Species Selectivity of Mixed-Lineage Leukemia/Trithorax and HCF Proteolytic Maturation Pathways▿

Site-specific proteolytic processing plays important roles in the regulation of cellular activities. The histone modification activity of the human trithorax group mixed-lineage leukemia (MLL) protein and the cell cycle regulatory activity of the cell proliferation factor herpes simplex virus host cell factor 1 (HCF-1) are stimulated by cleavage of precursors that generates stable heterodimeric complexes. MLL is processed by a protease called taspase 1, whereas the precise mechanisms of HCF-1 maturation are unclear, although they are known to depend on a series of sequence repeats called HCF-1PRO repeats. We demonstrate here that the Drosophila homologs of MLL and HCF-1, called Trithorax and dHCF, are both cleaved by Drosophila taspase 1. Although highly related, the human and Drosophila taspase 1 proteins display cognate species specificity. Thus, human taspase 1 preferentially cleaves MLL and Drosophila taspase 1 preferentially cleaves Trithorax, consistent with coevolution of taspase 1 and MLL/Trithorax proteins. HCF proteins display even greater species-specific divergence in processing: whereas dHCF is cleaved by the Drosophila taspase 1, human and mouse HCF-1 maturation is taspase 1 independent. Instead, human and Xenopus HCF-1PRO repeats are cleaved in vitro by a human proteolytic activity with novel properties. Thus, from insects to humans, HCF proteins have conserved proteolytic maturation but evolved different mechanisms

Oral Health Preventive Program in Patients with Autism Spectrum Disorder

: The aim of the study was to evaluate clinical hygienic parameters, patient collaboration, and dental habits in patients with ASD (autism spectrum disorder) before and after a tailored prevention program. A total of 100 patients (78 males and 22 females, mean age 8 ± 0.7 years old) was recruited, with ages ranging from 7 to 16 years old, and diagnoses of ASD. We evaluated the plaque index (IP), gingival index (IG), the dmft/DMFT, the frequency of tooth brushing, and the frequency of snacks for each patient. Patient behaviour was evaluated with the Frankl scale, and each patient was individually reassessed after five visits from the first one by the same operator. The t test was used to compare the parameters before and after the inclusion in the dedicated dental pathway. From T1 to T2 we found a significant improvement of the IP (p < 0.001), IG (p < 0.001), and the frequency of tooth brushing (p < 0.001). Concerning the frequency of snacks and the parameter dmft/DMFT, the differences in the observed averages were not significant (p > 0.05). The difference in collaboration between T1 and T2 evaluated by the Frankl scale was statistically significant (p < 0.001). It was found that the prevention program allowed a significant improvement in both clinical parameters and patient behaviour. The personalized digital supports can have a key role for success in familiarization and desensitization processes of patients affected by ASD, leading an increase in their collaboration

Steady-state antigen scavenging, cross-presentation, and CD8+ T cell priming: a new role for lymphatic endothelial cells

Until recently, the known roles of lymphatic endothelial cells (LECs) in immune modulation were limited to directing immune cell trafficking and passively transporting peripheral Ags to lymph nodes. Recent studies demonstrated that LECs can directly suppress dendritic cell maturation and present peripheral tissue and tumor Ags for autoreactive T cell deletion. We asked whether LECs play a constitutive role in T cell deletion under homeostatic conditions. In this study, we demonstrate that murine LECs under noninflamed conditions actively scavenge and cross-present foreign exogenous Ags to cognate CD8(+) T cells. This cross-presentation was sensitive to inhibitors of lysosomal acidification and endoplasmic reticulum-golgi transport and was TAP1 dependent. Furthermore, LECs upregulated MHC class I and the PD-1 ligand PD-L1, but not the costimulatory molecules CD40, CD80, or CD86, upon Ag-specific interactions with CD8(+) T cells. Finally, Ag-specific CD8(+) T cells that were activated by LECs underwent proliferation, with early-generation apoptosis and dysfunctionally activated phenotypes that could not be reversed by exogenous IL-2. These findings help to establish LECs as APCs that are capable of scavenging and cross-presenting exogenous Ags, in turn causing dysfunctional activation of CD8(+) T cells under homeostatic conditions. Thus, we suggest that steady-state lymphatic drainage may contribute to peripheral tolerance by delivering self-Ags to lymph node-resident leukocytes, as well as by providing constant exposure of draining peripheral Ags to LECs, which maintain tolerogenic cross-presentation of such Ags

