Next-generation neuropeptide Y receptor small-molecule agonists inhibit mosquito-biting behavior.

Background: Female Aedes aegypti mosquitoes can spread disease-causing pathogens when they bite humans to obtain blood nutrients required for egg production. Following a complete blood meal, host-seeking is suppressed until eggs are laid. Neuropeptide Y-like receptor 7 (NPYLR7) plays a role in endogenous host-seeking suppression and previous work identified small-molecule NPYLR7 agonists that inhibit host-seeking and blood-feeding when fed to mosquitoes at high micromolar doses.

Lead Optimization of Small Molecule ENL YEATS Inhibitors to Enable Studies: Discovery of TDI-11055.

Eleven-nineteen leukemia (ENL) is an epigenetic reader protein that drives oncogenic transcriptional programs in acute myeloid leukemia (AML). AML is one of the deadliest hematopoietic malignancies, with an overall 5-year survival rate of 27%. The epigenetic reader activity of ENL is mediated by its YEATS domain that binds to acetyl and crotonyl marks on histone tails and colocalizes with promoters of actively transcribed genes that are essential for leukemia.

Next Generation Neuropeptide Y Receptor Small Molecule Agonists Inhibit Mosquito Biting Behavior.

Female mosquitoes can spread disease-causing pathogens when they bite humans to obtain blood nutrients required for egg production. Following a complete blood meal, host-seeking is suppressed until eggs are laid. Neuropeptide Y-like Receptor 7 (NPYLR7) plays a role in endogenous host-seeking suppression and previous work identified small molecule NPYLR7 agonists that suppress host-seeking and blood feeding when fed to mosquitoes at high micromolar doses.

Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia.

Unlabelled: The chromatin reader eleven-nineteen leukemia (ENL) has been identified as a critical dependency in acute myeloid leukemia (AML), but its therapeutic potential remains unclear. We describe a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-11055, which displaces ENL from chromatin by blocking its YEATS domain interaction with acylated histones. Cell lines and primary patient samples carrying MLL rearrangements or NPM1 mutations are responsive to TDI-11055.

Upper Eyelid Reconstruction Surgeries; Comparison Of Outcomes Between Reverse Tenzel Flap Versus Cutler Beard Flap Procedure.

Background: Objective of this study was to compare Reverse Tenzel flap and Cutler Beard flap for upper eyelid defects.

Methods: This interventional study was carried out at occuloplasty department of LRBT (Layton Rahamatullah Benevoloent Trust), Karachi. Patients diagnosed with upper eye lid defect between 50 and 75 years were included after ethical approval from institutional ethical review committee and briefing patients about study dynamics.

Treatment of Chronic Large and Persistent Macular Hole by a new technique in a Tertiary Care Hospital.

Objective: To assess the anatomical and functional outcomes of treating chronic persistent large macular hole by macular hole hydrodissection technique in a tertiary eye care hospital.

Methods: This interventional case series study was conducted in the Vitreoretinal department of LRBT Tertiary Teaching Eye Hospital, Karachi, from October 2017 to March 2018, with follow-ups till February 2019. The study included eighteen cases of chronic (symptoms of loss of central vision ≥ 2years), persistent (previously failed macular hole surgery), large (aperture diameter of ≥ 400µm) macular hole.

Role of Concomitant Internal Limiting Membrane (ILM) Peeling During Rhegmatogenous Retinal Detachment (RRD) Surgery in Preventing Postoperative Epiretinal Membrane (ERM) Formation.

Objective: To investigate the role of concomitant Internal Limiting Membrane (ILM) peeling during surgery for macula off Rhegmatogenous Retinal Detachment (RRD) in preventing postoperative Epiretinal Membrane (ERM) formation; and its effect on the visual acuity.

Methods: This was a prospective, quasi-experimental study conducted from August 2018 to July 2019 at LRBT Tertiary Eye Care hospital, Karachi. Fifty-six patients with macula off RRD were divided into groups A (with ILM peeling) and B (without ILM peeling) via non-probability convenience sampling.

Pre-operative predicting factor in visual outcome after macular hole surgery.

Objective: To determine the effectiveness of macular hole index (MHI) as a predicting factor of visual outcome after full thickness macular hole surgery.

Methods: This quasi-experimental study was conducted at LRBT Free Base Eye Hospital, Karachi from January 2018 to March 2019. Total 45 eyes of 45 patients with full thickness macular hole (FTMH) underwent preoperative Best Corrected Visual Acuity (BCVA) assessment with logMar chart and Optical Coherence Tomography (OCT) scanning, with measurement of base diameter and macular hole height.

Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle.

Artemisin combination therapy (ACT) is the main treatment option for malaria, which is caused by the intracellular parasite Plasmodium. However, increased resistance to ACT highlights the importance of finding new drugs. Recently, the aspartic proteases Plasmepsin IX and X (PMIX and PMX) were identified as promising drug targets.

Synthesis of amino heterocycle aspartyl protease inhibitors.

Aspartyl proteases are important pharmacological targets. Historically aspartyl proteases have been commonly targeted with transition state derived peptidomimetics. The strategy to develop aspartyl protease inhibitors has undertaken a dramatic paradigm shift in the last 10 years.

