Impact of the COVID-19 pandemic on invasive pneumococcal disease in American Indian communities in the Southwest US.

American Indian (AI) communities in the Southwest have a high burden of invasive pneumococcal disease (IPD) and COVID-19. Through laboratory-based surveillance, the impact of the pandemic on IPD incidence and serotype distribution was evaluated in two AI communities. IPD rates were lower during the pandemic (21.

Impact of Pneumococcal Conjugate Vaccines on Otitis Media among American Indian/Alaska Native children in the Southwest United States.

We assessed the impact of pneumococcal conjugate vaccines on pneumococcal otitis media (OM) among children living in Navajo and White Mountain Apache Tribal lands. During the PCV7 era (2000-2009), the proportion of vaccine-type OM declined. However, vaccine-type OM (predominantly 3, 19A, and 19F) persisted in the PCV13 era (2010-2019).

Effects of a Polarizable Force Field on Membrane Dynamics: Surface Viscosity, Lipid Diffusion, and Peptide Induced Pore Formation.

The effects of the newly developed CHARMM polarizable lipid force field (FF), Drude2023, on selected lipid dynamical properties are compared with the additive CHARMM36 (C36), and an extension of C36, termed C36/LJ-PME, which includes long-range Lennard-Jones (LJ) interactions. Polarizability and long-range LJ interactions increase the membrane surface viscosity, which decreases the translational diffusion constants. Simulated diffusion constants for dipalmitoylphosphatidylcholine (DPPC) and dioleoylphosphatidylcholine (DOPC) extrapolated to infinite system size agree well with experiment for Drude2023, but overestimate experiment by 60% (on average) and a factor of 2.

Investigating How Lysophosphatidylcholine and Lysophosphatidylethanolamine Enhance the Membrane Permeabilization Efficacy of Host Defense Peptide Piscidin 1.

Lysophospholipids (LPLs) and host defense peptides (HDPs) are naturally occurring membrane-active agents that disrupt key membrane properties, including the hydrocarbon thickness, intrinsic curvature, and molecular packing. Although the membrane activity of these agents has been widely examined separately, their combined effects are largely unexplored. Here, we use experimental and computational tools to investigate how lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), an LPL of lower positive spontaneous curvature, influence the membrane activity of piscidin 1 (P1), an α-helical HDP from fish.

Simulating asymmetric membranes using P2 periodic boundary conditions.

Molecular dynamics (MD) simulations of symmetric lipid bilayers are now well established, while those of asymmetric ones are considerably less developed. This disjunction arises in part because the surface tensions of leaflets in asymmetric bilayers can differ (unlike those of symmetric ones), and there is no simple way to determine them without assumptions. This chapter describes the use of P2 periodic boundary conditions (PBC), which allow lipids to switch leaflets, to generate asymmetric bilayers under the assumption of equal chemical potentials of lipids in opposing leaflets.

Spontaneous curvature generation by peptides in asymmetric bilayers.

Peptides and proteins play crucial roles in membrane remodeling by inducing spontaneous curvature. However, extracting spontaneous curvatures from simulations of asymmetric bilayers is challenging because differential stress (i.e.

Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides.

Leishmaniasis, a neglected tropical disease caused by species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all approved therapies. We discovered 2,4,5-trisubstituted benzamides () that possess potent antileishmanial activity but poor aqueous solubility.

Initiation and evolution of pores formed by influenza fusion peptides probed by lysolipid inclusion.

The fusion peptide (FP) domain is necessary for the fusogenic activity of spike proteins in a variety of enveloped viruses, allowing the virus to infect the host cell, and is the only part of the protein that interacts directly with the target membrane lipid tails during fusion. There are consistent findings of poration by this domain in experimental model membrane systems, and, in certain conditions, the isolated FPs can generate pores. Here, we use molecular dynamics simulations to investigate the specifics of how these FP-induced pores form in membranes with different compositions of lysolipid and POPC.

Planar aggregation of the influenza viral fusion peptide alters membrane structure and hydration, promoting poration.

