A progranulin variant causing childhood interstitial lung disease responsive to anti-TNF-α biologic therapy.

Background: Childhood interstitial and diffuse lung diseases are a collection of rare disorders with significant associated morbidity. Only a small subset of these diseases have precise diagnostic or therapeutic options identified to date.

Methods: Whole-exome sequencing in a family identified a candidate pathogenic variant predicted to be causing fibrotic lung and liver disease in a child.

The role of ATP-binding Cassette subfamily B member 6 in the inner ear.

ABCB6 has been implicated in dyschromatosis universalis hereditaria, a condition characterized by hyperpigmented and hypopigmented skin macules. Dyschromatosis universalis hereditaria can also present with hearing loss. Dyschromatosis universalis hereditaria-associated mutations in ABCB6 have been reported, but the role of this protein in the inner ear has not been studied.

Age-associated clonal B cells drive B cell lymphoma in mice.

Although cancer is an age-related disease, how the processes of aging contribute to cancer progression is not well understood. In this study, we uncovered how mouse B cell lymphoma develops as a consequence of a naturally aged system. We show here that this malignancy is associated with an age-associated clonal B cell (ACBC) population that likely originates from age-associated B cells.

Exploring the Utility of Circulating Endothelial Cell-Derived Extracellular Vesicles as Markers of Health and Damage of Vasal Endothelium in Systemic Sclerosis Patients Treated with Iloprost.

Endothelial cell-derived extracellular vesicles (eEVs) are released from endothelial cells, signifying endothelial integrity. Systemic Sclerosis (SSc) is a rare disease causing skin and organ fibrosis with early vascular damage. Iloprost, an SSc treatment, might affect eEV release, showing long-term benefits.

Humanized V(D)J-rearranging and TdT-expressing mouse vaccine models with physiological HIV-1 broadly neutralizing antibody precursors.

Antibody heavy chain (HC) and light chain (LC) variable region exons are assembled by V(D)J recombination. V(D)J junctional regions encode complementarity-determining-region 3 (CDR3), an antigen-contact region immensely diversified through nontemplated nucleotide additions ("N-regions") by terminal deoxynucleotidyl transferase (TdT). HIV-1 vaccine strategies seek to elicit human HIV-1 broadly neutralizing antibodies (bnAbs), such as the potent CD4-binding site VRC01-class bnAbs.

Profibrotic Effects of Endothelin-1 on Fibroblasts Are Mediated by Aldosterone in Vitro: Relevance to the Pathogenesis and Therapy of Systemic Sclerosis and Pulmonary Arterial Hypertension.

Endothelin-1 (ET-1) is a vasoactive and profibrotic peptide that plays a pivotal role in diseases such as systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH), by inducing fibrosis and vascular remodeling. Such effects may be sustained by the induction of aldosterone production and reactive oxygen species (ROS). We have used fibroblasts obtained from skin of healthy donors and SSc patients and commercial fibroblasts from lung to evaluate whether ET-1 is able to stimulate ROS production directly or indirectly through aldosterone induction.

Structure of ABCB1/P-Glycoprotein in the Presence of the CFTR Potentiator Ivacaftor.

ABCB1/P-glycoprotein is an ATP binding cassette transporter that is involved in the clearance of xenobiotics, and it affects the disposition of many drugs in the body. Conformational flexibility of the protein within the membrane is an intrinsic part of its mechanism of action, but this has made structural studies challenging. Here, we have studied different conformations of P-glycoprotein simultaneously in the presence of ivacaftor, a known competitive inhibitor.

Identification of a Novel Serological Marker in Seronegative Rheumatoid Arthritis Using the Peptide Library Approach.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation mainly affecting the joints leading to cartilage and bone destruction. The definition of seropositive or seronegative RA is based on the presence or absence of rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPAs). Other autoantibodies have been identified in the last decade such as antibodies directed against carbamylated antigens, peptidyl-arginine deiminase type 4 and v-Raf murine sarcoma viral oncogene homologue B.

