Symbiosis, dysbiosis and the impact of horizontal exchange on bacterial microbiomes in higher fungus-gardening ants.

Advances in our understanding of symbiotic stability have demonstrated that microorganisms are key to understanding the homeostasis of obligate symbioses. Fungus-gardening ants are excellent model systems for exploring how microorganisms may be involved in symbiotic homeostasis as the host and symbionts are macroscopic and can be easily experimentally manipulated. Their coevolutionary history has been well-studied; examinations of which have depicted broad clade-to-clade specificity between the ants and fungus.

Impact of Modifying Abicipar Manufacturing Process in Patients with Neovascular Age-Related Macular Degeneration: MAPLE Study Results.

Purpose: To evaluate the impact of modifying the abicipar pegol (abicipar) manufacturing process on the safety and treatment effect of abicipar in patients with neovascular age-related macular degeneration (nAMD).

Methods: A new process for manufacturing abicipar was developed to reduce host cell impurities. In a prospective, Phase 2, multicenter, open-label, 28-week clinical trial, patients (n=123) with active nAMD received intravitreal injections of abicipar 2 mg at baseline (day 1) and weeks 4, 8, 16, and 24.

Outcome harvesting as a methodology for the retrospective evaluation of small-scale community development interventions.

Purpose: Undertaking evaluations of public health interventions can be problematic, particularly where there are multiple stakeholders and high degrees of complexity. This is especially true with regards to the evaluation of community interventions that can include multiple actors with differing priorities, budgets and resources. Using the example of a place-based community wellbeing project, this paper discusses the practical application of 'Outcome Harvesting' as a methodology for retrospective, responsive and collaborative evaluation in public health research.

Three-Dimensional Visualization With Virtual Reality Facilitates Complex Live Donor Renal Transplant.

Living donor renal transplant involves highly technical operations in both a healthy donor and a recipient with end-stage kidney disease. Contrast-enhanced computed tomography angiography (CTA) is used to assess critical donor anatomy, but its interpretation becomes increasingly difficult as renal anatomy becomes more complex. A related donor was denied because of prohibitive anatomy seen on the pretransplant evaluation CTA.

Environments and Hosts Structure the Bacterial Microbiomes of Fungus-Gardening Ants and their Symbiotic Fungus Gardens.

The fungus gardening-ant system is considered a complex, multi-tiered symbiosis, as it is composed of ants, their fungus, and microorganisms associated with either ants or fungus. We examine the bacterial microbiome of Trachymyrmex septentrionalis and Mycetomoellerius turrifex ants and their symbiotic fungus gardens, using 16S rRNA Illumina sequencing, over a region spanning approximately 350 km (east and central Texas). Typically, microorganisms can be acquired from a parent colony (vertical transmission) or from the environment (horizontal transmission).

Design, Synthesis, and Characterization of I-BET567, a Pan-Bromodomain and Extra Terminal (BET) Bromodomain Oral Candidate.

Through regulation of the epigenome, the bromodomain and extra terminal (BET) family of proteins represent important therapeutic targets for the treatment of human disease. Through mimicking the endogenous -acetyl-lysine group and disrupting the protein-protein interaction between histone tails and the bromodomain, several small molecule pan-BET inhibitors have progressed to oncology clinical trials. This work describes the medicinal chemistry strategy and execution to deliver an orally bioavailable tetrahydroquinoline (THQ) pan-BET candidate.

Effect of Anti-VEGF Therapy on the Disease Progression of Neovascular Age-Related Macular Degeneration: A Systematic Review and Model-Based Meta-Analysis.

Anti-vascular endothelial growth factor (VEGF) therapy is used to slow the disease progression of neovascular age-related macular degeneration. Due to the treatment burden of frequent intravitreal injections, anti-VEGFs are often used on treat and extend protocols rather than the labeled frequency. The current goal of anti-VEGF drug development is to minimize treatment burden by reducing the number of intravitreal injections.

Directed Donation: Special Considerations and Review for Contemporary Clinical Practices.

Directed blood donation is defined as the donation of blood or its components for the purpose of transfusion into a specified individual. Directed blood donation holds historic significance, and although practices as of 2021 encourage voluntary, nonrenumerated blood donations, public interest in directed donation remains. Requests to discuss the risks and benefits of directed donations are a common inquiry for transfusion medicine, transplant, and hematology/oncology professionals.

