Integrin beta 1 inhibition alleviates the chronic hyperproliferative dermatitis phenotype of SHARPIN-deficient mice

SHARPIN (Shank-Associated RH Domain-Interacting Protein) is a component of the linear ubiquitin chain assembly complex (LUBAC), which enhances TNF-induced NF-kappa B activity. SHARPIN-deficient (Sharpin(cpdm/cpdm)) mice display multi-organ inflammation and chronic proliferative dermatitis (cpdm) due to TNF-induced keratinocyte apoptosis. In cells, SHARPIN also inhibits integrins independently of LUBAC, but it has remained enigmatic whether elevated integrin activity levels in the dermis of Sharpin(cpdm/cpdm) mice is due to increased integrin activity or is secondary to inflammation. In addition, the functional contribution of increased integrin activation to the Sharpin(cpdm/cpdm) phenotype has not been investigated. Here, we find increased integrin activity in keratinocytes from Tnfr1(-/-) Sharpin(cpdm/cpdm) double knockout mice, which do not display chronic inflammation or proliferative dermatitis, thus suggesting that SHARPIN indeed acts as an integrin inhibitor in vivo. In addition, we present evidence for a functional contribution of integrin activity to the Sharpin(cpdm/cpdm) skin phenotype. Treatment with an integrin beta 1 function blocking antibody reduced epidermal hyperproliferation and epidermal thickness in Sharpin(cpdm/cpdm) mice. Our data indicate that, while TNF-induced cell death triggers the chronic inflammation and proliferative dermatitis, absence of SHARPIN-dependent integrin inhibition exacerbates the epidermal hyperproliferation in Sharpin(cpdm/cpdm) mice.Peer reviewe

Synthetic Membrane Shaper for Controlled Liposome Deformation

Shape defines the structure and function of cellular membranes. In cell division, the cell membrane deforms into a "dumbbell" shape, while organelles such as the autophagosome exhibit "stomatocyte" shapes. Bottom-up in vitro reconstitution of protein machineries that stabilize or resolve the membrane necks in such deformed liposome structures is of considerable interest to characterize their function. Here we develop a DNA-nanotechnology-based approach that we call the synthetic membrane shaper (SMS), where cholesterol-linked DNA structures attach to the liposome membrane to reproducibly generate high yields of stomatocytes and dumbbells. In silico simulations confirm the shape-stabilizing role of the SMS. We show that the SMS is fully compatible with protein reconstitution by assembling bacterial divisome proteins (DynaminA, FtsZ:ZipA) at the catenoidal neck of these membrane structures. The SMS approach provides a general tool for studying protein binding to complex membrane geometries that will greatly benefit synthetic cell research.</p

DAily time use, Physical Activity, quality of care and interpersonal relationships in patients with Schizophrenia spectrum disorders (DiAPASon): an Italian multicentre study

Background: Schizophrenia spectrum disorders (SSD) are ranked among the leading causes of disabilities worldwide. Many people with SSD spend most of their daily time being inactive, and this is related to the severity of negative symptoms. Here, we present the 3-year DiAPAson project aimed at (1) evaluating the daily time use among patients with SSD living in Residential Facilities (RFs) compared to outpatients with SSD and to the general population (Study 1); (2) evaluating the quality of staff-patient relationships, its association with specific patient outcomes and the quality of care provided in RFs (Study 2); and (3) assessing daily activity patterns in residential patients, outpatients with SSD and healthy controls using real-time methodologies (Study 3). Methods: Study 1 will include 300 patients with SSD living in RFs and 300 outpatients; data obtained in these clinical populations will be compared with normative data obtained by the National Institute of Statistics (ISTAT) in the national survey on daily time use. Time use assessments will consist of daily diaries asking participants to retrospectively report time spent in different activities. In Study 2, a series of questionnaires will be administered to 300 residential patients (recruited for Study 1) to evaluate the quality of care and staff-patient relationships, level of well-being and burnout of RFs' staff, and quality of RFs using a European standardized questionnaire (QuIRC-SA). In Study 3, the daily time use will be evaluated in a subgroup of 50 residential patients, 50 outpatients and 50 healthy controls using the Experience Sampling Method approach (participants will complete a brief questionnaire -about time use, mood and perceived energy- on a smartphone 8 times a day for 1 week) to compare retrospective and real-time reports. Moreover, their level of physical activity, sleep patterns, and energy expenditure will be monitored through a multi-sensor device. Discussion: This project is highly innovative because it combines different types of assessments (i.e., retrospective and real-time reports; multi-sensor monitoring) to trace an accurate picture of daily time use and levels of physical activity that will help identify the best therapeutic options promoting daily activities and physical exercise in patients with SSD. Trial registration: ISRCTN registry ID ISRCTN21141466

Hidden Comorbidities in Asthma: A Perspective for a Personalized Approach

: Bronchial asthma is the most frequent inflammatory non-communicable condition affecting the airways worldwide. It is commonly associated with concomitant conditions, which substantially contribute to its burden, whether they involve the lung or other districts. The present review aims at providing an overview of the recent acquisitions in terms of asthma concomitant systemic conditions, besides the commonly known respiratory comorbidities. The most recent research has highlighted a number of pathobiological interactions between asthma and other organs in the view of a shared immunological background underling different diseases. A bi-univocal relationship between asthma and common conditions, including cardiovascular, metabolic or neurodegenerative diseases, as well as rare disorders such as sickle cell disease, α1-Antitrypsin deficiency and immunologic conditions with hyper-eosinophilia, should be considered and explored, in terms of diagnostic work-up and long-term assessment of asthma patients. The relevance of that acquisition is of utmost importance in the management of asthma patients and paves the way to a new approach in the light of a personalized medicine perspective, besides targeted therapies

