Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent,broad-spectrum enzymatic activity

The bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) are essential enzymes that control the topological state of DNA during replication. The high degree of conservation in the ATP-binding pockets of these enzymes make them appealing targets for broad-spectrum inhibitor development. A pyrrolopyrimidine scaffold was identified from a pharmacophore-based fragment screen with optimization potential. Structural characterization of inhibitor complexes conducted using selected GyrB/ParE orthologs aided in the identification of important steric, dynamic and compositional differences in the ATP-binding pockets of the targets, enabling the design of highly potent pyrrolopyrimidine inhibitors with broad enzymatic spectrum and dual targeting activity.     

Evaluation of the Performance of Information Theory-Based Methods and Cross-Correlation to Estimate the Functional Connectivity in Cortical Networks

Functional connectivity of in vitro neuronal networks was estimated by applying different statistical algorithms on data collected by Micro-Electrode Arrays (MEAs). First we tested these “connectivity methods” on neuronal network models at an increasing level of complexity and evaluated the performance in terms of ROC (Receiver Operating Characteristic) and PPC (Positive Precision Curve), a new defined complementary method specifically developed for functional links identification. Then, the algorithms better estimated the actual connectivity of the network models, were used to extract functional connectivity from cultured cortical networks coupled to MEAs. Among the proposed approaches, Transfer Entropy and Joint-Entropy showed the best results suggesting those methods as good candidates to extract functional links in actual neuronal networks from multi-site recordings.     

Achievements and perspectives in yeast acetic acid-induced programmed cell death pathways

The use of non-mammalian model organisms, including yeast Saccharomyces cerevisiae, can provide new insights into eukaryotic PCD (programmed cell death) pathways. In the present paper, we report recent achievements in the elucidation of the events leading to PCD that occur as a response to yeast treatment with AA (acetic acid). In particular, ROS (reactive oxygen species) generation, cyt c (cytochrome c) release and mitochondrial function and proteolytic activity will be dealt with as they vary along the AA-PCD time course by using both wild-type and mutant yeast cells. Two AA-PCD pathways are described sharing common features, but distinct from one another with respect to the role of ROS and mitochondria, the former in which YCA1 acts upstream of cyt c release and caspase-like activation in a ROS-dependent manner and the latter in which cyt c release does not occur, but caspase-like activity increases, in a ROS-independent manner.     

Coralloid root regeneration on Macrozamia megagametophites

Abstract

Megagametophytes of Macrozamia communis were incubated in White's Basal Medium and in White's Basal Medium modified with 2,4-D and kinetin. On the medium enriched with growth substances, regeneration of coralloid roots was induced. These are morphologically identical to sporophytic coralloid roots, without any endosymbiont and displaying negative geotropism. These results confirm the fact that coralloid roots represent an inherent feature of the root system of the Cycadales rather than being the result of induction by microbial factors. Therefore it is possible to suggest that coralloid roots represent vestigial pneumatophores.     

Ticks (Acari: Ixodidae) of the state of Amazonas,Brazil

The tick fauna of Brazil is currently composed by 72 species. The state of Amazonas is the largest of Brazil, with an area of ≈ 19% of the Brazilian land. Besides its vast geographic area, only 19 tick species have been reported for Amazonas. Herein, lots containing ticks from the state of Amazonas were examined in three major tick collections from Brazil. A total of 5933 tick specimens were examined and recorded, comprising 2693 males, 1247 females, 1509 nymphs, and 484 larvae. These ticks were identified into the following 22 species: Amblyomma cajennense sensu lato, Amblyomma calcaratum, Amblyomma coelebs, Amblyomma dissimile, Amblyomma dubitatum, Amblyomma geayi, Amblyomma goeldii, Amblyomma humerale, Amblyomma latepunctatun, Amblyomma longirostre, Amblyomma naponense, Amblyomma oblongoguttatum, Amblyomma ovale, Amblyomma rotundatum, Amblyomma scalpturatum, Amblyomma varium, Dermacentor nitens, Haemaphysalis juxtakochi, Ixodes cf. Ixodes fuscipes, Ixodes luciae, Rhipicephalus microplus, Rhipicephalus sanguineus sensu lato. Ticks were collected from 17 (27.4%) out of the 62 municipalities that currently compose the state of Amazonas. The following four species are reported for the first time in the state of Amazonas: A. coelebs, A. dubitatum, H. juxtakochi, and Ixodes cf. I. fuscipes. The only tick species previously reported for Amazonas and not found in the present study is Amblyomma parvum. This study provides a great expansion of geographical and host records of ticks for the state of Amazonas, which is now considered to have a tick fauna composed by 23 species. It is noteworthy that we report 1391 Amblyomma nymphs that were identified to 13 different species.     

Manifestation of a probable lethal gene in Holstein Friesian cows

In a study of the causes of abortion and stillbirth in a Holstein-Friesian herd, the most probable cause detected was a lethal gene transmitted through the pedigree line. Findings of this nature have already been reported both in the United States and Canada for the same line.Replacing the sires with others solved the problem, thus demonstrating a genetic etiology for abortion and stillbirth in this lineage. The differences noted in the time of fetal mortality may indicate the action of more than one gene or variable expressivity of the mutant gene.The importance of the data is discussed in terms of the elimination of genetic factors that cause fetal mortality.     

Chemotactic responsiveness toward ligands for CXCR3 and CXCR4 is regulated on plasma blasts during the time course of a memory immune response

Plasma blasts formed during memory immune responses emigrate from the spleen to migrate into the bone marrow and into chronically inflamed tissues where they differentiate into long-lived plasma cells. In this study, we analyze the chemokine responsiveness of plasma blasts formed after secondary immunization with OVA. Starting from day 4 and within approximately 48 h, OVA-specific plasma blasts emigrate from spleen and appear in the bone marrow. Although these migratory cells have lost their responsiveness to many B cell attracting chemokines, e.g., CXC chemokine ligand (CXCL)13 (B lymphocyte chemoattractant), they migrate toward CXCL12 (stromal cell-derived factor 1 alpha), and toward the inflammatory chemokines CXCL9 (monokine induced by IFN-gamma), CXCL10 (IFN-gamma-inducible protein 10), and CXCL11 (IFN-inducible T cell alpha chemoattractant). However, the responsiveness of plasma blasts to these chemokines is restricted to a few days after their emigration from the spleen, indicating a role for these molecules and their cognate receptors, i.e., CXCR3 and CXCR4, in the regulation of plasma blast migration into the bone marrow and/or inflamed tissues.     

Current controversies in cholangiocarcinoma

Cholangiocarcinoma represents 10% of primary liver malignancies and accounts for less than 3% of all gastrointestinal malignant tumors, with an enormous geographical variation. This neoplasia can arise from the biliary tract epithelium or hepatic progenitor cells. Depending on the anatomic localization, it is classified into three subtypes: intrahepatic, perihilar and distal. This fact is one of the main difficulties, because there are many studies that indistinctly include the results in the management of these different types of cholangiocarcinoma, without differentiating its location and even including gallbladder cancer.There are many controversial points in epidemiology, liver transplantation as a treatment, limitations of different results by group and type of treatment, histological testing and chemotherapy. This is a narrative review about topics in cholangiocarcinoma. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.