Discovery of aminoquinazoline derivatives as human A(2A) adenosine receptor antagonists.

Novel bicyclic adenosine A(2A) antagonists with an aminoquinazoline moiety were designed and synthesized. The optimization of the initial lead compound based on in vitro and in vivo activity has led to the discovery of a potent and selective class of adenosine A(2A) antagonists. The structure-activity relationships of this novel series of bicyclic aminoquinazoline derivatives as adenosine A(2A) antagonists are described in detail.

Faecalibacterium prausnitzii A2-165 has a high capacity to induce IL-10 in human and murine dendritic cells and modulates T cell responses.

Faecalibacterium prausnitzii strain A2-165 was previously reported to have anti-inflammatory properties and prevent colitis in a TNBS model. We compared the immunomodulatory properties of strain A2-165 to four different F. prausnitzii isolates and eight abundant intestinal commensals using human dendritic cells (DCs) and mouse BMDCs in vitro.

Faecalibacterium prausnitzii Strain HTF-F and Its Extracellular Polymeric Matrix Attenuate Clinical Parameters in DSS-Induced Colitis.

A decrease in the abundance and biodiversity of intestinal bacteria within the Firmicutes phylum has been associated with inflammatory bowel disease (IBD). In particular, the anti-inflammatory bacterium Faecalibacterium prausnitzii, member of the Firmicutes phylum and one of the most abundant species in healthy human colon, is underrepresented in the microbiota of IBD patients. The aim of this study was to investigate the immunomodulatory properties of F.

Iminopyrimidinones: a novel pharmacophore for the development of orally active renin inhibitors.

The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.

Functional metabolic map of Faecalibacterium prausnitzii, a beneficial human gut microbe.

The human gut microbiota plays a central role in human well-being and disease. In this study, we present an integrated, iterative approach of computational modeling, in vitro experiments, metabolomics, and genomic analysis to accelerate the identification of metabolic capabilities for poorly characterized (anaerobic) microorganisms. We demonstrate this approach for the beneficial human gut microbe Faecalibacterium prausnitzii strain A2-165.

Antioxidants keep the potentially probiotic but highly oxygen-sensitive human gut bacterium Faecalibacterium prausnitzii alive at ambient air.

The beneficial human gut microbe Faecalibacterium prausnitzii is a 'probiotic of the future' since it produces high amounts of butyrate and anti-inflammatory compounds. However, this bacterium is highly oxygen-senstive, making it notoriously difficult to cultivate and preserve. This has so far precluded its clinical application in the treatment of patients with inflammatory bowel diseases.

How can Faecalibacterium prausnitzii employ riboflavin for extracellular electron transfer?

Faecalibacterium prausnitzii is one of the most abundant commensal microbes in the human gut. It is an important supplier of butyrate to the colonic epithelium, and low numbers of faecalibacteria have been associated with severe inflammatory bowel disease. Previous studies revealed that F.

The gut anaerobe Faecalibacterium prausnitzii uses an extracellular electron shuttle to grow at oxic-anoxic interphases.

Faecalibacterium prausnitzii is one of the most abundant bacteria in the human gut ecosystem and it is an important supplier of butyrate to the colonic epithelium. Low numbers of faecalibacteria have been associated with inflammatory bowel disease. Despite being extremely oxygen sensitive, F.

Cultured representatives of two major phylogroups of human colonic Faecalibacterium prausnitzii can utilize pectin, uronic acids, and host-derived substrates for growth.

Faecalibacterium prausnitzii is one of the most abundant commensal bacteria in the healthy human large intestine, but information on genetic diversity and substrate utilization is limited. Here, we examine the phylogeny, phenotypic characteristics, and influence of gut environmental factors on growth of F. prausnitzii strains isolated from healthy subjects.

Novel phosphorus radical-based routes to horsfiline.

[reaction: see text]. Radicals derived from the phosphorus reagents, ethylpiperidine hypophosphite (EPHP) and diethylphosphine oxide (DEPO), are used in two related approaches to synthesis of the alkaloid horsfiline (1). In particular, DEPO proves beneficial for effecting cyclizations at 80 degrees C that are difficult or impossible with Bu(3)SnH.

Direct conversion of N-methoxy-N-methylamides (Weinreb amides) to ketones via a nonclassical Wittig reaction.

[reaction: see text] N-Methoxy-N-methylamides (Weinreb amides) are converted efficiently into ketones by reaction with alkylidenetriphenylphosphoranes and in situ hydrolysis of the product.

Diethylphosphine oxide (DEPO): high-yielding and facile preparation of indolones in water.

[reaction: see text] Indolones are prepared in excellent yield at 80 degrees C in water by radical reaction (aryl radical formation, hydrogen atom abstraction, cyclization, and rearomatization) mediated by the reagent diethylphosphine oxide (DEPO). The reaction features V-501 as a water-soluble initiator; no other additives are needed. The process proceeds at a much lower temperature than is required for efficient reaction with toxic tributyltin hydride in benzene and permits significantly higher isolated yields than the corresponding reaction mediated by ethylpiperidine hypophosphite (EPHP).