Impaired pro‐resolving mechanisms promote abnormal NETosis , fueling autoimmunity in sickle cell disease

Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorders with still high mortality and morbidity and limited therapeutic options. SCD is characterized by anemia, chronic hemolysis, and acute vaso-occlusive painful crises. The biocomplexity of SCD goes beyond red cells, involving neutrophils and soluble factors such as cytokines or alternative complement pathway intensively cross-talking with vascular endothelial cells. In addition, in SCD, the overactivation of neutrophils contributes to the production of neutrophil extracellular traps (NETs) (1, 2). This might trigger endothelial vascular injury, promoting acute sickle cell related events and increasing the risk of infections in patients with SC

Novel integrin endocytosis motif

Integrins are heterodimeric cell-surface adhesion molecules comprising one of 18 possible α-chains and one of eight possible β-chains. They control a range of cell functions in a matrix- and ligand-specific manner. Integrins can be internalized by clathrin-mediated endocytosis (CME) through β subunit-based motifs found in all integrin heterodimers. However, whether specific integrin heterodimers can be selectively endocytosed was unknown. Here, we found that a subset of α subunits contain an evolutionarily conserved and functional YxxΦ motif directing integrins to selective internalization by the most abundant endocytic clathrin adaptor, AP2. We determined the structure of the human integrin α4-tail motif in complex with the AP2 C-μ2 subunit and confirmed the interaction by isothermal titration calorimetry. Mutagenesis of the motif impaired selective heterodimer endocytosis and attenuated integrin-mediated cell migration. We propose that integrins evolved to enable selective integrin-receptor turnover in response to changing matrix conditions.We gratefully acknowledge the following funding sources: N.d.F. FinPharma Doctoral Program, Instrumentarium Foundation, Orion Research Foundation, Liv och Halsa foundation, Finsk-Norska Medicinska Stiftelsen and the Magnus Ehrnrooth Foundation; J.I. Academy of Finland CoE, European Research Council Consolidator Grant, the Sigrid Juselius Foundation, The Finnish Heart Foundation and Finnish Cancer Organizations. DJO, AGW and TW are funded by Wellcome Trust fellowship 090909 (DJO).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nsmb.3161

Author Correction:Human ESCRT-III polymers assemble on positively curved membranes and induce helical membrane tube formation

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Cytoreductive Surgery and Hyperthermic Intrathoracic Chemotherapy by Video-Assisted Surgery for Pleural Malignancies: Technical Aspects and Safety Profile

Background: Pleural malignancies are challenging conditions in terms of possibility of cure. Recent growing interest towards Hyperthermic Intrathoracic Chemotherapy (HITHOC) after Cytoreductive Surgery (CRS) has been referred. Minimally invasive approach (VATS) may be suggest in this context but evidence is still lacking. Methods: A preliminary experience in seven patients submitted to cytoreductive surgery and HITHOC is described, with a focus on technical aspects related to VATS approach, operating median time and postoperative complication. Results: A triportal VATS approach has been employed in all cases. Median time of surgery including pleural perfusion was 200 min (range 165 to 370). Mean blood loss was 217 cc (range 100 and 600). Thirty days mortality was nothing. Conclusion: VATS cytoreductive surgery and HITHOC is a safe procedure and could be proposed in the setting of a multimodality strategy employing adjuvant radio-chemotherapy in referral centers

Mitochondrial DNA involvement in human longevity

AbstractThe main message of this review can be summarized as follows: aging and longevity, as complex traits having a significant genetic component, likely depend on a number of nuclear gene variants interacting with mtDNA variability both inherited and somatic. We reviewed the data available in the literature with particular attention to human longevity, and argued that what we hypothesize for aging and longevity could have a more general relevance and be extended to other age-related complex traits such as Alzheimer's and Parkinson's diseases. The genetics which emerges for complex traits, including aging and longevity, is thus even more complicated than previously thought, as epistatic interactions between nuclear gene polymorphisms and mtDNA variability (both somatic and inherited) as well as between mtDNA somatic mutations (tissue specific) and mtDNA inherited variants (haplogroups and sub-haplogroups) must be considered as additional players capable of explaining a part of the aging and longevity phenotype. To test this hypothesis is one of the main challenge in the genetics of aging and longevity in the next future

Cytoreductive Surgery and Hyperthermic Intrathoracic Chemotherapy by Video-Assisted Surgery for Pleural Malignancies. Technical Aspects and Safety Profile from A Single Center

Background Pleural malignancies are challenging conditions in terms of possibility of cure. Recent growing interest towards Hyperthermic Intrathoracic Chemotherapy (HITHOC) after Cytoreductive Surgery (CRS) has been referred. Minimally invasive approach (VATS) may be suggest in this context but evidence is still lacking. Methods A preliminary experience in seven patients submitted to cytoreductive surgery and HITHOC is described, with a focus on technical aspects related to VATS approach, operating median time and postoperative complication. Results A triportal VATS approach has been employed in all cases. Median time of surgery including pleural perfusion was 200 minutes (range 165-370). Mean blood losswas 217 cc (range 100 and 600). Thirty days’ mortality was nihil. Conclusions VATS cytoreductive surgery and HITHOC is a safeprocedure and could be proposed in the setting of a multimodality strategy employing adjuvant radio-chemotherapy in referral center