To infect, enveloped viruses employ spike protein, spearheaded by its amphipathic fusion peptide (FP), that upon activation extends out from the viral surface to embed into the target cellular membrane. Here we report that synthesized influenza virus FPs are membrane active, generating pores in giant unilamellar vesicles (GUV), and thus potentially explain both influenza virus' hemolytic activity and the liposome poration seen in cryo-electron tomography. Experimentally, FPs are heterogeneously distributed on the GUV at the time of poration.

Identification of Small Molecule Inhibitors against Dihydroorotase via HTS.

Drug-resistant is an imminent threat to public health, increasing the importance of drug discovery utilizing unexplored bacterial pathways and enzyme targets. pyrimidine biosynthesis is a specialized, highly conserved pathway implicated in both the survival and virulence of several clinically relevant pathogens. Class I dihydroorotase (DHOase) is a separate and distinct enzyme present in gram positive bacteria (i.

Amino-Substituted 3-Aryl- and 3-Heteroarylquinolines as Potential Antileishmanial Agents.

Leishmaniasis, a disease caused by protozoa of the species, afflicts roughly 12 million individuals worldwide. Most existing drugs for leishmaniasis are toxic, expensive, difficult to administer, and subject to drug resistance. We report a new class of antileishmanial leads, the 3-arylquinolines, that potently block proliferation of the intramacrophage amastigote form of parasites with good selectivity relative to the host macrophages.

Antimalarial activity of 2,6-dibenzylidenecyclohexanone derivatives.

Malaria remains one of the deadliest infectious diseases worldwide and continues to infect hundreds of millions of individuals each year. Here we report the discovery and derivatization of a series of 2,6-dibenzylidenecyclohexanones targeting the chloroquine-sensitive 3D7 strain of Plasmodium falciparum . While the initial lead compound displayed significant toxicity in a human cell proliferation assay, we were able to identify a derivative with no detectable toxicity and sub-micromolar potency.

Improvement of Oral Bioavailability of Pyrazolo-Pyridone Inhibitors of the Interaction of DCN1/2 and UBE2M.

The cullin-RING ubiquitin ligases (CRLs) are ubiquitin E3 enzymes that play a key role in controlling proteasomal degradation and are activated by neddylation. We previously reported inhibitors that target CRL activation by disrupting the interaction of defective in cullin neddylation 1 (DCN1), a CRL neddylation co-E3, and UBE2M, a neddylation E2. Our first-generation inhibitors possessed poor oral bioavailability and fairly rapid clearance that hindered the study of acute inhibition of DCN-controlled CRL activity in vivo.

Identification of Plasmodium falciparum heat shock 90 inhibitors via molecular docking.

A virtual screen was performed to identify anti-malarial compounds targeting Plasmodium falciparum heat shock 90 protein by applying a series of drug-like and commercial availability filters to compounds in the ZINC database, resulting in a virtual library of more than 13 million candidates. The goal of the virtual screen was to identify novel compounds which could serve as a starting point for the development of antimalarials with a mode of action different from anything currently used in the clinic. The screen targeted the ATP binding pocket of the highly conserved Plasmodium heat shock 90 protein, as this protein is critical to the survival of the parasite and has several significant structural differences from the human homolog.

Evaluation of 1,1-cyclopropylidene as a thioether isostere in the 4-thio-thienopyrimidine (TTP) series of antimalarials.

The 4-(heteroarylthio)thieno[2,3-d]pyrimidine (TTP) series of antimalarials, represented by 1 and 17, potently inhibit proliferation of the 3D7 strain of P. falciparum (EC 70-100 nM), but suffer from oxidative metabolism. The 1,1-cyclopropylidene isosteres 6 and 16 were designed to obviate this drawback.

Surveillance of spotted fever rickettsioses at Army installations in the U.S. Central and Atlantic regions, 2012-2018.

Spotted fever rickettsioses (SFR) are emerging in the Atlantic and Central regions of the U.S., though cases have been reported across the contiguous U.

Synthesis and Structure-Activity Relationship of Dual-Stage Antimalarial Pyrazolo[3,4-]pyridines.

