Membrane permeability is a key property to consider during the drug design process, and particularly vital when dealing with small molecules that have intracellular targets as their efficacy highly depends on ability cross membrane. In this work, we describe use of umbrella sampling molecular dynamics (MD) computational modeling comprehensively assess passive profile range compounds through lipid bilayer. The model was initially calibrated in vitro validation studies employing parallel...

Background. Tuberculosis (TB) leads to the death of 1.7 million people annually. The failure bacille Calmette-Guérin vaccine, synergy between AIDS and TB, emergence drug resistance have worsened this situation. It is imperative delineate mechanisms employed by Mycobacterium tuberculosis successfully infect persist in mammalian lungs.

The organisms in aerosol microenvironments, especially densely populated urban areas, are relevant to maintenance of public health and detection potential epidemic or biothreat agents. To examine aerosolized microorganisms this environment, we performed sequencing on the material from an surveillance program. Whole metagenome was applied DNA extracted air filters obtained during periods each four seasons. composition bacteria, plants, fungi, invertebrates, viruses demonstrated distinct...

The International Space Station (ISS) is a complex built environment physically isolated from Earth. Assessing the interplay between microbial community of ISS and its crew important for preventing biomedical structural complications long term human spaceflight missions. In this study, we describe one crewmember's profile body swabs mouth, nose, ear, skin saliva that were collected at eight different time points pre-, during post-flight. Additionally, environmental surface samples habitable...

Sequencing human viruses in wastewater is challenging due to their low abundance compared the total microbial background. This study impact of four virus concentration/extraction methods (Innovaprep, Nanotrap, Promega, and Solids extraction) on probe-capture enrichment for followed by sequencing. Different yielded distinct profiles. Innovaprep ultrafiltration (following solids removal) had highest sequencing sensitivity richness, resulting successful assembly several near-complete genomes....

Central nervous system disease is the most serious form of tuberculosis, and associated with high mortality severe neurological sequelae. Though recent clinical reports suggest an association distinct Mycobacterium tuberculosis strains central disease, microbial virulence factors required have not been described previously.We screened 398 unique M. mutants in guinea pigs to identify genes for tuberculosis. We found pknD (Rv0931c) be disease. These findings were tissue-specific observed lung...

The built environment of the International Space Station (ISS) is a highly specialized space in terms both physical characteristics and habitation requirements. It unique with respect to conditions microgravity, exposure radiation, increased carbon dioxide concentrations. Additionally, astronauts inhabit large proportion this environment. microbial composition ISS particulates has been reported; however, its functional genomics, which are pertinent due potential impact constituents on human...

Combat wound healing and resolution are highly affected by the resident microbial flora. We therefore sought to achieve comprehensive detection of populations in wounds using novel genomic technologies bioinformatics analyses. employed a microarray capable detecting all sequenced pathogens for interrogation 124 samples from extremity injuries combat-injured U.S. service members. A subset was also processed via next-generation sequencing metagenomic analysis. Array analysis detected targets...

This paper proposes a hierarchical Bayesian multitask learning model that is applicable to the general multi-task binary classification problem where assumes shared sparsity structure across different tasks. We derive computationally efficient inference algorithm based on variational approximate posterior distribution. demonstrate potential of new approach various synthetic datasets and for predicting human health status microbiome profile. Our analysis incorporates data pooled from multiple...

ABSTRACT Accurate metagenomic classification relies on comprehensive, up-to-date, and validated reference databases. While the NCBI BLAST Nucleotide (nt) database, encompassing a vast collection of sequences from all domains life, represents an invaluable resource, its massive size—currently exceeding 10 12 nucleotides—and exponential growth pose significant challenges for researchers seeking to maintain current nt-based indices classification. Recognizing that no exist widely used...

Bacteria can be selectively imaged in experimentally-infected animals using exogenously administered 1-(2'deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-[(125)I]-iodouracil ([(125)I]-FIAU), a nucleoside analog substrate for bacterial thymidine kinase (TK). Our goal was to use this reporter and develop non-invasive methods detect localize Mycobacterium tuberculosis.We engineered M. tuberculosis strain with chromosomally integrated TK under the control of hsp60 -- strong constitutive mycobacterial...

