Self-assembling DNA-caged particles: nanoblocks for hierarchical self-assembly

DNA is an ideal candidate to organize matter on the nanoscale, primarily due to the specificity and complexity of DNA based interactions. Recent advances in this direction include the self-assembly of colloidal crystals using DNA grafted particles. In this article we theoretically study the self-assembly of DNA-caged particles. These nanoblocks combine DNA grafted particles with more complicated purely DNA based constructs. Geometrically the nanoblock is a sphere (DNA grafted particle) inscribed inside a polyhedron (DNA cage). The faces of the DNA cage are open, and the edges are made from double stranded DNA. The cage vertices are modified DNA junctions. We calculate the equilibriuim yield of self-assembled, tetrahedrally caged particles, and discuss their stability with respect to alternative structures. The experimental feasability of the method is discussed. To conclude we indicate the usefulness of DNA-caged particles as nanoblocks in a hierarchical self-assembly strategy.Comment: v2: 21 pages, 8 figures; revised discussion in Sec. 2, replaced 2 figures, added new reference

How to build nanoblocks using DNA scaffolds

In recent years there have been a number of proposals to utilize the specificity of DNA based interactions for potential applications in nanoscience. One interesting direction is the self-assembly of micro- and nanoparticle clusters using DNA scaffolds. In this letter we consider a DNA scaffold method to self-assemble clusters of "colored" particles. Stable clusters of microspheres have recently been produced by an entirely different method. Our DNA based approach self-assembles clusters with additional degrees of freedom associated with particle permutation. We demonstrate that in the non-equilibrium regime of irreversible binding the self-assembly process is experimentally feasible. These color degrees of freedom may allow for more diverse intercluster interactions essential for hierarchical self-assembly of larger structures.Comment: 4 pages, 2 figures ; epl forma

Statistical Mechanics of DNA-Mediated Colloidal Aggregation

We present a statistical mechanical model of aggregation in colloidal systems with DNA mediated interactions. We obtain a general result for the two-particle binding energy in terms of the hybridization free energy $\Delta G$ of DNA and two model dependent properties: the average number of available DNA bridges \left and the effective DNA conccentration $c_{eff}$. We calculate these parameters for a particular DNA bridging scheme. The fraction of all the $n$-mers, including the infinite aggregate, are shown to be universal functions of a single parameter directly related to the two-particle binding energy. We explicitly take into account the partial ergodicity of the problem resulting from the slow DNA binding-unbinding dynamics, and introduce the concept of angular localization of DNA linkers. In this way, we obtain a direct link between DNA thermodynamics and the global aggregation and melting properties in DNA-colloidal systems. The results of the theory are shown to be in quantitative agreement with two recent experiments with particles of micron and nanometer size. PACS numbers: 81.16.Dn, 82.20.Db, 68.65.-k, 87.14.GgComment: 12 pages, 6 figures, v2: added reference, expanded conclusion, added journal re

Clinical course and genetic susceptibility of primary biliary cirrhosis: Analysis of a prospective cohort

Background: Natural history of primary biliary cirrhosis (PBC) is partially characterized in patients from the Mediterranean area whose genetic background differs from that of Northern Europeans. Objectives: We aimed to describe genetic susceptibility and clinical course of PBC in patients from Southern Italy. Methods: Socio-demographic, clinical, biochemical and histological data at diagnosis as well as disease progression of 81 PBC consecutive patients were collected. All subjects were treated with Ursodeoxycholic acid at a dose of 15 mg/kg. HLA class II DRB1 alleles were compared with those of 237 healthy control subjects. IL28B genotyping for IL28B rs12979860 C/T and rs80899917 G/T was performed in a sub-group of patients. Results: HLA-DRB1*07 (RR 5.3, P = 0.0008) and HLA-DRB1*08 (RR n.c. P = 0.0005) were significantly associated with the risk of PBC development. Patients younger than 45 years had significantly higher alanine aminotransferase (P = 0.038) and alkaline phosphatase levels (P = 0.047) than older cases. In comparison to non-CC rs12979860, patients with CC rs12979860 genotype showed an early histological stage at onset (93.8% vs. 62.5%, P = 0.03). After a mean follow-up of 61 months, three patients died, one underwent liver transplantation and sixteen (21.9%) had progression of the disease. At multivariate analysis, extrahepatic autoimmune disease (P = 0.04), pruritus (P = 0.008) and advanced histological stage (P < 0.0001) were independent risk factors for disease progression. Conclusions: HLA-DRB1*07 and HLA-DRB1*08 alleles increase susceptibility to disease development. At onset, higher biochemical activity was observed in younger patients, whereas rs12979860 CC genotype was associated with milder histological stage. Pruritus and coexistence of extrahepatic autoimmune diseases were significantly associated with poorer prognosis

On the six-dimensional origin of the AGT correspondence

We argue that the six-dimensional (2,0) superconformal theory defined on M \times C, with M being a four-manifold and C a Riemann surface, can be twisted in a way that makes it topological on M and holomorphic on C. Assuming the existence of such a twisted theory, we show that its chiral algebra contains a W-algebra when M = R^4, possibly in the presence of a codimension-two defect operator supported on R^2 \times C \subset M \times C. We expect this structure to survive the \Omega-deformation.Comment: References added. 14 page

COMEPA (COVID-19 Medicina Policlinico Palermo): a study in hospitalized patients.