Un monastero sul mare

The remains of the monastery of San Quirico stand on the slopes of Poggio Tondo, a hill not far from the ancient city of Populonia. They overlook the Tyrrhenian Sea, dotted with the islands of the Tuscan archipelago. Field research at this site, carried out in the first decade of the new millennium by two different teams, from Siena University and Venice’s Ca’ Foscari University, respectively, was part of ongoing efforts to expand the Baratti-Populonia Archeological Park, and to further explore the features present within it. This volume contains the results of this research work: a scientific publication of the excavation, and a critical analysis of the material found. Processing of the data collected during these investigations, together with a re-reading of written documentation, has made it possible to piece together the complex history of this important monastery, in a totally new narration. In this narration, the history of the monastery, and of the features which existed prior to it, are closely interwoven with the history of the promontory of Populonia and the surrounding area, ultimately producing a new overview which sets out the historical boundaries of this area, between Late Antiquity and the modern era.I resti del monastero di San Quirico si trovano sulle pendici del poggio Tondo, a poca distanza dall’antica città di Populonia, rivolti verso lo specchio del mare Tirreno costellato dalle isole dell’arcipelago toscano. Le ricerche archeologiche in questo sito, realizzate nel primo decennio del nuovo millennio da due differenti équipe, rispettivamente dell’Università di Siena e Ca’ Foscari di Venezia, si sono svolte nell’ambito degli interventi di ampliamento e di valorizzazione del parco archeologico di Baratti-Populonia. Questo volume contiene i risultati di quelle ricerche: l’edizione scientifica dello scavo e l’analisi critica dei materiali rinvenuti. La rielaborazione dei dati raccolti durante tali indagini, unita ad una rilettura della documentazione scritta, ha poi permesso di ricomporre le complesse vicende di questo importante monastero, in una nuova ed inedita narrazione. In tale narrazione le vicende del cenobio e delle sue preesistenze si intrecciano con quelle del promontorio di Populonia e dei territori limitrofi fino a delineare un quadro di sintesi che ridisegna i confini storici di questo territorio tra la Tarda Antichità e l’Età Moderna

O-GlcNAc transferase catalyzes site-specific proteolysis of HCF-1.

The human epigenetic cell-cycle regulator HCF-1 undergoes an unusual proteolytic maturation process resulting in stably associated HCF-1(N) and HCF-1(C) subunits that regulate different aspects of the cell cycle. Proteolysis occurs at six centrally located HCF-1(PRO)-repeat sequences and is important for activation of HCF-1(C)-subunit functions in M phase progression. We show here that the HCF-1(PRO) repeat is recognized by O-linked β-N-acetylglucosamine transferase (OGT), which both O-GlcNAcylates the HCF-1(N) subunit and directly cleaves the HCF-1(PRO) repeat. Replacement of the HCF-1(PRO) repeats by a heterologous proteolytic cleavage signal promotes HCF-1 proteolysis but fails to activate HCF-1(C)-subunit M phase functions. These results reveal an unexpected role of OGT in HCF-1 proteolytic maturation and an unforeseen nexus between OGT-directed O-GlcNAcylation and proteolytic maturation in HCF-1 cell-cycle regulation

Dapagliflozin treatment is associated with a reduction of epicardial adipose tissue thickness and epicardial glucose uptake in human type 2 diabetes

