Evaluation of Human Performance Aiding Live Synthetically Engineered Bacteria in a Gut-on-a-Chip.

Synbiotics are a new class of live therapeutics employing engineered genetic circuits. The rapid adoption of genetic editing tools has catalyzed the expansion of possible synbiotics, exceeding traditional testing paradigms in terms of both throughput and model complexity. Herein, we present a simplistic gut-chip model using common Caco2 and HT-29 cell lines to establish a dynamic human screening platform for a cortisol sensing tryptamine producing synbiotic for cognitive performance sustainment.

Exploration of novel TOSMIC tethered imidazo[1,2-a]pyridine compounds for the development of potential antifungal drug candidate.

New candidates of imidazo[1,2-a]pyridine were designed by combining 2-amino pyridine, TOSMIC and various assorted aldehydes to explore their antioxidant and antifungal potential. The design of these derivatives was based on utilizing the antifungal potential of azoles and TOSMIC moiety. These derivatives were synthesized by adopting multi-component reaction methodology, as it serves as a rapid and efficient tool to target structurally diverse heterocyclic compounds in quantitative yield.

Rate normalization for sweat metabolomics biomarker discovery.

As the demand for real-time exercise performance feedback increases, excreted sweat has become a biosource of interest for continuous human performance assessment. For sweat to truly fulfill this requirement, analyte concentrations must be normalized to adequately assess day-to-day differences within and among individuals. In this manuscript, data are presented highlighting the use of accurate localized sweat rate as a means for ion and global metabolomic data normalization.

Fast-Acting Small Molecules Targeting Malarial Aspartyl Proteases, Plasmepsins, Inhibit Malaria Infection at Multiple Life Stages.

The eradication of malaria remains challenging due to the complex life cycle of Plasmodium and the rapid emergence of drug-resistant forms of Plasmodium falciparum and Plasmodium vivax. New, effective, and inexpensive antimalarials against multiple life stages of the parasite are urgently needed to combat the spread of malaria. Here, we synthesized a set of novel hydroxyethylamines and investigated their activities in vitro and in vivo.

Drug Target Prioritization for Alzheimer's Disease Using Protein Interaction Network Analysis.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that accounts for numerous deaths worldwide. AD is the most common cause of dementia, characterized by accumulation of fibrous amyloid beta protein in the brain with clinical symptoms, such as loss of intellectual and social skills, gradually leading to the death of brain cells. The genetic complexity of AD during disease progression requires a systems-level understanding to design viable therapeutics.

Lipid, water, and protein composition to facilitate kinetic modeling of the auditory pathway.

Environments combining JP-8 jet fuel exposure with heightened ambient noise may accelerate hearing loss induced by noise. To reduce animal use and facilitate kinetic modeling of this military aviation fuel, tissue-specific parameters are required, including water, protein, and lipid content. However, tissues involved in hearing, including cochlea, brainstem, frontal, and temporal lobe, have not been characterized before.

CD4-gp120 interaction interface - a gateway for HIV-1 infection in human: molecular network, modeling and docking studies.

The major causative agent for Acquired Immune Deficiency Syndrome (AIDS) is Human Immunodeficiency Virus-1 (HIV-1). HIV-1 is a predominant subtype of HIV which counts on human cellular mechanism virtually in every aspect of its life cycle. Binding of viral envelope glycoprotein-gp120 with human cell surface CD4 receptor triggers the early infection stage of HIV-1.

Individual differences in biophysiological toughness: sustaining working memory during physical exhaustion.

Recent evidence suggests that increased dehydroepiandrosterone sulfate (DHEAS), in combination with decreased cortisol levels have been correlated with enhanced performance outcomes in stressful military environments. This study was implemented to replicate these findings in a group of active duty Air Force members to provide information on the usefulness of these biomarkers indices in the training and operational environment. Seventeen active duty males participated in the 4 sessions of this study.

New insights into schizophrenia disease genes interactome in the human brain: emerging targets and therapeutic implications in the postgenomics era.

Schizophrenia, a complex neurological disorder, is comprised of interactions between multiple genetic and environmental factors wherein each of the factors individually exhibits a small effect. In this regard a network-based strategy is best suited to capture the combined effect of multiple genes with their definite pattern of interactions. Given that schizophrenia affects multiple regions of the brain, we postulated that instead of any single specific tissue, a mutual set of interactions occurs between different regions of brain in a well-defined pattern responsible for the disease phenotype.

Inhibitors of catechol-O-methyltransferase in the treatment of neurological disorders.

Catechol-O-methyltransferase (COMT) is the enzyme which catalyzes the transfer of a methyl group from S-adenosylmethionine to catechols and catecholamines, like the neurotransmitters dopamine, epinephrine and norepinephrine. COMT has implications in many neurological and psychiatric disorders like schizophrenia, Parkinson's disease (PD), bipolar disorders, etc. and therefore, it serves as an important drug target.