Mechanisms of pathogenesis of missense mutations on the KDM6A-H3 interaction in type 2 Kabuki Syndrome.

Mutations in genes encoding for histone methylation proteins are associated with several developmental disorders. Among them, is the disease causative gene of type 2 Kabuki Syndrome, a rare multisystem disease. While nonsense mutations and short insertions/deletions are known to trigger pathogenic mechanisms, the functional effects of missense mutations are still uncharacterized.

crystals reveal critical features of the interaction between cystic fibrosis transmembrane conductance regulator (CFTR) and the PDZ2 domain of Na/H exchange cofactor NHERF1.

Crystallization of recombinant proteins has been fundamental to our understanding of protein function, dysfunction, and molecular recognition. However, this information has often been gleaned under extremely nonphysiological protein, salt, and H concentrations. Here, we describe the development of a robust Inka1-Box (iBox)-PAK4cat system that spontaneously crystallizes in several mammalian cell types.

Are Gaming-Enabled Graphic Processing Unit Cards Convenient for Molecular Dynamics Simulation?

In several fields of research, molecular dynamics simulation techniques are exploited to evaluate the temporal motion of particles constituting water, ions, small molecules, macromolecules, or more complex systems over time. These techniques are considered difficult to setup, computationally demanding and require high specialization and scientific skills. Moreover, they need specialized computing infrastructures to run faster and make the simulation of big systems feasible.

L-DOPA-quinone Mediated Recovery from GIRK Channel Firing Inhibition in Dopaminergic Neurons.

The oxidative degeneration of dopamine-releasing (DAergic) neurons in the substantia nigra pars compacta (SNc) has attracted much interest in preclinical research, due to its involvement in Parkinson's disease manifestations. Evidence exists on the participation of quinone derivatives in mitochondrial dysfunction, alpha synuclein protein aggregation, and protein degradation. With the aim to investigate the role of L-DOPA-quinone in DAergic neuron functions, we synthesized L-DOPA-quinone by use of 2-iodoxybenzoic acid and measured its activity in recovery from dopamine-mediated firing inhibition of SNc neurons.

Novel features in the structure of P-glycoprotein (ABCB1) in the post-hydrolytic state as determined at 7.9 Å resolution.

Background: P-glycoprotein (ABCB1) is an ATP-binding cassette transporter that plays an important role in the clearance of drugs and xenobiotics and is associated with multi-drug resistance in cancer. Although several P-glycoprotein structures are available, these are either at low resolution, or represent mutated and/or quiescent states of the protein.

Results: In the post-hydrolytic state the structure of the wild-type protein has been resolved at about 8 Å resolution.

Hand fasciae innervation: The palmar aponeurosis.

There are few data in the scientific literature about the innervation of fasciae of the hand. The present study first elucidates the density and location of nervous structures in the palmar aponeurosis and, for comparison, in the flexor retinaculum (both can be considered specializations of the deep fascia of the upper limbs). Second, it compares nonpathological with pathological palmar aponeurosis.

Natural Product Kuwanon-L Inhibits HIV-1 Replication through Multiple Target Binding.

In recent years many advances have been made in the fight against HIV-1 infection. However, the lack of a vaccine, together with the increasing resistance to the highly active anti-retroviral therapy (HAART), make HIV-1 infection still a serious global emergency. Thus, new compounds with original modes of action are continuously required, and natural products have ever been a very interesting class of pharmacologically active molecules.

Autoimmunity and infection in common variable immunodeficiency (CVID).

Common variable immunodeficiency (CVID) is a heterogeneous group of diseases, characterized by primary hypogammaglobulinemia. B and T cell abnormalities have been described in CVID. Typical clinical features of CVID are recurrent airway infections; lymphoproliferative, autoinflammatory, or neoplastic disorders; and autoimmune diseases among which autoimmune thrombocytopenia (ITP) is the most common.

Characterization of CD30/CD30L(+) Cells in Peripheral Blood and Synovial Fluid of Patients with Rheumatoid Arthritis.