Coronavirus disease 2019 (COVID-19) has dramatically changed our lives. In the past months, hospitals were saturated of patients; therefore, it is still important to have simple and standardized prognostic factors and to evaluate the efficacy and safety of medications commonly used for COVID-19. We aimed to collect data of the patients hospitalized in Internal Medicine and Geriatrics Wards at the University Hospital (Policlinico) ‘P. Giaccone’ in Palermo, Italy (COMEPA, COVID-19 Medicina Policlinico Palermo), with the main purpose of finding prognostic tools that can be easily used in clinical practice in order to identify patients hospitalized for/with COVID-19 at higher risk of negative outcomes, such as mortality, transfer to Intensive Care Unit (ICU) and institutionalization, as well as evaluating the efficacy/safety of medications commonly used for COVID-19. For reaching these aims, the medical records of approximately 600 patients will be recorded, having data on several parameters and including as outcomes mortality, ICU placement, institutionalization. With the COMEPA study, we therefore plan to update current literature, giving new data on prognostic factors and on the efficacy/safety of some medications used for COVID-19

Anti-KIT designer T cells for the treatment of gastrointestinal stromal tumor

Background: Imatinib mesylate is an effective treatment for metastatic gastrointestinal stromal tumor (GIST). However, most patients eventually develop resistance and there are few other treatment options. Immunotherapy using genetically modified or designer T cells (dTc) has gained increased attention for several malignancies in recent years. The aims of this study were to develop and test novel anti-KIT dTc engineered to target GIST cells. Methods: Human anti-KIT dTc were created by retroviral transduction with novel chimeric immune receptors (CIR). The gene for stem cell factor (SCF), the natural ligand for KIT, was cloned into 1st generation (SCF-CD3ζ, 1st gen) and 2nd generation (SCF-CD28-CD3ζ, 2nd gen) CIR constructs. In vitro dTc proliferation and tumoricidal capacity in the presence of KIT+ tumor cells were measured. In vivo assessment of dTc anti-tumor efficacy was performed by treating immunodeficient mice harboring subcutaneous GIST xenografts with dTc tail vein infusions. Results: We successfully produced the 1st and 2nd gen anti-KIT CIR and transduced murine and human T cells. Average transduction efficiencies for human 1st and 2nd gen dTc were 50% and 42%. When co-cultured with KIT+ tumor cells, both 1st and 2nd gen dTc proliferated and produced IFNγ. Human anti-KIT dTc were efficient at lysing GIST in vitro compared to untransduced T cells. In mice with established GIST xenografts, treatment with either 1st or 2nd gen human anti-KIT dTc led to significant reductions in tumor growth rates. Conclusions: We have constructed a novel anti-KIT CIR for production of dTc that possess specific activity against KIT+ GIST in vitro and in vivo. Further studies are warranted to evaluate the therapeutic potential and safety of anti-KIT dTc

C9orf72 ALS/FTD dipeptide repeat protein levels are reduced by small molecules that inhibit PKA or enhance protein degradation

Intronic GGGGCC (G4C2) hexanucleotide repeat expansion within the human C9orf72 gene represents the most common cause of familial forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of repeat-containing C9orf72 RNA results in the production of neurotoxic dipeptide-repeat proteins (DPRs). Here, we developed a high-throughput drug screen for the identification of positive and negative modulators of DPR levels. We found that HSP90 inhibitor geldanamycin and aldosterone antagonist spironolactone reduced DPR levels by promoting protein degradation via the proteasome and autophagy pathways respectively. Surprisingly, cAMP-elevating compounds boosting protein kinase A (PKA) activity increased DPR levels. Inhibition of PKA activity, by both pharmacological and genetic approaches, reduced DPR levels in cells and rescued pathological phenotypes in a Drosophila model of C9ALS/FTD. Moreover, knockdown of PKA-catalytic subunits correlated with reduced translation efficiency of DPRs, while the PKA inhibitor H89 reduced endogenous DPR levels in C9ALS/FTD patient-derived iPSC motor neurons. Together, our results suggest new and druggable pathways modulating DPR levels in C9ALS/FTD

Supersymmetric Gauge Theories, Intersecting Branes and Free Fermions

We show that various holomorphic quantities in supersymmetric gauge theories can be conveniently computed by configurations of D4-branes and D6-branes. These D-branes intersect along a Riemann surface that is described by a holomorphic curve in a complex surface. The resulting I-brane carries two-dimensional chiral fermions on its world-volume. This system can be mapped directly to the topological string on a large class of non-compact Calabi-Yau manifolds. Inclusion of the string coupling constant corresponds to turning on a constant B-field on the complex surface, which makes this space non-commutative. Including all string loop corrections the free fermion theory is elegantly formulated in terms of holonomic D-modules that replace the classical holomorphic curve in the quantum case.Comment: 67 pages, 6 figure

Modeling and simulating for the treatment of subjectivity in the process of choosing personnel using fuzzy logic

Every day organizations pay more attention to Human Resources Management, because the human factor is preponderant in the results of it. One of the important policies is the Selection of Personnel, these are needed for their decision-making results, which in many organizations is done in a subjective manner and which brings consequences not very favorable to them. Taking this problem into account, it is decided to design and apply procedures and tools of fuzzy mathematics to reduce subjectivity and uncertainty in decision-making, creating work algorithms for this policy that includes multifactorial weights and analysis with measurement indicators that they allow tangible and reliable results. In this case of personnel selection, eight candidates were taken into account and by applying a diffuse evaluation system, the candidate with the highest rating of 98% was chosen. This indicates that subjectivity was reduced when choosing the best evaluated candidate