A 13-week nose-only inhalation toxicity study for perfluoro-n-butyl iodide (PFBI) in rats with recommended occupational exposure levels.

A 13-week study was conducted to develop occupational exposure limits (OELs) for the solvent perfluoro-n-butyl iodide (PFBI). Fischer 344 rats (15 males & 10 females per group) were exposed for 6 h/day to 0 (air control), 500, 1500, or 5000 ppm PFBI vapor for 5 days/week for 13 consecutive weeks (at least 65 exposures) followed by a 4-week recovery period. Clinical observations, body weights, clinical pathology, organ weights, and histopathology as well as detailed evaluations of neurotoxicity and thyroid function parameters were conducted at the end of the treatment period for up to 10 animals/sex/group with 5 males/group held for a 4-week recovery period.

Molecular modeling studies of Fatty acyl-CoA synthetase (FadD13) from Mycobacterium tuberculosis--a potential target for the development of antitubercular drugs.

Tuberculosis (TB) is a global health problem and the situation has become more precarious due to the advent of HIV infections and continuous rise in the number of multi-drug resistant strains of Mycobacterium tuberculosis (M. tb). Biochemical studies on Fatty Acyl-CoA Synthetases (FadD13), one of the gene products of mymA operon, have provided insights into the involvement of this protein in the activation of fatty acids.

FRET-based optical assay for monitoring riboswitch activation.

Riboswitches are regulatory RNAs located in the 5'-untranslated region of mRNA sequences that recognize and bind to small molecules and regulate the expression of downstream genes. Creation of synthetic riboswitches to novel ligands depends on the ability to monitor riboswitch activation in the presence of analyte. In our work, we have coupled a synthetic riboswitch to an optical reporter assay based on fluorescence resonance energy transfer (FRET) between two genetically encoded fluorescent proteins.

Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6.

Defects in genes associated with DNA mismatch repair (MMR) have been linked to hereditary colon cancer. Because the MMR pathway includes multiple factors with both overlapping and divergent functions, we sought to compare the impact of deficiencies in each of several MMR genes on genetic instability using a collection of knock-out mouse models. We investigated mutation frequencies and patterns in MMR-deficient mice using two transgenic reporter genes, supFG1 and cII, in the context of mice deficient for Pms2, Mlh1, Msh2, Msh3 or Msh6 or both Msh2 and Msh3 or both Msh3 and Msh6.

Overexpression of the DNA mismatch repair factor, PMS2, confers hypermutability and DNA damage tolerance.

Inherited defects in genes associated with DNA mismatch repair (MMR) have been linked to familial colorectal cancer. Cells deficient in MMR are genetically unstable and demonstrate a tolerance phenotype in response to certain classes of DNA damage. Some sporadic human cancers also show abnormalities in MMR gene function, typically due to diminished expression of one of the MutL homologs, MLH1.

Evidence for competitive inhibition of iodide uptake by perchlorate and translocation of perchlorate into the thyroid.

Various published data sets that investigate the potential effect of exogenous perchlorate (ClO4-) on the uptake of iodide in the thyroid and subsequent changes in thyroid hormone levels are available. In order to best use the data towards the prediction of human health effects resulting from ClO4- exposure, the available literature data must be integrated into a self-consistent, coherent, and parsimonious quantitative model based on the most likely mode of action of perchlorate effect on thyroid function. We submit that the simplest mode of action for ClO4- in the thyroid that remains consistent with all available data involves competitive inhibition of iodide transport into the thyroid follicle, transport of perchlorate into the thyroid follicle against a concentration gradient, further transport into the thyroid lumen (where it may again interfere with iodide transport), and, finally, passive diffusion back into the blood.

Changes in cross-fostered Sprague-Dawley rat litters exposed to perchlorate.

Ammonium perchlorate is used as an oxidizer in rocket fuel. It has become a groundwater contaminant, dissociating to ammonium cation and perchlorate anion. The perchlorate ion competes with iodide for uptake into the thyroid, reducing thyroid hormone production.

Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cells.

The hypoxic tumor microenvironment has been shown to contribute to genetic instability. As one possible mechanism for this effect, we report that expression of the DNA mismatch repair (MMR) gene Mlh1 is specifically reduced in mammalian cells under hypoxia, whereas expression of other MMR genes, including Msh2, Msh6, and Pms2, is not altered at the mRNA level. However, levels of the PMS2 protein are reduced, consistent with destabilization of PMS2 in the absence of its heterodimer partner, MLH1.

The pharmacokinetics of perchlorate and its effect on the hypothalamus-pituitary-thyroid axis in the male rat.

Perchlorate, an environmental contaminant, is known to disturb the hypothalamus-pituitary-thyroid (HPT) axis by blocking iodide accumulation in the thyroid. Iodide deficiency can lead to hypothyroidism and goiter in rats. The objective of the study was to characterize the pharmacokinetics of perchlorate in male Sprague-Dawley rats relative to inhibition of thyroidal radiolabeled iodide uptake and onset of up-regulation of the HPT axis.