In vivo characterization of renal auto-antigens involved in human auto-immune diseases: the case of membranous glomerulonephritis

Renal auto-immune diseases represent a major source of morbidity in humans. For many years the knowledge on mechanisms of auto-immunity involving the kidney has been uniquely based on animal models. However, these findings often could not be readily translated to humans owing to notably difference in antigen expression by human podocytes. One example is Heymann nephritis (HN), the experimental model of human membranous glomerulonephritis (MGN), which is obtained in rats by injecting antibodies against megalin, a protein that is not present in human glomeruli. Human studies could not be done in the past since sequencing required too much material exceeding what obtainable from tissue biopsies in vivo. Research is now on the way to identify auto-antigens and isolate specific auto-antibodies in humans. New technology developments based on tissue microdissection and proteomical analysis have facilitated the recent discoveries, allowing direct analysis of human tissue in vivo. Major advances on the pathogenesis of MGN, the prototype for the formation and glomerular deposition of auto-antibodies, are now in progress. Two independent groups have, in fact, demonstrated the existence of specific IgG(4) against phospholipase A2 receptor, aldose reductase and Mn-superoxide dismutase in glomerular eluates and in plasma of a prominent part of patients with MGN, suggesting a major role of these proteins as auto-antigens in human MGN. This review will focalize these aspects outlining the contribution of proteomics in most recent developments.     

4‐Biphenylalanine‐ and 3‐Phenyltyrosine‐Derived Hydroxamic Acids as Inhibitors of the JumonjiC‐Domain‐Containing Histone Demethylase KDM4A

Overexpression of the histone lysine demethylase KDM4A, which regulates H3K9 and H3K36 methylation states, has been related to the pathology of several human cancers. We found that a previously reported hydroxamate‐based histone deacetylase (HDAC) inhibitor (SW55) was also able to weakly inhibit this demethylase with an IC₅₀ value of 25.4 μm . Herein we report the synthesis and biochemical evaluations, with two orthogonal in vitro assays, of a series of derivatives of this lead structure. With extensive chemical modifications on the lead structure, also by exploiting the versatility of the radical arylation with aryldiazonium salts, we were able to increase the potency of the derivatives against KDM4A to the low‐micromolar range and, more importantly, to obtain demethylase selectivity with respect to HDACs. Cell‐permeable derivatives clearly showed a demethylase‐inhibition‐dependent antiproliferative effect against HL‐60 human promyelocytic leukemia cells.     

Chip Pulse Shaping in Asynchronous Chaos-Based DS-CDMA

This paper extends and fully formalizes some previous results by developing an analytical method to account for the general chip pulse for DS-CDMA systems in an asynchronous environment with an integrate-and-dump receiver, applying it to commonly used pulses. Given the pulse, such a formal method allows us to define the optimum spreading code autocorrelation to be used and the relative signal-to-interference ratio performance. A chaos-based spreading code is plugged into this model to show that such an optimum performance can be very well approximated by practical sequence generators. This is shown by analyzing some typical bandlimited and substantially bandlimited pulses and determining the optimum spreading for each of them. These results prove that the gain of chaos-based spreading over conventional i.i.d.-like spreading can reach 75% when practical bandlimited pulses are considered.     

Investigation of beta-amyloid peptide by on-line high-performance liquid chromatography coupled to electrospray ionization mass spectrometry

beta(1-39) amyloid peptide is one of the components of the cerebral amyloid deposits that are characteristic of Alzheimer's disease. Solid-phase synthesis of this peptide resulted in a fairly complex crude product containing both the target peptide and a number of side products. High-performance liquid chromatography coupled to electrospray ionization mass spectrometry allowed rapid and reliable identification of both the desired peptide and most of the side products which were found to have relative molecular masses above and below that of the target peptide.     

An enhanced two-level Boolean synthesis methodology for fuzzy rulesminimization

A new methodology for the minimization of a given set of fuzzy rules is presented. It is based on a novel mapping of fuzzy relations on Boolean functions and exploits existing Boolean synthesis algorithms. In this mapping each fuzzy membership predicate is translated into a Boolean variable and proper constraints on Boolean manipulations are added to guarantee fuzziness translation. The formal consistency of the approach depends on a fuzzy semantic which easily generalizes most of the existing models, granting broad applicability to the suggested procedure. The applicability of an enhanced two-level Boolean minimizer is demonstrated, and the technique is applied to the fuzzy identification of nonlinear systems, consistently reducing the number of rules and easing application of further optimization interventions     

Algorithmic ADC Offset Compensation by Nonwhite Data Chopping: System Model and Basic Theoretical Results

This paper is devoted to show the impact of nonwhite chopping on the offset compensation in time-interleaved analog-to-digital converters. We develop a theoretical framework allowing the selection of optimal chopping sequences. We show that, on the one hand, the adoption of these (generally nonwhite) sequences allows to achieve faster offset compensation (thus increasing the signal-to-noise ratio) and, on the other hand, a better spectral shaping (thus increasing the spurious-free dynamic range). As a byproduct of our analysis, we prove that the average offset estimation which is used in many ADC implementations is asymptotically the best available linear estimation of offset that, in turn, is the best estimation when the signal to be converted can be assumed to be a Gaussian process.      

AXL Receptor in Breast Cancer: Molecular Involvement and Therapeutic Limitations

Breast cancer was one of the first malignancies to benefit from targeted therapy, i.e., treatments directed against specific markers. Inhibitors against HER2 are a significant example and they improved the life expectancy of a large cohort of patients. Research on new biomarkers, therefore, is always current and important. AXL, a member of the TYRO-3, AXL and MER (TAM) subfamily, is, today, considered a predictive and prognostic biomarker in many tumor contexts, primarily breast cancer. Its oncogenic implications make it an ideal target for the development of new pharmacological agents; moreover, its recent role as immune-modulator makes AXL particularly attractive to researchers involved in the study of interactions between cancer and the tumor microenvironment (TME). All these peculiarities characterize AXL as compared to other members of the TAM family. In this review, we will illustrate the biological role played by AXL in breast tumor cells, highlighting its molecular and biological features, its involvement in tumor progression and its implication as a target in ongoing clinical trials.     

Brain‐Penetrant Triazolopyrimidine and Phenylpyrimidine Microtubule Stabilizers as Potential Leads to Treat Human African Trypanosomiasis

In vitro whole‐organism screens of Trypanosoma brucei with representative examples of brain‐penetrant microtubule (MT)‐stabilizing agents identified lethal triazolopyrimidines and phenylpyrimidines with sub‐micromolar potency. In mammalian cells, these antiproliferative compounds disrupt MT integrity and decrease total tubulin levels. Their parasiticidal potency, combined with their generally favorable pharmacokinetic properties, which include oral bioavailability and brain penetration, suggest that these compounds are potential leads against human African trypanosomiasis.