Abstract Objective We recently demonstrated that treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) leads to an increase in myocardial flow reserve in patients with type 2 diabetes (T2D) with stable coronary artery disease (CAD). The mechanism by which this occurs is, however, unclear. One of the risk factors for cardiovascular disease is inflammation of epicardial adipose tissue (EAT). Since the latter is often increased in type 2 diabetes patients, it could play a role in coronary microvascular dysfunction. It is also well known that SGLT-2i modify adipose tissue metabolism. We aimed to investigate the effects of the SGLT-2i dapagliflozin on metabolism and visceral and subcutaneous adipose tissue thickness in T2D patients with stable coronary artery disease and to verify whether these changes could explain observed changes in myocardial flow. Methods We performed a single-center, prospective, randomized, double-blind, controlled clinical trial with 14 T2D patients randomized 1:1 to SGLT-2i dapagliflozin (10 mg daily) or placebo. The thickness of visceral (epicardial, mediastinal, perirenal) and subcutaneous adipose tissue and glucose uptake were assessed at baseline and 4 weeks after treatment initiation by 2-deoxy-2-[18F]fluoro-D-glucose Positron Emission Tomography/Computed Tomography during hyperinsulinemic euglycemic clamp. Results The two groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, BMI, renal and heart function). Dapagliflozin treatment significantly reduced EAT thickness by 19% (p = 0.03). There was a significant 21.6% reduction in EAT glucose uptake during euglycemic hyperinsulinemic clamp in the dapagliflozin group compared with the placebo group (p = 0.014). There were no significant effects on adipose tissue thickness/metabolism in the other depots explored. Conclusions SGLT-2 inhibition selectively reduces EAT thickness and EAT glucose uptake in T2D patients, suggesting a reduction of EAT inflammation. This could explain the observed increase in myocardial flow reserve, providing new insights into SGLT-2i cardiovascular benefits

Un monastero sul mare

The remains of the monastery of San Quirico stand on the slopes of Poggio Tondo, a hill not far from the ancient city of Populonia. They overlook the Tyrrhenian Sea, dotted with the islands of the Tuscan archipelago. Field research at this site, carried out in the first decade of the new millennium by two different teams, from Siena University and Venice’s Ca’ Foscari University, respectively, was part of ongoing efforts to expand the Baratti-Populonia Archeological Park, and to further explore the features present within it. This volume contains the results of this research work: a scientific publication of the excavation, and a critical analysis of the material found. Processing of the data collected during these investigations, together with a re-reading of written documentation, has made it possible to piece together the complex history of this important monastery, in a totally new narration. In this narration, the history of the monastery, and of the features which existed prior to it, are closely interwoven with the history of the promontory of Populonia and the surrounding area, ultimately producing a new overview which sets out the historical boundaries of this area, between Late Antiquity and the modern era

The \u3b1-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases

Abstract: A positron emission tomography (PET) tracer detecting alpha-synuclein pathology will improve the diagnosis, and ultimately the treatment of alpha-synuclein-related diseases. Here we show that the PET ligand, [18F]ACI-12589, displays good in vitro affinity and specificity for pathological alpha-synuclein in tissues from patients with different alpha-synuclein-related disorders including Parkinson's disease (PD) and Multiple-System Atrophy (MSA) using autoradiography and radiobinding techniques. In the initial clinical evaluation we include 23 participants with alpha-synuclein related disorders, 11 with other neurodegenerative disorders and eight controls. In vivo [18F]ACI-12589 demonstrates clear binding in the cerebellar white matter and middle cerebellar peduncles of MSA patients, regions known to be highly affected by alpha-synuclein pathology, but shows limited binding in PD. The binding statistically separates MSA patients from healthy controls and subjects with other neurodegenerative disorders, including other synucleinopathies. Our results indicate that alpha-synuclein pathology in MSA can be identified using [18F]ACI-12589 PET imaging, potentially improving the diagnostic work-up of MSA and allowing for detection of drug target engagement in vivo of novel alpha-synuclein targeting therapies. A PET tracer for alpha-synuclein would help diagnosis and treatment of alpha-syn-related diseases. Here the authors show that ACI-12589 shows an uptake in the cerebellar white matter in patients with multiple-system atrophy