A model for Scc2p stimulation of cohesin's ATPase and its inhibition by acetylation of Smc3p.

The evolutionarily conserved cohesin complex mediates sister chromatid cohesion and facilitates mitotic chromosome condensation, DNA repair, and transcription regulation. These biological functions require cohesin's two ATPases, formed by the Smc1p and Smc3p subunits. Cohesin's ATPase activity is stimulated by the Scc2p auxiliary factor. This stimulation is inhibited by Eco1p acetylation of Smc3p at an interface with Scc2p. It was unclear how cohesin's ATPase activity is stimulated by Scc2p or how acetylation inhibits Scc2p, given that the acetylation site is distal to cohesin's ATPase active sites. Here, we identify mutations in budding yeast that suppressed the in vivo defects caused by Smc3p acetyl-mimic and acetyl-defective mutations. We provide compelling evidence that Scc2p activation of cohesin ATPase depends on an interface between Scc2p and a region of Smc1p proximal to cohesin's Smc3p ATPase active site. Furthermore, substitutions at this interface increase or decrease ATPase activity to overcome ATPase modulation by acetyl-mimic and acetyl-null mutations. Using these observations and an existing cryo-EM structure, we propose a model for regulating cohesin ATPase activity. We suggest that Scc2p binding to Smc1p causes the adjacent Smc1p residues and ATP to shift, stimulating Smc3p's ATPase. This stimulatory shift is inhibited through acetylation of the distal Scc2p-Smc3p interface.

MHC-dressing on dendritic cells: Boosting anti-tumor immunity via unconventional tumor antigen presentation.

Dendritic cells are crucial for anti-tumor immune responses due to their ability to activate cytotoxic effector CD8+ T cells. Canonically, in anti-tumor immunity, dendritic cells activate CD8+ T cells in a process termed cross-presentation. Recent studies have demonstrated that another type of antigen presentation, MHC-dressing, also serves to activate CD8+ T cells against tumor cell-derived antigens. Understanding MHC-dressing's specific contributions to anti-tumor immunity can open up novel therapeutic avenues. In this review, we summarize the early studies that identified MHC-dressing as a relevant antigen presentation pathway before diving into a deeper discussion of the biology of MHC-dressing, focusing in particular on which dendritic cell subsets are most capable of performing MHC-dressing and how MHC-dressing compares to other forms of antigen presentation. We conclude by discussing the implications MHC-dressing has for anti-tumor immunity.

Dendritic cell-mediated cross presentation of tumor-derived peptides is biased against plasma membrane proteins.

BACKGROUND: For effective tumor elimination, cytotoxic CD8+ T cells must recognize tumor-derived antigens presented on class I major histocompatibility complex (MHC-I). Despite a general association between the expression of immunogenic antigens, typically neoantigens, and response to immunotherapy, the majority of patients lack strong endogenous responses to most putative neoantigens due to mechanisms that are not well understood. Cytotoxic CD8+ T-cell responses are induced by dendritic cells (DCs) cross-presenting tumor-derived peptides on MHC-I. We hypothesized that cross presentation may form an unappreciated source of bias in the induction of cytotoxic T-cell responses. METHODS: We used stable isotope labeling of amino acids combined with immunopeptidomics to distinguish cross-presented from endogenous MHC-I peptides on DCs. To test impacts on T-cell activation, we targeted the model antigen SIINFEKL to specific subcellular compartments in tumor cells, which were used as sources for cross presentation to T cells. In vitro observations were validated using DNA and RNA sequencing data from two cohorts of patients with melanoma undergoing checkpoint blockade therapy. We used a novel quantitative mass spectrometry approach to measure the levels of model antigen on cross-presenting DCs following various means of tumor cell death. RESULTS: DCs exhibited a strong bias for cross-presenting peptides derived from cytoplasmic proteins and against those from plasma membrane proteins, which was confirmed using the model antigen SIINFEKL. In patients with melanoma, the proportion of membrane-derived neoantigens was correlated with reduced survival and failure to respond to therapy. Quantification of cross-presented SIINFEKL revealed that the mode of cell death could overcome DCs' bias against plasma membrane proteins. CONCLUSIONS: Cross presentation of cellular antigens by DCs may impose constraints on the range of peptides available to activate CD8+ T cells that have previously gone unappreciated. The share of neoantigens arising from membrane-derived sources may render some tumors less immunogenic due to inefficient cross presentation. These observations carry important implications for the encounter and intracellular processing of cellular antigens by DCs and merit further clinical studies for their therapeutic potential in stratifying patient populations and design of vaccine-based therapies.Sorry this seems to be the only funciton that works yes I confirm TBF, LES and FC are joint first authors. Please that away the line TFB and FC contributed equally. thanks!!

Severe cortical damage associated with COVID-19 case report.

