement and interaction between forensic and mimetic dimensions of the self. Girls' ideals of friendship, and practices of making friends, suggest forensic pre-constituted selves acting with volition in order to become closer to other selves. However, bitching, exclusion, and breaking friendships foreground mimetic dimensions as girls shape each other and themselves according to gendered ethical criteria. Examining these analytical strands offers insight into how individuality is produced through sociality in everyday life. L'article explore le lien entre amitié, statut de personne et éthique parmi des jeunes filles d'une école de Londres. Bien que l'idéal occidental de l'amitié suppose une relation personnelle, privée et spontanée entre des individus autonomes, l'auteure avance que les amitiés entre filles sont un entremêlement complexe faisant interagir les dimensions forensiques et mimétiques du Moi. Les idéaux d'amitié des filles et leurs pratiques pour se faire des amies suggèrent l'existence d'un Moi forensique pré-constitué agissant volontairement pour se rapprocher d'autres Moi. Pourtant, les ragots, l'exclusion et les ruptures préfigurent des dimensions mimétiques dans lesquelles les filles se modèlent à la fois elles-mêmes et entre elles suivant des critères éthiques genres. L'examen de ces pistes d'analyse éclaire la manière dont l'individualité naît de la socialite dans la vie quotidienne.
Journal Article
Accuracy of the diagnosis of pneumonia in Canadian pediatric emergency departments: A prospective cohort study
The diagnosis of pediatric pneumonia and determination of the likely pathogen are complicated as the clinical picture overlaps with other respiratory illnesses, interpretation of radiographs is subjective, and laboratory results are rarely diagnostic. This study was designed to describe the relative rates of bacterial and viral pneumonia in the pediatric Emergency Department (ED), determine the accuracy of pediatric ED physicians' ability to diagnose pneumonia and distinguish bacterial from viral etiology, and to determine clinical and laboratory predictors of bacterial pneumonia.
Children 3 months to 16 years of age presenting to seven Canadian pediatric EDs before the COVID-19 pandemic with fever and cough who had a chest radiograph performed for possible pneumonia were enrolled and underwent standardized clinical investigations. An expert panel was convened and reached a Consensus Diagnosis of typical or atypical bacterial pneumonia, viral pneumonia or not pneumonia for each case.
The expert panel assessed 247 cases with the Consensus Diagnosis being typical bacterial pneumonia (N = 44(18%)), atypical bacterial pneumonia (N = 18(7%)), viral pneumonia (N = 46(19%)) and no pneumonia (N = 139(56%)). Treating ED physician diagnoses were typical bacterial pneumonia (N = 126(51%)), atypical bacterial pneumonia (N = 3(1%)), viral pneumonia (N = 10(4%)) and no pneumonia (N = 108(44%)) with low agreement between a diagnosis of bacterial pneumonia by the ED physician and the panel's Consensus Diagnosis (Kappa 0.15 (95% CI 0.08, 0.21)). Cut off values that predicted bacterial pneumonia as the Consensus Diagnosis were ESR ≥ 47 mm/hour, CRP ≥ 42 mg/L and procalcitonin ≥0.85 ng/m. Age greater than 5 years and cough for 5 or more days also predict bacterial pneumonia.
In this cohort, pediatric ED physicians over-diagnosed typical bacterial pneumonia and underdiagnosed viral and atypical bacterial pneumonia. Bacterial pneumonia is most likely in children over 5 years of age, with cough for 5 or more days and/or with elevated inflammatory markers.
Journal Article
PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene
PALB2 interacts with BRCA2, and biallelic mutations in
PALB2
(also known as
FANCN
), similar to biallelic
BRCA2
mutations, cause Fanconi anemia. We identified monoallelic truncating
PALB2
mutations in 10/923 individuals with familial breast cancer compared with 0/1,084 controls (
P
= 0.0004) and show that such mutations confer a 2.3-fold higher risk of breast cancer (95% confidence interval (c.i.) = 1.4–3.9,
P
= 0.0025). The results show that
PALB2
is a breast cancer susceptibility gene and further demonstrate the close relationship of the Fanconi anemia–DNA repair pathway and breast cancer predisposition.
Journal Article