Malaria remains one of the most deadly infectious diseases, causing hundreds of thousands of deaths each year, primarily in young children and pregnant mothers. Here, we report the discovery and derivatization of a series of pyrazolo[3,4-]pyridines targeting , the deadliest species of the malaria parasite. Hit compounds in this series display sub-micromolar activity against the intraerythrocytic stage of the parasite as well as little to no toxicity against the human fibroblast BJ and liver HepG2 cell lines.

Antimalarial activity of tetrahydro-β-carbolines targeting the ATP binding pocket of the Plasmodium falciparum heat shock 90 protein.

A series of tetrahydro-β-carboline derivatives of a lead compound known to target the heat shock 90 protein of Plasmodium falciparum were synthesized and assayed for both potency against the parasite and toxicity against a human cell line. Using a rationalized structure based design strategy, a new lead compound with a potency two orders of magnitude greater than the original lead compound was found. Additional modeling of this new lead compound suggests multiple avenues to further increase potency against this target, potentially paving the path for a therapeutic with a mode of action different than any current clinical treatment.

Lipopolysaccharide Simulations Are Sensitive to Phosphate Charge and Ion Parameterization.

The high proportion of lipopolysaccharide (LPS) molecules in the outer membrane of Gram-negative bacteria makes it a highly effective barrier to small molecules, antibiotic drugs, and other antimicrobial agents. Given this vital role in protecting bacteria from potentially hostile environments, simulations of LPS bilayers and outer membrane systems represent a critical tool for understanding the mechanisms of bacterial resistance and the development of new antibiotic compounds that circumvent these defenses. The basis of these simulations is parameterizations of LPS, which have been developed for all major molecular dynamics force fields.

Gastric emptying of milk in infants and children up to 5 years of age: normative data and influencing factors.

Background: Gastric emptying scintigraphy is widely used in infants and children, but there is a lack of age-specific normative data.

Objective: The objectives of this retrospective study were: 1) to establish a range of gastric emptying of milk or formula as a surrogate for normal gastric emptying in infants and young children ≤5 years of age, and 2) to investigate the effects of patient age, feeding volume, feeding route and gastroesophageal reflux on gastric emptying.

Materials And Methods: The reports of 5,136 gastric emptying studies of children ≤5 years of age performed at Children's National Medical Center from January 1990 to August 2012 were reviewed.

Membrane Structural Remodeling Increases Resistance to Antimicrobial Peptide LL-37.

Gram-negative bacteria are protected from their environment by an outer membrane that is primarily composed of lipopolysaccharides (LPSs). Under stress, pathogenic serotypes of remodel their LPSs through the PhoPQ two-component regulatory system that increases resistance to both conventional antibiotics and antimicrobial peptides (AMPs). Acquired resistance to AMPs is contrary to the established narrative that AMPs circumvent bacterial resistance by targeting the general chemical properties of membrane lipids.

Identification and design of novel small molecule inhibitors against MERS-CoV papain-like protease via high-throughput screening and molecular modeling.

The development of new therapeutic agents against the coronavirus causing Middle East Respiratory Syndrome (MERS) is a continuing imperative. The initial MERS-CoV epidemic was contained entirely through public health measures, but episodic cases continue, as there are currently no therapeutic agents effective in the treatment of MERS-CoV, although multiple strategies have been proposed. In this study, we screened 30,000 compounds from three different compound libraries against one of the essential proteases, the papain-like protease (PL), using a fluorescence-based enzymatic assay followed by surface plasmon resonance (SPR) direct binding analysis for hit confirmation.

Atomistic Scale Effects of Lipopolysaccharide Modifications on Bacterial Outer Membrane Defenses.

Lipopolysaccharides (LPS) are a main constituent of the outer membrane of Gram-negative bacteria. Salmonella enterica, like many other bacterial species, are able to chemically modify the structure of their LPS molecules through the PhoPQ pathway as a defense mechanism against the host immune response. These modifications make the outer membrane more resistant to antimicrobial peptides (AMPs), large lipophilic drugs, and cation depletion, and are crucial for survival within a host organism.