Cophylogenetic analyses of Trachymyrmex ant-fungal specificity: "One to one with some exceptions".

Over the past few decades, large-scale phylogenetic analyses of fungus-gardening ants and their symbiotic fungi have depicted strong concordance among major clades of ants and their symbiotic fungi, yet within clades, fungus sharing is widespread among unrelated ant lineages. Sharing has been explained using a diffuse coevolution model within major clades. Understanding horizontal exchange within clades has been limited by conventional genetic markers that lack both interspecific and geographic variation.

Fragment-based Scaffold Hopping: Identification of Potent, Selective, and Highly Soluble Bromo and Extra Terminal Domain (BET) Second Bromodomain (BD2) Inhibitors.

The profound efficacy of pan-BET inhibitors is well documented, but these epigenetic agents have shown pharmacology-driven toxicity in oncology clinical trials. The opportunity to identify inhibitors with an improved safety profile by selective targeting of a subset of the eight bromodomains of the BET family has triggered extensive medicinal chemistry efforts. In this article, we disclose the identification of potent and selective drug-like pan-BD2 inhibitors such as pyrazole (GSK809) and furan (GSK743) that were derived from the pyrrole fragment .

Identification of a Series of -Methylpyridine-2-carboxamides as Potent and Selective Inhibitors of the Second Bromodomain (BD2) of the Bromo and Extra Terminal Domain (BET) Proteins.

Domain-specific BET bromodomain ligands represent an attractive target for drug discovery with the potential to unlock the therapeutic benefits of antagonizing these proteins without eliciting the toxicological aspects seen with pan-BET inhibitors. While we have reported several distinct classes of BD2 selective compounds, namely, GSK620, GSK549, and GSK046, only GSK046 shows high aqueous solubility. Herein, we describe the lead optimization of a further class of highly soluble compounds based upon a picolinamide chemotype.

Male-biased dispersal in a fungus-gardening ant symbiosis.

For nearly all organisms, dispersal is a fundamental life-history trait that can shape their ecology and evolution. Variation in dispersal capabilities within a species exists and can influence population genetic structure and ecological interactions. In fungus-gardening (attine) ants, co-dispersal of ants and mutualistic fungi is crucial to the success of this obligate symbiosis.

Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors.

A number of reports have recently been published describing the discovery and optimization of bromo and extraterminal inhibitors which are selective for the second bromodomain (BD2); these include our own work toward GSK046 () and GSK620 (). This paper describes our approach to mitigating the genotoxicity risk of GSK046 by replacement of the acetamide functionality with a heterocyclic ring. This was followed by a template-hopping and hybridization approach, guided by structure-based drug design, to incorporate learnings from other BD2-selective series, optimize the vector for the amide region, and explore the ZA cleft, leading to the identification of potent, selective, and bioavailable compounds (GSK452), (GSK737), and (GSK217).

Liver Transplantation Using Hepatitis C Virus-Viremic Donors Into Hepatitis C Virus-Aviremic Recipients as Standard of Care.

Liver transplantation (LT) using allografts from hepatitis C virus (HCV)-viremic/nucleic acid testing-positive donors' (DNAT+) organs into HCV-aviremic recipients (rHCV-) has been limited owing to nearly universal HCV transmission and concerns regarding availability, safety, and efficacy post-LT with direct-acting antiviral (DAA) therapy. We report our experience of LT using DNAT+ organs into rHCV- as a routine standard of care. Following verification of DAA access, absence of critical drug-drug interactions (DDIs) with DAAs, and informed consent, allocated DNAT+ organs were offered to patients on the waiting list for LT irrespective of recipient HCV status.

Characterization of Apo-Form Selective Inhibition of Indoleamine 2,3-Dioxygenase*.

Indoleamine-2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the rate-limiting step in the kynurenine pathway of tryptophan (TRP) metabolism. As it is an inflammation-induced immunoregulatory enzyme, pharmacological inhibition of IDO1 activity is currently being pursued as a potential therapeutic tool for the treatment of cancer and other disease states. As such, a detailed understanding of the mechanism of action of IDO1 inhibitors with various mechanisms of inhibition is of great interest.

GSK973 Is an Inhibitor of the Second Bromodomains (BD2s) of the Bromodomain and Extra-Terminal (BET) Family.

