Novel peptidomimetics related to Gonadotropin releasing hormone (GnRH)

Novel GnRH I and II analogues were designed and synthesized by Solid Phase Peptides Synthesis (SPPS), since GnRH has antiproliferative property, but poor metabolic stability. To rationalize synthetic difficulties, molecular dynamics simulations were performed, showing the conformational behavior of three derivatives. Among the two peptidomimetics series (Ie,f and IIe,f , GnRH I and GnRH II analogues respectively) several compounds (Id-f and IIc-e) showed a significant binding affinity. In particular, derivative Ie has an increased metabolic stability with respect to the physiological ligand (Ie t1/2= 3.96 h versus GnRH I t1/2 = 2.63 h)

Mucopolysaccharidosis VI

Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease with progressive multisystem involvement, associated with a deficiency of arylsulfatase B leading to the accumulation of dermatan sulfate. Birth prevalence is between 1 in 43,261 and 1 in 1,505,160 live births. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic skeletal dysplasia includes short stature, dysostosis multiplex and degenerative joint disease. Rapidly progressing forms may have onset from birth, elevated urinary glycosaminoglycans (generally >100 μg/mg creatinine), severe dysostosis multiplex, short stature, and death before the 2nd or 3rd decades. A more slowly progressing form has been described as having later onset, mildly elevated glycosaminoglycans (generally <100 μg/mg creatinine), mild dysostosis multiplex, with death in the 4th or 5th decades. Other clinical findings may include cardiac valve disease, reduced pulmonary function, hepatosplenomegaly, sinusitis, otitis media, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease, and inguinal or umbilical hernia. Although intellectual deficit is generally absent in MPS VI, central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve atrophy and blindness. The disorder is transmitted in an autosomal recessive manner and is caused by mutations in the ARSB gene, located in chromosome 5 (5q13-5q14). Over 130 ARSB mutations have been reported, causing absent or reduced arylsulfatase B (N-acetylgalactosamine 4-sulfatase) activity and interrupted dermatan sulfate and chondroitin sulfate degradation. Diagnosis generally requires evidence of clinical phenotype, arylsulfatase B enzyme activity <10% of the lower limit of normal in cultured fibroblasts or isolated leukocytes, and demonstration of a normal activity of a different sulfatase enzyme (to exclude multiple sulfatase deficiency). The finding of elevated urinary dermatan sulfate with the absence of heparan sulfate is supportive. In addition to multiple sulfatase deficiency, the differential diagnosis should also include other forms of MPS (MPS I, II IVA, VII), sialidosis and mucolipidosis. Before enzyme replacement therapy (ERT) with galsulfase (Naglazyme®), clinical management was limited to supportive care and hematopoietic stem cell transplantation. Galsulfase is now widely available and is a specific therapy providing improved endurance with an acceptable safety profile. Prognosis is variable depending on the age of onset, rate of disease progression, age at initiation of ERT and on the quality of the medical care provided

Revisiting HIV-1 uncoating

HIV uncoating is defined as the loss of viral capsid that occurs within the cytoplasm of infected cells before entry of the viral genome into the nucleus. It is an obligatory step of HIV-1 early infection and accompanies the transition between reverse transcription complexes (RTCs), in which reverse transcription occurs, and pre-integration complexes (PICs), which are competent to integrate into the host genome. The study of the nature and timing of HIV-1 uncoating has been paved with difficulties, particularly as a result of the vulnerability of the capsid assembly to experimental manipulation. Nevertheless, recent studies of capsid structure, retroviral restriction and mechanisms of nuclear import, as well as the recent expansion of technical advances in genome-wide studies and cell imagery approaches, have substantially changed our understanding of HIV uncoating. Although early work suggested that uncoating occurs immediately following viral entry in the cell, thus attributing a trivial role for the capsid in infected cells, recent data suggest that uncoating occurs several hours later and that capsid has an all-important role in the cell that it infects: for transport towards the nucleus, reverse transcription and nuclear import. Knowing that uncoating occurs at a later stage suggests that the viral capsid interacts extensively with the cytoskeleton and other cytoplasmic components during its transport to the nucleus, which leads to a considerable reassessment of our efforts to identify potential therapeutic targets for HIV therapy. This review discusses our current understanding of HIV uncoating, the functional interplay between infectivity and timely uncoating, as well as exposing the appropriate methods to study uncoating and addressing the many questions that remain unanswered

Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management

The mucopolysaccharidoses (MPSs) are inherited lysosomal storage disorders caused by the absence of functional enzymes that contribute to the degradation of glycosaminoglycans (GAGs). The progressive systemic deposition of GAGs results in multi-organ system dysfunction that varies with the particular GAG deposited and the specific enzyme mutation(s) present. Cardiac involvement has been reported in all MPS syndromes and is a common and early feature, particularly for those with MPS I, II, and VI. Cardiac valve thickening, dysfunction (more severe for left-sided than for right-sided valves), and hypertrophy are commonly present; conduction abnormalities, coronary artery and other vascular involvement may also occur. Cardiac disease emerges silently and contributes significantly to early mortality

HIV infection of non-dividing cells: a divisive problem

Understanding how lentiviruses can infect terminally differentiated, non-dividing cells has proven a very complex and controversial problem. It is, however, a problem worth investigating, for it is central to HIV-1 transmission and AIDS pathogenesis. Here I shall attempt to summarise what is our current understanding for HIV-1 infection of non-dividing cells. In some cases I shall also attempt to make sense of controversies in the field and advance one or two modest proposals

A pattern language for FIPA agent interface design

This paper presents a pattern language supporting the design of web/mobile interfaces to static agents built by FIPA-compliant agent toolkits. The approach followed was to collaboratively gather the requirements the language should satisfy, and derive, select and combine appropriate patterns fulfilling them. The use of the language has been validated in four case studies and its suitability for meeting the agent interface development requirements has been evaluated using Force Resolution Maps (FRMs). It is has been found that the proposed language fully satisfies the identified requirements. © 2005 IEEE

Lp regular sparse hypergraphs

We study sparse hypergraphs which satisfy a mild pseudorandomness condition known as Lp regularity. We prove appropriate regularity and counting lemmas, and we extend the relative removal lemma of Tao to this setting. This answers a question from a 2014 paper by Borgs, Chayes, Cohn and Zhao. © Instytut Matematyczny PAN, 2018

Lp regular sparse hypergraphs: Box norms

We consider some variants of the Gowers box norms, introduced by Hatami, and show their relevance in the context of sparse hypergraphs. Our main results are the following. Firstly, we prove a generalized von Neumann theorem for Lp graphons. Secondly, we give natural examples of pseudorandom families, that is, sparse weighted uniform hypergraphs which satisfy relative versions of the counting and removal lemmas. © Instytut Matematyczny PAN, 2020

Szemerédi’s regularity lemma via martingales

We prove a variant of the abstract probabilistic version of Szemerédi’s regularity lemma, due to Tao, which applies to a number of structures (including graphs, hy- pergraphs, hypercubes, graphons, and many more) and works for random variables in Lp for any p &amp;gt; 1. Our approach is based on martingale difference sequences. © 2016, Australian National University. All rights reserved

Family B G protein-coupled receptors and their ligands: From structure to function

Background: Family B G protein-coupled receptors (GPCRs) play an important role in many physiological and pathophysiological processes. They are plasma-membrane proteins containing an extracellular N-domain, an intracellular C-tail, seven transmembrane domains (TMs), three extracellular (ELs) and three intracellular (ILs) loops. Objective: This review aims to summarize the current structural and functional information for family B GPCRs and their ligands, as well as, their physiological and pathophysiological role. Methods: ? thorough search of bibliographic databases for peer-reviewed research literature was undertaken. Moreover, molecular models of family B GPCRs were constructed and a structural alignment of their amino acid sequences was performed to demonstrate common structural characteristics. Results: In this review the family B GPCRs and their complexes with the receptor activity modifying proteins (RAMPs) were classified into five groups and the important physiological and pathophysiological role of these receptors was summarized. In addition, conserved residues of the Ndomain and the TMs of these receptors were numbered, thus making feasible the comparison of receptor structures and demonstrating common structural characteristics that are functionally important for all family B receptors. Molecular models created in this study were used to discuss the molecular mechanisms underlying ligand binding to family B GPCRs and receptor activation. Conclusion: The findings of this review provide information about the structural-functional determinants of family B GPCRs and their ligands, thus boosting the design of novel drugs with better potencies and bioavailabilities, which might enrich the therapeutic armory for the treatment of a wide spectrum of family B GPCRs-related disorders. © 2017 Bentham Science Publishers