Gut phages and their interactions with bacterial and mammalian hosts.

The mammalian gut microbiome is a dense and diverse community of microorganisms that reside in the distal gastrointestinal tract. In recent decades, the bacterial members of the gut microbiome have been the subject of intense research. Less well studied is the large community of bacteriophages that reside in the gut, which number in the billions of viral particles per gram of feces, and consist of considerable unknown viral "dark matter.

A human gut fatty acid amide hydrolase.

Undernutrition in Bangladeshi children is associated with disruption of postnatal gut microbiota assembly; compared with standard therapy, a microbiota-directed complementary food (MDCF) substantially improved their ponderal and linear growth. Here, we characterize a fatty acid amide hydrolase (FAAH) from a growth-associated intestinal strain of cultured from these children. This enzyme, expressed and purified from hydrolyzes a variety of -acylamides, including oleoylethanolamide (OEA), neurotransmitters, and quorum sensing -acyl homoserine lactones; it also synthesizes a range of -acylamides, notably -acyl amino acids.

Products of gut microbial Toll/interleukin-1 receptor domain NADase activities in gnotobiotic mice and Bangladeshi children with malnutrition.

Perturbed gut microbiome development has been linked to childhood malnutrition. Here, we characterize bacterial Toll/interleukin-1 receptor (TIR) protein domains that metabolize nicotinamide adenine dinucleotide (NAD), a co-enzyme with far-reaching effects on human physiology. A consortium of 26 human gut bacterial strains, representing the diversity of TIRs observed in the microbiome and the NAD hydrolase (NADase) activities of a subset of 152 bacterial TIRs assayed in vitro, was introduced into germ-free mice.

treatment promotes weight gain in Bangladeshi infants with severe acute malnutrition.

Disrupted development of the gut microbiota is a contributing cause of childhood malnutrition. subspecies is a prominent early colonizer of the infant gut that consumes human milk oligosaccharides (HMOs). We found that the absolute abundance of is lower in 3- to 24-month-old Bangladeshi infants with severe acute malnutrition (SAM) compared to their healthy age-matched counterparts.

A sparse covarying unit that describes healthy and impaired human gut microbiota development.

Characterizing the organization of the human gut microbiota is a formidable challenge given the number of possible interactions between its components. Using a statistical approach initially applied to financial markets, we measured temporally conserved covariance among bacterial taxa in the microbiota of healthy members of a Bangladeshi birth cohort sampled from 1 to 60 months of age. The results revealed an "ecogroup" of 15 covarying bacterial taxa that provide a concise description of microbiota development in healthy children from this and other low-income countries, and a means for monitoring community repair in undernourished children treated with therapeutic foods.

Origins and Evolution of tetherin, an Orphan Antiviral Gene.

Tetherin encodes an interferon-inducible antiviral protein that traps a broad spectrum of enveloped viruses at infected cell surfaces. Despite the absence of any clearly related gene or activity, we describe possible scenarios by which tetherin arose that exemplify how protein modularity, evolvability, and robustness can create and preserve new functions. We find that tetherin genes in various organisms exhibit no sequence similarity and share only a common architecture and location in modern genomes.

Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children.

Undernourished children exhibit impaired development of their gut microbiota. Transplanting microbiota from 6- and 18-month-old healthy or undernourished Malawian donors into young germ-free mice that were fed a Malawian diet revealed that immature microbiota from undernourished infants and children transmit impaired growth phenotypes. The representation of several age-discriminatory taxa in recipient animals correlated with lean body mass gain; liver, muscle, and brain metabolism; and bone morphology.

Feeding the brain and nurturing the mind: Linking nutrition and the gut microbiota to brain development.

The human gut contains a microbial community composed of tens of trillions of organisms that normally assemble during the first 2-3 y of postnatal life. We propose that brain development needs to be viewed in the context of the developmental biology of this "microbial organ" and its capacity to metabolize the various diets we consume. We hypothesize that the persistent cognitive abnormalities seen in children with undernutrition are related in part to their persistent gut microbiota immaturity and that specific regions of the brain that normally exhibit persistent juvenile (neotenous) patterns of gene expression, including those critically involved in various higher cognitive functions such as the brain's default mode network, may be particularly vulnerable to the effects of microbiota immaturity in undernourished children.

Mechanism of HIV-1 virion entrapment by tetherin.

Tetherin, an interferon-inducible membrane protein, inhibits the release of nascent enveloped viral particles from the surface of infected cells. However, the mechanisms underlying virion retention have not yet been fully delineated. Here, we employ biochemical assays and engineered tetherin proteins to demonstrate conclusively that virion tethers are composed of the tetherin protein itself, and to elucidate the configuration and topology that tetherin adopts during virion entrapment.

Intrinsic cellular defenses against human immunodeficiency viruses.

Viral infections are often detrimental to host survival and reproduction. Consequently, hosts have evolved a variety of mechanisms to defend themselves against viruses. A component of this arsenal is a set of proteins, termed restriction factors, which exhibit direct antiviral activity.

Nucleic acid therapeutic carriers with on-demand triggered release.

Biohybrid platforms such as synthetic polymer networks engineered from artificial and natural materials hold immense potential as drug and gene delivery vehicles. Here, we report the synthesis and characterization of novel polymer networks that release oligonucleotide sequences via enzymatic and physical triggers. Chemical monomers and acrylated oligonucleotides were copolymerized into networks, and phosphoimaging revealed that 70% of the oligonucleotides were incorporated into the networks.

Transport and structural analysis of molecular imprinted hydrogels for controlled drug delivery.

Molecular imprinting provides a rational design strategy for the development of controlled release drug delivery systems. We demonstrate that imprinting a hydrogel network results in macromolecular memory for the template molecule, indicated by the two or more times greater partitioning into these networks as compared to non-imprinted networks. Partitioning of drug into networks synthesized from multiple functional monomers was 8 times greater than networks synthesized from single monomers.

Zero-order therapeutic release from imprinted hydrogel contact lenses within in vitro physiological ocular tear flow.

Zero-order or concentration independent release kinetics are highly desirable from drug delivery devices. In this paper we demonstrate experimentally, for the first time, zero-order release of a small molecular weight therapeutic, ketotifen fumarate (MW=425), from molecularly imprinted hydrogels used as therapeutic contact lenses. We performed dynamic, in vitro drug release studies from imprinted hydrogel contact lenses within a novel microfluidic device that simulates the volumetric flow rates, tear volume and tear composition of the eye.

Biomimetic hydrogels for enhanced loading and extended release of ocular therapeutics.

We have applied the principles of biomimesis by incorporating a natural receptor-based rational design strategy in the synthesis of novel recognitive soft contact lenses. We have demonstrated the potential of biomimetic carriers to load significant amounts of ocular medication such as H(1)-antihistamines, as well as to release a therapeutic dosage of drug in vitro in a controlled fashion for 5 days, with an even further extension in the presence of protein. Gels of multiple complexation points with varying functionalities outperformed gels formed with less diverse functional monomers and showed superior loading with a six-fold difference over control gels and a three-fold difference over less biomimetic gels.

Applications of biomimetic systems in drug delivery.

This review article highlights recent activities in the field of biomimetic systems and their application in controlled drug delivery. A definition and overview of biomimetic processes is given, with a focus on synthesis and assembly for the creation of novel biomaterials. In particular, systems are classified on the basis of three subsets, which include biological, biohybrid and synthetic structures.