Symptoms of COVID-19, as reported during the SARS-CoV-2 pandemic in 2019-2020, are primarily respiratory and gastrointestinal, with sparse reports on neurological manifestations. We describe the case of a 17-year old female with Cornelia de Lange syndrome and well controlled epilepsy, who sustained significant cortical injury during a COVID-19 associated multi-inflammatory syndrome.

Communication between distinct subunit interfaces of the cohesin complex promotes its topological entrapment of DNA.

Cohesin mediates higher order chromosome structure. Its biological activities require topological entrapment of DNA within a lumen(s) formed by cohesin subunits. The reversible dissociation of cohesin's Smc3p and Mcd1p subunits is postulated to form a regulated gate that allows DNA entry and exit into the lumen. We assessed gate-independent functions of this interface in yeast using a fusion protein that joins Smc3p to Mcd1p. We show that in vivo all the regulators of cohesin promote DNA binding of cohesin by mechanisms independent of opening this gate. Furthermore, we show that this interface has a gate-independent activity essential for cohesin to bind chromosomes. We propose that this interface regulates DNA entrapment by controlling the opening and closing of one or more distal interfaces formed by cohesin subunits, likely by inducing a conformation change in cohesin. Furthermore, cohesin regulators modulate the interface to control both DNA entrapment and cohesin functions after DNA binding.

Infratentorial superficial siderosis: Classification, diagnostic criteria, and rational investigation pathway.

Central nervous system infratentorial superficial siderosis (iSS) is increasingly detected by blood-sensitive magnetic resonance imaging (MRI) sequences. Despite this, there are no standardized diagnostic criteria, and the clinical-radiological spectrum, causes, and optimum investigation strategy are not established. We reviewed clinical and radiological details of patients with iSS assessed at a specialist neurological center during 2004-2016 using predefined standardized radiological criteria. All imaging findings were rated blinded to clinical details. We identified 65 patients with iSS, whom we classified into 2 groups: type 1 (classical) and type 2 (secondary) iSS. Type 1 (classical) iSS included 48 patients without any potentially causal radiologically confirmed single spontaneous or traumatic intracranial hemorrhage, of whom 39 (83%) had hearing loss, ataxia, or myelopathy; type 2 (secondary) iSS included 17 patients with a potentially causal radiologically confirmed spontaneous or traumatic intracranial hemorrhage, of whom none had hearing loss, ataxia, or myelopathy. Of the patients with type 1 (classical) iSS, 40 (83%) had a potentially causal cranial or spinal dural abnormality, 5 (11%) had an alternative cause, and 3 (6%) had no cause identified. Intra-arterial digital subtraction angiography did not identify any underlying causal lesions for type 1 iSS. Type 1 (classical) iSS, defined using simple radiological criteria, is associated with a characteristic neurological syndrome. Rational investigation, including spinal MRI, nearly always reveals a potential cause, most often a dural abnormality. Catheter angiography appears to be unhelpful, suggesting that classical iSS is not associated with macrovascular arterial pathology. Recognition of type 1 (classical) iSS should allow timely diagnosis and early consideration of treatment. Ann Neurol 2017;81:333-343.

Non-perforating small bowel Crohn's disease assessed by MRI enterography: derivation and histopathological validation of an MR-based activity index.

OBJECTIVES: To develop and validate a qualitative scoring system for enteric Crohn's disease activity using MR enterography (MRE). METHODS: MRE was performed in 16 patients (mean age 33, 8 male) undergoing small bowel resection. Mural thickness, T2 signal, contrast enhancement, and perimural oedema were scored qualitatively (0-3) at 44 locations. Transmural histopathological scoring of acute inflammation (AIS) was performed at all locations (score 0-13). MRI parameters best predicting AIS were derived using multivariate analysis. The MRI activity index was applied to 26 Crohn's patients (mean age 32, range 13-69 years, 15 male) and correlated to terminal ileal biopsy scores of acute inflammation ("eAIS" score 1-6). Receiver operator characteristic curves were calculated. RESULTS: Mural thickness (coefficient 1.34 (95% CI 0.36, 2.32)], p=0.007) and T2 signal (coefficient 0.90 (95% CI -0.24, 2.04) p=0.06) best predicted AIS (AIS=1.79+1.34*mural thickness+0.94*mural T2 score [R-squared 0.52]). There was a significant correlation between the MRI index and eAIS (Kendall's tau=0.40, 95% CI 0.11-0.64, p=0.02). The model achieved a sensitivity of 0.81 (95% CI 0.54-0.96), specificity of 0.70 (0.35-0.93) and AUC 0.77 for predicting acute inflammation (eAIS ≥2). CONCLUSIONS: A simple qualitative MRI Crohn's disease activity score appears predictive against a histopathological standard of reference.