Background. Tuberculosis of the central nervous system (CNS) is a serious, often fatal disease primarily affecting young children. It develops after hematogenous dissemination and subsequent invasion CNS by Mycobacterium tuberculosis. The microbial determinants involved in are poorly characterized. Methods. Hematogenously disseminated M. tuberculosis infection was simulated BALB/c mice intravenous challenge. Bacteria were recovered using standard culture techniques. Host immune response to...

Bacillus anthracis is the potentially lethal etiologic agent of anthrax disease, and a significant concern in realm biodefense. One cornerstones an effective biodefense strategy ability to detect infectious agents with high degree sensitivity specificity context complex sample background. The nature B. genome, however, renders specific detection difficult, due close homology cereus thuringiensis. We therefore elected determine efficacy next-generation sequencing analysis microarrays for...

Microarrays have proven to be useful in rapid detection of many viruses and bacteria. Pathogen microarrays been used diagnose viral bacterial infections clinical samples evaluate the safety biological drug materials. In this study, Axiom Microbiome Array was evaluated determine its sensitivity, specificity utility microbiome analysis veterinary samples. The array contains probes designed detect more than 12,000 species viruses, bacteria, fungi, protozoa archaea, yielding most comprehensive...

The ability to forecast whether a wound will heal after closure without further debridement(s), would provide substantial benefits patients with severe extremity trauma. Wound effluent is readily available material which can be collected disturbing healthy tissue. For analysis of potential host response biomarkers, forty four serial combat samples from 19 either healing or failing traumatic- and other combat-related wounds were examined by 2-D DIGE. Spot map patterns correlated eventual...

The huemul (Hippocamelus bisulcus) is an endangered cervid endemic to southern Argentina and Chile. Here we report foot lesions in 24 from Bernardo O'Higgins National Park, Chile, between 2005 2010. Affected deer displayed variably severe clinical signs, including lameness soft tissue swelling of the limbs proximal hoof or interdigital space, ulceration swollen tissues, some developed proliferative changes that caused various types abnormal wear, entrapment, and/or displacement hooves...

Abstract To explore how airborne microbial patterns change with height above the Earth’s surface, we flew NASA’s C-20A aircraft on two consecutive days in June 2018 along identical flight paths over US Sierra Nevada mountain range at four different altitudes ranging from 10,000 ft to 40,000 ft. Bioaerosols were analyzed by metagenomic DNA sequencing and traditional culturing methods characterize composition diversity of atmospheric samples compared experimental controls. The relative...

We have previously identified Mycobacterium tuberculosis PknD to be an important virulence factor required for the pathogenesis of central nervous system (CNS) (TB). Specifically, mediates bacillary invasion blood-brain barrier, which can neutralized by specific antisera, suggesting its potential role as a therapeutic target against TB meningitis.We utilized aerosol challenge guinea pig model CNS and compared protective efficacy recombinant M. subunit protein with that bovis BCG...

Nerve agents have experienced a resurgence in recent times with their use against civilian targets during the attacks Syria (2012), poisoning of Sergei and Yulia Skripal United Kingdom (2018) Alexei Navalny Russia (2020), strongly renewing importance antidote development these lethal substances. The current standard treatment effects relies on small molecule-based oximes that can efficiently restore acetylcholinesterase (AChE) activity. Despite efficacy reactivating AChE, action drugs like...

Combat extremity wounds are highly susceptible to contamination from surrounding environmental material. This bioburden could be partially transferred materials in immediate proximity the wound, including fragments of uniform and gear. However, assessment microbial present on military gear during operational conditions deployment or training is relatively unexplored. Opportunistic pathogens that can survive represent risk factors for infection following injury, especially combat blasts,...

Subetadex-α-methyl (SBX-Me), a modified, polyanionic cyclodextrin scaffold, has been evaluated for its utilization as medical countermeasure (MCM) to neutralize the effects of fentanyl and related opioids. Initial in vitro toxicity assays demonstrate that SBX-Me nontoxic profile, comparable FDA-approved cyclodextrin-based drug Sugammadex. Pharmacokinetic analysis showed rapid clearance with an elimination half-life ∼7.4 h little accumulation major organs. was also ability counteract...

Abstract Battlefield injury management requires specialized care, and wound infection is a frequent complication. Challenges related to characterizing relevant pathogens further complicates treatment. Applying metagenomics wounds offers comprehensive path toward assessing microbial genomic fingerprints could indicate prognostic variables for future decision support tools. Wound specimens from combat-injured U.S. service members, obtained during surgical debridements before delayed closure,...