The CD30/CD30L signalling system has been implicated in the pathogenesis of several autoimmune and inflammatory conditions. In rheumatoid arthritis (RA), soluble CD30 (sCD30) levels reflect the recruitment of CD30(+) T cells into the inflamed joints and correlate with a positive response to immunosuppressive therapy. The aim of our report was to clarify the role of CD30/CD30L signalling system in the pathogenesis of RA.

Endothelin Receptors Expressed by Immune Cells Are Involved in Modulation of Inflammation and in Fibrosis: Relevance to the Pathogenesis of Systemic Sclerosis.

Endothelin-1 (ET-1) plays a pivotal role in vasoconstriction, fibrosis, and inflammation, the key features of systemic sclerosis (SSc). ET-1 receptors (ETA and ET(B)) are expressed on endothelial cells, smooth muscle cells, and fibroblasts, but their presence on immune cells has not been deeply investigated so far. Endothelin receptors antagonists such as bosentan have beneficial effects on vasoconstriction and fibrosis, but less is known about their potential anti-inflammatory effects.

Gene Expression Profiling in Peripheral Blood Cells and Synovial Membranes of Patients with Psoriatic Arthritis.

Background: Psoriatic arthritis (PsA) is an inflammatory arthritis whose pathogenesis is poorly understood; it is characterized by bone erosions and new bone formation. The diagnosis of PsA is mainly clinical and diagnostic biomarkers are not yet available. The aim of this work was to clarify some aspects of the disease pathogenesis and to identify specific gene signatures in paired peripheral blood cells (PBC) and synovial biopsies of patients with PsA.

Gene expression profiling in peripheral blood mononuclear cells of patients with common variable immunodeficiency: modulation of adaptive immune response following intravenous immunoglobulin therapy.

Background: Regular intravenous immunoglobulin treatment is used to replace antibody deficiency in primary immunodeficiency diseases; however the therapeutic effect seems to be related not only to antibody replacement but also to an active role in the modulation of the immune response. Common variable immunodeficiency is the most frequent primary immunodeficiency seen in clinical practice.

Methods: We have studied the effect of intravenous immunoglobulin replacement in patients with common variable immunodeficiency by evaluating the gene-expression profiles from Affimetrix HG-U133A.

In rheumatoid arthritis soluble CD30 ligand is present at high levels and induces apoptosis of CD30(+)T cells.

CD30 and CD30 ligand (CD30L) are members of TNF-receptor and TNF superfamilies respectively. CD30(+)T cells are increased in several diseases and interaction between CD30(+) and CD30L(+)T cells leads either to cell proliferation or apoptosis. In patients with rheumatoid arthritis (RA), soluble CD30 (sCD30) levels seem to reflect the recruitment of CD30(+)T cells into the inflamed joints and are predictive of a positive response to classical and biological immunosuppressive therapy.

Schnitzler syndrome, an autoimmune-autoinflammatory syndrome: report of two new cases and review of the literature.

Schnitzler syndrome is a rare disorder characterized clinically by chronic urticarial rash accompanied by fever, arthralgia or arthritis, bone pain and lymphoadenopathy and biochemically by monoclonal gammopathy and elevation of inflammatory indices. The disorder is very likely under-recognized and its origin remains obscure although it may be included among the immune mediated inflammatory diseases with features of autoinflammation and autoimmunity. We describe here two patients affected by Schnitzler syndrome, both refractory to corticosteroids and immunosuppressive therapy, successfully treated with the interleukin-1 receptor antagonist Anakinra.

[Geographical study on lung cancer mortality among residents in the neighbourhood of the coke plant in Piombino].

Objectives: To evaluate a possible risk of lung cancer related to environmental pollutants in the population living in Piombino, Italy in the neighborhood of the local coke plant.

Design: Geographical study.

Setting And Participants: Lung cancer deaths occurred in 1986-2000 in residents in Piombino were included in the study.