Pan-BET inhibitors have shown profound efficacy in a number of in vivo preclinical models and have entered the clinic in oncology trials where adverse events have been reported. These inhibitors interact equipotently with the eight bromodomains of the BET family of proteins. To better understand the contribution of each domain to their efficacy and to improve from their safety profile, selective inhibitors are required.

The Optimization of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor.

The profound efficacy, yet associated toxicity of pan-BET inhibitors is well documented. The possibility of an ameliorated safety profile driven by significantly selective (>100-fold) inhibition of a subset of the eight bromodomains is enticing, but challenging given the close homology. Herein, we describe the X-ray crystal structure-directed optimization of a novel weak fragment ligand with a pan-second bromodomain (BD2) bias, to potent and highly BD2 selective inhibitors.

Design and Synthesis of a Highly Selective and -Capable Inhibitor of the Second Bromodomain of the Bromodomain and Extra Terminal Domain Family of Proteins.

Pan-bromodomain and extra terminal domain (BET) inhibitors interact equipotently with the eight bromodomains of the BET family of proteins and have shown profound efficacy in a number of phenotypic assays and pre-clinical models in inflammation or oncology. A number of these inhibitors have progressed to the clinic where pharmacology-driven adverse events have been reported. To better understand the contribution of each domain to their efficacy and improve their safety profile, selective inhibitors are required.

Development, characterization, and cross-amplification of polymorphic microsatellite markers for North American Trachymyrmex and Mycetomoellerius ants.

Objective: The objective of this study is to develop and identify polymorphic microsatellite markers for fungus-gardening (attine) ants in the genus Trachymyrmex sensu lato. These ants are important ecosystem engineers and have been a model group for understanding complex symbiotic systems, but very little is understood about the intraspecific genetic patterns across most North American attine species. These microsatellite markers will help to better study intraspecific population genetic structure, gene flow, mating habits, and phylogeographic patterns in these species and potentially other congeners.

A Mechanistic and Translational Pharmacokinetic-Pharmacodynamic Model of Abicipar Pegol and Vascular Endothelial Growth Factor Inhibition.

Abicipar pegol (abicipar) is a novel DARPin therapeutic and highly potent vascular endothelial growth factor (VEGF) inhibitor intended for the treatment of neovascular age-related macular degeneration (nAMD). Here we develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for abicipar to guide dosing regimens in the clinic. The model incorporated abicipar-VEGF binding kinetics, VEGF expression levels, and VEGF turnover rates to describe the ocular and systemic PK data collected from the vitreous, aqueous humor (AH), choroid, retina, and serum of rabbits after a 1-mg abicipar intravitreal (IVT) dose.

Potential Distribution of Six North American Higher-Attine Fungus-Farming Ant (Hymenoptera: Formicidae) Species.

Ants are among the most successful insects in Earth's evolutionary history. However, there is a lack of knowledge regarding range-limiting factors that may influence their distribution. The goal of this study was to describe the environmental factors (climate and soil types) that likely impact the ranges of five out of the eight most abundant Trachymyrmex species and the most abundant Mycetomoellerius species in the United States.

Landscape genomics of an obligate mutualism: Concordant and discordant population structures between the leafcutter ant Atta texana and its two main fungal symbiont types.

To explore landscape genomics at the range limit of an obligate mutualism, we use genotyping-by-sequencing (ddRADseq) to quantify population structure and the effect of host-symbiont interactions between the northernmost fungus-farming leafcutter ant Atta texana and its two main types of cultivated fungus. Genome-wide differentiation between ants associated with either of the two fungal types is of the same order of magnitude as differentiation associated with temperature and precipitation across the ant's entire range, suggesting that specific ant-fungus genome-genome combinations may have been favoured by selection. For the ant hosts, we found a broad cline of genetic structure across the range, and a reduction of genetic diversity along the axis of range expansion towards the range margin.

Interleukin-33 / Cyclin D1 imbalance in severe liver steatosis predicts susceptibility to ischemia reperfusion injury.

Transplanting donor livers with severe macrosteatosis is associated with increased risk of primary non-function (PNF). The purpose of this study was to identify steatosis-driven biomarkers as a predisposition to severe liver damage and delayed recovery following ischemia reperfusion injury. Wistar rats were fed a methionine- and choline-deficient (MCD) diet for up to three weeks to achieve severe macrosteatosis (>90%).